Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH:58][C:57]3[CH:59]=[CH:60][C:54]([Cl:53])=[CH:55][CH:56]=3)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(C(=O)O)cc2)COC1(C)C
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(c2ccc(C(=O)Nc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 102.5 %

Procedure:
To a stirred suspension of (RS)-4-(4-carboxy-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (80 mg) in THF (4 ml) were added sequentially N-methylmorpholine (0.11 ml), TBTU (160 mg) and 4-chloro-aniline (48 mg) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-[4-(4-chloro-phenylcarbamoyl)-phenyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (110 mg, quant.) as a light yellow solid. MS (ISP): 455.2 ([{37Cl}M+Na]+), 453.2 ([{35Cl}M+Na]+), 433.3 ([{37Cl}M+H]+), 431.4 ([{35Cl}M+H]+), 377.3 ([{37Cl}M+H—C4H8]+), 375.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38].Cl>C1COCC1.O>[C:17]1([S:14]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([C:1](=[O:3])[CH2:2][C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[O:34][CH3:33])=[O:38])=[CH:5]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(=O)CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A solution of 500 mg (1.5 mmol) of 3-acetyl-1-benzenesulfonyl-5-chloroindole in THF (5 ml) was cooled it −78° C. Subsequently, to the reaction mixture was added 1.8 ml (1.8 mmol) of 1M LHMDS in THF. The solution was gradually warmed to 0° C. and cooled again to −78° C. To the solution was added 310 mg (1.8 mmol) of 2-methoxybenzoylchloride. The reaction mixyure was warmed to room temperature. After 30 minutes, the mixture was treated with water and acidified with 6 N hydrochloric acid. The mixture was extracted with ethyl acetate and washed with water, and then dried. The solvent was removed and the obtained residue was chromatographed on silica gel with ethyl acetate-n-hexane as eluent. The fraction of the objective was concentrated to give 160 mg of the titled compound as a foam. Yield: 23%.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](B(O)O)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3].Br[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc2oc(B(O)O)cc2c1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cc1ccc2oc(-c3ccc(C=O)cc3)cc2c1
Yield: 64.2 %

Procedure:
A mixture of 5-isobutylbenzofuran-2-ylboronic acid (70 mg, 0.33 mmol), 4-bromobenzaldehyde (61 mg, 0.33 mmol), triethylamine (1.7 mL, 12.6 mmol) and bis(triphenylphosphine)palladium(II)chloride (12 mg, 0.017 mmol) in ethanol (10 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (59 mg, 65% yield): >99% purity by LCMS, ESI-MS: 279.2 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:37])([F:36])[CH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([OH:35])=O)[N:32]=1.[O:38]1[C:43]2([CH2:48][CH2:47][N:46]([CH2:49][C:50]3[C:51]([F:59])=[C:52]([CH2:56][CH2:57][OH:58])[CH:53]=[CH:54][CH:55]=3)[CH2:45][CH2:44]2)[CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:59][C:51]1[C:52]([CH2:56][CH2:57][OH:58])=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:46]1[CH2:47][CH2:48][C:43]2([O:38][CH2:39][CH2:40][N:41]([C:33]([C:31]3[N:32]=[C:28]([CH2:27][C:26]([F:25])([F:37])[F:36])[S:29][CH:30]=3)=[O:35])[CH2:42]2)[CH2:44][CH2:45]1
Reactant: O=C(O)c1csc(CC(F)(F)F)n1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1csc(CC(F)(F)F)n1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.181 g) was added in one portion to a stirred solution at 0° C. of 2-(2,2,2-trifluoroethyl)thiazole-4-carboxylic acid (example 67, step d) (0.077 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.113 g) and triethylamine (0.153 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.180 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:33][S:34]([O:23][CH:21]([CH3:22])[CH2:20][O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:25]=[CH:24][C:9]=3[CH:10]=2)[CH2:14][CH2:15]1)(=[O:36])=[O:35]
Reactant: CC(O)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)propan-2-ol (555 mg), triethylamine (0.34 mL) and methanesulfonyl chloride (0.19 mL) in THF (5 mL) was stirred at room temperature for 1 hr and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (624 mg).
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.[ClH:43].CON.N1C=CC=CC=1>C1COCC1.C(O)C>[ClH:43].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:20]=[CH:21][C:22]([F:25])=[CH:23][N:24]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-3,5-difluoro-pyridine-2-carboxamide (330 mg, 0.53 mmol) is dissolved in THF (10 mL) and diluted with ethanol (10 mL). O-Methylhydroxylamine hydrochloride (453 mg, 5.32 mmol) and pyridine (430 μL, 5.91 mmol) are added and the reaction is stirred at room temperature over the weekend (70 hrs). The reaction is warmed to 60° C. and stirred for 24 hrs. The mixture is concentrated onto silica gel (˜10 g) and purified via silica gel chromatography using a 0-10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.49 mL, 490 μmol) is added. The solvent is removed in vacuo to give the title compound (159 mg, 54%). ES/MS (m/e): 486(M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=O)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.[NH2:27][OH:28].N1C=CC=CC=1.Cl>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=[N:27][OH:28])=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 150 °C

