Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br.[CH3:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CS(C)=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH3:16]
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccccc2n1Cc1cccc(Br)c1
Reaction time: 4 h

Procedure:
First 1.23 g (11 mmol) of potassium-tert-butoxide and after 45 minutes 2.62 g (10.5 mmol) of 3-bromo-benzylbromide are added to a solution of 1.32 g (10 mmol) of 2-methyl-benzimidazole in 10 ml of absolute dimethylsulphoxide and the reaction mixture is stirred for 4 hours. The mixture is then diluted with ethyl acetate, washed 3× with 14% NaCl solution, dried, concentrated and purified by flash chromatography (silica gel; petroleum ether/ethyl acetate=9:1 to ethyl acetate).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@H:19]([N:21]([C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])[CH:22]([CH3:24])[CH3:23])[C@@H:18]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:25](=[O:26])[N:21]([C@@H:19]2[C@@H:18]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:17][N:16]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:20]2)[CH:22]([CH3:23])[CH3:24])=[CH:29][CH:30]=1
Reactant: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of [(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester the title compound was prepared from 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-isopropyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester through cleavage of the protecting group with TFA. The title compound was obtained as off-white foam. MS m/e: 488.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.O[N:11]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][NH2:11])[CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: NOCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a solution of 2-morpholinoethanol (5 g, 38 mmol) in CH2Cl2 (250 mL) was added 2-hydroxyisoindolin-1,3-dione (9.3 g, 57 mmol) and triphenylphosphine (15 g, 57 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (11 ml, 57 mmol) was slowly added drop wise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (50% EtOAc-Hexane). The resultant clear oily compound was dissolved in CH2Cl2 (50 ml). Hydrazine hydrate (5.8 mL, 76 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear oil of O-(2-morpholinoethyl)hydroxylamine (3.5 g, 24 mmol). [M+H] calc'd for C6H14N2O2, 147. found, 147.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[C:28]([C:29]3[O:30][C:31](=[CH2:34])[CH2:32][N:33]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:35])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]([CH3:19])[C:17](=[O:20])[O:16][CH2:15][CH2:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.Cl.O1CCOCC1>C(#N)C>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[C:28]([C:29]3[O:30][C:31]([CH3:34])=[CH:32][N:33]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:35])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]([CH3:19])[C:17](=[O:20])[O:16][CH2:15][CH2:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: C=C1CN=C(c2cccc(F)c2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)O1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1cnc(-c2cccc(F)c2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)o1
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of 2-{5-chloro-4-[2-fluoro-6-(5-methylene-4,5-dihydro-oxazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (80 mg) in acetonitrile (10 mL) was added 4N HCl/dioxane (0.3 mL). The mixture was stirred for 16 hours, concentrated, and triturated with ethyl ether to provide 66 mg of 2-{5-chloro-4-[2-fluoro-6-(5-methyl-oxazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as an HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.22 (s, 1H), 7.94 (d, 1H), 7.58 (dd, 1H), 7.42 (t, 1H), 7.22-7.10 (m, 3H), 7.95 (s, 1H), 4.40 (t, 2H), 3.35 (s, 3H), 2.85 (t, 2H), 2.40 (s, 3H); MS (m/e) 495 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[CH:16]1([NH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)C1CCNCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 4-cyclohexylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (21.11 g, 68 mmol) in dioxane (250 mL) is treated with a 4M HCl solution in dioxane (51 ml, 204 mmol) at 0° C. for 1 h. The reaction mixture is stirred at 50° C. for 4 h. The resulting suspension is cooled down to RT and the product filtered, washed with cold dioxane (50 mL) and dried under HV. The subtitle compound (16.64 g, 99%) is obtained as a white powder; LC-MS A: tR=0.46 min; [M+H]+=211.20.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:13]=1)=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH3:3].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:13]=1)=[N:8][C:9]([NH:12][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=2)[CH2:2][CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCCc1nc2nc(N)ccc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2nc(NC(=O)C(C)C)ccc2[nH]1

