Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Cl)[CH:5]=[CH:6][CH:7]=1.CON(C)[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[O:14]>C1COCC1>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C:13](=[O:14])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cl[Mg]c1cccc(Cl)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.6 %

Procedure:
At −20° C., 3-chlorophenyl magnesium chloride (11 mL, 5.5 mmol, 0.5M THF solution) was added dropwise to a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (500 mg, 1.84 mmol) in THF (5 mL). The solution was stirred for 2 h and allowed to warm to rt. The reaction was quenched with satd ammonium chloride solution. The aqueous layer was extracted with ether (3×). The combined organic layers were washed with brine, dried over MgSO4 and filtered. Evaporation of solvent provided (3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine (0.79 g) as an oil that was used without purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](OC)=[C:8]([Cl:14])[C:7]=1[CH3:15].[C:17]1(O)C=CC=CC=1>>[NH2:1][CH2:2][C@@H:3]([OH:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([Cl:14])[C:7]=1[CH3:15]
Reactant: COc1ccc(OC[C@H](O)CN)c(C)c1Cl
Reactant: Oc1ccccc1
Product: Cc1ccc(OC[C@H](O)CN)c(C)c1Cl

Procedure:
(R)-1-Amino-3-(3-chloro-4-methoxy-2-methyl-phenoxy)-propan-2-ol tan solid, 0.51 g (starting from 3.0 mmol of phenol).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4].Br[CH2:28][CH2:29][CH3:30].Cl>CN(C)C=O>[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4]
Reactant: CCCBr
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C=O)cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reaction time: 1 h
Yield: 84.9 %

Procedure:
Sodium hydride (2.96 g of a 60% w/w dispersion in mineral oil) was added to dry dimethylformamide (DMF, 100 ml), under a nitrogen atmosphere. The mixture was stirred and cooled in an ice-bath, and a solution of methyl 4-(5-formylindol-3-ylmethyl)-3-methoxybenzoate (20 g) in DMF (75 ml) added slowly. After 1 h, 1-bromopropane (9.13 g) was added slowly. After 2 h, the mixture was carefully acidified with 2M hydrochloric acid (100 ml), extracted with ethyl acetate (twice), and the extract washed with 1M hydrochloric acid, water, and brine. The dried (MgSO4) solution was evaporated, and the residue dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was evaporated, and the product crystallised from ether to give methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (19.2 g, 85%) as white needles; mp 98-99°; partial NMR (250 MHz, DMSO-d6): 0.82(t, 3H, CH3), 1.75(m, 2H, CH2), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.1(m, 4H, ArCH2Ar' and NCH2), 9.95(s, 1H, CHO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccc(F)cc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Yield: 46 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IX, 1.5 g (6.9 mmol) of 2-(4-fluorophenyl)phenylboronic acid (Step 1) was reacted with 2.5 g (10.4 mmol) of 4-bromobenzenesulfonamide (Lancaster). Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7) and subsequent recrystallization from ethyl acetate/hexane gave 1.04 g (46%) of 4-[2-(4-fluorophenyl)phenyl] benzenesulfonamide as a colorless solid: mp 187.3--188.2° C.; NMR (CDCl3) δ 4.83 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.02-7.11 (m, 2H), 7.27 (d, J=9 Hz, 2H), 7.36-7.50 (m, 4H), 7.78 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 327 (75) 245 (100); HRMS Calc'd for C18H14FNO2S: 327.0729. Found: 327.0743. Anal. Calc'd for C18H14FNO2S: C, 66.04; H, 4.31; N, 4.28.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1[CH2:21][C:22](OCC)=O)[CH3:2].CC[O-].[Na+].C(O)C.C([O-])(=O)C.[NH4+:39]>C1CCCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9]([CH:8]2[CH2:21][C:22]=1[NH2:39])=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=3)=[O:27])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN1CCc2cc(OC)c(OC)cc2C1CC(=O)OCC
Agent: CC(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCCCC1
Product: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
A solution of 3-(1-ethoxycarbonylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 17.1 g, 45.0 mmol) in cyclohexane (340 mL) was treated with sodium ethylate (9.67 g, 135 mmol) and heated in an oil bath, and the ethanol formed during the reaction was removed by distillation over 30 min, while more cyclohexane was added in order to keep the reaction volume constant. After cooling the reaction mixture was neutralized with acetic acid and concentrated. The residue was dissolved in dichloromethane/water 1:1 and brought to pH 10 with concentrated ammonium hydroxide solution. The organic layer was separated, dried (MgSO4), and evaporated. The residue was dissolved in methanol (270 mL) and ammonium acetate (42.3 g, 548 mmol) was added. After stirring at r.t. for 90 min, the reaction mixture was evaporated and the residue partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was dried (MgSO4), evaporated, and chromatographed (SiO2, CH2Cl2/MeOH/NH4OH 97.5:2.5:0.25) to afford the title compound (9.90 g, 66%). Light yellow solid, MS (ISP) 333.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([C:28]#[N:29])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[H-].[Na+]>COCCOC>[CH3:12][O:11][C:9]([CH:8]1[CH2:7][C:6]([C:28]#[N:29])([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)[CH2:5][CH2:4][C:3]1=[O:2])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OCCCN2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CCC1=O
Temperature: 20 °C
Reaction time: 4.5 h
Yield: 81.4 %

