Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38 mg, 28%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH:31]([NH:34][C@@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)([CH3:33])[CH3:32].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]([CH:31]([CH3:33])[CH3:32])[C@@H:35]([CH3:49])[CH2:36][O:37][C:38](=[O:48])[C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@@H](C)COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3ccc([N+](=O)[O-])cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Over a period of about 5 min, a solution of 0.42 g of 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridin-6-yl)benzoyl chloride In 10 ml of acetonitrile is added dropwise to a mixture, cooled with ice/water, of 0.31 g of 4-nitro-benzoic acid (S)-2-isopropylamino-propyl ester hydrochloride and 0.5 g of triethylamine in 10 ml of acetonitrile. The reaction mixture is stirred at RT for about 15 h and then substantially concentrated under reduced pressure, and the highly viscous residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The resin-like residue is purified by silica gel chromatography, and the product fraction is separated off and concentrated. This gives 0.34 g of the the compound as a solid foam.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([C:5]([O:7]CC)=O)=[O:4].[Na:14].[N+:15]([CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:17])=[O:16]>O1CCCC1.C(Cl)Cl>[C:1]([CH:2]1[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:18]([N+:15]([O-:17])=[O:16])[C:5](=[O:7])[C:3]1=[O:4])([O:11][CH2:12][CH3:13])=[O:10].[Na:14]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CCCCCCCCCCCC=C[N+](=O)[O-]
Agent: [Na]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCC1C(C(=O)OCC)C(=O)C(=O)C1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 4 h

Procedure:
A suspension of 90% sodium diethyl oxalacetate (17.77 g., 76.1 mmol) in tetrahydrofuran (75 ml) was treated dropwise over a 15 minute period with a solution of 1-nitro-1-tridecene (17.30 g., 76.1 mmol) in methylene chloride (about 100 ml). After a complete solution was obtained the reaction mixture was heated in an 80°-90° C. oil bath and the solvent allowed to distill through a 10 cm vigreux column until the boiling point of the distillate reached 63° C. (100-120 ml of the solvent had distilled). Heating at reflux was continued, with no further distillations, for four hours and 150 ml of distilled water were added over a 5 minute period. The reaction mixture was allowed to cool to 30° C. and then cooled in an ice bath to 10° C. A precipitate began to form when the internal temperature reached about 35° C. and the mixture was stirred for one hour at 10° C. before the precipitate was collected by filtration. The solid was washed three times with 100 ml of isopropanol and then dried under vacuum over phosphorous pentoxide. About 23 g. of 3-carbethoxy-5-nitro-4-undecyl-1,2-cyclopentanedione, sodium salt, m.p. 166°-169° C. (dec) were obtained.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1.CI>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:1])[C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(OC)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 34.0 ml, 0.0667 mol) was added dropwise to a solution of methyl 4-methoxyphenylacetate (12.0 g, 0.0667 mol) in tetrahydrofuran (150 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (9.5 g, 0.0667 mol) in tetrahydrofuran (20 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexane 1:9, to give methyl 2-(4-methoxyphenyl)propionate (8.8 g) as a colourless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([NH2:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C(Cl)Cl>[C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])(=[S:25])[NH2:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=S
Reaction time: 8 h
Yield: 170.5 %

