Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:64]([C:67]1[CH:68]=[C:69]([S:73](Cl)(=[O:75])=[O:74])[CH:70]=[CH:71][CH:72]=1)([O-:66])=[O:65]>O>[N+:64]([C:67]1[CH:68]=[C:69]([S:73]([NH:1][C:2]2[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]3[C:11]=2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]3)(=[O:75])=[O:74])[CH:70]=[CH:71][CH:72]=1)([O-:66])=[O:65]
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a stirred solution of 21.9 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt and 11.4 g of anhydrous sodium carbonate in 280 ml of water is added 24.0 g of m-nitrobenzenesulfonyl chloride. The mixture is stirred at room temperature for 16 hours, then an additional 1.0 g of sodium carbonate and 2.0 g of m-nitrobenzenesulfonyl chloride are added and stirring is continued for 3 hours longer. The mixture is evaporated and the residue is dissolved in 200 ml of water. A copious amount of absolute ethanol is added and the solid formed is collected and washed with ethanol and ether, then is dried to yield 26.1 g of 8-m-nitrobenzenesulfonamido-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](Cl)(Cl)=[O:14].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].N1C=CC=CC=1>O1CCCC1.N.O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH:22][C:13](=[O:14])[NH:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([F:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(=O)CN
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CNC(=O)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 4,5-difluoro-2-nitroaniline (1.07 g, 6.15 mmol) in tetrahydrofuran is cooled to 2° C., treated with phosgene (3.8 mL, 1.93M, 7.33 mmol), stirred at ice-bath temperature for 2 hours, treated with glycine methyl ester hydrochloride (1.02 g, 8.12 mmol), treated with pyridine (1 mL, 12.64 mmol), stirred at room temperature for 3 days, diluted with concentrated ammonia solution and water, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and an ethyl acetate/hexanes (1:3) solution gives the title product as a solid, mp 118.9°-122.9° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].CCN(CC)CC.[Cl:30][C:31]1[CH:32]=[N+:33]([O-:60])[CH:34]=[C:35]([Cl:59])[C:36]=1[CH2:37][C@H:38]([O:49][C:50]([C:52]1[S:53][C:54]([CH:57]=O)=[CH:55][CH:56]=1)=[O:51])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[Cl:59][C:35]1[CH:34]=[N+:33]([O-:60])[CH:32]=[C:31]([Cl:30])[C:36]=1[CH2:37][C@H:38]([O:49][C:50]([C:52]1[S:53][C:54]([CH2:57][NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:5](=[O:6])[O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[CH:55][CH:56]=1)=[O:51])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3cccc(F)c3)s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A suspension of (R)-quinuclidin-3-yl 2-amino-2-(3-fluorophenyl)acetate bis hydrochloride salt (0.176 g, 0.500 mmol) in EtOAc (5 mL) was added with Et3N (0.150 mL, 1.10 mmol). The reaction mixture was stirred at room temperature for 2 h. The precipitate obtained was filtered, washed with EtOAc (˜5 mL) and the solvent was removed in vacuo. This residue was dissolved in CH3CN (5 mL) and to the solution was added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (0.220 g, 0.456 mmol) followed by acetic acid (0.026 mL, 0.456 mmol). The reaction mixture was stirred at room temperature for 20 h. NaBH(OAc)3 (0.265 g, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for a further 24 h. The excess solvent was removed in vacuo and the residue was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO3 solution (20 mL). The organic layer was washed with saturated brine (2×15 mL), separated and filtered through a phase separator cartridge and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound (1:1 mixture of diastereoisomers) as a pale yellow solid (200 mg, 59%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 41 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.78 mmol), and dichlorobis(triphenylphosphine)palladium (II) (65.3 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg, 41%) as a light yellow solid: LC/MS m/e calcd for C27H25FN2O4S2 [M+H]+ 525.64, observed 525.1.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1.COCC(O)C>>[CH3:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(NS(C)(=O)=O)c3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(NS(C)(=O)=O)c5)n4n3)cc2)CC1
Yield: 66.7 %

Procedure:
N-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (125.0 mg, 0.0003567 mol), N,N-Diisopropylethylamine (0.205 mL, 0.00118 mol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.136 g, 0.000713 mol) were dissolved in 1-Methoxy-2-propanol (0.410 mL, 0.00419 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 113.55 mg of N-(3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanesulfonamide as a lyophilized powder. (M+H)=478.1. 1H NMR (400 MHz, DMSO, d6) δ 9.78 (m, 1H), 9.32 (s, 1H), 8.98 (s, 1H), 7.90 (m, 2H), 7.67 (m, 2H), 7.53 (m, 1H), 7.27 (d, 1H, J=7.97 Hz), 7.06 (m, 1H), 6.94 (m, 2H), 6.89 (m, 1H), 3.76 (m, 2H), 3.53 (m, 2H), 3.19 (m, 2H), 3.04 (s, 3H), 2.96 (m, 5H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[CH2:29][CH2:30][CH2:31][Cl:32])=[CH:24][CH:23]=1.C(=O)(O)[O-].[K+]>C1(C)C=CC=CC=1>[ClH:32].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](=[O:33])[CH2:29][CH2:30][CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 45.4 g (0.17 mole) of α,α -diphenyl-4-piperidinemethanol, 49.99 g (0.19 mole) of 4'-bromo-4-chlorobutyrophenone, 30 g (0.3 mole) of potassium bicarbonate and 700 ml of toluene was refluxed for 3 days. Upon cooling to room temperature the mixture was filtered, and the filtrate was cooled and treated with ethereal HCl then ether. The resulting solid was washed with ether, dried, and dissolved in 2 liters of methanol. The solution was treated with charcoal, filtered, and concentrated to a 500 ml volume. Isopropyl alcohol was added to the concentrate and heated to a vapor temperature of 73°C. The concentrate was cooled to room temperature, and a product crystallized which was washed with isopropyl alcohol then ether and recrystallized from isopropyl alcohol-water, and isopropyl alcohol to give the title compound, M.P. 251°-252.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH2:3][CH2:2]1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C>C1COCC1.CO>[O:17]1[CH2:22][CH2:21][CH:20]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10]4)[CH2:5][CH2:6]2)[CH2:19][CH2:18]1
Reactant: O=C1CCOCC1
Reactant: O=C1Cc2cc(C3CCNCC3)ccc2N1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Cc2cc(C3CCN(C4CCOCC4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94.5 %

Procedure:
To a solution of 5-(piperidin-4-yl)indolin-2-one (64.6 mg, 0.299 mmol) in THF (1.5 ml) and MeOH (3 ml) were added dihydro-2H-pyran-4 (3H)-one (0.132 ml, 1.34 mmol), acetic acid (0.170 ml, 29.5 mmol) and NaBH3(CN) (61.6 mg, 0.931 mmol). After stirring at room temperature for 4 days, the reaction mixture was concentrated. The residue was diluted with sat. NaHCO3 aq. and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)indolin-2-one (84.9 mg, 95%).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]1[O:22][C:21]2[CH:20]=[C:19]3[C:15]([CH:16]=[CH:17][NH:18]3)=[CH:14][C:13]=2[O:12]1.[OH-].[Na+]>C(OCC)C.O>[CH2:11]1[O:22][C:21]2[CH:20]=[C:19]3[C:15]([C:16]([CH:4]=[O:5])=[CH:17][NH:18]3)=[CH:14][C:13]=2[O:12]1
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=Cc1c[nH]c2cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69 %

Procedure:
To an ice cold solution of DMF (50 mL, excess) was added POCl3 (8 mL, 85.7 mmol) in a drop wise fashion. After addition the mixture was stirred at 0° C. for 5 min and at room temperature for 45 min. The mixture was cooled to 0° C. and 5,6-methylenedioxy-indole (10 g, 62.1 mmol) was added in portion. After complete addition, the mixture was stirred at 0° C. for 10 min and at room temperature for 20 min and finally at 60° C. for 6 h. The mixture was cooled to room temperature and then to 0° C. followed by the addition of 1N NaOH solution (150 mL). The mixture was stirred at room temperature for 30 min as result a homogenous solution was obtained. To the mixture was added 100 mL of water and stirring was continued at room temperature overnight. The product, 5,6-methylenedioxy-indole-3-carboxaldehyde separated as a solid, which was filtered, washed (water followed by hexane) and dried. The filtrate also provided additional product upon extraction from ethyl acetate (3 times). The combined organic extractions were washed successively with water and brine. After drying over MgSO4, solvent was evaporated. A solid was obtained which was suspended in 100 mL of diethyl ether, sonicated for few minutes and was filtered. The solid was further washed with diethyl ether and was dried. A combined crude yield of 8.08 g (69%) of the 5,6-methylenedioxy-indole-3-carboxaldehyde was obtained which was subjected to N-methylation without further purifications. To a cold (0° C.) solution of 5,6-methylenedioxy-indole-3-carboxaldehyde (see above) (8 g, 42.32 mmol) in dry DMF (40 mL) was added NaH (60% dispersion in mineral oil, 2.1 g, 52.5 mmol). The resulting mixture was stirred at 0° C. for 30 min. Iodomethane (5 mL, 80.3 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0° C. for 15 min and at room temperature for 2 h. The mixture was cooled to 0° C. and was quenched with water. The mixture was further diluted with water (˜700 mL). The product, 5,6-methylenedioxy-1-methyl-indole-3-carboxaldehyde separated as a solid which was filtered, washed (water followed by hexane) and dried to provide 6.2 g (72% yield) of the desired product. MS: 204 (M+H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[CH2:22][C:23]([OH:25])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:38][NH:39][O:40][CH3:41].CN1CCCCC1>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[CH2:22][C:23]([N:39]([O:40][CH3:41])[CH3:38])=[O:25])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CNOC