Procedure:
To a solution of 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-heptanedioic acid dimethyl ester (8.8 g, 21.1 mmol) in 1,2-dimethoxyethane (176 mL) was charged portions of NaH (60% dispersion, 2.55 g, 63.4 mmol). The reaction mixture was heated to reflux. After 4.5 hr, the ¾ of solvent were evaporated and the mixture cooled to 20° C. with an ice bath and quenched with water (100 mL), HCl 1N (100 mL). The aqueous layer was extracted with ether (100 mL). After basification with NaOH the aqueous phases were extracted with dichloromethane. The combined organics were washed with water, dried over Na2SO4, filtered and concentrated to provide 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexane-carboxylic acid methyl ester (6.6 g, 81%) as an oil.
Reaction SMILES: [H-].[Na+:2].Cl[C:4]1[C:5]([C:12]([O:14]C)=O)=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1.[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18]([C:17]1[S:16][C:4]2[CH:9]=[N:8][C:7]([S:10][CH3:11])=[N:6][C:5]=2[C:12]=1[O-:14])=[O:19].[Na+:2]
Reactant: COC(=O)c1nc(SC)ncc1Cl
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(SC)nc2c1[O-]
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
1.2 g of sodium hydride (60% in oil) are added slowly to a mixture of 6.0 g of methyl 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate 2 and 3.0 g of methyl sulfanylacetate in 60 ml of DMF. After 15 min at ambient temperature, the mixture is heated at 60° C. for 3 h, and then cooled to ambient temperature overnight. The resulting suspension is filtered and the solid is washed with ethyl acetate and dried under vacuum so as to obtain 3.6 g of sodium 6-(methoxycarbonyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidin-7-olate 3 in the form of a beige solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C)C=O>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(C)Oc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1Cc1ncc[nH]1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a suspension of 5.7 g of 50% sodium hydride in 200 ml of dry dimethylformamide was added slowly 8.0 g of imidazole at room temperature, and then the mixture was stirred for 30 minutes. A solution of 34.1 g of ethyl 2-(o-bromomethylphenoxy)propionate in 50 ml of dry dimethylformamide was added to the mixture at room temperature over a period of 1 hour, and then the reaction mixture was stirred at the same temperature for 1 hour. After removal of the solvent under vacuum, 150 ml of dichloromethane was added to the residual oil and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residual oil was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 15 g of ethyl 2-[o-(1-imidazolylmethyl)phenoxy]propionate as colorless needles. M.P.: 84°-85° C.
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCl>[Cl:14][CH2:15][C:16]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Nc1ncns1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ncns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [1,2,4]-thiadiazol-5-ylamine (3.0 g) in dry dichloromethane (30 mL) under nitrogen at 0° C. was treated with triethylamine (4.6 mL) followed by slow addition of chloroacetyl chloride (2.6 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound (1.00 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:36]>>[CH3:1][N:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Cl:36])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CCCCCCO)c1ccccc1
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(CCCCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.31-1.42(4 H,m), 1.51-1.63(4 H,m), 2.91(3 H,s), 3.30(2 H,t,J=7.9 Hz), 3.63(2 H,t,J=6.6 Hz), 6.64-6.70(3 H,m), 7.18-7.21(2 H,m) 6-(N-Methy-N-phenylamino)hexyl alcohol (1.1 g) and triphenylphosphine (1.3 g) were dissolved in methylene chloride (40 ml), and N-chlorosuccinylimide (0.71 g) was added, which was followed by stirring at room temperature for 1 hr 20 min. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.90 g of 6-(N-methy-N-phenylamino)hexyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=[N:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:16][C:15]3=[O:31])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH:29]=[CH2:30])=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH2:16][C:15]3=[O:31])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(N=C3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1ccc(S(=O)(=O)N2CCN(NC3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
1-[1-(4-Pyridyl)-4-piperidinylideneamino]-4-(4-vinylphenylsulfonyl)-2-piperazinone (200 mg) was dissolved in methanol (10 ml), combined with acetic acid (110 mg) with cooling on ice followed by sodium cyanoborohydride (57 mg), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried, concentrated and purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (150 mg) as a colorless amorphous material.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH:45]1[C:50]#[N:51]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:47]2[CH2:48][CH2:49][NH:44][CH:45]([C:50]#[N:51])[CH2:46]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1NCC(=O)O
Reactant: N#CC1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a mixture of 2-(4,5-dichloro-2-methoxyphenylamino)acetic acid (260 mg, 1.04 mmol), EDCI (273 mg, 1.43 mmol), HOBt (194 mg, 1.43 mmol) and Et3N (288 mg 2.85 mmol) in DCM (10 mL) at 0° C., piperazine-2-carbonitrile was added. The resulting mixture was stirred at RT for 8 h. The mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (108 mg, 30% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:13]>CCO.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O-:6])=[O:5].[Na+:13]
Reactant: O=C(O)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 2,6-difluorobenzoic acid (1.00 g, 6.3 mmol) in EtOH and water (5:1, 60 mL) was added 1N aqueous sodium hydroxide solution (6.33 mL, 6.3 mmol). The reaction mixture was stirred for 10 minutes at room temperature and then solvents were removed in vacuo to yield sodium 2,6-difluorobenzoate (1.22 g, 6.3 mmol, quantitative) as an off white solid. 1H NMR (DMSO) δ 6.89 (2H, m), 7.15 (1H, m).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1Cl)#[N:2].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].CC([O-])(C)C.[K+].C1COCC1>CN(C=O)C>[NH2:2][C:1]1[C:3]2[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: N#Cc1c(Cl)ccnc1Cl
Reactant: COC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccnc(Cl)c2c1N
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To 3-cyano-2,4dichloropyridine (653 mg) and methyl thioglycolate (340 μL) in DMF (12 mL) at 5° C. was added a solution of 1.0M KOtBu/THF (4.5 mL). The reaction was stirred 20 min at 5° then 1 h at RT, then quenched in sat'd NH4Cl, the solid precipitate collected, washed with water and sucked dry to give 800 mg (88%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=2)[N:11]([C:19](=[O:42])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4[CH:37]=[CH:38][CH:39]=[CH:40][C:31]3=4)=[O:29])=[CH:24][C:23]=2[CH3:41])[CH2:10][C:9]1=[O:43])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]([C:19](=[O:42])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4[CH:37]=[CH:38][CH:39]=[CH:40][C:31]3=4)=[O:29])=[CH:24][C:23]=1[CH3:41])[CH2:10][C:9](=[O:43])[N:8]2[CH2:7][C:6]([OH:44])=[O:5]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)OC(C)(C)C)c2cccc(F)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)O)c2cccc(F)c21
Reaction time: 1.5 h

