Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([S:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13](Cl)(=[O:15])[CH3:14]>C(Cl)Cl>[CH3:14][C:13]([C:8]1[CH:9]=[CH:10][C:5]([S:11][CH3:12])=[CH:6][CH:7]=1)=[O:15]
Reactant: CSc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
123 g (0.92 mol) of AlCl3 are added with a spatula to a mixture of 100 g (0.8 mol) of thioanisole, 750 ml of CH2Cl2 and 63 ml (0.9 mol) of acetyl chloride, cooled to 0° C. beforehand, said addition being carried out so that the temperature does not exceed 10° C. The mixture is stirred for 1 h at room temperature, heated for 1 h at 40° C. and then poured into 800 ml of an ice/water mixture. The resulting mixture is separated and extracted with CH2Cl2. The organic phases are combined, washed with water and then dried over MgSO4 and concentrated to give 117.1 g of 4-(methylthio)acetophenone.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9].F[C:50](F)(F)C1C=C(C(N)C)C=CC=1>>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH:6]([C:5]4[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:4]=4)[CH3:50])[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Product: CC(NC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)O)c2)c1)c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared using the procedure used to prepare 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoic acid 1.1, using 1-(3-(trifluoromethyl)phenyl)ethanamine in place of 3-(trifluoromethyl)benzylamine. 1H-NMR (300 MHz, CD3OD, ppm): δ 9.044-9.062 (d, J=5.4 Hz, 1H), 8.786-8.816 (d, J=9.0 Hz, 1H), 8.378 (s, 1H), 8.125-8.133 (d, J=2.4 Hz, 1H), 8.003 (s, 1H), 7.875-7.905 (m, 2H), 7.707-7.754 (m, 3H), 7.499-7.623 (m, 4H), 5.324-5.393 (m, 1H), 3.913 (s, 2H), 3.678-3.714 (m, 4H), 2.709-2.754 (m, 2H), 2.574-2.618 (m, 2H), 2.043-2.060 (m, 4H), 1.831-1.846 (m, 2H), 1.641-1.664 (d, J=6.9 Hz, 3H). MS (ES, m/z): 692 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[O:23].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[CH:33]=[CH:34][C:35]3[N:36]=[C:4]([C:3]4[C:2]([CH3:1])=[CH:9][C:8]([O:10][CH2:11][C:12]5[NH:16][N:15]=[N:14][N:13]=5)=[CH:7][C:6]=4[CH3:17])[NH:18][C:19]=3[CH:20]=2)=[O:23])[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: Cc1cc(OCc2nnn[nH]2)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCc5nnn[nH]5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-benzaldehyde (50 mg) in DMSO (1 mL) were added 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (55 mg), Yb(OTf)3 (13 mg), and Cu(OTf)2 (8 mg). The reaction mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-[2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 468.16 (M+1).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:21](=[O:24])[CH2:22][CH3:23])[N:13]=[C:14]([C:18]([O-:20])=O)[C:15]([O-:17])=[O:16].O>C1COCC1>[OH:20][C:18]1[C:14]([C:15]([OH:17])=[O:16])=[N:13][N:12]([CH3:11])[C:21](=[O:24])[C:22]=1[CH3:23]
Reactant: CCC(=O)N(C)N=C(C(=O)[O-])C(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(O)c(C(=O)O)nn(C)c1=O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430 mL) at −78° C. was added a solution of 2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) in THF (10 mL). The resulting mixture was slowly warmed to −40° C. over 1 hour and stirred for 1.5 hours at −40° C. To the reaction mixture was added water (500 mL) at −40° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, quenched with 6 N aqueous HCl at 0° C., and acidified to pH 1 to 2. The resulting mixture was stirred for 16 hours at room temperature. The precipitates were filtered off and triturated with CH2Cl2 to afford 7.21 g (47%) of the desired product. The filtrate was extracted with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford additional 3.56 g (23%) of the desired product. The aqueous layer was extracted again with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford additional 1.32 g (9%) of the desired product. A total of 12.09 g (79%) of the desired product was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCC(=O)OCc2ccccc2)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3,5-dihydroxybenzoate (20 g) in N,N-dimethylformamide (200 ml) was added sodium hydride (60% in mineral oil, 5.23 g) slowly at 10° C. After stirring at 10° C. for 30 minutes, benzyl bromoacetate (20.7 ml) was added dropwise to the mixture over 10 minutes. The reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. Ethyl acetate (400 ml) and water (100 ml) was added to the residue and the mixture was adjusted to pH 5 with hydrochloric acid. Two layers were separated and the organic layer was washed successively with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1). The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-benzyloxycarbonylmethoxy-5-hydroxybenzoate (12.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[CH:9]2)=[CH:4][C:3]=1[F:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc2ccnc(Cl)c2cc1Cl
