Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH2:17][OH:18])([CH3:15])[C:12](=[O:14])[N:13]=1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:20]([O:18][CH2:17][CH2:16][C:11]1([CH3:15])[S:10][C:9]([NH:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[N:13][C:12]1=[O:14])(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(CCO)SC(NC2CC3CCC2C3)=NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(CCOC(=O)c2ccncc2)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 120 °C

Procedure:
A mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)-5-methylthiazol-4(5H)-one (0.080 g, 0.30 mmol), isonicotinoyl chloride hydrochloride (0.056, 0.30 mmol), and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) in CH2Cl2 (1.0 mL) was heated in a sealed tube in a microwave oven (SmithSynthesizer from Personal Chemistry) at 120° C. for 10 min. The reaction mixture was conc. in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, conc. in vacuo, and purified by RP-HPLC to give the title compound as a white solid. MS m/z: 374.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.FC1C=NC=CC=1[Li].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:29]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Fc1cccnc1
Reactant: CC(C)(C)N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]c1ccncc1F
Product: CC(C)(C)NC(=O)c1ccncc1F

Procedure:
Following the procedure of Gribble and Saulnier, Tetrahedron Lett., 21:4137-4140 (1980)) reacting 3-fluoropyridine (Aldrich) with LDA and reacting the 3-fluoro-4-lithiopyridine intermediate with t-butyl isocyanate, the title compound was prepared.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].O=[C:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14]1>>[ClH:1].[NH2:6][C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:2][C:13]2([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14]2)[N:7]=1
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: N=C(N)c1ccccc1N
Agent: Cl
Product: CCOC(=O)N1CCC2(C1)N=C(N)c1ccccc1N2

Procedure:
This was prepared by the method of Example 173 using 2-aminobenzamidine hydrochloride and ethyl 3-oxopyrrolidine-1-carboxylate to give the title compound, MS (+EI) 274 ([M+H]+), 1H NMR (d6 -DMSO) (rotamers) 10.48 (1H, s), 9.2-8.2 (2H, m), 7.94 (1H, s), 7.88 (1H, d), 7.49 (1H, t), 6.89 (1H, d), 6.85 (1H, t), 4.04 (2H, dt), 3.6-3.4 (4H, m) 2.86-2.7 (1H, m), 2.09-2.02 (1H, m), 1.18 (3H, dq).
Reaction SMILES: O=[C:2]1C[CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CO[CH:16]([O:19][CH3:20])[O:17][CH3:18]>CC1C=CC(S(O)(=O)=O)=CC=1.O.C(Cl)Cl.CO>[CH3:20][O:19][C:16]1([O:17][CH3:18])[CH2:2][CH2:3][CH:4]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5]1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of tert-butyl 3-oxocyclopentanecarboxylate (19.8 g, 107 mmol) in 1:1 DCM/methanol (150 mL) was added trimethylorthoformate (46.8 mL, 428 mmol), followed by TsOH.H2O (˜0.5 g). The reaction mixture was stirred at room temperature for 2 h. Then more TsOH.H2O (˜0.25 g) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated at room temperature and the resulting residue was dissolved in ether and washed with saturated NaHCO3 solution, then with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by flash chromatography (silica, 15% ethyl acetate/hexane) gave 22.2 g (90%) of tert-butyl 3,3-dimethoxycyclopentanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:13][C@H:14]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].F.[K]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:18]2[CH2:17][C:16](=[O:19])[N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:14]2[CH3:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: C[C@H]1C=CC(=O)N1C(=O)OC(C)(C)C
Agent: F
Agent: [K]
Product: COc1ccc([C@@H]2CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Temperature: 60 °C
Yield: 49.3 %

