Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4]C(OC1C2C(=CC=CC=2)C=CC=1)C(O)=O)#[N:2].[OH-].[K+].[CH2:22]([O:24][C:25](=[O:43])[CH:26]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23].C(#N)C=C>C(OCC)(=O)C>[CH2:30]([O:29][C:27](=[O:28])[C:26]([CH2:4][CH2:3][C:1]#[N:2])([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)[C:25]([O:24][CH2:22][CH3:23])=[O:43])[CH3:31]
Reactant: N#CCCC(Oc1cccc2ccccc12)C(=O)O
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C=CC#N
Product: CCOC(=O)C(CCC#N)(Oc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
4-Cyano-2(R,S)-α-naphthoxybutyric acid: 0.11 ml of a 50% aqueous KOH solution is added at 0°, while stirring, to a mixture of 5.0 g of α-naphthoxymalonic acid diethyl ester and 1.09 ml of acrylonitrile. The reaction mixture is stirred for 5 days at room temperature and then dissolved in ethyl acetate. The ethyl acetate solution is washed with 2N sodium bicarbonate solution, 2N hydrochloric acid and brine, dried over sodium sulphate and concentrated by evaporation, leaving (2-cyanoethyl)-α-naphthoxymalonic acid diethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:26]([C:25]1[CH:20]=[CH:21][C:22]([O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a solution of N-tert-butoxycarbonylphenylalanine (53 g, 0.2 mol) and p-nitrophenol (27.8 g, 0.2 mol) in ethyl acetate (200 ml) in an ice-water bath was dropwise added a solution of N,N'-dicyclohexylcarbodiimide (41.2 g, 0.2 mol) in ethyl acetate (100 ml), and the mixture was stirred in an ice-water bath for 3 hours and then at room temperature for 20 hours. The precipitated N,N'-dicyclohexylcarbodiurea was filtered off and the filtrate was concentrated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate-hexane to give N-tert-butoxycarbonylphenylalanine p-nitrophenyl ester [61.7 g, 80% (% by weight, hereinafter the same)].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22](Br)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])[CH2:32][CH2:31]1>CN(C=O)C>[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22]([S:11][C:8]1[S:9][C:10]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=1)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH3:38])[CH2:32][CH2:31]1
Reactant: Sc1nc2cccc(Cl)c2s1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-Chloro-2-mercaptobenzothiazole (0.020 g, 0.097 mmol) in DMF (2.0 mL) was added (CH3)3COK (0.011 g, 0.97 mmol) at room temperature and stirring continued for 30 min. To the above reaction mixture tert-butyl ((1S)-2-{4-[2-(6-amino-8-bromo-9H-purin-9-yl)ethyl]piperidin-1-yl}-1-methyl-2-oxoethyl)carbamate (0.040 g, 0.081 mmol) in (1 mL) of DMF was added at room temperature. The reaction mixture was heated to 130° C. for 6 h, at the end of this period solvent was evaporated and crude was purified by preparative HPLC [X-Terra prep-RP18 10 um, 19×250 mm (waters), Mobile phase: solvent A: Water HPLC grade containing 0.01% TFA, and solvent B: acetonitrile containing 0.01% TFA, general eluting gradient—solvent B 15% to 80 over 15 to 25 minutes run time]. After lyophilization of HPLC fractions to afford title product. 1H NMR 6 (CD3OD), 8.35 (s, 1H), 7.85-7.82 (m, 1H), 7.50-7.40 (m, 2H), 4.40 (t, J=7.2 Hz, 2H), 4.00-3.90 (m, 2H), 1.80-1.70 (m, 4H), 1.21-1.15 (m, 6H), 1.15 (s, 9H), 1.10 (s, 3H); LC-MS [M+H]+ 617.1
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[C:33]([OH:35])=O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH2:48]>CN(C=O)C>[CH3:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[C:33]([NH:48][C:44]2[S:43][CH:47]=[CH:46][N:45]=2)=[O:35])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
EDCI (80 mg, 420 μmol) and HOBt (56 mg, 420 μmol) were added to a stirred solution of 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 41, 100 mg, 320 μmol) in anhydrous DMF (6 mL). After 15 min, the solution was treated with thiazol-2-ylamine (38 mg, 380 μmol). The mixture was stirred at 20° C. for 16 h, before being concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous Na2CO3. The organic layer was washed with 1M HCl and dried (MgSO4). Filtration and solvent evaporation yielded the title compound: RTA=3.16 min; m/z (ES+)=436.2 [M+MeCN+H]+.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH2:37][CH2:38][CH3:39])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC(C)C)cc2)c1C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (50 mg) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL) was added 1-iodopropane (0.036 mL) at 50° C., and the mixture was stirred overnight. Water was added to the reaction mixture, and the resulting mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The resulting semi-purified material was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole (28 mg).