Procedure:
To a solution of {5-fluoro-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcarbamoyl]-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}acetic acid tert-butyl ester from Example 7B (105 mg, 0.175 mmol) in dichloromethane (4.0 ml) was added trifluoroacetic acid (4.0 ml). The mixture was stirred for 1.5 h, evaporated in vacuo and azeotroped with toluene to give a white solid; yield 95 mg, 100%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH:20]([CH:23]1[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH:23]3[CH:20]([CH3:22])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: CC(C)C1NCCNC1=O
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1C(=O)NCCN1Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (212 mg, 0.75 mmol), 3-isopropylpiperazin-2-one (128 mg, 0.90 mmol) and powdered 4 Å molecular sieves in DCE (18 mL) were stirred at RT. After 4 h, sodium triacetoxyborohydride (318 mg, 1.50 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. Trituration of the resulting residue with EtOAc gave 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one as a yellow oil (198 mg, 65%). LCMS (Method H): RT=2.82 min, [M+H]+ 408.4
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C1(C)C(C)=CC=CC=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][N:20]=1>CCCCCCC>[C:21]([C:18]1[S:17][C:16]([NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])=[N:20][N:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCCCCCC
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A 2-liter reaction flask with appropiate fittings was charged with 33.6 g (0.4 mole) of diketene, 965 ml of xylene and 59.7 g (0.38 mole) of 2-amino-5-tert-butyl-1,3,4-thiadiazole. The stirred mixture was heated to 70° at which time all solids had dissolved. After 1 hour, the solution was cooled and added to 2500 ml of chilled heptane. Product precipitation was judged complete after two hours. The solids were collected on a vacuum filter and air dried. There was obtained 54 g (58.9%) of white product, m.p. 166°-68°. N.M.R. (CDCl3 -dimethyl-d6 sulfoxide) ∂ 1.5 [C(CH3)3 ], 2.0 (CH3, enol), 2.3 (CH3, keto), 3.6 (CH2), 5.4 (CH, enol).
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH2:14]C(O)=O)[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:34]([NH:36][C@H:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56])[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:35])C=C>>[CH2:1]([C:8]1[N:13]([CH2:14][C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[CH2:38][C:39]([OH:41])=[O:40])=[O:35])[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O
Reactant: C=CCOC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Product: O=C(O)CC(NC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O)C(=O)COCc1ccccc1Cl

