Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:13]=1)=[O:11])[CH2:5][CH:6]1[CH2:8][CH2:7]1.O.O.[OH-].[Li+].Cl>C1COCC1>[CH:6]1([CH2:5][C@H:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:13]=2)=[O:11])[C:3]([OH:26])=[O:2])[CH2:7][CH2:8]1
Reactant: COC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CC1CC1)C(=O)O)c1ccc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (Example 258, 42 mg, 117 μmol) was dissolved in THF (2 mL). After addition of water (0.66 mL) and lithium hydroxide monohydrate (14.8 mg, 352 μmol) the mixture was heated and stirred for 3 hours at reflux temperature. The mixture was cooled to room temperature, water (7 mL) was added and the mixture was acidified with 1 N HCl. The mixture was then extracted with ethyl acetate (14 and 7 mL), organic layers were washed with brine (10 mL), combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (36 mg, quant) as white solid; LC-MS (UV peak area/ESI) 100%, 345.1814 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=C(C=CCC(C2C=CC(C)=CC=2)(C)C)C=CC=1)C1C=CC=CC=1.[H][H]>[Pd].C([O-])(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([CH3:18])[CH3:19])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)(C)C=CCc2cccc(Oc3ccccc3)c2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1ccc(C(C)(C)CC=Cc2cccc(Oc3ccccc3)c2)cc1
Product: Cc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 3 h

Procedure:
To 30 ml of ethyle acetate, 1.9 g of a mixture of 50% 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-2-pentene and 50% 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-pentene was added and dissolved, and thereto 0.4 g of 5% Pd-C was added, and the mixture was stirred under a pressure of 20 kg/cm2G with hydrogen gas at room temperature. After three hours, Pd-C was removed by filtration, and ethyl acetate was evaporated under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][PH:4](=[O:6])[OH:5].[C:12]([O:31][CH3:32])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OOC(CC)(C)C)(CC)(C)C>[CH3:32][O:31][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([P:4]([OH:5])([CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CCCCCCCCC(CCCCCCCCC(=O)OC)P(=O)(O)CC(C)CC(C)(C)C
Temperature: 140 °C
Yield: 97.1 %

Procedure:
10 g (0.056 moles) of 2,4,4-trimethylpentyl phosphinic acid, 15.82 g (0.056 moles) of methyl oleate (CE-1897 from P&G Chemical) and 0.5 mL (0.0023 moles) of di-tert-amylperoxide are mixed in a 100 mL single neck flask. The mixture is purged with argon to remove oxygen and is heated under argon for 6 hours at 140° C. Tert-amyl alcohol is removed by distillation and 25.8 g (quantitative yield) of 10-[hydroxy-(2,4,4-trimethyl-pentyl)-phosphinoyl]-octadecanoic acid methyl ester is obtained as a slightly yellow oil.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[Cl:14][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Product: O=S1(=O)N=C(Cl)c2ccccc21
Yield: 28 %

Procedure:
Following the procedure of Stephen et al., J. Chem. Soc., 1957, 490-92, 1 mol of saccharin (1,2-benzisothiazol-3(2H)-one 1,1-dioxide) is heated with 1.1 mol phosphorus pentachloride at 170° C. for 1.5 hours. Phosphorus oxychloride is removed at 60°/30 mm and the yellow crystalline residue of ψ-saccharin chloride and o-cyanobenzene sulfonyl chloride is treated with ether in which the latter is soluble. The sparingly soluble ψ-saccharin chloride in a yield of 28% is collected and crystallized from ether as white needles, m.p. 132°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15]
Reactant: C/C([O-])=C/C#N
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 2.74 g (15.5 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 17A) and 2.6 g (24.8 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate to yield 1.6 g (42% of th.) of the crude product which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:3][N:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:21]
Reactant: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Temperature: 90 °C

