Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)=[C:23]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34]([NH:1][C:2]3[C:15]([O:16][CH3:17])=[CH:14][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:33]=2)=[C:23]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:26])=[O:27])[CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(Cl)cc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.058 g, 48%). MP: 194-199° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.22 (s, 1H), 8.47 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.95 (s, 1H), 7.87-7.85 (m, 1H), 7.53-7.47 (m, 2H), 6.66 (s, 1H), 3.88 (s, 3H), 3.67-3.62 (m, 2H), 2.91-2.86 (m, 2H), 2.77 (s, 6H), 2.75-2.65 (m, 8H). MS: 581.14 (MH)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[CH2:11]([SH:13])[CH3:12]>>[CH2:11]([S:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1)[CH3:12]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CCS
Product: CCSc1ccc(C#N)c(C)c1

Procedure:
4 g of 4-bromo-2-methylbenzonitrile was used in Procedure Q with ethanethiol to afford 4-(ethylthio)-2-methylbenzonitrile. 2 g of 4-(ethylthio)-2-methylbenzonitrile was reacted via Procedure R to give 4-(ethylsulfonyl)-2-methylbenzonitrile. 2.5 g of 4-(ethylsulfonyl)-2-methylbenzonitrile was reacted via Procedure T to give 4-(ethylsulfonyl)-2-methylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(ethylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)-2-methylbenzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cc(C)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(C)cc1C(=O)OC
Yield: 104.7 %

Procedure:
To a solution of methyl 2-amino-5-methylbenzoate (8.1 g) and triethylamine (6.0 g) in methylene chloride (50 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (6.5 g). The reaction was allowed to stir for two hours, then the reaction mixture was washed with an aqueous solution of sodium carbonate, dilute hydrochloric acid and water, followed by drying. The solvent was evaporated to dryness to give a pale brown oil (12.8 g, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[N:3]=[C:4]([S:19][CH3:20])[N:5]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Product: CSc1nc(Nc2c(F)cccc2F)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2,6-difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ0.31 (s, 3H), 6.98-7.20 (m, 3H), 7.26 (m, 2H), 7.38-7.42 (m, 2H), 9.79 (s, 1H), 10.39 (br s, 1H). LC MS (m/e)=376 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH2:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:62]([C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:29])([F:31])[F:30])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:8][CH2:7]2)=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Br)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2C=Cc2ccccc2)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Yield: 83.9 %

Procedure:
A mixture of N-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.525 g), palladium diacetate (0.011 g), tris(o-tolyl)phosphine (0.03 g), triethylamine (0.15 g) and styrene (0.16 g) were combined in acetonitrile and warmed to reflux for 23 h. The mixture was cooled, partitioned between dichloromethane/water, the organic phase separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ethyl acetate/hexane mixtures as eluant) to provide the title compound (0.46 g).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][OH:24])[CH2:6]1)(=O)C.C[O-].[Na+].[C:28]1([C:34](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO.O1CCCC1.C(OCC)(=O)C>[OH:24][CH2:23][C@@H:7]1[CH2:6][C@H:5]([S:4][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (15 g) in a mixture of methanol (150 ml) and tetrahydrofuran (150 ml) was added a 28% solution of sodium methoxide in methanol (8.95 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added triphenylmethyl chloride (12.39 g) on ice bath, followed by stirring at the same temperature for 1 hour. The precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (200 ml), washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was chromatographed on silica gel (200 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (22.24 g).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][CH:12]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:23])[CH2:21][CH3:22])[CH3:13].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:13][CH:12]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:23])[C@H:21]([CH3:22])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:11]
Reactant: BrCc1ccccc1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of lithium hexamethyl-disilazane (LiHMDS, 1.0M in THF, 120 mL, 120 mmol) was added to dry THF (300 mL). The resultant solution was cooled to 0°. Meanwhile, a solution of (4S)-(1-methylethyl)-3-(1-oxopropyl)-2-oxazolidinone (20.9 g, 113 mmol) in dry THF (200 mL) was cooled to 0°, and then cannulated into the LiHMDS solution. After 30 min at 0°, benzyl bromide (13.4 mL, 113 mmol) was added. The resultant mixture was stirred at 0° for 2 h and then allowed to warm to room temperature. The mixture was treated with 10% aqueous citric acid and then extracted with EtOAc (2 X). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to provide a yellow oil mixed with a solid. This material was purified by flash chromatography [SiO2, eluent: EtOAc-hexane (1:10 to 1:3)] to provide 4(S)-(1-methylethyl)-3-(2(R)-methyl-1-oxo-3-phenylpropyl)-2-oxazolidinone as a clear pale yellow liquid (26.8 g, 86% yield). 1H NMR (CDCl3) δ 7.29-7.24 (m, 4H), 7.22-7.16 (m, 1H), 4.45-4.41 (m, 1H), 4.26-4.13 (m, 3H), 3.13 (dd, J=13, 7.5 Hz, 1H), 2.64 (dd, J=13, 7.5 Hz, 1H), 2.22-2.12 (m, 1H), 1.16 (d, J=6.5 Hz, 3H), 0.84 (d, J=7 Hz, 3H), 0.61 (d, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5](OCC)(OCC)OCC.[CH3:15][O:16][C:17]1[CH:33]=[CH:32][C:20]([C:21]([C:23]23[O:30][C:29](=[O:31])[CH:28]2[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[SiH3:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1([OH:30])[C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:33][CH:32]=1)=[O:31]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2(O)CCCCC2C(=O)NCCC[SiH3])cc1