Procedure:
To a 100 mL RBF were added (3-chloro-4-methoxyphenyl)boronic acid (1.89 g, 10.14 mmol), (S)-tert-butyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 5.07 mmol), hydroxy(cyclooctadiene)rhodiumRhodium(I)dimer (0.116 g, 0.254 mmol), potassium hydrogen fluoride (1.58 g, 20.28 mmol). The mixture was degased and filled back with N2. Dioxane (45 mL) and water (5 mL) were then added. The mixture was degased again and filled with N2. The reaction mixture was heated at 60° C. overnight. It was diluted with EtOAc (200 mL), washed with water, brine. Organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluted with 30% EtOAc/Hexane to give (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1, 0.85 g) as white crystalline solid. 1H NMR (500 MHz, CDCl3): δ 7.20 (s, 1H), 7.05 (d, 1H), 6.87 (d, 1H), 4.08 (m, 1H), 3.86 (s, 3H), 2.95 (m, 2H), 2.53 (m, 1H), 1.52 (s, 9H), 1.41 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:23](=[O:25])[CH3:24])[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)([OH:28])=[O:27]>>[C:1]([C:5]1[CH:6]=[C:7]([C:23](=[O:25])/[CH:24]=[CH:33]/[C:32]2[CH:35]=[CH:36][C:29]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)[CH:8]=[C:9]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1cc(-c2ccc(C)cc2)c(OCC(C)C)c(C(C)(C)C)c1
Product: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc(C(C)(C)C)c2OCC(C)C)cc1
Yield: 50 %

Procedure:
In a similar manner to that of Example 2 b, by reacting 1 g (2.9 mmol) of 1-(5-tert-Butyl-6-isobutoxy-4′-methyl-3-biphenylyl)ethanone with 400 mg (2.6 mmol) of 4-carboxybenzaldehyde. A yellow solid is obtained (m=700 mg; yield=50%; m.p.=243° C.).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[N:27]=[CH:26][N:25](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:24]=5)[CH:21]=4)[N:16](C4CCCCO4)[N:15]=3)[CH:9]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:24]1[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[N:25]1
Reactant: O=C(NCC1CC1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 54.1 %

Procedure:
To a stirred solution of N-(Cyclopropylmethyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.241 g, 0.352 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 4 h. The mixture was cooled and poured into aqueous saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30-80% acetonitrile/water) gave the title compound (0.0682 g, 54% yield). 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.45 (m, 1H), 8.19 (dt, 1H), 8.11 (d, 1H), 7.90 (dt, 1H), 7.69 (d, 1H), 7.66 (t, 1H), 3.30 (m, 2H), 1.18 (m, 1H), 0.55 (m, 2H), 0.32 (m, 2H). ES-MS (m/z) 359 [M+1]+.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH:27][C:28](=O)[O:29]C1C=CC=CC=1.CS(C)=O.O>C(OCC)(=O)C>[CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:19][C:28]([NH:27][C:23]4[S:22][CH:26]=[CH:25][N:24]=4)=[O:29])=[CH:20][CH:21]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1)Nc1nccs1

Procedure:
4-(2-Cyclobutanecarbonylaminopyridin-4-yl)oxyaniline (130 mg), phenyl N-(2-thiazolyl)carbamate (110 mg) and dimethylsulfoxide (3 ml) were stirred at 80° C. for 30 minutes. Water and ethyl acetate were added to the reaction solution for extraction, and the ethyl acetate layer was washed 5 times with ammonium chloride water and then dried over magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the precipitated solid was filtered out to obtain 130 mg of the target substance as a light brown solid.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]([NH:14]C(=O)OC(C)(C)C)=[N:11][C:10]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:2]1([C:1]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Compound 135 (6.18 g, 16.7 mmol) was dissolved in trifluoroacetic acid (17 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the entitled Compound 136 (4.39 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]([C:15]#[C:16][C:17](OCC)=[O:18])=[O:14])[CH3:11]>CO>[OH:18][C:17]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[N:9]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:16]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccc(N)cc1
Solvent: CO
Product: CCOC(=O)c1cc(O)c2cc(OC)ccc2n1
Temperature: 55 °C

Procedure:
To a solution of p-anisidine (2.7 g, 22 mmol) in methanol (50 mL) was added diethyl-acetylene dicarboxylate (3.74 g, 22 mmol). The resulting solution was heated at 55° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in phenyl ether (40 mL) and refluxed at 240° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with hexanes and filtered. A light brown solid was obtained. LC-MS: 1.39 min; (M+H)=248.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCCC1
Yield: 68.7 %

Procedure:
A solution of pyrrolidine (50 g, 0.7 mol) and 3-chloropropan-1-ol (66.15 g, 0.7 mol) in acetonitrile (1l) containing potassium carbonate (145 g, 1.05 mol) was refluxed for 20 hours. After cooling, the mixture was filtered, the solid was washed with acetonitrile and the filtrate was evaporated. The residue was distilled at about 130° C. under about 70 mmHg to give 1-(3-hydroxypropyl)pyrrolidine (62.1 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:18]2[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[Cl:1][C:2]1[C:3]([S:8][C:25]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][N:22]=[C:17]([NH:9][C:10]4[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=4)[C:18]=3[N:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ncccc1Cl
Reactant: Cn1ccc(N)n1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cn1ccc(Nc2ncnc3ccc(Sc4ncccc4Cl)nc23)n1

