Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C[CH:32]=[CH:33][CH2:34][NH2:35].[OH-].[Na+].[CH3:38]N(C=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][N:35]([CH2:34][CH:33]=[CH2:32])[CH3:38])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Reactant: CC=CCN
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(C)CCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Yield: 67 %

Procedure:
A solution of 30 mg (0.066 mmol) of 6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester and 0.1 ml (0.10 mmol) N-methylallylamine in 0.5 ml of DMF was stirred at 80° C. for 2 hours. The mixture was poured into 0.5 M aqueous NaOH and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with EtOAc/MeOH/NEt3 10:1:0.1 gave 19 mg (67%) of 5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as a light brown oil, MS: 427 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CCN1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(CC)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 22.6 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), 1-ethyl-1,4-diazepane (0.120 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The mixture was diluted with a saturated solution of sodium hydrogencarbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-30%) in dichloromethane furnished 0.030 g (21%) of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.O[CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>>[C:49]([O:48][C:46]([CH2:45][CH2:44][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)CCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with tert-butyl 3-hydroxypropanoate to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-tert-butoxycarbonyl-ethyl ester. MS (ES+) m/z calcd. for C38H42Cl2F2N3O6: [(M+H)+]: 744. found: 744.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.O1CCOCC1>[C:1]([CH2:2][CH2:3][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:4]
Reactant: C=CC#N
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Solvent: C1COCCO1
Solvent: O
Product: N#CCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 80 °C

Procedure:
1.6 ml of Triton B at 40% in water and 4 ml of acrylonitrile are mixed in 40 ml of dioxane, and 9.44 g of benzyl 2-indolecarboxylate are then added with stirring. The mixture is heated at 80° C. for 24 hours and is then poured into 500 ml of ice-cold water. The precipitate formed is filtered off, taken up in EtOAc and this solution is then dried over Na2SO4 and concentrated to give 10.1 g of the expected compound, which crystallizes: m.p.=98-100° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][N:42]([CH3:47])[C:43](=[O:46])[CH:44]=[CH2:45]>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([CH2:45][CH2:44][C:43]([N:42]([CH3:47])[CH3:41])=[O:46])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C=CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(CCC(=O)N(C)C)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol) and N,N-dimethyl-acrylamide (28 mg, 0.283 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. N,N-dimethylacrylamide (28 mg, 0.283 mmol) was added every 2 hour three times. The organic solvent was removed. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28-30% solution) (80:20:0.05) mixture as the mobile phase to give the title compound. 1H NMR (DMSO, d6) δ 1.39 (m, 1H), 1.51 (m, 1H), 1.70 (m, 1H), 1.81 (m, 1H), 1.98 (m, 2H), 2.48 (m, 2H), 2.58 (m, 2H), 2.76 (m, 1H), 2.81 (s, 3H), 2.91 (m, 1H), 2.99 (s, 3H), 3.91 (s, 3H), 3.99 (m, 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.18 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.60 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.16 (d, 1H), 8.59 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a): MH+=654.1, Rt=2.55 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[C:15]([Sn](CCCC)(CCCC)CCCC)=[C:14]([CH3:29])[O:13][N:12]=1>CN(C=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>[Br:1][C:2]1[C:3]([C:15]2[C:11]([CH3:10])=[N:12][O:13][C:14]=2[CH3:29])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)noc1C
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1nc(Cl)ncc1Br
Temperature: 70 °C
Reaction time: 16.5 h
Yield: 73.1 %

Procedure:
To a degassed with argon solution of 5-bromo-2,4-dichloropyrimidine (228 mg, 1.0 mmol) and 3,5-dimethyl-4-(tributylstannyl)isoxazole (772 mg, 2.0 mmol) in anhydrous DMF (2 mL), was added Pd(PPh3)2Cl2 (35 mg, 1.04 mmol). The mixture was stirred at 70° C. for 16.5 h. DMF was evaporated. The resulting orange oil was purified on ISCO (hexane/ethyl acetate gradient, 5-25%) to give the title compound (211 mg, 73.0%). 1HNMR (CDCl3): 8.81 (s, 1H), 2.44 (s, 3H), 2.30 (s, 3H). MS (ESI) m/z: Found: 288.0 (M++1), 290.0 (M++3), Calc. 286.9 (M+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[CH2:12](Br)[CH3:13].[Li].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18].[OH-].[Na+]>O1CCCC1.CO>[C:16]([O:11][C:2]1([CH2:12][CH3:13])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CCBr
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Yield: 29 %