Procedure:
The semi-crude 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde from step (d) was mixed with hydroxylamine hydrochloride (200 mg, 2.89 mmol) and pyridine (0.3 mL, 3.71 mmol) in dry ethanol (3 mL) and heated at 150° C. for 10 minutes in the microwave. 1 M HCl and CH2Cl2 were added and the phases were separated. The oxime was purified on preparative IIPLC, to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (13 mg, 0.037 mmol).
Reaction SMILES: I.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[C:13]3=[N:20][O:21][C:22]([CH3:23])=[C:12]3[C:11]2=[O:24])[CH2:5]1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:22]1[O:21][N:20]=[C:13]2[C:14]3[C:19](=[N:18][CH:17]=[CH:16][CH:15]=3)[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=4)[CH2:5]3)[C:11](=[O:24])[C:12]=12
Reactant: O=C(O)c1cccnc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3cccnc3)C1)c1ncccc21
Yield: 46.8 %

Procedure:
Combine 5-(3-aminomethyl-cyclohexyl)-3-methyl-5H-2-oxa-1,5,6-triaza-cyclopenta[a]naphthalen-4-one hydroiodide (200 mg, 0.45 mmol) with nicotinic acid (56 mg, 0.45 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (87 mg, 0.45 mmol), 1-hydroxy-7-azabenzo-triazole (62 mg, 0.45 mmol), and N,N-diisopropylethyl amine (0.24 mL, 1.38 mmol), in N,N-dimethylformamide (4 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel using methanol/dichloromethaneto give 88 mg (47%) of the desired amide as a light tan solid. MS(ES): (M+1)+ 418.2, 419.2 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][S:6][C:7]1[NH:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[N:8]=1)[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:31](O)=[O:32]>O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][S:6][C:7]1[NH:11][C:10]2[C:12]([CH:31]=[O:32])=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc2ccc(OC)cc2[nH]1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CCOC(=O)CSc1nc2ccc(OC)c(C=O)c2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
A mixture of (6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethyl ester (14.70 g, 55.26 mmol), hexamethylenetetramine (15.47 g, 100.53 mmol) and trifluoroacetic acid (61 mL) was stirred under argon atmosphere at 120° C. for 1 h. The solution was cooled to room temperature and water (950 mL) was added. This aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4 and evaporated. The title compound (1.432 g, 4.87 mmol, 9%) was obtained by column chromatography in 2 consecutive steps followed by trituration with diethyl ether.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)([CH3:8])([CH3:7])[CH3:6].[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[C:23]=1[C:30]1[CH:31]=[C:32]2[CH:38]=[CH:37][NH:36][C:33]2=[CH:34][N:35]=1)[CH3:21].C(N(CC)C(C)C)(C)C>C(Cl)Cl.C1COCC1>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([C:14]([N:36]2[C:33]3=[CH:34][N:35]=[C:30]([C:23]4[C:22]([CH2:20][CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:28][CH3:29])[CH:31]=[C:32]3[CH:38]=[CH:37]2)=[O:16])[CH:17]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1cccc(CC)c1-c1cc2ccn(C(=O)c3cc(C(C)(C)C)ccc3OC)c2cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
Thionyl chloride (0.3 mL, excess) is added dropwise to a solution of 5-tert-butyl-2-methoxy-benzoic acid (30 mg, 0.2 mmol) in CH2Cl2 (1 mL) at room temperature. The mixture is heated to 60° C. for 1.5 hours. The solvent is removed to dryness. A solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (10 mg, 0.04 mmol) and N,N-diisopropylethylamine (0.2 mL, excess) in THF (1 mL) is added to the residue. The mixture is stirred at room temperature for 16 hours. The solvent is removed to dryness in vacuo. The crude product is purified by PTLC and eluted with 20% EtOAc in hexane to give 12 mg of (5-tert-butyl-2-methoxy-phenyl)-[5-(2,6-diethyl-phenyl)-pyrrolo-[2,3-c]pyridine-1-yl]-methanone. 1H NMR (CDCl3) 7.56-6.98 (m, 9H), 6.60-6.58 (d, 1H), 3.81 (s, 3H), 2.41-2.24 (q, 4H), 1.31 (s, 9H), 1.08-1.00 (t, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[C:31]([Cl:35])[C:32]([NH2:34])=[CH:33][C:21]=3[N:20]=2)[CH:18]=1)=[O:13])[CH3:10].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[C:31]([Cl:35])[C:32]([N:34]=[CH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:33][C:21]=3[N:20]=2)[CH:18]=1)=[O:13])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc3cc(N=Cc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Benzaldehyde (93.0 mg, 0.876 mmol), 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol), THF (3 mL), and 4 Å molecular sieves (0.910 g) were combined and stirred for 18 h at 23° C. Sodium triacetoxyborohydride (0.242 g, 1.14 mmol) was added and stirring was continued for 4 days. The reaction was quenched with saturated aqueous sodium bicarbonate (15 mL) and stirred with dichloromethane (25 mL). This mixture was filtered and the layers were separated. The aqueous layer was extracted with dichlormethane (2×25 mL) and the combined organic layers were washed with brine (20 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.288 g, 78% yield) as a 4:3 mixture of regioisomers. The titled compound was not stable enough to obtain a mass spectrum. 1H NMR (400 MHz, CDCl3): 8.87 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 8.03-7.94 (m, 2H), 7.73 (s, 1H), 7.58-7.48 (m, 3H), 7.39 (s, 1H), 6.12 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.7-3.6 (m, 2H), 3.5-3.4 (m, 2H), 3.32 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:7][C:6]1[O:5][N:4]=[C:3]([CH3:8])[C:2]=1[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: Cc1noc(N)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 95 °C