Temperature: 25 °C

Procedure:
2.6 g (12.0 mmol) of 7-Chloro-6-fluoro-isoquinoline 2-oxide (57) were heated in 40 ml of POCl3 at reflux for 4 h. After the mixture has cooled down to room temperature, it was poured on ice. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried with MgSO4 and evaporated to yield 2.91 g of the title compound, which was used without further purification. Rt=2.34 min (Method A). Detected mass: 216.0/218.0 (M+H+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([C:21]1[CH:22]=[C:23](OS(C(F)(F)F)(=O)=O)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:15])[CH:16]([C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:24]=[C:23]([C:50]2[CH:51]=[CH:52][C:47]([C:46]([F:57])([F:56])[F:45])=[CH:48][CH:49]=2)[CH:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 79.8 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 5-[1-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-3-methyl-butyl]-4′-trifluoromethyl-biphenyl-3-yl ester (4.03 g, 6.27 mmol), 4-(trifluoromethyl)phenylboronic acid (1.34 g, 7.05 mmol), 1,2-dimethoxyethane (24 mL) and aqueous Na2CO3 (2 M, 3.2 mL, 6.4 mmol) was stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (1.45 g, 1.25 mmol) and heated to reflux (95° C.) for 1 h. The red-brown mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (2×50 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-benzyl-3-[2-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (3.2 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:17][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:8][C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1-c1ccc(Br)nn1
Reactant: CC(C)(C)OC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
37.6 mg (0.285 mmol) of hydroxyacetic acid tert-butyl ester were dissolved in 10 ml of DMF, 12.4 mg of sodium hydride (55% in mineral oil) were added, and the mixture was stirred at room temperature for 15 min. Then 60 mg (0.237 mmol) of 3-bromo-6-(2-fluoro-phenyl)-pyridazine in 2 ml of DMF were added, and the reaction mixture was stirred at 60° C. for 5 h and at 120° C. for 5 h. After evaporation to dryness, the crude product was directly employed in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
55.6 mg (230 μmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) are suspended in 5 ml of water. 47.2 mg (230 μmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) and 0.01 ml of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline using saturated sodium bicarbonate solution and extracted 3× with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)CCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-4-phenylbutanoate (prepared from (+)-α-amino-4-phenylbutyric acid (Bachem) using General Procedure AG), the title compound was prepared as a solid (mp=147-149.5° C). The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using EtOAc/hexanes as the eluent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][C:14]([Cl:24])=[CH:13][CH:12]=2.[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:40]2[C@@H:39]([NH2:43])[CH2:38][CH2:37][CH2:36][C:35]=2[N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:40]2[C@H:39]([NH:43][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]3[C:11]4[C:16]([N:17]=[C:18]5[C:23]=3[CH2:22][CH2:21][CH2:20][CH2:19]5)=[CH:15][C:14]([Cl:24])=[CH:13][CH:12]=4)[CH2:38][CH2:37][CH2:36][C:35]=2[N:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H]1CCCc2nc(OCc3ccccc3)ccc21
Reactant: Clc1ccc2c(NCCCCCCCBr)c3c(nc2c1)CCCC3
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c(NCCCCCCCN[C@@H]3CCCc4nc(OCc5ccccc5)ccc43)c3c(nc2c1)CCCC3
Temperature: 25 °C
Yield: 32.3 %

Procedure:
A solution of (7-bromo-heptyl)-(6-chloro-1,2,3,4-tetrahydro-acridin-9-yl)-amine (180 mg, 0.43 mmoL) and (S)-2-benzyloxy-5,6,7,8-tetrahydro-quinolin-5-ylamine (108 mg, 0.43 mmoL) in dried N,N-dimethylformamide (2.1 ml) was heated up to 120 degree Celsius under nitrogen for 5 h. After cooling to room temperature, the reaction mixture was poured into icy water. The mixture was extracted with ethyl acetate. The combined ethyl acetate was dried, filtered and concentrated. The resulting crude product was purified by column chromatography on silica gel using hexane/ethyl acetate/triethyl amine (8/2/1) to give the desired product (80 mg, 0.14 mmoL) in 33% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH:7]=[CH:8][N:9]=1.CO.[ClH:21].[CH:22](=O)[CH2:23][CH3:24].C([BH3-])#N.[Na+].Cl>CO>[ClH:21].[ClH:21].[CH2:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:10][C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)[CH:7]=[CH:8][N:9]=1)[CH2:23][CH3:24]
Reactant: NCCSc1nccn1Cc1cc(F)cc(F)c1
