Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[Cl:18][C:19]1[C:24]([C:4]2([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(c2nccnc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a vial containing 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (408 mg, 1.678 mmol) and 2,3-dichloropyrazine (250 mg, 1.678 mmol) in THF (2.5 mL) at rt under N2 is added dropwise LiHMDS (1.678 mL, 1.678 mmol). The reaction was stirred at rt 16 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated NaCl (10 mL), dried (MgSO4), and concentrated. Purification by ISCO (40 g SiO2, 0-75% EtOAc/Hexane) gives 1-tert-butyl 4-methyl 4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (565 mg, 1.588 mmol, 95% yield) as a clear, colorless oil. [M+Na]=378.0
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cccc3nc(N)nn23)cc1
Temperature: 150 °C

Procedure:
5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2 g, 9.4 mmol), 4-methoxybenzeneboronic acid (1.71 g, 11.26 mmol), potassium phosphate (3.98 g, 18.77 mmol) and tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol) were added to a microwave tube containing a stirrer bar. Dimethylacetamide (12 mL) and water (4 mL) were then added and the reaction was heated to 150° C. for 10 min. The reaction was filtered through silica and washed through with methanol and concentrated under reduced pressure. The crude was suspended in diethyl ether and the solid collected and was used without further purification. Yield: 1.70 g, 71%; LCMS method: 1, RT: 3.43 min, MI: 241 [M+1]. NMR 1H (DMSO): 3.82 (s, 3H), 6.16 (brs, 2H), 6.96 (d, 1H), 7.06 (d, 2H), 7.29 (d, 1H), 7.46 (t, 1H), 7.92 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].N1CCOCC1>>[Br:12][C:13]1[CH:14]=[C:15]([CH:23]2[C:11]3[C:2](=[C:3]4[CH:4]=[CH:5][N:6]=[CH:7][C:8]4=[CH:9][CH:10]=3)[O:1][CH:25]([OH:26])[CH2:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]
Reactant: Oc1cccc2cnccc12
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2cnccc32)cc(Br)c1OC
Yield: 29 %

Procedure:
The title compound was prepared following the procedure in Example 18 from 5-hydroxyisoquinoline (9 mg; 0.062 mmol) and 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (30 mg; 0.11 mmol) using morpholine as a base (10 μl; 0.11 mmol) (yield: 29%). 1H NMR (acetone-d6): 9.16 (s, 1H), 8.50 and 8.49 (d each, J=5.7 Hz; 1H), 7.95 (d, J=6.4 Hz) and 7.94 (d, J=5.9 Hz) (1H), 7.51 (d, J=8.4 Hz) and 7.49 (d, J=7.0 Hz) (1H), 6.98-7.07 (m, 3H), 6.65 (d, J=6.6 Hz) and 6.59 (d, J=3.9 Hz) (1H), 5.91-5.93 (m) and 5.74-5.77 (m) (1H), 4.46-4.54 (overlapping dd, J=6.2, 10.5 Hz; 1H), 3.84, 3.81 and 3.80 (s each, 6H), 2.54 (ddd, J=2.1, 6.4, 13.3 Hz) and 2.19-2.38 (m) (2H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].Cl[C:17]([O:19][CH2:20][CH2:21][Cl:22])=[O:18]>COCCOC.O>[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:17](=[O:18])[O:19][CH2:20][CH2:21][Cl:22])([O-:8])=[O:7]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCCCl
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
135 g of calcium carbonate are added to a solution of 345.3 g of 2-nitroaniline in a mixture of 1020 g of monoethylene glycol dimethyl ether and 150 g of water and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are then added in the course of 3 hours. The mixture is subsequently stirred at the reflux temperature for 1.5 hours, until the reaction is complete, and is cooled to 35° C., and the product is precipitated with water and ice. The product is filtered off, washed with water and dried.
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]4[CH:4]=[C:3]([CH3:25])[C:2]([S:35][CH:32]5[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]5)=[CH:24][C:6]=43)[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(C)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (146 mg, 0.363 mmol), 1-isopropylpiperidine-4-thiol (87 mg, 0.545 mmol), Pd2(dba)3 (17 mg, 5 mol %), XantPhos (21 mg, 10 mol %) and DIPEA (254 μl, 1.45 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 2 h using microwave irradiation. The reaction mixture was then diluted with DCM (80 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM) followed by (C18, gradient 20-55% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (112 mg, 64%). LCMS: RT 2.23 and 2.28 min [M+H]+ 480.9
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a 3 L round bottom flask was added the resultant compound from Example 1E (370.5 g, 1.34 mol) and dichloromethane (2 L). The mixture was cooled to 0° C. in an ice water bath and a solution of N-benzyl piperazine (295.8 g, 1.68 mol) was added dropwise with vigorous stirring over 2 h. After the addition was completed, the mixture was stirred an additional 4 h while at 0° C. The solution was then poured into a separatory funnel containing 2 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 1 kg of silica gel using 3:2 hexane/ethyl acetate as an eluant. Concentration gave 467 g (84%) Of the desired product: 1H NMR (CDCl3) δ7.37-7.12 (m, 10H) , 3.66 (s, 3H) , 3.51 (s, 2H) , 3.42 (dd, 1H) , 3.29-3.13 (m, 5H) , 3.06 (dd, 1H) , 2.96-2.84 (m, 2H) , 2.50-2.42 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].O.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH2:32][CH3:33])=[CH:40][CH:39]=3)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C

