Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:13][N:14](C)C=O>>[C:13]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1)#[N:14]
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CN(C)C=O
Product: CC1(C)COc2ccc(C#N)cc21

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethylbenzofuran (15 g, 0.066 mole) was heated under reflux with cuprous cyanide (7.2 g, 0.08 mole) in dimethyl formamide (15 ml) as in Example 2. Work up yielded, after recrystallisation from petroleum ether (bp 60°-80° C.) with charcoaling, 5.7 g of product, mp 72°-75° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])[N:4]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:9])[Cl:10])[N:4]=1)[C:14](=[O:15])[C:13]([Cl:18])([Cl:17])[Cl:12]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CNc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1
Product: CN(C(=O)C(Cl)(Cl)Cl)c1nc(C(Cl)(Cl)Cl)ns1
Temperature: -10 °C
Yield: 79.4 %

Procedure:
A solution of 5.8 grams (0.02 mole) 5-methylamino-3-trichloromethyl-1,2,4-thiadiazole and 9.0 grams (0.05 mole) trichloroacetyl chloride in 200 milliliters toluene was refluxed at about 110° C. for 20 hours. Upon cooling to -10° C., 2.7 grams pure product precipitated; m.p. 223° C. An additional 6.0 grams product was isolated by removal of the low boiling materials in vacuo. Total yield was 92%.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:14])[NH:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:15]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([NH:1][CH:2]([C:5]2[C:6](=[O:14])[NH:7][C:8]([CH:11]3[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:26])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(C2CC2)[nH]c1=O
Product: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C2CC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 250 mg (1.29 mmol) 6-(1-aminopropyl)-3-cyclopropyl-1.2,4-triazin-5(4H)-one, 260 mg (1.29 mmol) 4-tert-butyl-cyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14].Cl>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2cccn3nc(Cl)nc23)c1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) and 3-methanesulfonyl-phenylamine; hydrochloride (245.0 mg, 1.180 mmol) in a manner analogous to Example 2d. Product was isolated as a pale yellow solid (0.268 g, 77%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=6.7 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.03 (s, 1H), 6.99 (t, J=6.9 Hz, 1H), 3.09 (s, 3H). MS=323, 325 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][N:5]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(O)(=O)C>>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[C:8]([CH2:10][NH:17][CH:14]2[CH2:16][CH2:15]2)[CH:7]=[CH:6][N:5]=1
Reactant: NC1CC1
Reactant: COC(OC)c1cc(C=O)ccn1
Solvent: CC(=O)O
Product: COC(OC)c1cc(CNC2CC2)ccn1

Procedure:
By General Procedure A from 2-(dimethoxymethyl)pyridine-4-carbaldehyde, cyclopropylamine, and acetic acid (1 equiv.). Purification by column chromatography (CH2Cl2/MeOH, 97:3) gave the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.55 (d, 1H), 7.50 (S, 1H), 7.22 (m, 1H), 5.40 (s, 1H), 3.90 (s, 2H), 3.40 (s, 6H), 2.18 (m, 1H), 0.5 (m, 4H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[Cl:19])(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:19][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.95 g, 2.79 mmol) with 4-methoxyphenyl boronic acid (0.59 g, 3.9 mmol) according to method A to yield 0.71 g (85%) of a white solid: mp 126-128° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 3.95 (3H, s), 7.01 (2H, d, J=8.60 Hz), 7.16 (1H, d, J=2.49 Hz), 7.27 (1H, dd, J=1.97 Hz, J=8.99 Hz), 7.41 (1H, d, J=8.45 Hz), 7.46 (2H, d, J=8.61 Hz), 7.68 (1H, d, J=8.48 Hz), 8.28 (1H, d, J=9.27 Hz); MS (ESI) m/z 299/301 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:31]([S:35](Cl)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:35]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 120 °C
Yield: 29.2 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 1-butanesulfonyl chloride (26 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (8 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=7.35 Hz, 3 H) 0.98 (d, J=6.62 Hz, 6 H) 1.37 (m, 2 H) 1.56 (m, 2 H) 1.69 (m, 3 H) 3.19 (t, J=7.74 Hz, 2 H) 4.48 (t, J=7.74 Hz, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=9.01, 2.39 Hz, 1 H) 7.65 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.55 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.41, 1.84 Hz, 1 H) 10.35 (s, 1 H) 14.07 (s, 1 H) 15.13 (s, 1 H). MS (ESI+) m/z 548 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:35][S:36]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:6]=[C:5]1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Combine tert-butyl 4-(1-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (4.40 g, 11.60 mmol) and triethylamine (4.9 mL, 3.0 eq) in dichloromethane (72 mL). Cool to 0° C. and add methanesulfonyl chloride (1.1 mL, 1.2 eq). After 1 hour, dilute with additional dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a light yellow solid (5.05 g, 95%). MS (ES) m/z=458 [M]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2 g) was mixed with CH2Cl2 (20 ml), and TFA (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with CH2Cl2 (30 ml), and TEA (6 ml) and TBSCl (2.5 g) were added thereto, followed by stirring at 60° C. overnight. Water was added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was mixed with MeOH (20 ml), and a 1 M aqueous NaOH solution (5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, CHCl3 and water were added to the obtained residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/EtOAc) to obtain 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (673 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1
Reactant: CCOC(=O)CCc1cc(CCNC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1cc(CCN)cc(Cc2cccnc2)c1
Yield: 72.1 %