Procedure:
15 g (0.1 mol) of 2-adamantanone obtained in Example 3 was dissolved in 50 ml of tetrahydrofuran, and 12 g (0.11 mol) of ethyl bromide was added to the resulting solution. 0.1 g of metal lithium was added to the solution each time until the total amount became 1.3 g (0.19 mol) in such a manner that the temperature of the solution should not exceed 30° C. while they were violently stirred. After the proceeding of a reaction was checked by gas chromatography and it was confirmed visually that the metal lithium disappeared, 10 g (0.1 mol) of methacrylic acid chloride was added to the reaction solution. After it was confirmed by gas chromatography that the reaction proceeded to the full, 3 ml of methanol and 3 ml of a 5% aqueous solution of sodium hydroxide were added to the reaction solution and stirred at room temperature for 1 hour to stop the reaction. Thereafter, the organic solvent was distilled off under reduced pressure, 200 ml of hexane was added, and the obtained solution was washed with a 10% aqueous solution of sodium hydroxide and 20% brine sequentially. Thereafter, hexane was distilled off under reduced pressure to obtain a crude product which was then recrystallized in isopropanol to obtain 7.2 g (0.029 mol, 29%) of 2-ethyl-2-adamantyl methacrylate.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32]1([CH3:42])[C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:38]([C:33]3[C:32]([CH3:42])=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:40])=[O:39])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(SCc2ccc(CCCCO)cc2)c(Cl)c1=O
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 2 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-chloro-5-(4-(4-hydroxybutyl)benzyl)thio-3(2H)-pyridazinone (0.15 g, 0.39 mmol) is added pyridine. Toluenesulfonyl chloride (88.9 mg, 0.42 mmol) is then added to it and the mixture stirred for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using ethyl acetate-hexanes as the eluting mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=O>O.C(O)C.O1CCCC1>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:13])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: NCC(=O)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1c(-c2ccc(Cl)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 85 °C
Yield: 95.3 %

Procedure:
To a stirred suspension of 7 g of 5-fluoroisatin in 58 ml of water was added a solution of 9.36 g of sodium hydroxide in 33 ml of water. The solution was heated to 85° C. and a solution of 12 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride in a mixture of 92 ml of ethanol and 40 ml of tetrahydrofuran and 92 ml of water was added drop-wise over 2 hours. After the addition was complete, the solution was refluxed for an additional 30 minutes and then the ethanol and tetrahydrofuran were removed by distillation. The mixture was cooled to 20° C. and filtered through celite. The filtrate was acidified to pH 4 with acetic acid. The solid was filtered off, washed with water and dried, giving 12.8 g of the desired compound as a yellow solid, mp 241°-243° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[Br-:15].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: [Br-]
Product: c1ccc([P+](Cc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of 4-(benzoxazol-2-yl)benzyl bromide (0.6 g; 2.08 mmol) and triphenylphosphine (0.55 g; 2.08 mmol) in 40 ml benzene is refluxed for 48 hrs. The reaction mixture is cooled, the white solid which precipitates is filtered off, dried under vacuum to get 4-(benzoxazol-2-yl)benzyltriphenylphosphonium bromide and used directly in the next step.
Reaction SMILES: C([N:4](CC=C)[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][CH3:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:6][NH2:7])C=C.[CH:23](=O)[CH3:24].[C:26](O)(=O)[CH3:27].C([BH3-])#N.[Na+].CN1C(=O)CC(=O)N(C)C1=O>CO>[CH2:26]([N:7]([CH2:23][CH3:24])[CH2:6][CH:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][CH2:18][CH3:19])(=[O:15])=[O:16])=[CH:12][CH:13]=1)[NH2:4])[CH3:27]
Reactant: CC(=O)O
Reactant: C=CCN(CC=C)C(CN)c1ccc(S(=O)(=O)CCC)cc1
Reactant: CC=O
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCS(=O)(=O)c1ccc(C(N)CN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of N1,N1-diallyl-1-[4-(propylsulphonyl)phenyl]ethane-1,2-diamine (473 mg, 1.47 mmol, prepared as described in Example 47c in methanol (10 mL) was added acetaldehyde (approximately 0.5 mL, approx. 9 mmol), acetic acid (0.42 mL, 7.3 mmol) and finally, sodium cyanoborohydride (203 mg, 3.2 mmol). The mixture was stirred at room temperature, under nitrogen, overnight and then quenched by addition of satd. NaHCO3(aq). Methanol was removed in vacuo, the residue diluted with water and the product extracted into ethyl acetate (×3). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The crude material was dissolved in dichloromethane and to this solution was added 1,3-dimethylbarbituric acid (1.37 g, 8.8 mmol) and palladium (tetrakis)triphenylphosphine (85 mg, 0.07 mmol). The mixture was heated at reflux for 6 h, then cooled and concentrated. The title compound was partially purified using an SCX cartridge (330 mg obtained, 75% yield over two steps, approximate since not pure). m/z (ES+) 282 (M−NH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(CCCBr)c1
Yield: 78.8 %