Procedure:
{4′-Bromo-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (14.5 g, 30.6 mmol) was dissolved in DME (100 mL) and water (50 mL) along with 2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (9.1 g, 36.5 mmol) and potassium carbonate (10.7 g, 77.4 mmol) under N2 atmosphere. The mixture was purged with N2, and then tetrakis(triphenylphosphine)palladium(0) (0.500 g, 0.43 mmol) was added and the reaction was heated to 80° C. The reaction was monitored by analytical LCMS and when the starting material was consumed, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-35% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:30].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([NH:10][C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([CH3:30])[CH:24]=2)[C:3]([O:2][CH3:1])=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CCCCNCc1ccc(F)c(C)c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 63 h
Yield: 87.5 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.400 g, 1.009 mmol), 4-fluoro-3-methylbenzaldehyde (0.139 g, 1.009 mmol), and triethylamine (0.204 g, 2.018 mmol) in 10 mL of dichloroethane, was added NaBH(OAc)3 (0.299 g, 1.413 mmol). After stirring at room temperature for 63 h, the reaction was quenched with 30 mL of saturated NaHCO3 solution and the reaction mixture was extracted with ethyl acetate (30 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-10% methanol/dichloromethane to give the title compound as brown oil (0.357 g, 87% yield). GC-MS: tR=7.5 min; m/z 404 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[N:3]=1
Reactant: NCC1CC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCC2CC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(cyclopropyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, aminomethylcyclopropane, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:22])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CCOCC>[CH2:15]([C@H:13]([CH2:14][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10])[C:12]([NH:33][C@H:32]([C:34]([OH:36])=[O:35])[CH2:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
A solution of 0.5 g of (S,S)-2,4-dibenzylglutaric anhydride and 0.82 g of O-benzyl-(L)-serine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester in 10 ml of methylene chloride is stirred at room temperature overnight. The solution is diluted with ether, washed with 1N hydrochloric acid, water, dried (Na2S04), filtered and concentrated to give N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-O-benzyl-(L)-serine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester melting at 55°-58°; [α]D =+2.2°.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14](I)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>O.[Cu]>[F:10][C:11]1[CH:19]=[C:15]([C:14]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1)[C:16]([OH:18])=[O:17]
Reactant: Sc1ccccc1
Reactant: O=C(O)c1cc(F)ccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)ccc1Sc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 150 g of potassium hydroxide in 850 ml of water is treated with 47.5 ml of thiophenol at 55° C under a nitrogen atmosphere. The mixture is stirred for 15 minutes and subsequently treated with 1.9 g of copper powder and 207 g of 5-fluoro-2-iodo-benzoic acid. The mixture is heated under reflux for 7 hours, filtered while hot, cooled and acidified with concentrated hydrochloric acid. The precipitated product is filtered off, washed with water and dried. There is obtained 3-fluoro-6-(phenylthio)-benzoic acid which melts at 146°-148° C.
Reaction SMILES: C(S(N1CCC(C2C3C(=C(C(N)=O)C=C(C4SC(CNCC(C)CC)=CC=4)C=3)NC=2)CC1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.[CH3:46][O:47][CH2:48][CH2:49][NH2:50].[BH3-]C#N.[Na+]>>[CH3:46][O:47][CH2:48][CH2:49][NH:50][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1
Reactant: COCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCNCc1ccc(B(O)O)s1
Yield: 61 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 42 mg of crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give impure title compound. The impure title compound was repurified using the HPLC and ammonium hydroxide SPE workup shown in preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide to give 15 mg of the title compound (15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([CH3:50])([CH3:49])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([CH2:40][C:41]([CH3:50])([CH3:49])[C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(N)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(CC(C)(C)C(=O)OC(C)(C)C)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.50 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 24 ml of dichloromethane, 320 mg (2.40 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 364 μl (4.5 mmol) of pyridine and 510 mg (1.80 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate were then added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, and the crude product obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethylacetate 20:1). This gave 462 mg of the target compound (58% of theory).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH2:45][CH2:44][CH3:43]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 7.54-7.57 (m, 2H), 7.43 (d, J=5.0 Hz, 1H), 7.32-7.39 (m, 2H), 6.09-6.11 (m, 1H), 4.79-4.82 (m, 4H), 4.08-4.14 (m, 2H), 3.58-3.68 (m, 2H), 2.39-2.55 (m, 2H), 2.34 (dt, J=19.9, 7.4 Hz, 2H), 1.47-1.62 (m, 2H), 0.88-0.93 (m, 3H); MS (ESI(+)) m/e 391 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[N:38]([CH3:39])[N:37]=[N:36][N:35]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(Cl)Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:40]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][N:35]=2)[CH:22]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Reaction time: 1 h

Procedure:
To a solution of 4-{6-butyl-5-[4-cyclohexyloxy-3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.52 mmol, 308 mg) in DCM (3 mL) was added 4 N HCl in dioxane (1 mL) and the reaction mixture was stirred for 1 h. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The yellow solid was dried overnight under high vacuum to give 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (229.3 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:31][C:32]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:20])=[O:33])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: COc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 151A and (adamantan-1-yl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.02 (m, 2H), 7.75-7.78 (m, 1H), 7.52-7.55 (m, 2H), 7.11-7.14 (m, 2H), 3.85 (s, 3H), 2.05 (s, 2H), 1.94-1.97 (m, 3H), 1.59-1.70 (m, 12H); MS (ESI+) M/Z 444 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: CO
Product: COC(=O)c1ccc(C)cc1F
Reaction time: 48 h

Procedure:
2-Fluoro-4-methylbenzoic acid (30.0 g, 195 mmol) was dissolved in MeOH (600 mL, 10 mol), and 12 M HCl (3.2 mL, 39 mmol) was added. The mixture was heated to reflux and stirred for 48 hours, then cooled and concentrated. The recovered material was dried in vacuo for 24 hours to obtain Intermediate (6a) as a white solid that was used without further purification.