Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=CCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.300 g, 1.19 mmol), hydrocinnamaldehyde (0.192 g, 1.43 mmol), and sodium cyanoborohydride (0.188 g, 2.99 mmol) were combined in CH2Cl2 and stirred overnight at room temperature. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[C:25]([Cl:26])=[CH:24][N:23]([CH3:27])[N:22]=1>CN(C=O)C>[Cl:26][C:25]1[C:21]([CH2:20][S:1][C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=2)=[N:22][N:23]([CH3:27])[CH:24]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: Cn1cc(Cl)c(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c(CSc2nc(O)cc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (721 mg, 3.7 mmol) was dissolved in anhydrous DMF (20 mL), and then potassium carbonate (1.53 g, 11.0 mmol) and 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole (4.7 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-10% DCM/MeOH to afford 2-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (135 mg, 11% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 3.78 (s, 3H), 4.39 (s, 2H), 6.66 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8])([O-])=O>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8]
Reactant: CN(C)C(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(N)cc(C(F)(F)F)c1

Procedure:
Hydrogenation of (3-nitro-N,N-dimethyl-5-trifluoromethyl-benzamide (12.6 g, 48 mmol) in THF (250 ml) in the presence of Raney-Nickel (3 g), filtration through celite, concentration of the filtrate and crystallization from hexane gives the title compound: m.p.: 154° C.; MS: [M+1]+=233; 1H-NMR (CD3OD): 6.97 (s, 1H), 6.84 (s, 2H), 3.09 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].N1(C2C=CN=CC=2)CCCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: OCCCc1ccncc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C=C(C)C(=O)[O-]

Procedure:
After 6.85 g (50 mmol) of 4-pyridinepropanol (manufactured by Aldrich Co.) represented by formula (19), 4.73 g (55 mmol) of methacrylic acid (manufactured by Aldrich Co.) represented by formula (20), and 740 mg (5 mmol) of 4-(1-pyrrolidinyl)pyridine (manufactured by Aldrich Co.) were dissolved in 100 ml of dehydrated dichloromethane (manufactured by WAKO Co.), 11.3 g (55 mmol) of N,N′-dicyclohexylcarbodiimide (DCC) (manufactured by Aldrich Co.) was added thereto and allowed to react at room temperature for 1 hour. Then, insoluble urea was removed by filtration, followed by removal of solvent under reduced pressure. The residual material was purified by column chromatography (column: silica (manufactured by WAKO Co.), solvent: hexane/ethyl acetate) to obtain 4-pyridinepropanol-methacrylate represented by formula (21) (yield amount: 8.5124 g, yield rate: 82.8%). The reaction scheme is shown below.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[Br-:12].[C:13]1([PH+:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C.C(OCC)(=O)C>C(OCC)C.CCCCCC>[Br-:12].[CH3:1][C:2]1[S:3][C:4]([S:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSc1sc(C)c(CO)c1C
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1sc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C

Procedure:
14.0 G. of 2,4-dimethyl-3-hydroxymethyl-5-(methylthio)thiophene and 26.0 G. of triphenylphosphonium bromide were dissolved in 75 ml. of acetonitrile and stirred at 40° C. for 1 hour. The resulting mixture was cooled and poured into 150 ml. of ethyl acetate then treated with ethyl ether/hexane (5:1). The resulting solution was decanted from a gum-like residue. The residue was treated with hot acetone and the resulting white crystals were filtered, washed with cold acetone and dried under high vacuum at 80° C. to yield [2,4-dimethyl-5-(methylthio)-3-thenyl]triphenylphosphonium bromide, m.p. 245°-248° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([NH2:21])=[C:18]([NH2:20])[N:19]=2)=[N:6]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[NH2:20][C:18]1[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:15]=[N:16][C:17]=1[NH:21][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 72 h