Procedure:
N-2-(6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl)acetyl-3-amino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid (90) was prepared from 52b and (3S)t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chlorophenylmethoxyl)-4-oxo-pentanoate (prepared by a similar method as 82) to give a white solid: 1H NMR(DMSO-d6) δ 9.2(s, 1H), 8.75(d, 1H), 7.7-7.1(m, 14H), 6.4(d, 1H), 4.65(d, 6H), 4.56(s, 1H), 4.6-4.35(dd, 1H), 3.9(s, 2H), 2.9-2.6(m, 6H) ##STR155##
Reaction SMILES: CN(C)CC(C)C([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.O.NN.[OH-].[Na+].ClC1C=CC([C:28]2[CH:32]([CH3:33])[CH2:31][NH:30][N:29]=2)=CC=1>C(O)CC>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([N:30]2[CH2:31][CH:32]([CH3:33])[CH:28]=[N:29]2)=[CH:12][CH:11]=1
Reactant: CC1CNN=C1c1ccc(Cl)cc1
Reactant: CC(CN(C)C)C(=O)c1ccc(Cl)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC1C=NN(c2ccc(Cl)cc2)C1

Procedure:
In a 500 ml round bottomed flask equipped with a reflux condensor was placed 100 g of 3-dimethylamino-2-methyl-4'-chloropropiophenone (0.47 mole), 200 ml of n-propanol, 48 g of hydrazine monohydrate (0.96 mole), and 5 g of 50% aqueous sodium hydroxide. The mixture was refluxed for 2 hours. The solvent was removed in vacuo and the product was partitioned between methylene chloride and water. The organic layer was washed 3 times with water and dried over anyhdrous magnesium sulfate. The organic layer contains 82 g (0.42 mole) of 3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole an air sensitive solid. NMR data was consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH3:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: COc1ccc(N)cc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Product: COc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 60 °C
Yield: 40.2 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-7-methane-sulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 0.32 ml (2.6 mmol) of 4-methoxyaniline was heated at 60° C. for 4 hours and then cooled. 10 ml of 2M aqueous hydrochloric acid were added to the residue. The precipitated yellow solid was filtered off, washed in sequence with 2M aqueous hydrochloric acid, water and diethyl ether and then dried to give 45 mg (40%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(4-methoxyanilino)-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid of melting point 175° C. (decomposition).