Procedure:
To a stirred solution Boc-D-prolinamide (2.63 g, 12.3 mmol) in CH2Cl2 (25 mL) at rt was added Lawesson's reagent (2.73 g, 6.75 mmol). The mixture was stirred overnight and concentrated. The oily residue was purified by chromatography on a 40-g silica gel cartridge, eluted with a 0-20% MeOH in CH2Cl2 gradient, to afford (R)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (2.65 g, 94%) as a tan solid. LC-MS Method 1 tR=1.23 min, m/z=231, 173, 131.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].C[CH2:14][N:15](C(C)C)C(C)C.CN>CN(C)C=O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of 4-bromo-3-methylbenzene-1-sulfonyl chloride (500 mg, 1.86 mmol) and DIEA (0.65 mL, 3.7 mmol) in N,N-dimethylformamide (5 mL) was added methylamine as a 2.0 M solution in methanol. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness and was dissolved in dichloromethane (3 mL). The solution was washed with 1 N HCl (2×3 mL) and a saturated solution of NaHCO3 (3 mL). The organics were dried over Na2SO4 and evaporated to dryness to give 4-bromo-N,3-dimethylbenzenesulfonamide (340 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][S:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[C:27]([Cl:31])=[CH:26][N:25]=1
Reactant: Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CS(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of N-(3-aminophenyl)-1-(3-nitrophenyl)methanesulfonamide-hydrogen chloride (0.10 g, 0.29 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was added and stirred again overnight. The reaction was then quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude was purified by column chromatography to give the desired product (0.080 g, 60%). LCMS for C17H13Cl2N5O4S (M+H)+: m/z=453.9, 455.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.[OH-].[Na+]>CC(O)=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]([C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]3)=[CH:38][CH:37]=2)[N:7]=1
Reactant: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cccc(C)c1N(c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2)n1)c1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
A pressure tube was charged with a solution of 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole (50 mg, 0.14 mmol), from Example 155 Step F, 4-(4-methylpiperazin-1-yl)-phenylamine (27 mg, 0.14 mmol) in glacial AcOH (2 mL). The reaction, a dark brown solution, was heated to 100° C. for 18 h. The reaction was cooled to RT then basified by careful addition of 5M NaOH (15 mL). The aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica; CH2Cl2:MeOH; 9:1; containing TEA (0.2%)) to afford a light brown solid. MS m/z=505 (M+H). Calc'd for C30H32N8=504.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:40])([F:39])[C:30]([OH:38])([C:34]([F:37])([F:36])[F:35])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[C:30]([OH:38])([C:29]([F:28])([F:39])[F:40])[C:34]([F:37])([F:36])[F:35])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F) and 3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=473.3 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])C=C.CN(C)[C:21]1[CH:26]=CC=C[CH:22]=1>CCOC(C)=O>[CH2:26]([C:14]1[C:5]([OH:4])=[CH:6][C:7]([C:15]([O:17][CH3:18])=[O:16])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH2:22]
Reactant: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of dimethyl 5-(allyloxy)isophthalate (1.5 g, 5.994 mmol) in N,N-dimethylaniline (15 mL) was heat at 200° C. for 14 hours. After it was cooled to room temperature, the reaction was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried with Na2SO4. The solvent was evaporated under reduced pressure. The desired product was purified via silica gel gradient column chromatography with EtOAc/Hex (10-25%) to afford the title compound (750 mg, yield 70%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.82 (d, J=6.22 Hz, 2 H) 3.92 (d, J=5.84 Hz, 6 H) 5.02-5.11 (m, 1 H) 5.10-5.17 (m, 1 H) 5.81 (s, 1 H) 5.90-6.13 (m, 1 H) 7.70 (d, J=1.70 Hz, 1 H) 8.11 (d, J=1.51 Hz, 1 H); LC-MS (ESI)+m/z=251.00 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Clc1nc2ccccc2s1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3s2)cc1
Yield: 71.5 %

Procedure:
Followed the same procedure as that of step 1 in Example 99 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (293 mg, 1 mmol) and 2-chloro-benzothiazole (169 mg, 1 mmol) to afford the title product (305 mg, 75% yield); LCMS, 100% APCI+, Calcd: 426.50. Found m/z: 427.26 (M+1). 1H NMR (400 MHz, DMSO-d6); δ 1.41 (s, 9H), 1.78-2.13 (m, 4H), 3.24-3.36 (m, 2H), 3.89-4.12 (m, 3H), 7.08 (d, J=9.2 Hz, 2H), 7.31 (t, J=8.4 Hz, 1H), 7.37 (d, J=9.2 Hz, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][CH2:28][S:29]([N:1]([S:29]([CH2:28][Cl:27])(=[O:31])=[O:30])[C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N(S(=O)(=O)CCl)S(=O)(=O)CCl)cc2)cc1

