Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
1155 g (6.4 mol) of 6-chloro-3,4-dihydro-2(1H)-naphthalenone were dissolved in 5 l of toluene, 500 g (7.0 mol) of pyrrolidine and subsequently a solution of 26 g (0.14 mol) of p-toluenesulphonic acid in toluene were added dropwise thereto and the mixture was boiled under reflux. When about 120 ml of water had separated, 4 l of toluene were distilled off and the mixture was left to cool slowly. A solid crystallized out. Filtration and washing with acetone gave 1-(6-chloro-3,4-dihydro-2-naphthyl)pyrrolidine of melting point 117°-118°. Concentration of the mother liquor, suspension of the residue in ether, filtration and washing with acetone gave a further portion of the above product of melting point 117°-118°.
Reaction SMILES: FC1C=CC([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=CC=1.BrC1C=CC(CCC[C:30]([NH2:32])=[S:31])=CC=1>C(#N)C.C(O)C>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:31][CH:30]=[N:32][CH:8]=2)=[CH:12][CH:13]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)CCCc1ccc(Br)cc1
Solvent: CC#N
Solvent: CCO
Product: CSc1ccc(-c2cncs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl) ethanone (Example 1, Step 3 ) (2.70 g, 7.90 mmol) in acetonitrile (90 mL) and ethanol (10 mL) in a 125 mL round bottom flask was added 4-(4-bromophenyl) thiobutyramide from Step 1, (1.4 g, 7.90 mmol) and the mixture was heated to reflux for 7 hours. The reaction was cooled to room temperature and let stand overnight. The crude product was concentrated in vacuo yielding an oil which was purified by flash chromatography (1: 1 hexane:methylene chloride) yielding 2-(3-[4-bromophenyl]propyl)-4- (4-fluorophenyl))-5-(4-methylthiophenyl)thiazole (1.4 g, 36%) as a clear colorless oil (ca. 90% purity by 1H NMR): 1H NMR (CDCl3) 3 00 mHz δ7.50-7.46 (m, 2H), 7.41 (d, J=8.46 Hz, 2H), 7.22 (d, J=8.66 Hz, 2H), 7.16 (d, J=8.66 Hz, 2H), 7.10 (d, J=8.26 Hz, 2H), 6.97 (t, J=8.86, 2H), 3.03 (t, J=7.45 Hz, 2H), 2.74 (t, J=7.45 Hz, 2H), 2.49 (s, 3H), 2.20-2.09 (m, 2H). MS (EI): m/z 529, 531 (M+) 497, 499. HRMS Δ=-2.1 mmu.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]3)[CH2:32][CH2:33][CH3:34])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C1COCC1>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:35][C@H:36]3[CH2:37][CH2:38][C@H:39]([CH2:42][CH2:43][OH:44])[CH2:40][CH2:41]3)[CH2:32][CH2:33][CH3:34])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: CCCN(C[C@H]1CC[C@H](CCO)CC1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](propyl)amino]methyl}cyclohexyl)acetic acid (8.8 mg, 0.0126 mmol) in THF (1 mL) was added a 1 M solution of BH3 in THF (75 μL, 0.075 mmol). The reaction was stirred at room temperature for 2 hours and then quenched with water (5 mL), diluted with EtOAc (15 mL), and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}(propyl)amino]-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.09 (25% EtOAc/hexanes). LCMS=685.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.78 (s, 2H), 7.16 (d, J=8.9 Hz, 2H), 7.10 (d, J=8.8 Hz, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.72 (d, J=16.4 Hz, 1H), 4.58 (d, J=16.4 Hz, 1H), 4.02-3.98 (m, 1H), 3.66-3.64 (m, 2H), 2.77-2.73 (m, 4H), 1.77-0.81 (m, 17H), 0.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4](F)[CH:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1Oc1ccccc1
Temperature: 85 °C

