Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15](=[O:17])[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1CCNC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added pyrrolidine (13 μL, 0.16 mmol), HOBt (20 mg, 0.15 mmol) and DIPEA (51 μL, 0.29 mmol). After 5 min, EDCI (36 mg, 0.19 mmol) was added and the reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the solid was triturated with water, filtered and dried to give the title compound as a beige solid. m/z (ES+)=397 [M+H]+; RT=3.38 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[Cl:15])[NH:8][CH:7]=1.[CH2:18]=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[NH:16][CH2:18][C:7]2[NH:8][C:9]3[N:10]=[CH:11][CH:12]=[C:13]([Cl:15])[C:14]=3[C:6]=2[CH2:5]1)=[O:17]
Reactant: C=O
Reactant: COC(=O)C(N)Cc1c[nH]c2nccc(Cl)c12
Solvent: c1ccncc1
Product: COC(=O)C1Cc2c([nH]c3nccc(Cl)c23)CN1
Temperature: 100 °C

Procedure:
A suspension of 2-amino-3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid methyl ester (3.5 g, 10 mmol) in pyridine (25 mL) was treated with formaldehyde solution (37% in water, 0.90 mL) and the resulting mixture was heated to 100° C. for 1.25 hours. The mixture was allowed to cool to ambient temperature then evaporated in-vacuo. The resultant residue was treated with saturated aqueous sodium carbonate solution (15 mL) and the resultant solid collected by filtration and washed with water (20 mL). The filtrate was extracted with 20% methanol in dichloromethane (6×25 mL). The combined organic phase was combined with solid and concentrated in-vacuo to afford the title compound as a brown residue (2.1 g, 87%). LCMS (Method B): RT=2.36 min, M+H+=266. 1H NMR (400 MHz, DMSO-d6): 11.66 (s, 1H), 8.02 (d, J=5.2 Hz, 1H), 7.06 (d, J=5.1 Hz, 1H), 4.01-3.71 (m, 3H), 3.69 (s, 3H), 3.19 (dd, J=15.4, 4.7 Hz, 1H), 2.94 (dd, J=15.4, 8.9 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:14][CH2:13][CH2:12][O:11][CH3:10])=[O:6]
Reactant: COCCN
Reactant: COC(=O)C(C)(C)CO
Product: COCCNC(=O)C(C)(C)CO
Yield: 100 %

Procedure:
Prepared as in Example 215d (Method A) from methyl 3-hydroxy-2,2-dimethylpropanoate and 2-methoxyethanamine in 100% yield. MS 176 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:5]=1[N+:16]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][CH2+:38]1SC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][C:38]1=[N:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH:14]=[CH:15][C:4]=1[NH:3][CH2:1][CH3:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCNc1ccc(NC(=O)COC)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.99 (1H, s), 7.39–7.44 (3H, m), 7.17–7.28 (5H, m), 7.05–7.11 (2H, m), 6.94 (1H, d), 6.50 (1H, d), 5.08 (2H, s), 3.92 (2H, s), 3.66 (3H, s), 3.41 (3H, s), 2.91 (2H, q), 0.96 (3H, t); MS(ESI): 560(MH+).
Reaction SMILES: Cl.[C:2]([NH:5][C@@H:6]1[CH2:10][NH:9][C@@H:8]([CH3:11])[CH2:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:2]([NH:5][C@@H:6]1[CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]([CH3:11])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)N[C@@H]1CN[C@@H](C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1