Procedure:
200 mg (0.595 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5,6-diamine were admixed with 8 ml of dichloromethane and cooled to 0° C. 545 mg (4.757 mmol) of methanesulphonyl chloride and 481 mg (4.757 mmol) of triethylamine were added and the mixture was stirred at RT for 72 h. The mixture was diluted with dichloromethane and the precipitate was filtered off with suction. The filtrate was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 57 mg (18% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([O:40][CH3:41])=[O:39])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:42]1([CH:37]([CH:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[O:16])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)[C:38]([O:40][CH3:41])=[O:39])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Yield: 77.3 %

Procedure:
DMF (0.5 ml) was added to a solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.014 mole) in DCM (50 ml) and thionyl chloride (0.028 mole). The mixture was stirred and refluxed for one hour. The solvent was evaporated. DCM (50 ml) was added twice and the solvent was evaporated. The residue was dissolved in DCM (20 ml) and this solution was added to a mixture of intermediate (15) (0.014 mole) and DIPEA (0.028 mole) in DCM (80 ml). The mixture was stirred at room temperature for three hours and washed with water. The organic layer was dried and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried, yielding 6.2 g of methyl α-phenyl-1-[4-[[[4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetate (melting point 151° C.) identified as compound No. 39 in the following table F-1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][N:30]=[C:31]3[Cl:34])=[CH:26][CH:25]=2)[C:19]1=[O:35]>>[Cl:34][C:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][S:12]([C:9]4[S:8][C:7]([C:5]5[S:6][C:2]([Cl:1])=[CH:3][CH:4]=5)=[CH:11][CH:10]=4)(=[O:14])=[O:13])[C:19]3=[O:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Agent: Cl
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccc(Cl)s3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1

Procedure:
The title compound is prepared as described in EXAMPLE 56, Part A using 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride as starting material. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: BrCC1CCCCC1
Reactant: O=Cc1cc(O)ccc1Br
Product: O=Cc1cc(OCC2CCCCC2)ccc1Br

Procedure:
Alkylation of 2-bromo-5-hydroxybenzaldehyde using (bromomethyl)cyclohexane following the method used in Example 1 gave 2-bromo-5-(cyclohexylmethoxy)benzaldehyde. The crude aldehyde was used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:10][C:8]([F:11])([F:9])[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:12])=[CH:7][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)cn1

Procedure:
5-Methyl-2-trifluoromethylpyridine (see J. Org. Chem., vol. 29, pages 569-571) (8.1 g) was dissolved in 50 ml of carbon tetrachloride, and N-bromosuccinimide (8.9 g) and a catalytic amount of benzoyl peroxide were added. The mixture was refluxed for 7 hours with stirring. The reaction mixture was cooled, and insoluble materials were collected by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-trifluoromethyl-5-pyridylmethyl bromide (also known as 5-bromomethyl-2-trifluoromethylpyridine) (7.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:3][CH:2]=1.[ClH:19]>[Pt]=O>[ClH:19].[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccncc1
Agent: O=[Pt]
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1CC1CCNCC1

Procedure:
To a mixture of 148.0 g (1.0 mol) of phthalic anhydride and 15 mL of triethylamine in 1.5 L of xylene was slowly added 108.0 g (1.0 mol) of 4-(Aminomethyl)pyridine with mechanical stirring. The resulting solid was collected by filtration. The N-Pyridin-4-ylmethyl-phthalamic acid was then cyclized, by heating 235 g (0.88 mol) to the melt stage for 15 min. The mixture was allowed to cool slightly and 2.5 L of ethanol was added to the warm reaction mixture, and the solution filtered. Upon cooling, the mixture crystallized to give 188.0 g of 2-Pyridin-4-ylmethyl-isoindole-1,3-dione (m.p. 166-167.5° C.). A mixture of 23.8 g (0.1 mol) of 2-Pyridin-4-ylmethyl-isoindole-1,3-dione and 1.3 g of platinum oxide in 400 mL of methanolic HCl was reduced at 50 psi until no starting material could be detected by TLC. The mixture was filtered through celite and concentrated to give 22.0 g of 2-Piperidin-4-ylmethyl-isoindole-1,3-dione hydrochloride as a white solid. A small sample was recrystallized from ethanol to give an analytically pure sample of 16A (m.p. 241-242.5° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[C:4]([CH3:20])[CH:3]=1.Br[C:22]1[CH:27]=[C:26]([Br:28])[C:25]([Cl:29])=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[Br:28][C:26]1[C:25]([Cl:29])=[CH:24][N:23]=[C:22]([NH:1][C:2]2[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=3)=[C:4]([CH3:20])[CH:3]=2)[CH:27]=1
Reactant: Clc1cnc(Br)cc1Br
Reactant: COC(=O)c1ccc(-c2cc(OC)c(N)cc2C)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(OC)c(Nc3cc(Br)c(Cl)cn3)cc2C)cc1
Temperature: 150 °C