Procedure:
Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg, 0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.) and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in anhydrous N,N-dimethylformamide and was heated at 85° C. for 5 hours. The mixture was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4×), dried (MgSO4), and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted with 95:5 hexanes/ether to provide the title compound as a colorless oil that crystallized upon standing (110 mg, 34%): 1H NMR (300 MHz, CDCl3) δ 7.84 (d, 1 H), 7.39-7.27 (m, 7 H), 7.17-7.10 (m, 1 H), 6.98-6.91 (m, 2 H), 6.85 (d, 2 H), 5.30 (s, 2 H); Rf 0.51 (4:1 hexanes/diethyl ether).
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:44])[C@H:25]([CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([OH:42])=[CH:37][C:36]=1[CH3:43])[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([OH:5])=[O:4].[OH-].[Li+].O>C1COCC1>[C:30]([O:29][C:27]([NH:26][C@H:25]([C:24]([NH:23][C@@H:10]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[O:44])[CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([OH:42])=[CH:37][C:36]=1[CH3:43])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCCCC(C)C(=O)O)C(=O)NCCCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCCCCC(=O)O)C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (7R)-7-{[N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl]amino}-8-oxo-8-[(3-phenylpropyl)amino]octanoic acid (400 mg, 0.65 mmol) from preparation 14 in 3 ml dry THF was added a 0.5M solution of lithium hydroxide in water (3 ml, 1.5 mmol) and the reaction mixture stirred at rt overnight. Volatiles were evaporated and the residue acidified with 0.5M KHSO4. Product was extracted with ethyl acetate and the organic extract washed with brine, dried over MgSO4 and concentrated to a fine white solid which was taken directly into boc deprotection (preparation 28) on basis of LRMS m/z 598 [M+H].
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[OH-].[Na+].[CH2:9]([CH:11]([C:15](=O)[CH3:16])[C:12](=O)[CH3:13])[CH3:10]>O>[CH2:9]([C:11]1[C:15]([CH3:16])=[N:2][C:1]([N:4]2[C:12]([CH3:13])=[C:11]([CH2:15][CH3:16])[C:9]([CH3:10])=[N:5]2)=[N:3][C:12]=1[CH3:13])[CH3:10]
Reactant: CCC(C(C)=O)C(C)=O
Reactant: N=C(N)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1c(C)nc(-n2nc(C)c(CC)c2C)nc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To aminoguanidine hydrochloride (1.76 g, 15.9 mmol), water (5 ml), sodium hydroxide (636 mg, 15.9 mmol), and 3-ethyl-2,4-pentanedione (manufactured by Tokyo Chemical Industry, purity: 90.0% or higher) (4.50 g, 35.0 mmol) were added, and then stirred at 80° C. for 8 hours. To the reaction mixture, water (30 ml) was added, and then stirred at 0° C. for 1 hour. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 5-ethyl-2-(4-ethyl-3,5-dimethylpyrazol-1-yl)-4,6-dimethylpyrimidine (1.35 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8](=O)[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:17].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][CH2:8][N:9]2[CH:12]2[CH2:13][CH2:14]2)=[CH:4][C:3]=1[F:17]
Reactant: O=c1[nH]c2cc(F)c(Cl)cc2n(C2CC2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc2c(cc1Cl)N(C1CC1)CCN2
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.8 %

Procedure:
To a suspension of 390 mg (1.532 mmol) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-quinoxaline-2,3-dione in 20 mL tetrahydrofuran was added 3.37 mL (3.369 mmol) 1M borane tetrahydrofuran complex. The reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The mixture was stirred for 30 min. at room temperature and the layers were separated. The aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 211 mg (61%) of the desired compound as a white solid. MS (ESI): m/z=225.0 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][S:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH3:19])([CH3:18])[CH2:5][N:4]2[C:1](=[O:3])[CH3:2])=[CH:8][C:9]=1[F:17])(=[O:15])=[O:14]
Reactant: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21
Reactant: ClCCCI
Product: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)CCCCl)cc21
Yield: 88 %

Procedure:
Prepared from 1-acetyl-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (500 mg, 1.64 mmol) and 1-chloro-3-iodo-propane (863 μL, 8.2 mmol) following similar methods to those described in Preparation 64. The title compound (502 mg) was obtained as a pale yellow oil. 1H NMR (CDCl3): 8.72 (1H, d), 7.01 (1H, d), 3.88 (2H, s), 3.75-3.57 (2H, m), 3.57-3.35 (2H, m), 2.37-2.18 (5H, m), 1.41 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc23)CC1
Yield: 41.9 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol) 4-nitrobenzoic acid, 13.8 mg (41.8%) of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8].[H][H]>[Pd].C(O)C>[C:7]([NH:6][CH2:5][C:4]1[CH:10]=[C:11]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[NH2:14])(=[O:9])[CH3:8]
Reactant: COc1ccc([N+](=O)[O-])cc1CNC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1CNC(C)=O

