Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[C:5](=[O:20])[CH2:4][CH2:3]1.[CH3:22][Si:23](C#C)([CH3:25])[CH3:24].[CH2:28](N(CC)CC)[CH3:29]>O1CCCC1.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:10]=2)[C:5](=[O:20])[CH:4]([C:28]#[CH:29])[CH2:3]1
Reactant: CCN(CC)CC
Reactant: CC1(C)CCC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC1CC(C)(C)c2cc([Si](C)(C)C)ccc2C1=O
Temperature: 70 °C
Yield: 72 %

Procedure:
A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 11, 0.46 g, 1.43 mmol) in triethyl amine (3 mL) and anhydrous tetrahydrofuran (8 mL) was treated with cooper(I)iodide (0.1 g, 0.53 mmol) and sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.85 mL, 6 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol). The resulting reaction mixture was heated at 70° C. for 17 h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celte. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound (0.28 g, 72%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[CH:12][CH:11]=1
Reactant: N#CCCCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCCCOc1ccc(Cl)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
6-Bromohexanenitrile (2.65 mL, 20 mmol) and 4-chlorophenol (2.57 g, 20 mmol) were dissolved in DMF (50 mL). After addition of K2CO3 (5.53 g, 40 mmol) the mixture was stirred at 95° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (80 mL) and Et2O (200 mL). The org. layer was separated, washed with pH 7 phosphate buffer solution (1×50 ml), dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound, pure enough for further reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].C([S-])C.[Na+].CN(C=O)C.C(=O)(O)[O-]>O>[NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Agent: CC[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)c2ccc(C(C)C)cc2)c(N)cc1O

Procedure:
A mixture of 1.34 g (4.48 mmol) (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 1.88 g sodium ethanethiolate and 10 ml DMF are heated for 5 h to 110° C. Saturated aqueous bicarbonate solution (10 ml) and 100 ml water are added. The product is extracted with CH2Cl2 and chromatographed on silica (hexane/ethyl acetate).
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].CSCl.[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH:17]=[C:16]([CH3:30])[CH2:15]1.N>ClCCl>[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[C:25]([S:8][CH3:9])[NH:24]4)[CH:17]=[C:16]([CH3:30])[CH2:15]1
Reactant: CSSC
Reactant: CC1=C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: CSCl
Agent: N
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CSc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C=C(C)CN1C
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (0.74 g,) in dichloromethane (15 ml) was added dropwise over 15 minutes at -20° C. to a stirred solution of dimethyl disulphide (0.46 g), in dichloromethane (15 ml). After allowing it to reach room temperature the solution of methyl sulphenyl chloride was added dropwise to a suspension of 8,9-didehydro-6,8-dimethylergoline (2.4 g) in dichloromethane (150 ml) at -70° C. The reaction mixture was stirred and allowed to reach room temperature overnight. Cold ammonia solution was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness. Chromatography on neutral alumina (CH2Cl2) and crystallisation from cyclohexane gave the title compound, m.p. 148°-150° C. The mesylate was also prepared, m.p. 220°-222° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)(C)(C)C.[Cl:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25]C)=[CH:22][CH:23]=3)[C:18]([S:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:17]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:13][CH:12]=1.Cl>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[C:18]([S:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[C:17]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)(C)S
Solvent: ClCCl
Product: CCOC(=O)c1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
To a 0° C. suspension of anhydrous aluminum chloride (4.8 g, 36 mmol) in CH2Cl2 (15 ml) was added t-butyl mercaptan (12 ml) followed by ethyl 1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindole-2-carboxylate (3.77 g; 11 mmol), prepared as in step 2, and the resulting mixture was stirred at 0° C. for 45 min. The reaction mixture was then poured into ice and aqueous 1N hydrochloric acid (100 ml) and extracted with ethyl acetate. The organic phase was concentrated in vacuo to provide 4.2 g of crude oily ethyl 1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindole-2-carboxylate which was used without further purification.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCOCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[C:1]([Br:5])[Br:2])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 hours. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formyl-piperidine (from Step 2 above) in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5 % NaHCO3, 300 mL water (2×), and 150 mL brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0˜15% EtOAc in hexanes) gave title compound as a white solid. RF: 0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ 6.25 (d, J=8.9 Hz, 1H), 4.04˜4.12 (m, 2H), 2.75˜2.83 (m, 2H), 2.42˜2.50 (m, 1H), 1.69˜1.75 (m, 2H), 1.47 (s, 9H), 1.29˜1.37 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:25][O:26][CH:27]([F:29])[F:28])[C:4]([NH:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].Cl.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][CH:27]([F:28])[O:26][CH2:25][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)[C:4]([NH:6][C@@H:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5]
Reactant: N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCOCC1)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of benzyl (2S)-2-[[(2S)-2-amino-3-(difluoromethoxy)propanoyl]amino]-3-phenyl-propanoate hydrochloride (1.65 g, 3.84 mmol), 2-morpholinoacetic acid hydrochloride (768 mg, 4.23 mmol) and HOBt hydrate (648 mg, 4.23 mmol) in DCM (20 mL) was added EDC hydrochloride (811 mg, 4.23 mmol). The resulting mixture was cooled to 0° C. and treated with DIPEA (0.736 mL, 4.23 mmoL), dropwise, warmed to room temperature and stirred overnight. The mixture was diluted with DCM (30 mL) and washed with saturated sodium bicarbonate (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then chromatographed on silica gel eluting with 0%-100% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the compound of Formula XVII(a) (1.54 g, 77%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.72 (m, 1H), 7.35-6.90 (m, 10H), 6.12 (t, J=74 Hz, 1H), 5.14-5.04 (m, 2H), 4.81-4.75 (m, 1H), 4.65-4.55 (m, 1H), 4.26-4.20 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.50 (m, 4H), 3.15-2.90 (m, 4H), 2.45-2.35 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O1CCOCC1.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([C:6]3[CH:25]=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:3]=[CH:4][C:5]=3[N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:8])[CH2:14][CH2:13]2)=[C:16]([F:24])[CH:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(N)ccc3N3CCOCC3)CC2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(NS(C)(=O)=O)ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 1-{4-[4-(5-Amino-2-morpholin-4-yl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (50 mg, 0.12 mmol) and triethylamine (33 ul, 0.234 mmol) in dioxane (1.5 ml) was added a solution of methanesulfonyl chloride (15 mg, 0.13 mmol) in dioxane (0.5 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred in water. The yellow solid was filtered, washed with water and dissolved in CH2Cl2. The solution was dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel eluent: Heptane/ethyl acetate 0%-100% (5 minutes) to provide the title compound (35 mg, 59%) as a yellow solid MS (m/e): 505.3 (M+H, 100%)
Reaction SMILES: I[C:2]1[CH:3]=[N:4][O:5][C:6]=1[CH3:7].[Cl:8][C:9]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:10]=1[NH2:11]>COCCOC.O.CCOC(C)=O>[Cl:8][C:9]1[CH:15]=[C:14]([C:2]2[CH:3]=[N:4][O:5][C:6]=2[CH3:7])[CH:13]=[CH:12][C:10]=1[NH2:11]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: Cc1oncc1I
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1oncc1-c1ccc(N)c(Cl)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 44 %