Procedure:
3-Pyridazin-4-ylbiphenyl-4-ol (Preparation 4, 50 mg, 0.2 mmol) and 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 47, 50 mg, 0.2 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (83 mg, 0.6 mmol) was added and the reaction heated to 90° C. for 16 hours. The crude material was then purified by reverse phase column chromatography (ISCO™, 4 g, C18, 20:1 water:acetonitrile to 3:2 water acetonitrile). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as an off white solid (25 mg, 24%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[Cl:14][CH2:15][CH2:16][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2CCCl)c1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Into a flask of 500 ml capacity fitted with a stirrer and cooling tube, there were introduced 7.2 g (corresponding to 0.21 mol) of an oil dispersion of NaH, and 50 ml of tetrahydrofuran, and stirred on an ice-water bath. To this mixture there was added dropwise, a little at a time, a solution of 30.87 g (0.21 mol) of 5-methoxyindole dissolved in 100 ml of tetrahydrofuran. After completion of the dropwise addition, the ice-water bath was removed and the mixture was cooled for one hour at room temperature. Then, 49.29 g (0.21 mol) of 2-chloroethyl-p-toluene sulfonate were added, and reacted for 15 hours while stirring, heating under reflux. After completion of the reaction, the insoluble material was removed by filtration, and concentration was performed under reduced pressure. The reaction mixture was then purified by column chromatography using silica gel, to obtain 15.7 g of 1-(2-chloroethyl)-5-methoxyindole.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:23]12[CH2:28][CH:27]([CH:25]=[CH:24]1)[CH2:26][CH:22]2[CH2:21][N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CC3C=CC2C3)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from c-bicyclo[2.2.1]hept-5-en-2-yl-methylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10]>CN(C)C=O>[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([O:16][CH3:3])=[O:15])([O-:11])=[O:10]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
390 mg (2.76 mmol) of methyl iodide and 320 mg (2.3 mmol) of powdered potassium carbonate were added to 940 mg (2.3 mmol) of 2-nitro-5-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid in 30 ml of dimethylforamide (freshly eluted through neutral alumina). After 1 hour, the mixture was poured into 300 ml of water, extracted with ether, the ether layer was washed with saturated sodium chloride solution, then dried and evaporated to 820 mg of light yellow oil (84%) diphenyl ether methyl benzoate having the following elemental analysis, calculated (found): C: 45.14 (47.54); H: 2.13 (2.69); Cl: 8.33 (6.19); F: 22.31 (21.26); N: 3.29 (2.72); O: 18.79.
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:10]1([NH:13][CH:5]2[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: CC1(O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(O)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
4-Hydroxy-4-methylcyclohexanone (440 mg, 3.43 mmol) was dissolved in 1,2-dichloroethane (15 ml), followed by sequential addition of cyclopropylamine (0.26 ml, 3.78 mmol), NaBH(OAc)3 (1.16 g, 5.49 mmol), and acetic acid (0.20 ml, 3.43 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 20 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (15 ml×4). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 417 mg of yellow solid (72%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=O)(C)(C)C.[N:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH:26]=[CH:25][CH:24]=[CH:23]1>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:19]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1-n1cccc1
Product: CC(C)(C)ON=C1CN[C@H](C(=O)Nc2ccccc2-n2cccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 83% purity by LC/MS. MS(ESI+): m/z=341.2.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:16]([O:18][C:19](=[O:38])[CH:20]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:21](N1C2C=CC=CC=2N=N1)=[O:22])[CH3:17]>C1COCC1>[CH2:16]([O:18][C:19](=[O:38])[CH:20]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:21](=[O:22])[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1=[O:15])[CH3:17]
Reactant: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Reactant: O=C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCC1=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a −78° C. cold solution of LDA (2 M solution in heptane/ethylbenzene/THF, 1.8 ml, 3.66 mmol) in THF (16.8 ml) under an argon atmosphere was added a solution of cyclohexanone (380 μl, 3.66 mmol; CAS Reg. No. 108-94-1) in THF (12.6 ml) within 10 min. The mixture was stirred for 1 h at −78° C. A solution of 3-benzotriazol-1-yl-2-cyclohexyl-3-oxo-propionic acid ethyl ester (1.05 g, 3.33 mmol) in THF (11.1 ml) was added and the solution was stirred at ambient temperature for 14 h. Ice water was added, the mixture was poured onto ice water/brine 1/1 and extracted two times with TBME. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (209 mg, 0.71 mmol; 21%) as yellow oil. MS: m/e=295.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CCCBr