Reactant: CCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCCSc1nccn1Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2-aminoethylthio)-1-(3,5-diflorobenzyl)imidazole (2.69 g, 0.010 mole) in absolute methanol (25 ml) is added 5 N hydrochloric acid methanol (1 ml, 0.005 mole) followed by propionaldehyde (4.25 g, 0.10 mole) and sodium cyanoborohydride (0.38 g, 0.006 mole). The reaction mixture is stirred at 25° C. for 72 hours and then concentrated hydrochloric acid is added until the pH is at least 2. The volatiles are removed in vacuo and then the residue is partitioned between water and ether. The layers are shaken together and separated, the pH of the aqueous extract is adjusted to greater than 10 with solid potassium hydroxide and then the product is extracted into ether. The ether extract is dried with anhydrous magnesium sulfate and then hydrogen chloride in ether is added slowly until a slight excess is present. The precipitated solid is filtered and recrystallized from ethanol-ether to give 2-(2-propylaminoethylthio)-1-(3,5-difluorobenzyl)imidazole dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[CH:11]=1
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cc(Br)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in chloroform is cooled, treated with a solution of bromine (0.52 g, 0.00323 mol) in chloroform, stirred at room temperature overnight, diluted with chloroform, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark syrup. Flash chromatography of the syrup using silical gel and a 1:5 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.31 g, mp 73°-76° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH:1]#[C:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>O1CCCC1>[CH:1]#[C:2][C:3]([NH:6][Si:15]([CH3:18])([CH3:17])[CH3:14])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
In 5000 ml flask were combined 250 g of commercial HC≡CCMe2NH2, 581.8 g of triethylamine, and 1637.5 g of tetrahydrofuran solvent. The flask and contents were cooled at 17° and addition of 625.5 g of trimethylchlorosilane begun with rapid stirring under nitrogen. The addition was completed in 90 min, followed by stirring for 85 min. Analysis by gas chromatography (GC) showed a small amount of HC≡CCMe2NH2, which was converted to product by an additional 53.4 g of trimethylchlorosilane. Reaction mixture was pressure-filtered and the solids triturated with fresh tetrahydrofuran and refiltered. The organic solutions were combined and distilled, providing the desired product, HC≡CCMe2NHSiMe3, as a liquid boiling at 135° at atmospheric pressure. Its structure was confirmed by NMR analysis.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>O.CCOC(C)=O>[Cl:34][C:33]([Cl:36])([Cl:35])[CH2:32][O:31][C:29](=[O:30])[NH:10][C:8]1[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
To a stirred mixture of Intermediate 113b (1.14 g, 3.28 mmol) in water (6 mL) and EtOAc (12 mL) was added NaOH (263 mg, 6.57 mmol). After 10 min, 2,2,2-trichloroethyl chloroformate (543 μL, 3.94 mmol) was added and the reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to afford the title compound (1.57 g, 91%). LCMS (Method 4): Rt 3.99 min, m/z 522, 524 [MH+].
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[S:16])=[CH:13][CH:12]=1>CCO>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[S:16][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:17]=2)=[CH:13][CH:12]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc(Cl)cc2)n1

Procedure:
A solution of ethyl bromopyruvate (354 mg, 1.8 mmol) and 4-chlorothiobenzamide (283 g, 1.65 mmol) in EtOH (40 mL) was refluxed for 3 h. The mixture was evaporated to dryness and the resulting oil was purified by flash chromatography to give ethyl 2-(4-chlorophenyl)thiazole-4-carboxylate as a colourless oil: 1H NMR (80 MHz, CDCl3) δ (TMS) 8.15 (s, 1H, thiazole), 7.95 (dt, Jt =2, Jd =8.5, 2H, arom), 7.42 (dt, Jt =2, Jd =8.5, 2H, arom), 4.45 (q, J=7, 2H, OCH2), 1.43 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H10ClNO2S: C 53.84; H 3.76; N 5.23; S 11.97. Found: C 53.65; H 3.77; N 5.23; S 11.51.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]3[O:27][CH2:26]3)[CH:18]=2)[CH:14]=1)=[O:7].[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:18]=2)[CH:14]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Reactant: CNCCCN(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN(C)CCCN(C)C)c1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 31, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 45% yield; NMR Spectrum: (DMSOd6) 1.8 (m, 2H), 2.18 (s, 3H), 2.33 (s, 3H), 2.58 (s, 6H), 2.6 (m, 2H), 2.92 (t, 2H). 2.96 (s, 6H), 4.03 (m, 5H), 6.9 (m, 1H). 7.15 (m, 1H), 7.2 (m, 3H), 7.28 (t, 1H), 7.48 (t, 1H), 7.56 (m, 2H), 7.8 (d, 1H), 9.95 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=O)[CH:4]=1)#[N:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:24])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 81 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and t-butylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 81%.