Reaction SMILES: NC1SC(C2C(F)=CC=CC=2F)=NC=1C(NC1C=NN(C)C=1N1CCCN(C2CNC2)CC1)=O.[CH3:35][N:36]1[C:40]([N:41]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[C:39]([N+:48]([O-:50])=[O:49])[CH:38]=[N:37]1.[C:51]([O:55][C:56]([NH:58][CH2:59][C:60](O)=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:35][N:36]1[C:40]([N:41]2[CH2:47][CH2:46][CH2:45][N:44]([C:60](=[O:61])[CH2:59][NH:58][C:56](=[O:57])[O:55][C:51]([CH3:52])([CH3:53])[CH3:54])[CH2:43][CH2:42]2)=[C:39]([N+:48]([O-:50])=[O:49])[CH:38]=[N:37]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCNCC1
Agent: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCN(C2CNC2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In the preparation of 362, 1-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane (105 mg, 0.47 mmol), 2-(tert-butoxycarbonylamino)acetic acid (106 mg, 0.61 mmol) and PyBOP (396 mg, 0.75 mmol) were dissolved in DCM (6 mL). DIPEA (0.49 ml, 2.80 mmol) was added and the mixture was stirred at room temperature for 18 h. The crude reaction mixture was concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to gave tert-butyl N-[2-[4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepan-1-yl]-2-oxo-ethyl]carbamate (qualitative yield).
Reaction SMILES: C(O[C:4]([CH:6]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5])C.CO.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:4]([CH:6]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Solvent: CO
Product: CNC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In methylamine (40% in water, 10 ml), 1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.5 mmol) was placed. To this mixture 10 ml of methanol were added, to enhance solubility. The resulting mixture was stirred at room temperature for about 64 hours, after which time the reaction mixture was concentrated in vacuo. The residue was taken up in 200 ml of methylene chloride. The organic fraction was washed once with 200 ml of water. The organic fraction was dried over potassium carbonate and the solvents were removed in vacuo to yield 0.967 grams of a viscous oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient of methylene chloride to a 1:1 methylene chloride:ethyl acetate mixture. The fractions containing the desired material were combined and concentrated under reduced pressure to yield 305 mg (26%) of the desired title product as a crystalline material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.C[Si](C)(C)[C:12]([F:15])([F:14])[F:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[C:12]([F:15])([F:14])[F:13])[CH:5]=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cncc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-pyridine-3-carbaldehyde (2.0 g, 10.8 mmol) in THF (25 mL) are added trimethyl-trifluoromethyl-silane (2.8 mL, 18.8 mmol) and TBAF in THF solution (1.0 M; 10.8 mL, 10.8 mmol). The mixture is warmed to room temperature for 3 hrs. The solvent is evaporated to give the crude product. Purification by flash column chromatography affords 1.9 g of 1-(5-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[C:4]([F:33])[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1.O1CCOCC1>O1CCCC1>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:42])[CH:7]=[CH:6][C:5]=1[N:8]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:31])([C:23]([F:24])([F:25])[F:26])[C:27]([F:30])([F:28])[F:29])=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)[CH3:32]
Reactant: CN(c1ccc(N)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN(c1ccc(NC(=O)Nc2ccncc2)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 67 %

Procedure:
2-(4-((4-((4-Amino-2-fluorophenyl)(methyl)amino)piperidin-1-yl)methyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.209 mmol, 100 mg) and phenyl pyridin-4-ylcarbamate (0.313 mmol, 67.0 mg) were combined in tetrahydrofuran (1 mL) and dioxane (1 mL) and heated to 80° C. overnight. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to afford title compound (83.9 mg). MS (ESI) m/z 600.2 [M+H]+
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[NH:12][C:11](=O)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([Cl:16])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reaction time: 3 h

Procedure:
(R)-2-(1-Acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 3.00 g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between chloroform and saturated aqueous sodium carbonate. The layers were separated and the organic layer was washed twice with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 2.88 g (87%). 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 5.68 (q, 1H), 6.32 (d, 1H), 8.21 (d, 1H); MS (CI) 201, 203 (MH+); [α]D+27.6 (c 1.0, MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([F:36])([F:35])[F:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C(F)(F)F)c3O2)cc1
Yield: 93 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.01 g, 10.0 mmol) with 2-(trifluoromethyl)-phenyl boronic acid (2.85 g, 15.0 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.786 g, 1.00 mmol), and potassium carbonate (3.46 g, 25.00 mmol) generally according to the procedure described for Intermediate 37 provided 4.34 g (93%) of (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.54 (silica, ethyl acetate:hexanes 3:7); Anal. calcd. for C23H18F4O4S: C, 59.22; H, 3.89. Found: C, 60.19; H, 4.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:33]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:32]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1Cc2ccccc2C1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydroisoindole as in General Procedure 10 to give the title compound. LCMS: m/z=548.94 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CN
Product: CNC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A suspension of ethyl indole-2-carboxylate (25.30 g, 133.7 mmole) in 40% aqueous CH3NH2 (400 mL) was stirred at RT. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded the product began to precipitate. The reaction was stirred at RT for 3 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (500 mL), and the solid was collected by suction filtration and washed with H2O. Drying under high vacuum left the title compound (21.50 g, 92%) as a light yellow solid: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CO)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Reaction time: 1.25 h
Yield: 99.8 %

Procedure:
To a bi-phasic mixture of Intermediate 29b (737 mg, 3.00 mmol) in EtOAc (22.5 mL) and 1N NaOH solution (8.11 mL, 8.11 mmol) at 0° C. was added 2,2,2-trichloroethyl chloroformate (0.45 mL, 3.30 mmol) and the mixture stirred for 1.25 h. The layers were separated and the organic layer was washed with brine, dried and concentrated in vacuo to give the title compound as an off-white solid (1.26 g, 99%). LCMS (Method 3): Rt 4.00 min, m/z 420, 422 [MH+].
