Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH3:19]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (10.0 g) in DMF (120 ml) were added potassium carbonate (15.8 g) and 1-bromopropane (12.1 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, which was extracted with ethyl acetate and washed with 1N sodium hydroxide solution twice, with water three times and with saturated brine once. After dried with magnesium sulfate, the solvent was evaporated under reduced pressure to give 3-propoxybenzaldehyde (13.4 g) as colorless liquid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][C@H:33]([CH3:36])[C:34]#[N:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([C@H:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:36])#[N:35]
Reactant: C[C@@H](N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 40 mg, 0.093 mmol) and (R)-2-aminopropanenitrile (Int-X, 13.00 mg, 0.185 mmol) were dissolved in DMF (1 mL). 4-Methylmorpholine (37.5 mg, 0.371 mmol) and HATU (45.8 mg, 0.121 mmol) were added. After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 35 min, 20 mL/min, 220 nM, product retention=28.5 min) to provide single enantiomer N-((R)-1-cyanoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (27 mg, 0.055 mmol, 59.6% yield): [M+H]+=484.0; 1H NMR (400 MHz, methanol-d4) δ ppm 8.93 (1 H, d, J=7.70 Hz), 8.13-8.24 (2 H, m), 7.50-7.80 (7 H, m), 5.17 (1 H, s), 4.86-4.91 (1 H, m), 1.56 (3 H, d, J=7.04 Hz); HPLC peak RT=9.9 min (Method A).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:25]
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Reactant: O=C(Cl)CCCCCl
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCCl)cc2C)cc1

Procedure:
Similar procedure to Description 3 from D2 and 5-chlorovaleryl chloride.
Reaction SMILES: [C:1](=[O:4])([O-:3])O.[Na+].[CH2:6]([O:8][C:9]([C:11]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:10])[CH3:7]>ClCCl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:3][C:1]([N:13]1[CH2:14][CH2:15][C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:12]1)=[O:4]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Oc2ccccc2OC)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 146.7 %

Procedure:
Sodium hydrogen carbonate (244 mg, 2.9 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (200 mg, 0.58 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. 2-Methoxy phenyl chloroformate (0.09 mL, 0.64 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed brine (25 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate in hexane to afford the title compound as a white solid (210 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:10])([CH3:14])[C:11]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from N-t-butoxycarbonyl-2-methylalanine and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (200 MHz, CDCl3): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H) and 8.65 (s, 1H). FAB-MS: calculated for C22 H25N3O4 395; found 396 (M+H, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23]1([S:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8](=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)[S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: ClSc1ccccc1
Reactant: COC(=O)C1SC(=CC(=O)OC(C)(C)C)S1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1SC(=C(Sc2ccccc2)C(=O)OC(C)(C)C)S1

Procedure:
A mixture of methyl 2-(t-butoxycarbonylmethylene)-1,3-dithietane-4-carboxylate (689 mg), pyridine (430 μl) and benzenesulfenyl chloride is allowed to react in methylene chloride at 0° C. until no starting carboxylate is detected. The reaction mixture is washed with water, dried, and vacuum evaporated to give methyl 2-(1-t-butoxycarbonyl-1-phenylthiomethylene)-1,3-dithietane-4-carboxylate. Yield: 713 mg (73%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(C(C)=O)CC2)cc1
Yield: 102 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (7.7 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in dimethylformamide (50 ml) was stirred at 80° C. for 5 hr. The reaction mixture was poured into water (250 ml) and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil. The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (11.5 g) as a colorless transparent oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][OH:1])[CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCCCN
Product: CCCCNC(=O)C(C)(C)CO
Yield: 100 %

Procedure:
Prepared as in Example 197d (Method A) from methyl 3-hydroxy-2,2-dimethylpropanoate and n-butyl amine in 100% yield. MS 174 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C

Procedure:
A solution of 2,4-dicloro-5-nitropyrimidine (930 mg) in DCM (40 mL) was treated with DIEA (0.9 mL) and trans-4-aminocyclohexanol (345 mg) at −78° C. for 6 hours. The mixture was allowed to slowly warm to room temperature and stirred for 12 more hours. The solvent was evaporated and the crude mixture was purified by silica gel chromatography (DCM:EtOAc 70:30) to provide 630 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
To a solution of compound 1 (600 mg, 1.36 mmol) in dry DMF (10 mL) was added NaH (60%, 60 mg, 1.50 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. Ethyl 2-bromoacetate (225 mg, 1.36 mmol) was added and then this mixture was stirred at rt for 5 h. Water was added for quench and the solution was extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=5/1) to give compound 42 (150 mg, 21%) as a white solid.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Cc1csc(I)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(N2CCNCC2)n1
Temperature: 160 °C
Yield: 65 %

