Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[C:23]([CH2:33][CH3:34])=[N:24][N:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[N:27][C:26]=23)=[CH:17][CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1>O.CCO.Cl>[CH2:33]([C:23]1[C:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([NH2:14])=[CH:20][CH:19]=2)=[C:26]2[N:27]=[C:28]([CH3:32])[CH:29]=[C:30]([CH3:31])[N:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzhydrylidene-[4-(2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-amine (12) (3.97 g, 8.93 mmol) was dissolved in a mixture of water (40 ml), EtOH (10 ml) and conc. HCl (10 ml) and stirred at rt for 1 h. The reaction mixture was basified to pH 11 with Na2 CO3. The organic layer was extracted with EtOAc, washed with water and brine, dried over Na2 SO4 and concentrated to afford an orange oil. The crude product was purified by chromatography (2-50% EtOAc in cyclohexane) to afford a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[Cl:17][CH2:18][C:19](N(OC)C)=[O:20]>O1CCCC1.CCOCC>[Cl:17][CH2:18][C:19]([C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:3]=2[CH:2]=1)=[O:20]
Reactant: Cc1cccc2scc(Br)c12
Reactant: CON(C)C(=O)CCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2sc(C(=O)CCl)cc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of 3-bromo-4-methylbenzo[b]thiophene (2 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 4.58 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (1.04 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, then the mixture was stirred at −70° C. for 5 hours, allowed to stand at ambient temperature for 18 hours and quenched by the addition of saturated aqueous ammonium chloride solution (40 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (40 ml), and dried (MgSO4). The solvents were removed in vacuo to give 2-chloro-1-(4-methylbenzo[b]thiophen-2-yl]ethan-1-one (1.65 g) as a brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S-:35].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([S:35][CH3:34])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(Br)c32)C1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O

Procedure:
A solution of 10-(benzyloxy)-4-bromo-2-(4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (133 mg, 0.26 mmol) and sodium thiomethoxide (73 mg, 1.04 mmol) in anhydrous DMF (2.6 mL) was stirred at room temperature for 2 hours. The product mixture was concentrated under vacuum and the residue partitioned between chloroform and dilute hydrochloric acid. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with ethyl acetate. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: CC[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1)[CH2:4][CH3:5].[CH3:16]C(C)CC(Cl)=O>>[CH2:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH:4]([CH3:5])[CH3:16]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)c1csc(C(CC)CC)n1
Product: CC(C)Cc1nc(C(=O)O)cs1

Procedure:
Prepared by the method of Carboxylic Acid 3, using 3-methylbutanoyl chloride (10 mL) in place of 2-ethylbutanoyl chloride in step a. Yield 3.8 g.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[C:18]([CH3:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][CH:15]([CH3:17])[CH3:16]>C(O)C.[Pd]>[NH2:22][C:20]1[CH:21]=[C:2]([CH3:1])[C:3]([O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:18]([CH3:25])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(CC(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc2[nH]nc(CC(C)C)c2c1
Yield: 63.7 %

Procedure:
In an analogous manner to the procedure of Example 1, 172 mg (0.507 mmol) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isobutyl-1H-indazole are reacted with 25 mg of palladium/carbon (10%) in 15 ml of ethanol under hydrogen in the course of 3 h to give 100 mg (64%) of 5-(4-amino-2,6-dimethylphenoxy)-3-isobutyl-1H-indazole.
Reaction SMILES: [F:1][C:2]1[C:3]([C:40]([F:43])([F:42])[F:41])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]4[CH2:24][N:23]([C:25]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[O:26])[CH2:22][C:19]=4[NH:20][N:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:40]([F:43])([F:41])[F:42])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]4[CH2:24][N:23]([C:25]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:26])[CH2:22][C:19]=4[NH:20][N:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2Cc3[nH]nc(C(=O)N4CCC(c5ccc(F)c(F)c5C(F)(F)F)CC4)c3C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CN(C(=O)N1CCNCC1)C2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate (47 mg, 0.077 mmol) in anhydrous CH2Cl2 (1.5 mL) was cooled to 0° C. under an atmosphere of N2 and treated with TFA (1.5 mL). When the addition was complete, the cooling bath was removed and the reaction stirred at room temperature for 1 h. After this time, the mixture was concentrated to dryness under reduced pressure, diluted in CH2Cl2 (100 mL) and washed with 2 M aqueous NaOH (2×50 mL). The organic layer was dried over Na2SO4 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure and the resulting residue chromatographed over silica gel (Isco CombiFlash Rf unit, 120 g Redisep column, 0% to 40% CH3OH in CH2Cl2). The combined column fractions were concentrated to dryness under reduced pressure and found to contain residual TFA (˜17%). The resulting residue (21 mg) was diluted in a mixture of CH2Cl2 (5 mL) and CH3OH (1 mL), treated with MP-carbonate and stirred at room temperature for 2 h. After this time the mixture was filtered and the filtrate concentrated to dryness under reduced pressure to provide (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone as a white solid (13 mg, 33%): mp 153-155° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.20 (br s, 1H), 7.75 (dd, J=18.0, 9.0 Hz, 1H), 7.55-7.52 (m, 1H), 4.65-4.51 (m, 6H), 3.24-3.22 (m, 2H), 3.14 (t, J=5.0 Hz, 4H), 2.96-2.80 (m, 1H), 2.70-2.68 (m, 3H), 2.32-2.22 (m, 1H), 1.79-1.70 (m, 4H), 1 proton not readily observed; ESI MS m/z 513 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1>CC#N>[CH2:28]([O:8][C:6]1[CH:5]=[CH:4][C:3](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]([Br:1])[CH:7]=1)[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1Br