Reaction SMILES: CNC(NC)=O.[P:7]([O:16]CCCl)([O:12]CCCl)[O:8]CCCl.C(C(CCCC)C=O)C.ClCCOP1(=O)[CH:37]([CH:38]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40])[N:36]([CH3:45])[C:35](=[O:46])[N:34]1[CH3:47]>C1CCCCC1.O>[CH3:45][N:36]([CH:37]([P:7](=[O:8])([OH:12])[OH:16])[CH:38]([CH2:39][CH3:40])[CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([NH:34][CH3:47])=[O:46]
Reactant: CCCCC(CC)C1N(C)C(=O)N(C)P1(=O)OCCCl
Reactant: ClCCOP(OCCCl)OCCCl
Agent: CCCCC(C=O)CC
Agent: CNC(=O)NC
Solvent: O
Solvent: C1CCCCC1
Product: CCCCC(CC)C(N(C)C(=O)NC)P(=O)(O)O

Procedure:
A mixture of 88.1g (1.0 mole of 1,3-dimethylurea, 269.5g (1.0 mole) of tris(2-chloroethyl) phosphite, and 135g (1.05 moles) of 2-ethylhexaldehyde is warmed at 105°-110° for 2 hr, giving a clear colorless solution containing 2-(2-chloroethoxy)-1,4-dimethyl-3-(3-heptyl)-1,4,2-diazaphospholidin-5-one-2-oxide, as an intermediate ester product, 31P nmr-30.8. Four-fifths of the reaction mixture is dissolved in 200ml of cyclohexane containing 34.5g of H2O, and the mixture is warmed at 82° for 0.5 hr. Filtration after cooling, and extraction of the solid with hot acetonitrile gives 54.7g of white solid (100.8g more separates from the filtrate while standing); mp 184-186° dec; 31P nmr (CD3SOCD3) -23.5 ppm(m); 1H nmr δ 9.8 (broad, 2, OH), 4,4 (d of d, 1, J = 10 and 20Hz, PCH), 2.7 (s, 3, NCH3), 2.5 (s, 3, NCH3), 0.5 - 2.0 (broad, 15, hexyl); acidity 1.985 equiv/mole, pK1 = 1.76, pK2 = 5.29.
Reaction SMILES: [C:1]1([C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N+:23]([O-])=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:16]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.ClCCl>FC(C1C=CC=CC=1)(F)F>[C:42]([NH:46][C:24]1[CH:25]=[C:20]([C:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:8]=[C:7]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:10]=3)=[N:16][N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH:18]=2)[CH:21]=[CH:22][N:23]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: FC(F)(F)c1ccccc1
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
200 mg (0.4 mmol) of N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-(1-oxidopyridin-4-yl)-1H-pyrazol-3-yl]aniline were suspended in 50 ml of trifluoromethylbenzene and 210 μl (2 mmol) of tert-butylamine were added under stirring at room temperature. The mixture was cooled to 0° C. and 260 mg (0.8 mmol) of p-toluensulfonic anhydride were added. The reaction was maintained in the same conditions for 2.5 hours. Then the same amounts of reactants and 2 ml of dichloromethane to obtain a clear solution were added and after further 2 hours the reaction went to completion. The solvent was evaporated and the residue taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, giving 161 mg (73% yield) of the title compound.
Reaction SMILES: Cl.[CH2:2](N=C=NCCCN(C)C)[CH3:3].Cl.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C>CN(C1C=CN=CC=1)C.ClCCl>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:2][CH3:3])=[O:31])[CH2:28][CH2:29]1
Reactant: O=C(O)C1CCN(c2ccc3ccccc3n2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.79 g, 9.34 mmol) was added to a solution of 1-(quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride (1.14 g, 3.89 mmol), N,N-dimethyl-4-aminopyridine (1.42 g, 11.6 mmol), and ethanol (546 μL, 9.34 mmol) in dichloromethane (20 mL), and the mixture was stirred overnight at room temperature. Then, the solvent in the reaction solution was distilled off under reduced pressure. A solution of the obtained residue in ethyl acetate was washed with water twice and brine once and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=95/5-60/40 (gradient)] to obtain the title compound (1.07 g, yield: 96%).