Procedure:
The compound of Example 59 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-chloro-2-mercapto-pyridine, 3-amino-1-methyl-1H-pyrazole and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][CH:38]=4)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)Nc2c(C)cc(Cl)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)Nc2c(C)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
Diethyl azodicarboxylate (DEAD) (83 μL, 0.53 mmol) was added drop-wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (125 mg, 0.38 mmol), 4-hydroxyquinoline (76.3 mg, 0.53 mmol) and Ph3P (138 mg, 0.53 mmol) in THF (2.5 mL) at room temperature. The mixture was stirred at room temperature for 3 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL) and the solution was successively washed with 1 N aqueous NaOH (3×10 mL) and brine (15 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH, 9:1) to give the title compound (52 mg, 30% yield) as a white solid: MS (ESI) m/z 460/462 (MH)+.
Reaction SMILES: NC1[C:3](=[CH:8][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])(C)CC=1C)C(OC)=O.[C:19]1([N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[NH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=[O:36])C>>[CH2:17]([O:16][C:14]([C:9]1[C:8]([CH3:3])=[C:24]2[C:23](=[CH:22][C:21]=1[CH3:20])[N:27]=[CH:26][N:25]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:19]2=[O:36])=[O:15])[CH3:18]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1(C)C=C(C(=O)OC)C(N)=C(C)C1
Reactant: CCOC(C)=O
Product: CCOC(=O)c1c(C)cc2ncn(-c3ccccc3)c(=O)c2c1C
Temperature: 200 °C
Yield: 71.9 %

Procedure:
In an open flask a mixture consisting of 600 mg of methyl 2-amino-5-ethoxycarbonyl-3,5-dimethylbenzoate and 850 ml of N,N-diphenylformamidine was heated to 200° C. with occasional swirling. The temperature of the reaction mixture was maintained at around 200° C. for 1.5 hours. After cooling, the mixture was taken up in ethyl acetate, and the ethyl acetate extract was washed successively with dilute hydrochloric acid and water, and dried over sodium sulfate. The solvent was removed by evaporation. Chromatography on silica gel column and recrystallization from ethanol/water yielded 556 mg (71.9% of theory) of 6-ethoxycarbonyl-5,7-dimethyl-3-phenyl-4(3H)-quinazolinone melting at 102°-103° C. 1H NMR: (CDCl3) 1.43 (t, 3H), 2.48 (s, 3H), 2.83 (s, 3H), 4.48 (q, 2H), 7.30-7.90 (m, 6H), 8.14 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:14][N:15]([CH2:17][C:18](O)=[O:19])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:28][CH3:29])[C:4]1=[O:30])[CH3:2].C(N1C=CN=C1)([N:33]1[CH:37]=[CH:36]N=C1)=O.C(N)C>ClCCl>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:14][N:15]([CH2:17][C:18]([NH:33][CH2:37][CH3:36])=[O:19])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:28][CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC(=O)O)nc3-c3cccc(C)c3)ccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: ClCCl
Product: CCNC(=O)Cn1cc(-c2ccc3c(c2)n(CC)c(=O)n3CC)c(-c2cccc(C)c2)n1
Temperature: 23 °C
Yield: 66.3 %

Procedure:
To a dichloromethane (2 mL) solution of [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetic acid (0.106 g) was added carbonyldiimidazole (0.055 g). After stirring at 23° C. for 0.5 hours ethyl amine (0.2 mL, 2M in tetrahydrofuran) was added. The reaction was stirred at 23° C. for an additional hour then was concentrated. Preparative thin layer chromatography gave 2-[4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-N-ethyl-acetamide (0.075 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:6]([S:7][CH3:8])[N:5]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:4]1=[O:23].C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.Br[CH2:39][C:40](=[O:42])[CH3:41].[C:43](=[S:45])=[S:44]>>[OH:42][C:40]1([CH3:41])[CH2:39][S:45][C:43](=[C:9]([N:5]2[CH:6]([S:7][CH3:8])[CH:3]([O:2][CH3:1])[C:4]2=[O:23])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[S:44]1
Reactant: CC(=O)CBr
Reactant: COC1C(=O)N(CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1SC
Reactant: S=C=S
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Product: COC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C2SCC(C)(O)S2)C1SC