Procedure:
(2S,4S)-4-acetamido-2-methylpyrrolidine hydrochloride from the previous step is suspended in methylene chloride, triethylamine and benzyl bromide are added and the mixture heated at reflux. The product is obtained after washing and evaporation of the solvent.
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[C:15]3[O:23][C:22]([CH:24]([CH3:26])[CH3:25])=[C:21]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:20](=[O:34])[C:16]3=[CH:17][CH:18]=2)[C:13]([CH3:35])=[CH:12]1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.Cl.[Pd]>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:21]2[C:20](=[O:34])[C:16]3[C:15]([O:23][C:22]=2[CH:24]([CH3:25])[CH3:26])=[C:14]2[C:19](=[CH:18][CH:17]=3)[NH:11][CH:12]=[C:13]2[CH3:35])=[CH:32][CH:31]=1
Reactant: Cc1cn(C(=O)OCc2ccccc2)c2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c[nH]c2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A stirred suspension of 3-(4-chlorophenyl)-2-isopropyl-9-methyl-4-oxo-4H-pyrano[2,3-e]indole-7-carboxylic acid benzyl ester and its positional isomer (0.063 g, 0.13 mmol) and 20% Pd on activated carbon (0.013 g) in tetrahydrofuran (1.5 ml), ethanol (1.5 ml) and 5M HCl solution (0.75 ml) is stirred under a hydrogen atmosphere for 3.5 h at room temperature. The catalyst is removed by filtration through Celite filter aid, and the pad of Celite is washed with ethyl acetate and methylene chloride. The combined filtrates are evaporated in vacuo, and the residue is purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 5:1) to afford the title compound as a pale orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22](O)=[O:23])=[CH:16][CH:17]=3)[N:12]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:11]=2)[CH:3]=1.[CH:35]1([C:38]#[C:39][CH2:40][NH2:41])[CH2:37][CH2:36]1>>[CH:35]1([C:38]#[C:39][CH2:40][NH:41][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[NH:19][C:15]2[CH:14]=[C:13]3[C:18]([C:10]([CH:9]=[CH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)=[N:11][N:12]3[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:17][CH:16]=2)[CH2:37][CH2:36]1
Reactant: NCC#CC1CC1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Product: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CC4CC4)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using 2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid and 3-Cyclopropyl-prop-2-ynylamine. 1H NMR (DMSO-d6): δ 9.88 (1H, bs), 8.93 (1H, bt), 8.46 (1H, d, J=4.9 Hz), 8.08 (1H, d, J=8.7 Hz), 7.85 (1H, d, J=16.4 Hz), 7.69 (1H, d, J=7.6 Hz), 7.54–7.40 (5H, m), 7.14–7.11 (2H, m), 6.90 (1H, t, J=6.1 Hz), 5.81 (1H, d, J=7.5 Hz), 4.02 (2H, d, J=3.6 Hz), 3.95–3.85 (1H, m), 3.79–3.72 (1H, m), 2.49–2.35 (1H, m), 2.35 (3H, s), 2.15–2.01 (2H, m), 1.87–1.55 (3H, m), 1.30–1.25 (1H, m), 0.77–0.70 (2H, m), 0.59–0.54 (2H, m).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[C:16]=1[O:23][CH3:24])([O-])=O>CN(C=O)C>[N:1]1([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[C:16]=2[O:23][CH3:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1c([N+](=O)[O-])ccnc1C#N
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(-n2ccnc2)ccnc1C#N
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 0.2 g (0.51 mmol) 2-{N-meta-[4-(trifluoromethylphenoxy)phenyl]} aminocarbonyl-3-hydroxy-4-amino pyridine (prepared according to the method described in WO 0149666) and 78 mg (0.56 mmol) of 2,5-dimethoxytetrahydrofuran) in 1 ml of glacial acetic acid, is heated at 110° C. for 1 hour. The reaction is cooled and solvent evaporated, the residue is dissolved in dichloromethane and washed with aqueous sodium bicarbonate, the organic phase was dried over MgSO4 and solvent evaporated. The crude product was chromatographed on silica to yield 137 mg (61% yield) of a yellow solid. (M+1=440) 2-N-(3-trifluoromethyl phenyl) aminocarbonyl-3-hydroxy-4-(imidazol-1-yl) pyridine (compound 2-24) A mixture of 1.36 g (20 mmol) of imidazol and 60.52 g (20 mmol) of cesium carbonate is stirred at room temperature in 20 ml of DMF for 20 minutes. 3.58 g (20 mmol) of 4-nitro-3-methoxy-2-cyano pyridine (prepared according to the methods described in WO 0149667) is added in one pot and the mixture is stirred overnight. DMF is removed in vacuo and the residue is partitioned between water and ethyl acetate. The aqueous phase is further extracted with ethyl acetate. The organic phases are washed with dilute brine, dried and solvent evaporated. Purification on silica gave 1.4 g of 4-(imidazol-1-yl)-3-methoxy-2-cyano pyridine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[S:8])[NH2:7])=[CH:2]1.[CH3:9][I:10]>>[IH:10].[S:1]1[CH:5]=[CH:4][C:3]([C:6]([S:8][CH3:9])=[NH:7])=[CH:2]1
Reactant: CI
Reactant: NC(=S)c1ccsc1
Product: CSC(=N)c1ccsc1
Product: I