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Heat a suspension of methyl 5-bromo-2-isopropoxycarbonylaminobenzoate (10.0 g, 31.6 mmol), methyl 4-bromobutyrate (22.9 g, 126 mmol) and cesium carbonate (41.6 g, 126 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 80° C. for 24 h. Cool the mixture to room temperature and pour into water (200 mL). Extract with ethyl acetate (3×100 mL) and wash the organic extracts with water (3×100 mL) and brine (100 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a colorless oil (11.8 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 1.05-1.07 (m, 4H), 1.30-1.32 (m, 2H), 1.89-1.94 (m, 2H), 2.38-2.44 (m, 2H), 3.46-3.60 (m, 1H), 3.65 (s, 3H), 3.68-3.79 (m, 1H), 3.86 (s, 3H), 4.85-5.01 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.62 (dd, J=1.7, 8.4 Hz, 1H), 8.07 (brs, 1H); ESI MS m/z 416 [C17H22BrNO6+H]+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(O)CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To ethyl 3-(cyclohexylamino)-2-hydroxy-2-methylpropanoate (6.7 g, 29.2 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (5.2 ml, 43.8 mmol) dropwise, followed by K2CO3 (12 g, 87.6 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 7 g product (75%). [M+H] calc'd for C19H29NO3, 320; found 320.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1C.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:12]([OH:13])=[O:15]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Br)cccc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
To a mixture of 2-bromo-6-nitrotoluene (8 g), sodium carbonate (18.1 g) and water (500 mL) was added potassium permanganate (23.4 g), and the mixture was heated for reflux overnight. The insoluble material was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (three times). The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-bromo-6-nitrobenzoic acid (2.78 g). Tin (II) chloride dihydrate (9.18 g) was dissolved in concentrated hydrochloric acid (30 mL). To the solution was added 2-bromo-6-nitrobenzoic acid (2.78 g), and the mixture was stirred at 80° C. for 1.5 hours. The insoluble material was collected by filtration, washed with 2 mol/L hydrochloric acid and dried under reduced pressure. The obtained crystal (2.05 g) was suspended in concentrated hydrochloric acid (35 mL). To the suspension was added a solution of sodium nitrite (0.79 g) in water (6 mL) under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of tin (II) chloride dihydrate (5.78 g) in concentrated hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (1.27 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:18])(C(F)(F)F)[CH2:10][C:9]=2[Cl:19])[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[Br:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:18])=[CH:10][C:9]=3[Cl:19])[CH:5]=[C:4]([C:20]([F:21])([F:22])[F:23])[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1cc(C2=C(Cl)CC(Cl)(C(F)(F)F)C=C2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2,4-dichloro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.61) (1.50 g, 4.58 mmol) and commercially available 3-bromo-benzene-boronic acid (1.01 g, 5.03 mmol) according to the general procedure IVb. Obtained as a white solid (1.26 g, 61%). MS (EI) 447.9 [(M)+]; mp 124.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[NH2:20][CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(O)C>[C:22]([CH2:21][NH:20][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)([OH:24])=[O:23]
Reactant: NCC(=O)O
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Yield: 77.5 %

Procedure:
A suspension of 3.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 5.5 g of glycine, 5.5 g of sodium carbonate, 100 ml of ethanol and 30 ml of water was refluxed with stirring for an hour and the mixture was poured into water. The pH of the solution was adjusted to 4 by addition of 2 N hydrochloric acid and was extracted with chloroform. The mixture was filtered and the filtrate was dried over magnesium sulfate and evaporated to dryness. The gummy residue was crystallized by trituration with methanol and the mixture was filtered. The recovered solid was crystallized from ethanol to obtain 3.1 g (77% yield) of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine melting at 215°-220° C.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:14]([CH:24]=1)[C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16].O>C1COCC1>[OH:23][C:20]1([CH3:4])[CH2:19][CH2:18][N:17]([C:15]([C:14]2[CH:24]=[C:10]([CH3:9])[CH:11]=[CH:12][C:13]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(=O)CC2)c1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(C)(O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 M methylmagnesium bromide-diethyl ether solution (0.84 mL) was added to a solution of 1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-one (0.37 g) in THF (10 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.19 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:76][N:77]([CH3:81])[CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][N:77]([CH3:81])[CH3:76])=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0120 g (0.134 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0359 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-ethyl-benzamide (I-198) as a white solid.