Procedure:
2.62 g (15 mMol) of 2-n-propyl-5-amino-imidazo[4,5-b]pyridine are suspended in 100 ml of absolute methylene chloride and 3.16 g (30 mMol) of isobutyric acid chloride are added, with stirring and cooling with ice. Then, at -5° C., a solution of 3.03 g (30 mMol) of triethylamine in 5 ml of methylene chloride is added dropwise. After one hour at ambient temperature the reaction mixture is combined with 100 ml of 2N hydrochloric acid and the mixture is stirred for a further hour. Then the solution is poured onto ice water and mixed with saturated sodium hydrogen carbonate solution. The aqueous phase is extracted 3 times with 100 ml of ethyl acetate, the combined organic phases are then washed with saline solution, dried over sodium sulphate and concentrated by evaporation. The crude product is taken up in methylene chloride and purified over a silica gel column (particle size 0.063-0.2 mm), using as eluant methylene chloride to begin with, followed by mixtures of methylene chloride and ethanol of increasing polarity (25:1 and 19:1). The unified fractions are concentrated by evaporation and the residue is triturated with petroleum ether/ether=1:1 and suction filtered.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C@@H:41]2[CH2:44][C@H:43]([OH:45])[CH2:42]2)=[C:37]([O:46][CH3:47])[CH:36]=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[OH-].[Na+]>O1CCCC1>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C@H:41]2[CH2:42][C@H:43]([OH:45])[CH2:44]2)=[C:37]([O:46][CH3:47])[CH:36]=1
Reactant: COc1cc(Br)ccc1[C@H]1C[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of triphenylphosphine (142.7 mg, 0.546 mmol) in tetrahydrofuran (2 mL) was added diisopropyl azodicarboxylate (11 mg, 0.54 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was cooled to −50° C. and cis-3-(4-bromo-2-methoxyphenyl)cyclobutanol (100 mg, 0.389 mmol) in tetrahydrofuran (0.5 mL) was added. The reaction was stirred for 20 min, followed by addition of solid 4-nitrobenzoic acid (90.97 mg, 0.546 mmol), the resulting mixture was warmed to room temperature and allowed to stir at room temperature for 15 hr. The reaction was then cooled to 0° C., to which was added sodium hydroxide (5 mL, 0.5 M in methanol). After 40 min the reaction was quenched with sat. ammonium chloride (5 mL), and diluted with ethyl acetate (15 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness to give the title compound (78 mg, 54%) as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11]>C1C=CC=CC=1.O1CCCC1.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>[Br:8][C:4]1[CH:3]=[C:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[Mg]Br
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)Cc1cccc(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 1-iodo-3-bromobenzene (6.0 g, 21.2 mmol) in 100 mL of benzene at room temperature under argon, 1.2 g (1.06 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and to this mixture a 2M solution in tetrahydrofuran of isobutyl magnesium bromide (10.6 mL) was added dropwise over 15 minutes. The mixture was stirred 2 hours, diluted with 100 mL of water, the organic layer was separated and the aqueous layer was extracted with 2×100 mL of ether. The combined organic extracts were dried and evaporated to provide 4.3 g of a colorless liquid, which upon distillation in vacuo provided 1.95 g (43%) of compound A as a colorless liquid; b.p. 124-125° C. (15-20 mm).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[NH2:26][C:24]([C:23]1[CH:22]=[C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])[S:20][C:19]=1[NH:18][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1)=[O:25]
Reactant: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COC(=O)c1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1

Procedure:
The title compound was prepared as described in Example 1 using methyl 1-[(6-bromopyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (357 mg, 1.20 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (375 mg, 1.20 mmol) as starting materials.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])=[CH:11][C:9]=2[CH:10]=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[S:34](=[O:36])(=[O:35])[CH2:33][CH2:32][C:31]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:54])[CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:42][CH:41]=3)=[O:38])=[CH:30][C:29]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:54][N:47]([CH2:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([C:31]2[CH2:32][CH2:33][S:34](=[O:36])(=[O:35])[C:28]3[CH:27]=[CH:26][C:25]([C:6]4[O:7][C:8]5[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])=[CH:11][C:9]=5[CH:10]=4)=[CH:55][C:29]=3[CH:30]=2)=[O:38])=[CH:41][CH:42]=1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CCCOCCOc1ccc2oc(OB([O-])[O-])cc2c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc2oc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)cc2c1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 5-propoxyethoxy-benzofuran-2-yl borate (198 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(5-propoxyethoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 140) (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O.CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2cc(Cl)cc(Cl)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1c1cc(Cl)cc(Cl)c1
Yield: 90.5 %

Procedure:
Dimethyl 2-(3,5-dichlorophenyl)piperidine-1,4-dicarboxylate (5.3 g, 15.31 mmol) was dissolved in acetonitrile (51.7 mL). Water (1.033 mL), lithium bromide (10.64 g, 122.47 mmol) and triethylamine (8.53 mL, 61.24 mmol) were added and the resulting mixture was heated under reflux for 2.5 h. It was diluted with water and MTBE. The aqueous layer was extracted with water. The combined aqueous layers were acidified with 3 M HCl, extracted with MTBE, dried over MgSO4, filtered and evaporated to give 2-(3,5-dichlorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.60 g, 90%) as a greenish foam. MS m/z 330 (M−H)−
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:4][N:5](CC(C)C)[CH2:6][C:7]1[CH:12]=CC=C[CH:8]=1.Cl>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:2][CH:3]([C@@H:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:4][NH:5][CH2:6][CH:7]([CH3:12])[CH3:8]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CN(Cc1ccccc1)CC(C)C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)CNCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
1-[(RS)-1-Hydroxy-2-[(2-methylpropyl)(phenylmethyl)amino]ethyl]-3-methylbutylcarbamic acid, 1,1-dimethylethyl ester, hydrochloride (1.67 g, 4.25 mmol) was dissolved in methanol (50 ml) and hydrochloric acid (1N, 4.25 ml) was added. The solution was stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.36 g) for two hours. It was filtered through Hyflo and concentrated to dryness in vacuo (1.31 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[CH3:40])([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:33][C:32]=1[CH3:40])([CH3:29])[CH3:28]
Reactant: Cc1cc(B(O)O)ccc1OC(C)C
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-isopropoxy-3-methylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.34 g, 94%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C1COCC1.C(Cl)Cl>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:15](=[O:17])[CH3:16])[CH2:3]1
Reactant: OC1CCCNC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCCC(O)C1
Temperature: -78 °C
Yield: 83.1 %