Procedure:
A solution of ethyl 3-[3-(2-t-butoxycarbonylaminoethyl)-5(3-pyridylmethyl)phenyl]propanoate (Preparation 39; 4.10 g) and trifluoroacetic acid (.4.1 ml) in dry dichloromethane (41 ml) was stirred for 6 hours, additional 4.1 ml portions of trifluoroacetic acid being added after 2 and 5 hours. The solution was evaporated under vacuum and the residue basified with aqueous sodium bicarbonate solution. The mixture was extracted several times with dichloromethane and the combined extracts were dried (MgSO4) and evaporated under vacuum. Water (ca 75 ml) was added and this mixture was acidified to pH 4 with glacial acetic acid and then extracted several times with ethyl acetate. The aqueous layer was basified with aqueous ammonia solution (SG 0.880) and extracted several times with dichloromethane. The combined dichloromethane extracts were washed with water, dried (MgSO4) and evaporated under vacuum to give the title compound as an oil (2.24 g); Rf 0.10 (SS 2); δ (CDCl3): 1.07(2H,br), 1.20(3H,t,J=7.1 Hz), 2.56(2H,t,J=7.8 Hz), 2.66(2H,t,J=6.9 Hz), 2.85-2.93(4H,m), 3.90(2H,s), 4.09(2H,q,J=7.1 Hz), 6.84 (2H,s), 6.88(1H,s), 7.16-7.20(1H,m), 7.43(1H,d,J=7.8 Hz), 8.43-8.47(2H,m).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Nc1ccc(CCNCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CCN)cc1

Procedure:
4'-(2-Benzylaminoethyl)methanesulfonanilide (XXIX.HCl) (8.0 g) and 20% Pd/C (0.5 g) were combined in MeOH (200 ml) and heated at 40° for 18 hours in a Parr hydrogenator under an average hydrogen pressure of 3 atmospheres. The catalyst was filtered off. Concentration of the filtrate caused precipitation of Compound (XXVIII).HCl, 5.5 g as a white solid, m.p. 244°-246° (decomp.), whose elemental analysis for C, H, and N, and NMR spectrum were consistent with the structure indicated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)nc(SCc2ccc(O)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a 0° C. mixture of 2-{[(2-chloro-4-methoxyphenyl)methyl]sulfanyl}-6-methyl-pyrimidin-4-ol (500 mg, 1.7 mmol) in anhydrous dichloromethane (20 mL) was added a solution of boron tribromide (1 M in THF, 2 mL, 2 mmol). The solution was stirred at room temperature overnight. Water (20 mL) and more dichloromethane (50 mL) were added to the mixture. The undissolved solid material was recovered by filtration, washed with diethyl ether (2×25 mL), and dried in vacuo. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2), affording the title compound (65 mg, 13% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.37 (s, 2H), 6.00 (s (br), 1H), 6.70 (dd, 1H, J=2.3 Hz, 8.4 Hz), 6.84 (d, 1H, J=2.3 Hz), 7.40 (d, 1H, J=8.6 Hz), 9.96 (s, 1H); M+ 283; HPLC purity: 98.0%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1.O>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:14]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cn1ccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a 0° C. suspension of NaH (60% in mineral oil, 658 mg, 16.5 mmol) in THF (20 mL) under nitrogen was slowly added a solution of imidazole (1.03 g, 15.1 mmol) in THF (20 mL). The resulting suspension was stirred at 0° C. for 15 minutes, then ethyl bromoacetate (2.2 mL, 20 mmol) was added. The reaction was stirred at room temperature for 4.5 hours, then was diluted with H2O (25 mL). The THF was evaporated under reduced pressure and the remaining aqueous solution was extracted with CH2Cl2 (25 mL×3). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2/MeOH, 19:1) gave the ester as a yellow liquid (1.52 g, 9.87 mmol, 65%). 1H NMR (CDCl3) δ 1.28 (t, 3H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.68 (s, 2H), 6.95 (s, 1H), 7.09 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[F:26][C:14]([F:13])([F:25])[C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-trifluoromethylbenzenesulfonyl chloride according to METHOD A, giving 0.26 g (62%) of an orange solid after recrystallization from acetone/ether/petroleum ether: mp 145° C.; MS (Ionspray, [M+H]+) m/z 395; Anal. Calcd (found) for C14H13F3N2O4S2: C, 42.6 (42.8)%, H, 3.3 (2.9)%, N, 7.1 (6.9)%
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>>[CH:2]([CH:3]1[CH2:4][C:8]1([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[CH2:1]
Reactant: COC(=O)CC(=O)OC
Reactant: ClC/C=C/CCl
Product: C=CC1CC1(C(=O)OC)C(=O)OC