Procedure:
Into a 100-mL round-bottom flask, was placed ethyl (2E)-3-(2-bromo-4-hydroxyphenyl)prop-2-enoate (1.0 g, 3.69 mmol, 1.00 equiv), CH3CN (20 mL), potassium carbonate (1.027 g, 7.43 mmol, 2.01 equiv). This was followed by the addition of BnBr (660 mg, 3.86 mmol, 1.05 equiv) dropwise with stirring. The resulting solution was stirred overnight at 15° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The solids were removed by filtration. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (20:80). This resulted in 1.32 g (94%) of ethyl (2E)-3-[4-(benzyloxy)-2-bromophenyl]prop-2-enoate as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][S:22][CH2:23][CH2:24][CH:25]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:25][CH2:24][CH2:23][S:22][CH3:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CSCCC=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCSC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (150 mg, 0.547 mmol) in 1,2 dichloroethane (2 mL) was added 3-(methythio)propionaldehyde (82 μL, 0.821 mmol), acetic acid (156 μL, 2.74 mmol), and sodium triacetoxyborohydride (232 mg, 1.09 mmol) respectively. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(methylthio)propyl]amino}-2-pyridinecarboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=1.5 Hz, 1 H), 7.73 (t, J=5.1 Hz, 1 H), 7.11 (dd, J=8.4, 5.5 Hz, 2 H), 6.96 (t, J=8.6 Hz, 2 H), 6.82 (s, 1 H), 4.40 (q, J=7.1 Hz, 2 H), 3.90 (s, 2 H), 3.24 (m, 2 H), 2.58 (m, 2 H), 2.07 (s, 3 H), 1.90 (m, 2 H), 1.41 (t, J=7.1 Hz, 3 H); MS m/z 363 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=2)=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]([S:33]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:11](=[O:16])[N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc(=O)[nH]cc1F)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
To a suspension of 4-chloro-N-(5-fluoro-2-oxo-1,2-dihydropyrimid-4-yl)benzamide (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) were added Et3N (0.08 g, 0.82 mmol) and 4-chlorobenzenesulfonyl chloride (0.087 g, 0.41 mmol) at 0° C., and the resulting mixture was warmed to room temperature and stirred for 3 h. The reaction was diluted with CH2Cl2 (10 mL) and washed with brine. The phases were separated and the organic phase was dried over sodium sulfate (Na2SO4), filtered, and concentrated to an amber oil (0.295 g). Purification by normal phase chromatography (12 g SiO2; gradient, 0 to 35% EtOAc/hexanes) afforded 4-chloro-N-[1-(4-chlorobenzenesulfonyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]benzamide (0.025 g, 26%) as a white solid: mp 169-172° C.; 1H NMR (300 MHz, CDCl3) δ 12.59 (s, 1H), 8.29-8.15 (m, 3H), 8.05 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H); ESIMS m/z 442 ([M+H]+), 440 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-])=O)[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1>C(O)C.[Pd].[C]>[NH2:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:17]2
Reactant: O=C(NC1Cc2ccc([N+](=O)[O-])cc2C1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2