Procedure:
3-Hydroxypiperidine (3.0 g, 30.0 mmol) was dissolved in THF (40 mL) and methylene chloride (40 mL). Triethylamine (7.47 g, 74.0 mmol) was added. The mixture was cooled to −78° C. and acetyl chloride (2.35 g, 30.0 mmol) was added drop wise. The mixture was warmed to r.t. and stirred under nitrogen for 1 about an hour. The solvents were removed under reduced pressure, and the resulting oil was purified using silica chromatography (2% methanol in ethyl acetate) to afford the title compound (3.57 g, 83%) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:39]=[CH:38][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:25]1([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([CH:42]=[CH:41][CH:40]=4)[C:1]([NH2:2])=[O:3])[C:14]([C:15]([F:17])([F:16])[F:18])=[CH:13][N:12]=3)=[CH:39][CH:38]=2)[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cccc(CCc2nc(Nc3ccc(CN4CCNCC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
tert-Butyl 4-(4-((4-(3-carbamoylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I146) (65 mg, 0.11 mmol) was dissolved in DCM (10 mL) then TFA (1 mL) was added and the resulting mixture stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between 10% sodium hydroxide (25 mL) and ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL) then the combined ethyl acetate phases washed with brine, dried over sodium sulfate and evaporated. The residue was washed with toluene (2×2 mL) and DCM (2×0.5 mL) to give the title compound (37) (22 mg, 40% yield) as a white solid; 1H NMR (400 MHz, de-DMSO) δ 10.19 (s, 1H), 8.66 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.74-7.64 (m, 3H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.23 (d, J=8.2 Hz, 2H), 3.38 (s, 2H), 3.17-3.02 (m, 4H), 2.75-2.61 (m, 4H), 2.29 (s, 4H). LCMS Method C: rt 4.52 min; m/z 485.1 [M+H]+; m/z 483.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[O:4][N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:37]([C:36]4[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:26]5[CH:25]=[C:24]6[C:29](=[CH:28][CH:27]=5)[NH:21][CH:22]=[CH:23]6)=[O:32])=[CH:40][CH:39]=4)[NH:18][C:11]=3[CH:10]=2)[O:4][N:3]=1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Product: Cc1noc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc6[nH]ccc6c5)cc4)[nH]c3c2)n1

Procedure:
Compound 659 was prepared according to the procedure similar to that described in Scheme III from 1-(3-methyl-1,2,4-oxadiazol-5-yl)methoxy-3,4-dinitrobenzene and 4-(5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C26H20N6O3: 465.16; found: 464.98.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1>CCO.[Pd]>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1C=Cc2ccccc2C1c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of ethyl 1-(4-(trifluoromethyl)phenyl)isoquinoline-2(1H)-carboxylate (2.0 g, 5.7 mmol) in EtOH (20 mL) was stirred with 10% Pd/C (0.6 g, 5.7 mmol) under a hydrogen atmosphere at RT for 2 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to provide the title compound as colorless oil. MS (ESI pos. ion) m/z: 350 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:36]2[C:35](=[O:37])[N:34]([CH3:38])[C:33](=[O:39])[N:32]([CH3:40])[C:31]=2[N:30]=[CH:29]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH3:40][N:32]1[C:31]2[N:30]=[C:29]3[N:28]([C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[C:33]1=[O:39])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]31
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2CC2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(nc3n2-c2ccccc2CC2CNCCN32)n(C)c1=O
Reaction time: 0.5 h

Procedure:
2-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl)benzyl]piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.055 g) was dissolved in trifluoroacetic acid (0.5 ml), the mixture was stirred for 30 minutes, and the solvent was removed by distillation at reduced pressure. The residue was dissolved in N,N-dimethylformamide, and N-chlorosuccinimide (0.025 g) was added to the solution. The mixture was stirred at room temperature for 14 hours, 1,8-diazabicyclo-[5,4,0]-7-undecene (0.050 ml) was added thereto, and was further stirred for 1 hour. After removing the solvent by distillation at reduced pressure, the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 0.0079 g of the title compound.