Procedure:
Methyl 4′-amino-5′-methoxy-2′-methylbiphenyl-4-carboxylate generated in Step 1 (200 mg, 0.75 mmol), 2,4-dibromo-5-chloropyridine (222 mg, 0.82 mmol, 1.1 equiv), Pd2(dba)3 (17 mg, 0.02 mmol, 0.025 equiv.), xantphos (22 mg, 0.04 mmol, 0.05 equiv.), and Cs2CO3 (365 mg, 1.1 mmol, 1.5 equiv.) are added to THF (5 mL). The resulting mixture is bubbled with N2 gas for 5 minutes and then heated at 150° C. for 4 hours. After cooling to room temperature, the reaction mixture is diluted into EtOAc and washed with H2O. The EtOAc layer is dried over Mg2SO4 and concentrated in vacuo. Silica gel chromatography (hexanes-EtOAc) affords Methyl 4′-(4-bromo-5-chloropyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19]>>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:9]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-chloro-2-(ethoxycarbonylamino)benzonitrile (K. O. Geolotte et al, J. Heterocyclic Chem., 1990, 27, 1549) and 2-bromo-3′-chloroacetophenone (M. Kihara et al., Tetrahedron, 1992, 48, 67-78).
Reaction SMILES: [C:1]1([CH:7]([SH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([Si:12]([Cl:15])([Cl:14])[Cl:13])=[CH2:11]>N(C(C)(C)C#N)=NC(C)(C)C#N>[Si:12]([CH2:10][CH2:11][S:9][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])([Cl:15])([Cl:14])[Cl:13]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: CC(S)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC(SCC[Si](Cl)(Cl)Cl)c1ccccc1
Reaction time: 6 h

Procedure:
Into a 500 ml. three-necked flask were charged 108 g. (0.78 mole) 1-phenyl-ethanethiol, 126 g. (0.78 mole) vinyltrichlorosilane and 1.2 g. (0.5 weight percent) azobisisobutyronitrile catalyst. The contents were heated and stirred for 6 hours at 80°-90°C. Fractional distillation of the reaction mixture gave the product fraction, Cl3SiCH2CH2SCH(CH3)C6H5, b.p. 110°/0.53 mm Hg. Vapor phase chromatographic analysis of the distilled product (120 g.) showed it contained a mixture of alpha and beta isomers. Yield of (1-phenylethylthio)ethyltrichlorosilane was 85 percent, based on ViSiCl3 reacted.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:13][S:14]([CH2:17][CH2:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:29]1[CH:34]=[CH:33][N:32]=[C:31](S(CCC)(=O)=O)[N:30]=1)(=[O:16])=[O:15]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:31]2[N:30]=[C:29]([N:24]3[C:25]4[C:21](=[C:20]([O:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:28]=[CH:27][CH:26]=4)[CH:22]=[N:23]3)[CH:34]=[CH:33][N:32]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CCCS(=O)(=O)c1nccc(-n2ncc3c(OCCS(C)(=O)=O)cccc32)n1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ncc4c(OCCS(C)(=O)=O)cccc43)n2)CC1