Procedure:
Prepared according to Method B (Preparation 83) using 4-iodo-5-methylisoxazole and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in DME/H2O 1/1 (1.4 mL). The reaction mixture was stirred at 80° C. for 7 hours before being diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified using Biotage silica gel column chromatography eluting with Cyclohexane/EtOAc 99/1 to 80/20 to give the title product as a colourless oil (36 mg, 44%). 1H NMR (500 MHz, CDCl3): δ 2.54 (s, 3H), 4.16 (br s, 2H), 6.83 (d, J=8.2 Hz, 1H), 7.09 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 8.28 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH2:21])=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O>C1(C)C=CC=CC=1.ClCCl>[Cl:22][CH2:23][C:24]1[N:21]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[O:20][CH:26]=1
Reactant: O=C(CCl)CCl
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc2c(-c3nc(CCl)co3)cn(CC3CCCCC3)c12
Yield: 81.1 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid amide (500 mg, 1.75 mmol) in toluene (4 ml) was added 1,3-dichloroacetone (333 mg, 2.62 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 30 minutes. The resulting black solution was diluted with dichloromethane (50 ml) and washed with 5% aqueous sodium carbonate solution (5×20 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown oil was purified by flash column chromatography using 5% (v/v) acetone in petroleum ether 40-60 to give 3-(4-chloromethyl-oxazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (510 mg, 1.42 mmol) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[N:40][NH2:41])=[CH:35][CH:34]=1>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:41][N:40]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:43])[F:42])=[CH:38][CH:37]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: NN=Cc1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4,6-Dichloro-N-(3-trifluoromethyl-4-fluorophenyl)-1,3,5-triazine-2-amine (XVII) (2.0 g, 6.2 mmol) was dissolved in dioxane (40 mL). Diisopropylethylamine (1.6 mL, 9.32 mmol) was added followed by [4-(trifluoromethoxy)benzylidene]hydrazine (XX) (1.3 g, 6.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue diluted with ethyl ether (25 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to a yellow powder. This powder was washed with acetonitrile to give {4-chloro-6-[N′-(4-trifluoromethoxybenzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)-amine (XXI) as a white solid; (2.1 g, 67% yield): m.p. 109-111° C.; 1H NMR (CDCl3): δ 8.9, (bs, 1H); 8.5 (bs, 1H); 7.95 (s, 1H); 7.75 (bs, 2H); 7.45 (bs, 1H); 7.24 (m, 4H); ESI/MS 494 (M+H).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(O)(=O)=O)=CC=1>>[CH3:6][C:7]1[C:8]([CH:18]2[CH2:19][CH2:20][CH2:15][CH2:25]2)=[C:9]([OH:14])[C:10]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:11]([CH3:13])[CH:12]=1
Reactant: C1=CCCC1
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)c(C2CCCC2)c(O)c1C1CCCC1
Yield: 656.4 %