Procedure:
Compound 23-1 (10.0 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (17.5 g) and N-bromosuccinimide (11.8 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (11.1 g) as a colorless oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1.C1COCC1.O.O>C(OCC)(=O)C>[S:17]1[CH:18]=[C:14]([S:13][C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[C:5]([OH:23])=[O:4])[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: COC(=O)c1cc(C)ccc1Sc1csc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Sc2csc3ccccc23)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
LiOH (480 mg, 20 mmol) is added to 2-(benzo[b]thiophen-3-ylsulfanyl)-5-methyl-benzoic acid methyl ester (630 mg, 2 mmol) in 16 mL mixture of THF/water (3:1). The reaction mixture is refluxed for 2 hours and cooled to room temperature. Water and ethyl acetate is added and the organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].C(N(CC)C(C)C)(C)C>CO.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:32](=[O:33])[NH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3Cl)CC2)c1C
Yield: 4.6 %

Procedure:
A solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 153 mg, 0.485 mmol) in methanol (6.0 mL) was added to neat 1-chloro-2-isocyanatobenzene (81.9 mg, 0.534 mmol) at room temperature under nitrogen. The resulting light brown solution was heated at reflux for 15 hours at which time LCMS analysis indicated the presence of significant starting material. Reflux was continued over the weekend. LCMS analysis indicated little change in the reaction progress. To the reaction mixture was added N,N-diisopropylethylamine (93.2 μL, 0.534 mmol) at room temperature and the reaction mixture was then refluxed again for 24 hours. Significant starting material still remained. The reaction mixture was diluted with water (25 mL) and resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give the crude product as a semi-solid (230 mg). Flash chromatography (40 g ISCO column, eluting with 0-100% ethyl acetate/hexanes and finally 25% MeOH/dichloromethane) provided {4-[1-(2-chloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (10.5 mg, 4.6%) as a viscous oil. MS cald. for C26H27ClFN2O3 [(M+H)+] 469, obsd. 469.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([C:20]([OH:22])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[CH:23]1([NH:26][C:20]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH2:17][CH2:18][CH3:19])=[O:22])[CH2:25][CH2:24]1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC)cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.40 g) obtained in Example 43b) in acetonitrile-DMF (7:2, 9 ml) were successively added cyclopropylamine (0.11 ml), triethylamine (0.22 ml), HOBt (0.24 g) and WSC (0.30 g), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a white powder (0.20 g, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.C12NC(CC1)CC2>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([N:36]3[CH:43]4[CH2:44][CH2:39][CH:40]3[CH2:41][CH2:42]4)=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Agent: C1CC2CCC1N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.9 %

Procedure:
To a stirred solution of (S)-2-[3-(2-tert-butoxycarbonylamino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (2.5 g in 25 mL dry methylene chloride) at 0° C. was added 1-hydroxybenzotriazole (1.0 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.24 g) and the reagents allowed to mix for 1 hour. At this time a solution of 7-aza-bicyclo[2.2.1]heptane hydrochloride (1.44 g) was added followed by 1.5 mL triethylamine and the reaction stirred at room temperature. After 21 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 1:1) to give the title compound (2.6 g).