Procedure:
1.20 g (4.0 mmol) 4-fluoro-N-(5-nitro-indan-2-yl)-benzamide were hydrogenated in 100 ml of ethanol on a Pd/carbon catalyst at RT.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].O>C(O)CCC>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: Cc1c(OCCN(C)C)cccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 100 %

Procedure:
To a slurry containing 5.0 g (33 mmol) of 2-methyl-3-nitrophenol, 9.4 g (65.2 mmol) of (2-chloroethyl)dimethylamine hydrochloride, 9.0 g (65.3 mmol) of K2CO3, and 100 mL of H2O was added 100 mL of butanol and the reaction mixture was heated at 80° C. for 13 h. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4 and filtered. The solvents were removed under reduced pressure and the residue was subjected to silica gel chromatography to give 7.4 g (100%) of dimethyl{2-[(2-methyl-3-nitrophenyl)oxy]ethyl}amine as a brown oil. 1HNMR (400 MHz, DMSO-d6) δ 7.29-7.42 (m, 3H), 4.11 (t, J=5.6 Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.22 (s, 3H), 2.20 (s, 6H). MS (ESI+) m/z 225 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:17]=[C:16]([O:18]COCC[Si](C)(C)C)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:6])[CH3:2].C[Si](C)(C)CCOCOC1C2C(=CC=CC=2)C=C(O)C=1.BrC(C)(C)C(OCC)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CCO>CCO>[CH2:1]([O:3][C:4](=[O:28])[C:5]([O:7][C:8]1[CH:17]=[C:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([CH3:27])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCOCC[Si](C)(C)C)c2ccccc2c1
Agent: CCOC(=O)C(C)(C)Br
Agent: C[Si](C)(C)CCOCOc1cc(O)cc2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
1.58 g (3.90 mmol) of 2-methyl-2-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-yloxy]-propionic acid ethyl ester (prepared from 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ol, ethyl bromoisobutyrate, cesium carbonate, in analogy to the procedure described in example 14B] was dissolved in 20 ml of EtOH; then, 1.95 ml of HCl/EtOH-solution (6 molar) was added drop by drop. After 7 hours stirring at room temperature, the solvent was removed by evaporation and the residue was partitioned between water and MeCl2. The organic phase was separated, washed with water, dried (MgSO4) and evaporated. The crude product was purified by chromatography over silica gel with a gradient of AcOEt/heptane to give 1.06 g of pure 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester as light brown oil.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[NH:12][C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.Cl[CH2:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:24]1[CH2:26][CH2:25]1>CN(C)C=O>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:24]2[CH2:25][CH2:26]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Fc1cccc(C2CC2)c1CCl
Reactant: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 6-bromo-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (7, 2.12 g, 7.8 mmol) in anhydrous dimethylformamide (40 mL) sodium hydride (60% on mineral oil, 467 mg, 11.7 mmol) was added and the reaction was stirred at room temperature for 30 min. A solution of 2-chloromethyl-1-cyclopropyl-3-fluorobenzene (1.58 g, 8.6 mmol) in anhydrous dimethylformamide (10 mL) was added slowly and the reaction was stirred for 18 h. The mixture was poured onto ice water (250 g) and extracted with dichloromethane (3×80 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was triturated with n-hexane, the precipitated product was collected, washed with methanol, then diethyl ether. The crude product was recrystallized from ethyl acetate to give the title compound (1.31 g, 3.1 mmol, 54%) as a pale yellow solid. ESMS m/z 420 (M+H)+.
Reaction SMILES: [CH2:1]1[C:11]2[C:12]3[C:3](=[CH:4][CH:5]=[C:6]4[C:16](=[O:17])[O:15][C:13](=[O:14])[C:8](=[CH:9][CH:10]=2)[C:7]4=3)[CH2:2]1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CC(N(C)C)=O>[CH:18]1([N:24]=[C:16]([C:6]2[C:7]3=[C:12]4[C:3]([CH2:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]3[C:13]([OH:15])=[O:14])=[CH:4][CH:5]=2)[OH:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: O=C1OC(=O)c2ccc3c4c(ccc1c24)CC3
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc2c3c(ccc(C(O)=NC4CCCCC4)c13)CC2
Temperature: 157.5 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A slurry of 5,6-acenaphthenedicarboxylic acid anhydride (33.6 g, 0.150 mol) (B. M. Trost, G. Michael Bright, Charles Frihart, and David Brittelli, Journal of the American Chemical Society, 93(3), 737-45 (1971); James J. Jordan, Jr; U.S. Pat. No. 3,935,226) in 175 ml of DMAc was treated with cyclohexylamine (34.2 ml, 0.300 mol) over one minute and a thick paste formed. This mixture was heated at 155-160° C. for 2 hours. The resulting deep green solution was poured into 2 liters of water. The mixture was stirred for 10 minutes and then was filtered. The accumulated solid was washed with water and air-dried to provide a yellow solid (45.1 g, 98.5%), mp 264-265° C. A portion (2.00 g) of this material was recrystallized from a mixture of n-propyl acetate and heptanes (200 ml, 1:1 v/v) to provide fine yellow needles (1.42 g, 70%), mp 266-267° C. Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found C, 78.39; H, 6.15; N, 4.83.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16](Br)=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:19])=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2Cc3sc(Br)cc3C2C1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC2Cc3sc(C)cc3C2C1
Temperature: 22 °C
Yield: 59 %