Procedure:
N-(2-Methoxy-5-nitrobenzyl)acetamide (5 g), with palladium on carbon (1 g) in ethanol (50 ml) was hydrogenated at room temperature under 104 tms. of hydrogen. The reaction was filtered through celite and the ethanol distilled from the filtrate. The residue was recrystallised from benzene to give 3-(acetylaminomethyl)-4-methoxyaniline as pale brown needles. MP; 123-125° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14]([Cl:25])=[CH:15][C:16]2[O:21][CH2:20][CH2:19][C:18](=[N:22][OH:23])[C:17]=2[CH:24]=1>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([Cl:25])=[CH:15][C:16]2[O:21][CH2:20][CH2:19][C:18](=[N:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:17]=2[CH:24]=1
Reactant: ON=C1CCOc2cc(Cl)c(Cl)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCOc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of p-toluenesulfonyl chloride (103 g) in 125 ml pyridine was added dropwise at 5°-10° to 6,7-dichloro-2,3-dihydro-4-(hydroxyimino)-4H-1-benzopyran (62.5 g) in 250 ml pyridine. The reaction mixture was then stirred for 20 hours at room temperature, poured into ice-water to separate out the title compound, which was filtered, washed several times with water, then once with ether, and finally dried in air. Yield: 101.8 g; m.p. 180°-184°.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:15]C1C=CC(C(Cl)=O)=CC=1>>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=1)[NH2:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Product: CC(C)(C)N(N)C(=O)c1ccc(Cl)cc1

Procedure:
N'-t-butyl-N'-(4-chlorobenzoyl)hydrazine was prepared substantially according to the procedure for preparing N'-t-butyl-N'-benzoylhydrazine described for Example 220, Step 3, except 4-chlorobenzoyl chloride was used in place of benzoyl chloride.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[CH3:18][O-:19].[Na+]>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18](=[O:19])[CH:2]([CH3:4])[CH3:3])=[C:12]([O:17][C:8](=[O:9])[CH:10]([CH3:15])[CH3:11])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen there was added 17 g. of sodium methoxide. By distillation under reduced pressure, 50 ml. of liquid was removed and the mixture was then cooled and under an atmosphere of nitrogen 25 g. of isobutyryl chloride was added rapidly at 5-25° C. The reaction mixture was stirred at 25° C. for one hour and then was warmed to 70° C. and the solvent was removed by distillation. The resulting residue was slurried in 400 ml. of diethyl ether, and the slurry was filtered to remove about 10 g. of insoluble solid. The ethereal layer in the filtrate was separated, washed with dilute aqueous sodium hydroxide solution and then with water. There was thus obtained an ether solution of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone. To this solution there was added a solution obtained by adding 4 ml. of hydrochloric acid to 25 ml. of water, and the resulting mixture was shaken. The crystalline solid which formed was collected on a filter and dried at 70° C. There was thus obtained 8.5 g. of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline powder which melted at 221- 223° C. (dec.)(uncorr.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][SH:19])[CH:15]=[N:14]1.[OH-].[Na+].O.[CH2:23]([N:26]1[C:30]([C:31]#[N:32])=[C:29]([C:33]#[N:34])[N:28]=[C:27]1Br)[CH:24]=[CH2:25]>O1CCOCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][S:19][C:27]2[N:26]([CH2:23][CH:24]=[CH2:25])[C:30]([C:31]#[N:32])=[C:29]([C:33]#[N:34])[N:28]=2)[CH:15]=[N:14]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CS)n2)c(Cl)c1
Reactant: C=CCn1c(Br)nc(C#N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(SCc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)n2)nc(C#N)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-mercaptomethyl-2H-1,2,3-triazole, prepared as in EP No. 350 237, (0.33 g) and sodium hydroxide (0.04 g) were stirred in dioxane (2 ml) and water (1 ml) at ice bath temperature. 1-Allyl-2-bromo-4,5-dicyanoimidazole (0.24 g) in dioxane was added and the mixture stirred at room temperature for 2 hours. Aqueous work up and silica gel column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(4,5-dicyano-1-allyl-1H-imidazol-2ylthio)methyl]-2H-1,2,3-triazole, m.p. 125°-127°. (Compound 24a)
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:7]4[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[C:27](O)(=[O:29])[CH3:28]>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:8]1[C:7]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: Nc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Reactant: CC(=O)O
Product: CC(=O)Nc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Yield: 43 %