Procedure:
Following the procedure of Preparation 9, but using p-nitrobenzyl 2-(3-methoxy-4-methylthio-2-azetidinon-1-yl)-acetate (151 mg), hexamethyldisilazane (185 μl), butyllithium (540 μl), carbon disulphide (26 μl) and bromoacetone (37 μl), there were obtained 121 mg of the desired product, which was a mixture of two isomers. The isomers were isolated by silica gel column chromatography (eluent: a 6:1 by volume mixture of methylene chloride and ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([OH:50])=O)[CH2:15]2)=[CH:10][CH:9]=1.Cl.[CH3:53][NH:54][O:55][CH3:56]>>[CH3:56][O:55][N:54]([CH3:53])[C:48](=[O:50])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:51])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38]
Reactant: CNOC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
According to general procedure D, 1.0 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid are reacted with N,O-dimethylhydroxylamine hydrochloride to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:2]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)C(=O)OC(C)(C)C)=[CH:18][CH:17]=1.C1CCN2C(=NCCC2)CC1>ClCCCl>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][NH:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[S:11](=[O:13])(=[O:12])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[S:7]2(=[O:9])=[O:8])=[CH:17][CH:18]=1.[ClH:10]
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)c1ccc(N)cc1
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cl
Product: O=S1(=O)c2ccccc2S(=O)(=O)N1c1ccc(NCc2ccccn2)cc1
Reaction time: 48 h

Procedure:
To a solution of 1,2-benzenedisulfonyl dichloride (72 mg, 0.26 mmol) and DCE (3 mL) at 40° C. was added a solution of tert-butyl (4-aminophenyl)(pyridin-2-ylmethyl)carbamate (78 mg, 0.26 mmol) and DBU (0.09 mL, 0.57 mmol) in dry DCE (2 mL). After 48 h, the heat was removed and the r×n was added to DCM:H2O (1:1, 5 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2×5 mL) and the collected organic layers were washed with Brine (5 mL), and dried over MgSO4. After filtration and concentration under reduced pressure, the residue was purified by preparative HPLC. The pure material was dissolved in DCM (1 mL) and 4M HCl in dioxane (0.5 mL) was added. After 3 h, the solvent was removed to provide 2-(4-((pyridin-2-ylmethyl)amino)phenyl)benzo[d][1,3,2]dithiazole 1,1,3,3-tetraoxide as an HCl Salt
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:11][C:12](=O)[CH2:13][C:14]([F:17])([F:16])[F:15]>>[F:15][C:14]([F:17])([F:16])[CH2:13][C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[S:9][CH:11]=1
Reactant: NC(=S)N1CCNCC1
Reactant: O=C(CBr)CC(F)(F)F
Product: FC(F)(F)Cc1csc(N2CCNCC2)n1
Yield: 24 %

Procedure:
Prepared in analogy to example 49 (a) from 1-piperazinecarbothioamide and 1-bromo-4,4,4-trifluoro-butan-2-one. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a brown oil (yield 24%). MS (m/e): 252.3 (M+H+, 100%).
Reaction SMILES: C[Li].[Li+].[Br-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:14]=[C:15]([C:17](N(OC)C)=[O:18])[N:16]=2)=[CH:8][CH:7]=1.C[Li].[C:35](O)(=O)C>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[CH:14]=[C:15]([C:17](=[O:18])[CH3:35])[N:16]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: CON(C)C(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Methyl lithium-LiBr complex (1.5 M in ethyl ether) (0.47 ml, 0.7 mmol) was added by syringe to a cold (−70° C.) solution of 2-(4-chlorophenyl)-N-methoxy-N-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxamide from step 2 (250 mg, 0.6 mmol) in 50 ml tetrahydrofuran. The reaction was warmed to 0° C. and re-cooled to −60° C. before additional methyl lithium (0.47 ml) was added. The reaction was warmed to room temperature. After stirring for two days, 50 ml of 10% acetic acid was added and the mixture was concentrated to a gum. The gum was dissolved in 50 ml ethyl acetate, washed with water (2×50 ml), dried over Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography: Anal. Calc'd. C18H15N2O3SCl.¼H2O: C, 56.99; H, 4.12; N, 7.38. Found: C, 56.88; H, 4.05; N, 7.6838