Procedure:
A solution of the product from step b) (863 mg, 2.62 mmol) in dioxane (13.1 ml) was treated with Pd(dppf)2Cl2 (128 mg, 0.157 mmol) and a 2M solution of dimethylzinc in toluene (2.62 ml, 5.24 mmol) at 102° C. for 1 h. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic extracts were dried (MgSO4), concentrated and eluted through a plug of silica-gel using 50:50 hexanes:EtOAc to give 411 mg (59%) of the subtitle compound. MS calculated for C14H19NO2S +H 266, observed 266.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:11]=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 0 °C
Yield: 42.4 %

Procedure:
To an ice-cold solution of 3-(methylsulfonyl)benzoic acid (1.4 g, 7.1 mmol) in 2:1 Et2O/THF (60 mL) was added LiAlH4 (8.5 mL of 1.0 M solution in THF, 8.5 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0° C., and the reaction was quenched with water (15 mL) and 15% NaOH in water (35 mL). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 1:2 to 3:1 EtOAc/hexanes) provided (3-methanesulfonyl)phenyl methanol as a clear oil (0.56 g, 42%): 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.83 (d, J=7 Hz, 1H), 7.64 (d, J=7 Hz, 1H), 7.53 (t, J=7 Hz, 1H), 4.78 (d, J=6 Hz, 2H), 3.05 (s, 3H), 2.61 (br s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:25])=O.[NH2:26][C:27]([NH2:29])=[S:28]>CCO>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:26]=[C:27]([NH2:29])[S:28][CH:2]=3)=[C:6]([CH3:25])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COCCCOc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COCCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 88.8 %

Procedure:
A mixture of 2-bromo-1-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}ethanone (21-4, 0.34 g, 0.82 mmol) and thiourea (0.07 g, 0.96 mmol) in 95% EtOH (5.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (21-5, 0.28 g) as yellow solids in 90% yield, which was used directly for the next step without further purification.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C([C:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=5)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(OCC)=O)(C)(C)C.Br[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[C:53]([C:56]3[S:57][C:58]4[C:64]([C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=5)=[C:63]([C@H:72]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])[C:73]([O:75][CH2:76][CH3:77])=[O:74])[C:62]([CH3:83])=[CH:61][C:59]=4[N:60]=3)[CH:54]=2)[N:49]([CH3:84])[N:48]=1>>[C:79]([O:78][C@@H:72]([C:63]1[C:62]([CH3:83])=[CH:61][C:59]2[N:60]=[C:56]([C:53]3[CH:54]=[C:55]4[C:50](=[CH:51][CH:52]=3)[N:49]([CH3:84])[N:48]=[C:47]4[C:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH:30]=3)[S:57][C:58]=2[C:64]=1[C:65]1[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=1)[C:73]([O:75][CH2:76][CH3:77])=[O:74])([CH3:82])([CH3:81])[CH3:80]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C5=CCN(C)CC5)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(Br)nn4C)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(C3=CCN(C)CC3)nn4C)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-6-yl)benzo[d]thiazol-6-yl)acetate except using (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate instead of (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. LCMS-ESI+: calc'd for C36H39ClN4O3S: 643.2, 645.2 (M+H+); Found: 643.1, 645.0 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.13 (dd, J=8.9, 1.5 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.65-7.47 (m, 4H), 6.66 (s, 1H), 5.25 (s, 1H), 4.37-4.15 (m, 2H), 4.11 (s, 3H), 4.03-3.87 (m, 2H), 3.87-3.63 (m, 2H), 3.57-3.37 (m, 2H), 3.07 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.00 (s, 9H).