Procedure:
700 g of cyclopentene are added dropwise to 610 g of 3,5-dimethylphenol and 60 g of p-toluene sulphonic acid at 120° C. The catalyst is removed by washing with sodium hydrogen carbonate solution. The mixture is fractionated. At boiling point 141° C (0.6 mm Hg) 591 g of 3,5-dimethyl-2,6-dicyclopentylphenol are obtained. Melting point: 69° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]1([CH2:22][N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)[CH:31]=[C:30]([CH3:45])[CH:29]=3)[CH:25]=[N:24]2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl>[CH3:45][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][C:9]3([OH:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH:27]=2)[CH:33]=[C:32]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=2)[CH:31]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3(O)CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
TFA (0.1 mL 1.298 mmol) was added to the solution of racemic tert-butyl 4-hydroxy-4-((4-(3-methyl-5-((4-(trifluoromethyl) pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (120 mg, 0.23 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 2 days. Additional TFA (0.2 mL) was added and the mixture was stirred for 16 hours. The mixture was purified on reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford 4-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol. MS ESI calc'd for C21H24F3N6O [M+H]+433. found 433. 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=4.8, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.31 (s, 1H), 7.06 (s, 1H), 7.05 (d, J=4.2, 1H), 4.20 (s, 2H), 3.31-3.17 (m, 4H), 2.33 (s, 3H), 1.94-1.78 (m, 2H), 1.73-1.65 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)C=C(S(C)(=O)=O)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1CCN.CC[N:34]([CH:38]([CH3:40])C)[CH:35]([CH3:37])C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:38]([NH:34][CH2:35][CH2:37][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[CH:40]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NCCc1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(NCCc2cccc(Cl)c2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-chlorophenyl)ethanamine (300 mg, 1.94 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (120 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.87 (t, J=7.2 Hz, 2H), 3.52-3.54 (m, 2H), 5.39 (s, 2H),), 6.05 (s, 2H), 6.29 (s, 1H), 6.97 (s, 1H), 7.25-7.44 (m, 5H), 7.71 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[N:23]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:22]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1>CN(C=O)C.C(OCC)(=O)C>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:2][CH3:3])[CH:28]=4)[N:23]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:22]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: CCI
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(O)ccc2n1Cc1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC)ccc2n1Cc1cccc(OC)c1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
Iodoethane (468 mg, 3.0 mmol) and powdered potassium carbonate (138 mg, 1.0 mmol) was added to a solution of ethyl 3-[4-(cyclopropylmethoxy)phenyl]-5-hydroxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 66, 120 mg, 0.25 mmol) in DMF (5 mL). The mixture was heated (50° C.) for 16 h and then cooled. The resulting mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC using 4:1 ethyl acetate/hexane as the eluant, to afford 52 mg (42%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.42 (d, 1 H), 7.37 (d, 2 H), 7.19 (t, 1 H), 6.92-7.01 (m 4 H), 6.74-6.77 (m, 1 H), 6.64-6.68 (m, 2 H), 5.80 (s, 2 H), 4.13 (q, 2 H), 3.88-3.98 (m, 4 H), 3.69 (s, 3 H), 1.34-1.45 (m, 4 H), 1.04 (t, 3 H), 0.56-0.66 (m, 2 H), 0.34-0.44 (m, 2 H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([CH3:38])[C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:26]1[C:25]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:24][C:23]([C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([CH3:38])[C:30]=2[CH3:39])=[CH:22][CH:21]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(-c2ccc(OC)c(Br)c2)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)c(C)c1C
Temperature: 97.5 °C
Yield: 21.9 %

Procedure:
4-aminosulfonylbenzene boronic acid (0.54 g, 2.68 mmol) and potassium carbonate (0.67 g, 4.86 mmol) were added to the solution of methyl 5-(3-bromo-4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-4, 0.9 g, 2.43 mmol) in a mixture of toluene:ethanol (5:20 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0) palladium (0.14 g, 0.12 mmol) was added to the reaction mixture under nitrogen atmosphere and tube was sealed. The reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound 9e (0.23 g, 21.2%).