Procedure:
The title compound was prepared from 3-thiophenecarbothioamide and methyl iodide by a procedure analogous to that described in WO 95/05363, Example 1 (d). M.p. 157-158° C.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:28].C>CO>[ClH:28].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (anti isomer, 2.5 g.), conc. hydrochloric acid (2.5 ml.) and methanol (38 ml.) was stirred at room temperature for two hours. After treating the resultant solution with activated charcoal, the solution was concentrated in vacuo. The residue was crystallized out with diisopropyl ether (100 ml.), and the precipitates were collected by filtration, and washed with diisopropyl ether (30 ml.) to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid hydrochloride (anti isomer, 2.1 g.). The crystals were added to water (20 ml.) and adjusted to pH 6.0 with sodium bicarbonate. The solution was subjected to column chromatography on nonionic adsorption resin "Diaion HP-20" [Trademark: manufactured by Mitsubishi Chemical Industries Ltd.] (75 ml.) with 10% diisopropyl ether. The eluate was adjusted to pH 3.5 with 10% hydrochloric acid, and the precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (anti isomer, 0.7 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:22][CH:19]3[CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: NC1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CC3)c2n1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclopropanamine (0.038 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 μmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (0.060 g, 54%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 0.76-0.79 (2H, m), 0.99-1.03 (2H, m), 3.02-3.06 (1H, m), 7.12 (1H, brs), 7.61-7.63 (1H, m), 8.04-8.07 (1H, m), 8.73 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.Cl[S:16]([OH:19])(=O)=[O:17].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[N:20]1([S:16]([C:7]2[CH:6]=[CH:5][C:4]3[NH:3][C:2](=[O:1])[N:11]4[CH2:12][CH2:13][N:14]=[C:10]4[C:9]=3[CH:8]=2)(=[O:19])=[O:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2ccccc2C2=NCCN12
Reactant: O=S(=O)(O)Cl
Reactant: C1COCCN1
Solvent: O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCOCC3)cc2C2=NCCN12
Reaction time: 3 h

Procedure:
30 mmols of 5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline were added, whilst cooling with ice, to 20 ml of chlorosulphonic acid, and the mixture was stirred for 3 hours at 50° to 60° C. After this solution had been cooled, it was carefully added dropwise to 80 ml of cooled morpholine, and the mixture was thereafter diluted with 150 ml of water. The residue was filtered off under suction, washed with water and boiled up with alcohol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cc(F)ccc4F)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.090 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.39 mmol) and methylamine (0.120 g, 3.9 mmol). mp 189-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(N)cc2)CC1
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 1-(4-nitro-phenyl)-cyclopropanecarbonitrile (500 mg, 2.65 mmol, Journal of the American Chemical Society, 71, 2031-5; 1949) in 7 mL of EtOH-2.5 mL of EtOAc was added 350 mg 5% Pd—C. The mixture was stirred under 1 atm of H2 overnight. The reaction was filtered, concentrated in vacuo and then purified using preparative thin layer chromatography (CHCl3) to afford the title compound as an oil (96 mg, 23%). Mass spectrum (ESI, m/z): Cald. C10H10N2, 159.0. found 159.2.
Reaction SMILES: [Na].Br[CH:3]([CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)(C)(C)C.C1C=CC=CC=1>[Cl:15][C:14]([Cl:17])([Cl:16])[CH2:13][CH:3]1[C:4]([CH3:12])([CH3:11])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: CCOC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Yield: 85.9 %

Procedure:
To a solution of 46 mg of sodium in a mixture of 12ml of t-butanol and 6 ml of benzene was added, at room temperature, 709 mg of ethyl 4-bromo-6,6,6-trichloro-3,3-dimethylhexanoate. The mixture was treated as described in Example XII A to produce 470 mg (86% yield) of ethyl 2-(β,β,β-trichloroethyl)-3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=O.[NH2:24][O:25][CH3:26].Cl>>[CH3:26][O:25][N:24]=[CH:1][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: CON
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Agent: Cl
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Yield: 28.1 %

Procedure:
was synthesized as described in Example 22 but using (62) (200 mg, 0.66 mmol) instead of (55) and NH2OMe.HCl (250 mg, 2.0 mmol). The reaction gave (64) (61 mg, 28%). Mp. 180-182° C.
Reaction SMILES: Cl[C:2]([C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[CH3:16])=[O:3].N1C=CC=CC=1.[CH2:23]([OH:25])[CH3:24]>C(Cl)Cl.CCOCC.CCOCC>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:7]1[N:8]([CH3:9])[C:4]([C:2]([O:25][CH2:23][CH3:24])=[O:3])=[C:5]([CH3:16])[CH:6]=1)[CH3:15]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)Cl)n1C
Reactant: CCO
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)OCC)n1C
Reaction time: 3 h
Yield: 87 %