Reactant: CCOc1cc(C(CC(=O)O)NC(=O)OC(C)(C)C)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CCOc1cc(C(CC(=O)N(C)OC)NC(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of carbonyldiimidazole (0.96 g, 5.9 mmol), 3-(tert-butoxycarbonylamino)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (2.0 g, 5.9 mmol) and methylene chloride (25 mL) was stirred at room temperature for 1 hr and then cooled to 5° C. A solution of N,O-dimethylhydroxyamine hydrochloride (0.86 g, 8.85 mmol) and 1-methylpiperidine (0.87 g, 8.85 mmol) in methylene chloride (10 mL) was added slowly. The mixture was stirred at room temperature for 1 hr and then quenched with water (20 mL). The organic layer was separated and then was washed with 1N citric acid, water, and brine. The organic layer was dried and concentrated in vacuo to give an oil. This oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to afford 3-(tert-butyloxycarbonylamino)-3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-N-methylpropanamide as a white solid (1.76 g, 78%); 1H NMR (CDCl3) δ 6.86-6.78 (m, 3H), 6.07 (b, 1H), 5.01 (m, 1H), 4.10 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.50 (s, 3H), 3.10 (s, 3H), 3.02 (m, 2H), 2.84-2.75 (dd, J=5.3 and 15.2 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 171.81, 155.18, 148.39, 148.19, 134.82, 118.12, 111.41, 111.18, 79.27, 64.26, 61.19, 55.90, 51.25, 37.80, 31.87, 28.33, 14.73.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:42])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:40])(=[O:39])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:41])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:41][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:42])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:39])(=[O:40])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)C(C)C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(C(C)C)S(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(Cl)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
Lithium hydroxide monohydrate (0.034 g, 0.80 mmol) was added to a solution of (6-chloro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (0.115 g, 0.20 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave (6-chloro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid (0.096 g, 86%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 8.01 (d, J=8.31 Hz, 2 H), 7.98 (d, J=8.80 Hz, 1 H), 7.92 (s, 1 H), 7.46-7.52 (m, 3 H), 7.34 (d, J=8.80 Hz, 2 H), 7.00 (s, 1 H), 6.91 (d, J=8.80 Hz, 2 H), 4.43 (s, 2 H), 4.13 (spt, J=6.60 Hz, 1 H), 3.87 (s, 2 H), 3.74 (s, 3 H), 2.08 (s, 3 H), 0.93 (d, J=6.85 Hz, 6 H). MS calcd. for C30H29ClNO2S [(M−H)−] 550, obsd. 550.2.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.[N:17]([C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23])=[N+:18]=[N-:19]>ClCCCl>[N:17]([C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:5][CH2:4][C:3]([F:7])([F:6])[F:2])=[O:23])=[N+:18]=[N-:19]
Reactant: NCC(F)(F)F
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CC(=O)NCC(F)(F)F)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred ice cold solution of 2,2,2-trifluoroethanamine hydrochloride (7.10 g, 1 equiv, 52.4 mmol) and DIEA (18.0 mL, 2.0 equiv, 0.103 mol) in anhydrous DCE (150 mL) was added 3-azido-3-methylbutanoyl chloride (8.46 g, 52.4 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. Water (150 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (2×150 mL) and brine (150 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (10.9 g, 94.4). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.42 (s, 6H), 2.40 (s, 2H), (dq, J=2.4 & 8.8, 2H). LRMS (ESI+) for C7H11F3N4O (224.1); Found: 225 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].CCN(C1C=CC=CC=1)CC.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24](=[O:25])[O:26][CH:27]([CH3:29])[CH3:28])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1c(Cl)cc(N)cc1Cl
Solvent: CCN(CC)c1ccccc1
Solvent: c1ccccc1
Product: COc1c(Cl)cc(NC(=O)OC(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
3,5-Dichloro-4-methoxyaniline (1.8 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3,5-dichloro-4-methoxyphenyl)carbamate (Compound No. 2) (2.4 g) in a yield of 91.8%.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.97 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) were added to a solution of 4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 32-(1); 3 g, 8 mmol) in dichloromethane (30 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (2 g, 49%).
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[NH2:19]>O1CCOCC1>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:6]2[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: CC(C)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(Nc2nccc(C(C)C)n2)c1
Temperature: 120 °C
Yield: 98.1 %

Procedure:
Acetic acid (0.192 mL, 3.35 mmol) was added to commercially available 2-chloro-4-(propan-2-yl)pyrimidine (0.5 g, 3.19 mmol) and 3-bromo-5-methylaniline (0.900 g, 3.19 mmol) suspended in dioxane (6.39 mL). Reaction was heated to 120° C. (bath temp) overnight. Then, the reaction was cooled to room temperature and purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give N-(3-bromo-5-methylphenyl)-4-(propan-2-yl)-pyrimidin-2-amine (959.8 mg, 3.13 mmol, 98%) as a white solid.