Procedure:
3-Aminopropyltriethoxysilane (22.14 g, 0.100 mol) is added to a solution of 26.03 g (0.100 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one in methylene chloride. The reaction mixture is heated at reflux for several hours and monitored by thin layer chromatography. Upon completion of the reaction, solvent is evaporated to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][C:38]1[CH:40]=[CH:41][C:35]([S:32]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=2[Br:31])(=[O:34])=[O:33])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(CN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
To a solution of the product of Example 1A (339 mg, 0.676 mmol) dissolved in anhydrous CH2Cl2 (6.76 mL) was added TsCl (155 mg, 0.812 mmol), DMAP (99 mg, 0.812 mmol) and Et3N (0.141 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 1.5 h then concentrated to a yellow oil. The crude material was directly purified using silica gel chromatography (4:1 hexanes:EtOAc) to yield a colorless oil (384.3 mg, 87% yield). 1H NMR (CDCl3, 600 MHz): δ 7.74 (d, J=8.4 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.21 (m, 3H), 6.70 (d, J=8.4 Hz, 1H), 5.08 (brs, 2H), 4.30 (t, J=6.0 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.16 (m, 2H), 1.51 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 160.6, 154.9, 154.0, 145.0, 133.0, 132.9, 132.7, 130.0, 128.0, 112.9, 111.9, 84.7, 79.0, 67.0, 64.1, 46.4, 29.0, 28.5, 28.2, 21.8.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.C([O:17][C:18]([C:20]1[N:21]=[N:22][S:23][C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C>C1COCC1.C1CCCCC1>[N:4]1([CH2:3][CH2:2][NH:1][C:18]([C:20]2[N:21]=[N:22][S:23][C:24]=2[NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1nnsc1Nc1ccccc1
Yield: 60 %

Procedure:
To a solution of N-aminoethylmorpholine (228 mg, 10 mmole) in 2 mL anhydrous THF at −40° C. was added 0.8 mL of 2 M n-BuLi solution in cyclohexane. Some white solid was precipitated instantly. The suspension was stirred for about a half an hour. When the bath temperature reached −10° C., a solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in anhydrous THF was added to the mixture. After it was stirred at room temperature for an hour, the reaction was quenched with saturated NH4Cl solution. The solution was extracted with EtOAc and residue obtained after the removal of EtOAc was purified by preparative TLC (silica gel, CH2Cl2.MeOH=15:1). The title compound was isolated as a white powder in 60% yield (48 mg). 1H NMR (ppm, in CDCl3): 10.91 (br. s, 1 H), 7.77 (br. s, 1 H), 7.00-7.60 (m, 5 H), 3.70 (m, 4 H), 2.60 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([CH2:11][N:12]3[C:20]4[C:15](=[C:16]([O:22][C:23]5[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=5)[C:26]#[N:27])[C:17]([Cl:21])=[CH:18][CH:19]=4)[CH:14]=[N:13]3)[C:5]2=[CH:4][CH:3]=1.Cl>CO.C(Cl)(Cl)Cl>[Cl-:21].[Cl:21][C:17]1[C:16]([O:22][C:23]2[CH:24]=[C:25]([C:26]#[N:27])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][C:10]1[C:5]3[C:6](=[N:7][C:2]([NH3+:1])=[CH:3][CH:4]=3)[NH:8][N:9]=1)[N:13]=[CH:14]2
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3nc(N)ccc23)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3nc([NH3+])ccc23)c1
Product: [Cl-]