Procedure:
Amine (919) prepared as described in example 467 and acetic acid were reacted using the procedure described in example 468 with a reaction time of 4 h to give the acetamide (926) (43%) as a yellow powder, mp 240–245° C. 1H NMR δ [(CD3)2SO] 12.04 (br s, 1H), 11.07 (br s, 1H), 10.10 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.8, 2.1 Hz, 1H), 7.58 (m, 2H), 7.42–7.51 (m, 4H), 2.10 (s, 3H). FABMS found: [M+H]+=404.0787, 406.0776. C22H15ClN3O3 requires 404.0802, 406.0772.
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1([C:10]2[N:11]=[C:12]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=3)[C:13]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15][C:14]=3[N:30]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CCOCC.C1COCC1>[N:4]1([C:10]2[N:11]=[C:12]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:40])([CH3:1])[CH3:39])=[CH:36][CH:37]=3)[C:13]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15][C:14]=3[N:30]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of methylmagnesium bromide (170 mL of a 3.0 M solution in Et2O, 0.51 mmol) in THF at 0° C. was added a solution of 1-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone (Example 156; 59.8 mg, 0.117 mmol) in THF. The solution was allowed to warm to rt over 1 h, and stirred at rt for an additional 5 min. The reaction mixture was then quenched with satd. aq. NH4Cl and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The crude residue was purified (FCC) to give the title compound (51 mg, 83%). MS (ESI): mass calcd. for C28H33F3N6O, 526.27; m/z found, 527.3 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.46-7.41 (m, 2H), 6.94-6.90 (m, 1H), 6.35 (s, 1H), 3.77-3.69 (m, 4H), 3.63-3.53 (m, 4H), 3.10-3.03 (m, 2H), 2.87-2.80 (m, 2H), 1.70 (s, 1H), 1.66-1.60 (m, 6H), 1.54 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Br-].[C:12]([CH2:14][CH2:15][CH2:16][Zn+])#[N:13]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH2:16][CH2:15][CH2:14][C:12]#[N:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: N#CCCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: N#CCCCc1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of 5-bromoindole (0.25 g, 1.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.12 mmol) was stirred under a nitrogen atmosphere for 10 minutes. 3-cyanopropyl zinc bromide [0.5 M in THF] (5.0 mL, 2.50 mmol) was added to the mixture and heated in the microwave at 100° C. for 15 minutes. The solvent was removed and the crude mixture was purified via column chromatography with silica gel, eluting with hexane/ethyl acetate (4/1) to afford the title compound in 63% yield. 1H NMR (CDCl3) δ 8.22 (br, 1H), 7.43 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.28 (t, J=7.2 Hz, 2H), 2.02 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C12H13N2 185.1 (M+H); found 185.1.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]>>[I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])[N:3]=1
Reactant: Cc1ccc2c(I)n[nH]c2n1
Reactant: COC(=O)NCCCBr
Product: COC(=O)NCCCn1nc(I)c2ccc(C)nc21

Procedure:
3-Iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine and methyl (3-bromopropyl)carbamate were treated in the similar manner to Reference Example 102(1) to give methyl [3-(3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate [REx(104-3)] as a colorless powder.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:4])(=[O:3])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]([CH3:23])[CH3:22]>CC(N(C)C)=O>[CH3:20][CH:21]([CH3:23])[CH2:22][S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4]
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)CS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
To a suspension of 3-sulfo-benzoic acid (1 g) and potassium carbonate (1.2 g) in dimethylacetamide (10 ml) was added iso-butyl iodide (0.65 ml). The mixture was heated by microwaves (600W) at 150° C. for 15 minutes. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the aqueous layer was separated, acidified to pH 1 with HCl (2N) and extracted with ethyl acetate (100 ml). The extract was evaporated to leave a residue which was purified by flash chromatography (Biotage 12S eluting with ethyl acetate:hexane:acetic acid, 29:70:1) to give the title product as a white solid (0.34 g).