Procedure:
The procedure of Example 2 was followed except that trans-1,4-dichlorobutene-2 as obtained by the procedure of Example 4 was condensed with dimethyl malonate. High yields of dimethyl 2-vinylcyclopropane-1,1-dicarboxylate of high purity were obtained.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[N:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[N:40]1[CH:44]=[CH:43][N:42]=[CH:41]1)=[O:23]
Reactant: Cc1c(-n2ccnc2)n(CCCCCCO)c2ccccc12
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(-n2ccnc2)n(CCCCCC=O)c2ccccc12
Reaction time: 0.42 h

Procedure:
To a solution of Collins Reagent prepared with chromium trioxide (5.6 g) and pyridine (8.86 g) in dichloromethane (150 ml) at 0°-5° under a nitrogen atmosphere is added all at once 1.8 g of 1-(6-hydroxyhexyl)-3-methyl-2-(1-imidazolyl)-indole in dichloromethane (15 ml). The mixture is stirred for an additional 25 minutes, then filtered through celite. The filtrate is then passed through a silica gel column. The product is eluted from the silica gel with a 1:1 mixture of ethyl acetate:dichloromethane (500 ml). Concentration in vacuo yields 1-(5-formylpentyl)-2-(1-imidazolyl)-3-methylindole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[F:31][C:32]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:33]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C>ClC(Cl)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:34](=[O:35])[C:33]2[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:32]=2[F:31])[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cc(C)ccc3F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To the mixture of methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate, (85.6 mg, 0.2 mmol, 1 eq) and 2-fluoro-5-methylbenzoic acid (32.7 mg, 1.05 eq) in dichloroethane (2 mL) at 60° C. was added catalytic amount of DMAP (5 mg, 0.2 eq) and EDCI (46.1 mg, 1.2 eq). The reaction was stirred at that temperature for 4 h and then cooled to room temperature. It was then partitioned between EtOAc and saturated aq NaHCO3. The organic layer was further washed with aq NH4Cl, brine and then dried with anhydrous sodium sulfate. The organic layer was decanted, concentrated, and the residue was subject to a gradient column chromatography (EtOAc-Hex 1:4 to neat EtOAc). The product containing fractions were concentrated to give the title compound as a white foam (92 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25]/[CH:26]=[CH:27]\[CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:21])([CH3:20])[CH:14]=[C:13]4[CH3:22].[I-].[CH:30]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25][CH:26]=[C:27]([CH3:30])[CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:20])([CH3:21])[CH:14]=[C:13]4[CH3:22]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C/C=C\CC1Oc2ccc(O)c(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Agent: [I-]
Product: COc1c(O)ccc2c1-c1ccc3c(c1C(CC=C(C)C)O2)C(C)=CC(C)(C)N3

Procedure:
The intermediate aldehyde from Example 282 and isopropyltriphenylphosphonium iodide were processed according to Example 282 to give the desired compound. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.91 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 6.46 (d, J=9 Hz, 1H), 6.14 (s, 1H), 5.60 (dd, J=9, 3 Hz, 1H), 5.43 (s, 1H), 5.15 (m, 1H), 3.64 (s, 3H), 2.45-2.18 (m, 2H), 2.15 (s, 3H), 1.63 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); MS (APCI) m/e (M+H)+ 392, (M−H)− 390.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=2[CH3:22])=[N:5][N:6]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=3[CH3:22])[S:3][CH2:2]2)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1-c1nnc(Br)s1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(F)c(C#N)c2)CS1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
tert-Butyl 3-(4-(2-Bromo-1,3,4-thiadiazol-5-yl)-3-methylphenyl)propenoate (0.15 g, 0.39 mmol, from Step A), 3-cyano-4-fluorophenyl boronic acid (0.097 g, 0.59 mmol, from Step B) and sodium carbonate (0.21 g, 1.95 mmol) were dissolved in DMF (6 mL) and water (0.2 mL). The reaction mixture was degassed for 5 min with a balloon of argon after which tetrakis(triphenylphosphine) palladium (0.1 g) was added. The reaction was heated at 80° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% ethyl acetate/hexane afforded 0.05 g of product: ESI-MS (m/z) 422.2; HPLC A: 4.21 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:13]([N:15]1[CH2:16][CH2:17][N:18]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:19][CH2:20]1)=[O:14]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 0.83 h
Yield: 101 %

Procedure:
(S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (7.30 g, 14.6 mmol, Example 50) was dissolved in CH2Cl2 (50 mL) under nitrogen at ambient temperature. To this solution was added trifluoroacetic acid (12 mL). The resulting reaction mixture was stirred for 50 minutes, then concentrated in vacuo. The viscous pale-amber oil obtained was mixed with 50 mL of saturated aqueous NaHCO3 solution and stirred for 10 minutes, 50 mL of CH2Cl2 was then added. The resulting mixture was stirred until bubbling ceased. The two layers were separated, organic layer was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording 5.92 g (92%) of the pure titled compound as a off-white foam: mp 61-68° C. APCI-MS m/z 402.3 (MH+);