Procedure:
To 3-({1-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-5-chloro-1H-indazol-4-yl}oxy)-5-chlorobenzonitrile (0.936 g, 2.079 mmol) as a solution in 20% methanol in chloroform (300 mL) was added 1N HCl (2.079 mL, 2.079 mmol), and the resulting mixture was then concentrated under reduced pressure. The resulting white paste was diluted with acetonitrile (100 mL) and the solvent evaporated in vacuo. The dilution-evaporation was repeated twice more for a total of three times. The resulting residue was placed under vacuum overnight to give product. 1H NMR (DMSO-d6): 6.7.91 (s, 1H), 7.81 (s, 3H), 7.68-7.60 (m, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 6.50-6.30 (m, 2H), 6.00-5.86 (m, 2H). HRMS (M+1)=450.06
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:13](=[O:15])[CH:14]=1)[CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]([OH:26])[OH:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([B:24]([OH:26])[OH:25])=[CH:20][CH:19]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Reactant: OB(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Reaction time: 40 h
Yield: 99.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 180 mg) was added to a mixture of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (660 mg) and 4-bromomethylphenylboronic acid (800 mg) (obtained as described in J. Amer. Chem. Soc. 1958, 80, 835) in DMF (12 ml) under an atmosphere of argon. The mixture was stirred for 40 hours and then water (0.2 ml) was added. Volatile material was removed by evaporation and the residue was dissolved in warm 0.5M sodium hydroxide solution (10 ml). Insoluble material was removed by filtration and the filtrate was acidified to pH 4 with 20% citric acid solution. The precipitate solid was collected by filtration, washed with water (20 ml) and dried under high vacuum to give 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yl)oxymethyl]phenylboronic acid (C) (1.15 g), m.p. 229°-231° C.; NMR (d6 -DMSO): 1.3(t,3H), 1.6-1.9(m,4H), 2.5-2.7(m,2H), 2.75-2.95(m,4H), 5.4(s,2H), 7.3(d,2H), 7.4(s,1H, 7.5(d,2H).
Reaction SMILES: [O:1]1[C:5]([C:6](OC)=[O:7])=[CH:4][C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[OH:7][CH2:6][C:5]1[O:1][CH:2]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[CH:4]=1
Reactant: COC(=O)c1coc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1coc(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
408 mg of dimethyl furan-3,5-dicarboxylate [see J. Chem. Soc., Perkin I, 1130 (1973)] was dissolved in 4 ml of anhydrous tetrahydrofuran, and 59 mg of lithium aluminium hydride was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and ethyl acetate was added to extract it. The extract was worked up in a customary manner and purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: hexane/ethyl acetate=2/1] to give 44 mg (yield 13%) of methyl 5-hydroxymethylfuran-3-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].O1CCC[CH2:30]1.CCOCC.C[Mg]Br>C(OCC)(=O)C>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]([OH:27])[CH3:30])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCN(c1ccc(C)c2cc(-c3ncc(C(C)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 4 h
Yield: 65 %

Procedure:
To a mixed solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4-methyl-1H-indol-7-yl]thiophene-2-sulfonamide (0.30 g) and tetrahydrofuran (30 mL) was added ether solution (0.60 mL) of 3M-methylmagnesium bromide under ice-cooling, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed successively with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2-2:1), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (201 mg, yield 65%) as pale-yellow prism crystals. melting point 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:39]=1[C:40](Cl)=[O:41]>O1CCCC1>[C:18]([O-:41])(=[O:23])[CH3:24].[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][N:25]([C:40]([C:39]1[C:38]([Cl:37])=[CH:46][CH:45]=[CH:44][C:43]=1[Cl:47])=[O:41])[CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)[O-]
Product: CCN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(Cl)cccc1Cl
Reaction time: 0.33 h
Yield: 174.3 %

Procedure:
To a solution of 5-amino-N-{2-[(ethylamino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (56 mg, 0.15 mmol) in anhydrous tetrahydrofuran (2 ml) cooled in ice was added diisopropylethylamine (0.052 ml, 0.3 mmol) followed by 2,6-dichlorobenzoyl chloride (0.023 ml, 0.164 mmol). After 20 minutes, the mixture was removed from the ice and left at 21° C. for 19 hours. The mixture was blown down, the residue was dissolved in dichloromethane (3 ml) and washed with 2M hydrochloric acid (1 ml) and water (1 ml). It was again blown down and purified on a 5 g SPE cartridge, eluting with dichloromethane and then mixtures of cyclohexane/ethyl:acetate (10:1), (5:1), (3:1) and finally (2:1) to give the title compound (73.5 mg).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C>[S:13]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:3])(=[O:2])=[O:1]
Reactant: O
Reactant: CCOC(=O)C1=C(S)CCCC1
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 145.8 %

Procedure:
Sodium peroxyborate tetrahydrate (74.3 g) was admixed with acetic acid (400 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cyclohexene-1-carboxylate (30.0 g) in acetic acid (50 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (660 ml) and stirred at room temperature for 1 hour and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (50 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (500 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (1000 ml) and the powder which precipitated was isolated by filtration to obtain ethyl 2-sulfo-1-cyclohexene-1-carboxylate as a white powder (55 g) containing inorganic substances. This was treated dropwise with thionyl chloride (150 ml) at 0° C. over 1 hour and then stirred at 80 to 85° C. for 20 hours. The mixture was evaporated under reduced pressure to dryness and the residue was partitioned between ethyl acetate (300 ml) and a dilute brine (400 ml) and the aqueous layer was extracted with ethyl acetate (200 ml). The ethyl acetate layers were combined and washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate/hexane=1/8→ethyl acetate/hexane=1/5) to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (21.5 g) as yellow crystals.