Procedure:
The product from Example 3 (500 mg, 1.45 mmol), chloromethanesulfonyl chloride (0.65 g, 4.36 mmol), and triethylamine (1 mL, 7.19 mmol) were stirred in CH2Cl2 (15 mL) overnight at room temperature. The reaction mixture was then diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (99:1 CH2Cl2:CH3OH, eluant) to provide the title compound as a solid. 1 NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.87 (dd, J=4.7 Hz, 1.3 Hz, 1H), 8.32 (dd, J=8.2 Hz, 1.7 Hz, 1H), 8.14 (d, J=8.5 Hz, 2H), 7.68 –7.77 (m, 3H), 7.38 (d, J=8.8 Hz, 2H), 5.46 (s, 1H), 5.42 (s, 1H), 4.97 (s, 1H), 4.92 (s, 1H), 1.29 (s, 9H).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:24]>O1CCOCC1>[ClH:24].[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COc1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirring solution of (3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (E-1, the first eluting enantiomer from step F, 44 mg, 0.134 mmol) in 1,4-dioxane (3 mL) at 0° C. was added 2 mL (8 mmol) of 4 M HCl in dioxane, and the resulting mixture was stirred at rt for 12 h. The solvent was removed under reduced pressure to afford (3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg) as a white solid which was used without further purification. LCMS (Method J) RT=0.60 min, m/z 228.2 (M+H+). 1H NMR (400 MHz, methanol-d4) δ ppm 7.01-7.19 (m, 3H) 4.88-4.99 (m, 1H) 4.71-4.83 (m, 1H) 3.89 (s, 3H) 3.67-3.78 (m, 1H) 3.40-3.53 (m, 1H) 3.00-3.25 (m, 3H) 2.12-2.27 (m, 1H) 1.93-2.08 (m, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][OH:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][O:18][CH3:25])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CNc2n[nH]cc2CO)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1c[nH]nc1NCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
A solution of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (1.0 g, 3.15 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 1.0 mmol) in methanol (100 mL) was kept at room temperature for 10 min. The reaction mixture was neutralized with 1 N aqueous sodium hydroxide and evaporated under reduced pressure at room temperature. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were washed with water and evaporated under reduced pressure. The residue was taken up in a small volume of methylene chloride and applied to a 4 mm silica gel disk on a Chromatotron. Elution with 525 mL of methylene chloride and 275 mL of 1% methanol/methylene chloride removed some impure material. Continued elution with 75 mL of 1% methanol/methylene chloride afforded 380 mg (36%) of pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-methyoxymethylpurazole, mp. 112-115°.
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:11]=1[F:24])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:24][C:11]1[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[C:9]([OH:25])=[O:8]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reaction time: 0.25 h

Procedure:
To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (52, 2.0 g, mmol) in methanol (30 mL) was added 20% palladium hydroxide on carbon (100 mg). The reaction was stirred under hydrogen at 1 atm for 15 minutes. The reaction was filtered and the filtrate concentrated under vacuum to provide the desired compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=O.[O-:26][C:27]#[N:28].[K+]>CN(C=O)C>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C:4]1[NH:28][C:27](=[O:26])[NH:2][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: N#C[O-]
Reactant: CC(C)c1nnc2ccc(C(N)C(=O)c3ccc(F)cc3F)nn12
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3[nH]c(=O)[nH]c3-c3ccc(F)cc3F)nn12
Temperature: 110 °C
Reaction time: 2 h
Yield: 7.9 %

Procedure:
To a solution of 2-amino-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone hydrochloride (1.18 g, 3.21 mmol) in DMF (10 mL) was added potassium cyanate (0.65 g, 8.0 mmol). The reaction mixture was stirred at about 110° C. for about 2 h. The temperature was reduced to about 80° C. and stirring continued for about 15 h. The solvent was removed under reduced pressure. The crude material was purified by RP-HPLC (Table 1, Method f). The appropriate fractions were combined and solvent removed under reduced pressure. The sample was dissolved in DCM (20 mL) and washed with saturated NaHCO3 solution (3×10 mL). The organic layer was dried over MgSO4, filtered, and solvent removed under reduced pressure to afford a solid that was dried under vacuum to give the title compound (0.09 g, 8%): LC/MS (Table 1, Method a) Rt=2.25 min; MS m/z: 357.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 117 °C
Reaction time: 2 h

Procedure:
7 g of (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and toluene (25 ml) are warmed gently to form a solution. A slight excess of 2-morpholinoethanol (3 g) and toluene (25 ml) are added. The reaction mixture is stirred for half an hour and then heated to reflux at an initial pot temperature of 117° C. (which increases a few degrees during reflux) under a Dean-Stark trap for 80 hours. The reaction mixture is cooled, washed with water (2×15 ml), 10% aqueous sodium bicarbonate (2×15 ml) and finally with water (15 ml). The toluene layer is stripped to a volume of about 20 ml in vacuo, n-hexane (30 ml) is added and the resulting slurry is aged at room temperature for 2 hours. The product is filtered, washed with n-hexane (ca. 10 ml) and dried in vacuo at 60° C. to yield 2-(morpholin-4-yl)ethyl (E)-6 -(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:5]([CH3:18])=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:9]=1.[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>>[ClH:2].[CH3:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]([CH2:3][N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])[C:5]([CH3:18])=[N:6][CH:7]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccc(-c2cnc(C)c(CCl)c2)cc1C
Agent: Cl
Product: Cc1ccc(-c2cnc(C)c(Cn3ccnc3C)c2)cc1C

Procedure:
The title compound, MS: m/e=292.2 (M+H+) was obtained as a beige solid (77% yield) by the reaction of 3-chloromethyl-5-(3,4-dimethyl-phenyl)-2-methyl-pyridine hydrochloride (1:1) with 2-methylimidazole (5 eq.), using sodium hydride (3 eq.) as base followed by formation of the hydrochloride salt.