Procedure:
4-{4-[4-(2-Methanesulfonyl-ethoxy)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester was prepared by reaction of 4-amino-cyclohexanecarboxylic acid ethyl ester with 4-(2-methanesulfonyl-ethoxy)-1-[2-(propane-1-sulfonyl)-pyrimidin-4-yl]-1H-indazole following generally the procedure of Example 5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1>[CH2:24]([O:23][C:21]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc2c(N)ncnc2c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Compound 11 (0.20 g) obtained in Example 11 was dissolved in 5 ml of pyridine, and 0.1 ml of ethyl chloroformate was added to the solution. The resulting mixture was stirred at room temperature for 3 hours and then concentrated. Water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.21 g (82%) of 6-(4-ethoxycarbonylamino-quinazolin-7-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Compound 53).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]([CH3:37])([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:24]2[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[C:26]([CH3:33])[CH:25]=2)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=1[CH3:34]>>[C:5]([OH:7])(=[O:4])[CH3:6].[CH3:37][C:9]([CH3:8])([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:24]2[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[C:26]([CH3:33])[CH:25]=2)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=1[CH3:34]
Reactant: COC(C)=O
Agent: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: [Li+]
Agent: [OH-]
Product: CC(=O)O

Procedure:
Using LiOH hydrolysis as described in Example 137, (5-{1-[4-(4,4-dimethyl-3-oxo-pentyl)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (quant).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]=[C:12]2[N:20]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[S:21])[S:13]2)=[C:4]([F:22])[CH:3]=1>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:11]=[C:12]2[N:20]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[S:21])[S:13]2)[CH:6]=1
Reactant: O=[N+]([O-])c1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: 75 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred, hot (75° C.) mixture of 1.4 g (0.025 mole) of iron powder in 200 mL of acetic acid was added 1.5 g (0.0042 mole) of 9-(4-chloro-2-fluoro-5-nitrophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione. The mixture was stirred at 75° C. for one hour, then filtered and the filtrate evaporated under reduced pressure leaving a residue. The residue was partitioned between ethyl acetate and an aqueous, saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to yield 1.1 g of 9-(5-amino-4-chloro-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione as a solid, mp 59°-61° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:17]([CH3:19])[CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 77.7 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and isopropylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.29 g, 78%) was provided after purification. MS (ESI) m/z 362. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=1>>[C:31]([CH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]=[C:6]([C:17]([OH:19])=[O:18])[CH:7]([C:13]([F:16])([F:14])[F:15])[O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:28][CH:27]=1)([OH:33])=[O:32]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: COC(=O)CCc1ccc(O)cc1
Product: O=C(O)CCc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Yield: 27.6 %

Procedure:
Using the two step parallel synthesis route from ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate and methyl 3-(4-hydroxyphenyl)propionate, a mixture of two components was obtained. The two products were separated by reverse phase chromatography (C18, 4 cm i.d.×10 cm, 5% to 95% gradient CH3CN/H2O/0.1%TFA). The less retained component (analytical LC retention time=3.40 min, ELS purity >99%) was concd in vacuo to afford 61.1 mg (27.6%) of a white solid: 1H NMR (d6-acetone/400 MHz) 2.59 (t, 2H, J=7.6 Hz), 2.92 (t, 2H, J=7.6 Hz), 5.78 (q, 1H, J=7.1 Hz), 7.04 (d, 2H, J=8.6 Hz), 7.36 (d, 2H, J=8.6 Hz), 7.66 (s, 1H), 7.82 (s, 1H); 19F NMR (d6-acetone/100 MHz) −79.2 (d, 3F, J=6.8 Hz); MS(ES+) 443 (75%, M+1), 465 (100%, M+Na); MS(ES−) 441 (M−1, 100); HRMS (ES−) m/z calcd for (M−1; C20H13O6ClF3) 441.0347, found 441.0347.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:23])([F:22])[F:21])[NH2:15]>>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:22])([F:23])[F:21]
Reactant: O=C(O)c1cccc(I)c1
Reactant: Nc1ccc(OC(F)(F)F)c(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cccc(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 30.1 using 3-iodobenzoic acid and 3-fluoro-4-(trifluoromethoxy)aniline to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=3.39 min, m/z=425.9 [M+H]+, m/z=423.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.32-7.40 (m, 1H) 7.54-7.62 (m, 1H) 7.64 (dd, 1H) 7.93-8.01 (m, 3H) 8.29 (s, 1H) 10.64 (s, 1H).