Procedure:
A mixture of 1.33 mmol 2-iodo-4-methyl-thiazole, 4.00 mmol piperazine and 4.00 mmol triethylamine in 4 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 2 h under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to afford the title compound as a yellow oil (yield 65%). MS (m/e): 184.3 (M+H+, 100%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:22]([CH3:23])[C:21]5[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=5[N:19]=4)[CH:13]=3)[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([CH2:4][N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:13]=[C:14]([C:18]4[N:22]([CH3:23])[C:21]5[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=5[N:19]=4)[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: Cn1c(-c2cccc(N3CCN(C(=O)C4CC4)CC3)c2)nc2ccccc21
Solvent: CSC
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(N3CCN(CC4CC4)CC3)c2)nc2ccccc21
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of cyclopropyl-{4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-yl}-methanone (0.17 g, 0.47 mmol) in dry THF (3.50 mL) was added (CH3)2S.BH3 in THF (0.11 mL, 1.18 mmol) and the resulting suspension was heated at 65° C. overnight. The reaction solution was then cooled to room temperature, solvent was removed under reduced pressure and 1N HCl (3 mL) was added to the residue before heating at 100° C. for 6 h. The reaction was cooled to room temperature, then made basic by the dropwise addition of 15% NaOH and extracted with EtOAc (3×10 mL) The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue that was purified by Preparative HPLC, to obtain 0.05 g (32%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11])[O:23][S:32]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=1)(=[O:34])=[O:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccc(OS(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, step 5, 183 mg, 0.5 mmol) in dichloromethane (8 ml) was treated with triethyl amine (116 ml, 1.15 mmol) and cooled down to 0° C. To the cooled solution, 4-(chlorosulfonyl)benzoic acid (132 mg, 0.6 mmol) was added in three portions (10 min). The reaction mixture was stirred at 0° C. for 15 min. and 2 h at r.t., followed by dilution with dichloromethane (8 ml). The reaction mixture was extracted with 1M aq HCl, the organic phase was washed twice with water and brine, dried over MgSO4, filtered and concentrated. The solid residue was dried under high vacuum to give the title compound (275 mg) as a white solid. MS (m/e)=550.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH2:11]Cl)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([SH:17])[CH2:15][SH:16].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:16][CH2:15][CH2:14][S:17][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: SCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.3 %

Procedure:
A solution of ethyl 2-methoxyimino-3-oxo-4-chlorobutyrate (41.4 g.) in dried chloroform (100 ml.) was added dropwise over 1 hour at 20° C. to a mixture of ethane-1, 2-dithiol (20.6 g.), triethylamine (21 g.) and dried chloroform (60 ml.). After stirring for 2.5 hours at 18° to 21° C., the mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The chloroform layer was separated, washed with water (100 ml.×3), dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40° C. The residue was dissolved in toluene (300 ml.), p-toluenesulfonic acid (3 g.) was added thereto and the resulting mixture was refluxed for 3 hours with removal of water. The reaction mixture was cooled to ambient temperature and an insoluble material was filtered off. The filtrate was concentrated under reduced pressure at 40° C. The residue was dissolved in ethyl acetate (300 ml.). The solution was in turn washed with a saturated aqueous solution of sodium bicarbonate (3 times) and water (twice), dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40° C. to give yellow oil. The oil was subjected to column chromatography on silica gel (1 kg) and eluted with benzene. The eluate was concentrated under reduced pressure at 40° C. The residue was washed with diisopropyl ether and dried to give white crystals of ethyl 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetate (syn isomer) (11 g.), mp. 65° to 67° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f14) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Yield: 75.2 %

Procedure:
To a cold (5° C.) vigorously stirred mixture of 121.87 g (0.936 mole) of ethyl acetoacetate, 314 ml. of benzene and 626 ml. of water was added 41.25 ml. of 33% sodium hydroxide. To the above mixture was added simultaneously, in two dropping funnels, 177.0 g (1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of 33% sodium hydroxide in 2 hours. The reaction mixture became pasty. The reaction mixture was heated at 35° C. for 1 hour, cooled and filtered to give 170.0 g of sodium salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this salt was added to a mixture of 39.0 g (0.729 mole) of ammonium chloride and 78 ml. of concentrated ammonium hydroxide in 780 ml. of water. The mixture was stirred at 40°-50° C. for 3 hours and cooled in an ice bath. The precipitate was filtered to give 115.5 g of yellow solid which was Kugelrohr distilled to give 76.0 g (38% based on ethyl acetoacetate) of crude ethyl p-chlorobenzoylacetate. A mixture of 40.0 g (0.175 mole) of crude ethyl p-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl chloride and some chloroform was held at reflux for 6 hours, cooled and concentrated to give 49.0 g of crude ethyl 2-chloro-p-chlorobenzoylacetate. A mixture of 46.0 g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoylacetate, 13.25 g (0.174 mole) of thiourea, and 174 ml. of ethanol was held at reflux for 2 hours and cooled. The precipitate was filtered and neutralized with saturated sodium bicarbonate. The insoluble material was filtered to give 37.0 g (80%) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate, m.p. 198°-200° C.
Reaction SMILES: [CH2:1]([NH:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([N:6]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)CN(NC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-neopentyl-1-benzoylhydrazine in toluene (40 ml) at 5° C., were added dropwise and simultaneously solutions of benzoyl chloride (1.4 g, 10 mmoles) in toluene (5 ml) and aqueous 50% sodium hydroxide solution (0.8 g) while maintaining the temperature below 10° C. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with hexane and the precipitated product isolated by filtration. The product was washed with water and hexane and dried. The crude product was recrystallized from methanol to afford N'-neopentyl-N,N'-dibenzoylhydrazine as a white powder: m.p. 237°-239° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]1C=CC=C(N)C=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:2]=[N:23][CH:3]=[CH:4][CH:5]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cccnc1
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccnc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using pyridin-3-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (s, 3H), 2.35 (s, 3H), 4.71 (d, J=3.0 Hz, 2H), 5.97 (bs, 1H), 6.41 (bs, 1H), 7.13-7.20 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 8.05 (d, J=4.0 Hz, 1H), 8.26 (bs, 1H), 8.56-8.63 (m, 2H); MS (ESI) m/z 307.9 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 50, N-methylpiperazine (0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were added N-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (0.045 ml, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=25:1 eluate was concentrated under reduced pressure to afford the title compound (86 mg, 0.17 mmol, 80%) as a white powder.