Procedure:
Ethyl 5-chlorocarbonyl-1,4 dimethylpyrrole-2-acetate (29.3 g, 0.12 mol, prepared acc. to U.S. Pat. No. 3,950,355) is dissolved in 150 ml of 1:1 methylene chloride/ether and added over 10 minutes to a solution of pyridine (15 ml) and absolute ethanol (20 ml) in ether (100 ml) with stirring. After addition is complete, 4-N,N-dimethylaminopyridine (300 mg) is added. Stirring is continued for three hours. Ether (250 ml) is then added and deposited solids are removed by filtration. The organic solution is washed with aqueous 1 N HCl (2×100 ml), then brine (100 ml), and the ether layer is dried with magnesium sulfate. The solvent is then removed to give 26.3 g (87%) of ethyl-1,4 dimethyl-5-ethoxycarbonylpyrrole-2-acetate as a low melting red solid.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:4])[CH3:3].[ClH:17].O1CCOCC1>C(Cl)Cl.CCOC(C)=O>[ClH:17].[NH:7]1[CH2:8][CH2:9][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(C)O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate (0.69 g, 3.01 mmol) in DCM (15 mL) and EtOAc (5 mL) was added 4 M HCl in dioxane (3.01 mL, 12.04 mmol). The reaction was stirred overnight at RT and then concentrated to generate 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride as a yellow oil (0.51 g, 102% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12]O.[C:14]([OH:18])(=O)[CH2:15][CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:11][CH2:10][NH:9][C:14](=[O:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: CCC(=O)O
Reactant: Sc1ccc(Cl)cc1
Product: CCC(=O)NCCCSc1ccc(Cl)cc1

Procedure:
The experiment of Example 1A was repeated in all essential details except that p-chlorobenzenethiol 50 g (0.67 mole), 3-aminopropanol 40.9 g (0.67 mole) and propionic acid 49.6 g (0.67 mole) were reacted. There was obtained N-[3(p-chlorophenylthio)propyl]propionamide, m.p. 69°-70° C. It was designated P-2135 for convenience. The nmr spectrum was consistent with the proposed structure. It analyzed as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Cl:29])=[CH:18][CH:17]=2>O1CCCC1>[Cl:29][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:11])=[C:22]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Nc1cnc2ccc(Cl)cc2c1-c1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1cnc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 20 h
Yield: 77.8 %

Procedure:
2,4-Difluorophenyl isocyanate (0.24 ml) was added to a solution of 3-amino-6-chloro-4-phenylquinoline (509 mg) in anhydrous tetrahydrofuran (8 ml), and the mixture was allowed to stand at room temperature for 20 hrs. The precipitated crystals were collected by filtration. The filtrate was concentrated and the precipitated crystals were collected by filtration. Thus obtained crystals were combined and recrystallized from ethanol to give 6-chloro-3-[3-(2,4-difluorophenyl)ureido]-4-phenylquinoline as colorless crystals (638 mg, 77.8 %). m.p. 206°14 207° C.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10](=O)[NH:9][C:8]=2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:10]1[NH:9][C:8]2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[N:11]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2[nH]c(Cl)nc12

Procedure:
The benzoimidazol-2-one from step (b) above (1.8 g, 7.3 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 266 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>ClCCl.CS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
5-Fluoro-indan-1-one (4.00 g, 26.6 mmol) was dissolved in 40 mL dichloromethane and 40 mL methanesulfonic acid. This was cooled to 0° C. and sodium azide (3.46 g, 53.2 mmol) was added. After 2 hours, the solution was made basic by slowly adding 20% aq. sodium hydroxide. The resulting mixture was partitioned between dichloromethane and water. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 50 to 100% ethyl acetate/hexanes) to yield 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (2.72 g, 16.5 mmol). MS (ESI) 166.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[F:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][CH2:44][C:45]1[C:50]([CH2:51][CH3:52])=[N:49][C:48]2[N:53]([CH2:56][CH3:57])[N:54]=[CH:55][C:47]=2[C:46]=1[NH:58][CH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([NH:43][CH2:44][C:45]2[C:46]([NH:58][CH:59]3[CH2:60][CH2:61][O:62][CH2:63][CH2:64]3)=[C:47]3[CH:55]=[N:54][N:53]([CH2:56][CH3:57])[C:48]3=[N:49][C:50]=2[CH2:51][CH3:52])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)CCCC(=O)NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
A mixture of 5-{[(3-bromo-4-fluorophenyl)methyl]amino}-5-oxopentanoic acid (920 mg, 2.89 mmol), HBTU (1130 mg, 2.98 mmol), 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (820 mg, 2.71 mmol) and diisopropyl ethyl amine (1 mL) in DCM/THF (1:1, 100 mL) was stirred at room temperature overnight. The mixture was concentrated, mixed with EtOAc (50 mL) and washed by NaHCO3 (50 mL) and NH4Cl (50 mL). The organic parts were collected, dried and concentrated to afford the desired product (1.84 g).