Procedure:
To 4-bromo-3-methylisoxazol-5-amine (2.63 g, 14.85 mmol), 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (5.7 g, 18.57 mmol, prepared as described in Example 1) and catalyst PdCl2(dppf) (365 mg, 0.45 mmol) in DMF (100 mL) under dry nitrogen was added aqueous sodium carbonate (2.0 M, 18.6 mL, 37 mmol). The reaction was heated to 95° C. for 1 hour and an additional aliquot of PdCl2(dppf) (365 mg, 0.45 mmol) was added and the reaction mixture was heated overnight. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6, then 1/1) to afford tert-butyl 4-[4-(5-amino-3-methylisoxazol-4-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([O:17][C:18]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][C:19]=1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(#N)C.CCOCC>[CH2:10]([O:17][C:18]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:31][C:19]=1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:29])=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCO
Reactant: O=C(Cl)CCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCOC(=O)CCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Yield: 53.6 %

Procedure:
0.66 g (5 mmol) of 1-octanol was dropwise added to the solution of 1.5 g (3.2 mmol) of 6-{N-[2,5-di(benzyloxy)benzoyl]amino}hexanoyl chloride in 15 ml of anhydrous acetonitrile and 0.29 g (3.7 mmol) of anhydrous pyridine during 5 minutes under cooling and stirring at 0°-5° C. The reaction mixture was stirred at room temperature for 10 hours, then evaporated under reduced pressure to dryness at a temperature below 50° C. The residue obtained was dissolved in 40 ml of ether and was successively washed with water, 2% sodium hydroxide solution and finally with water, then dried and evaporated under reduced pressure. The residue was purified on a silicagel column by using ethyl acetate as eluent to give 0.96 g (54%) of the aimed compound, m.p.: 48°-50° C.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.Cl.[CH:15]1([NH:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>C(O)C>[CH:15]1([N:21]2[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: NNC1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnn(C2CCCCC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
3.96 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt was suspended in 40 ml of ethanol, and 3.13 g of cyclohexylhydrazine hydrochloride was added. The mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.01 g of methyl 1-cyclohexyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCCC1.O>[CH2:15]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound (15) can be prepared according to the following procedure. Carbazole (16.7 g, 0.1 mol, commercially available from Aldrich, Milwaukee, Wis.), 1-bromopentane (15.1 g, 0.1 mol, commercially available from Aldrich, Milwaukee, Wis.), and benzyltriethyl ammonium chloride (1.7 g) are dissolved in tetrahydrofuran (60 mL) and a concentrated solution of sodium hydroxide (17 g) in water (17 mL) is added. The mixture is heated at reflux with strong mechanical stirring for 4 hours, then cooled to room temperature and poured into an excess of water. The solid that precipitated is filtered off and the tetrahydrofuran layer is dried (MgSO4) and concentrated to dryness. The combined organic solids were recrystallized to form 9-pentylcarbazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](O)=[O:13])=[C:7]([OH:15])[CH:6]=[CH:5]2.CS(Cl)(=O)=O.[CH3:21][NH2:22].Cl>C1COCC1.C1COCC1.CO.[OH-].[Na+].C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:22][CH3:21])=[O:13])=[C:7]([OH:15])[CH:6]=[CH:5]2
Reactant: O=C(O)c1c(O)ccc2cc(Br)ccc12
Reactant: CN
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(O)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a ice-cooled solution of 6-Bromo-2-hydroxy-1-naphthoic acid (10.0 g) and triethylamine (26.1 mL) in anhydrous THF (300 mL) was added dropwise methanesulfonyl chloride (7.0 mL), and the mixture was stirred for 90 min at room temperature. A solution of methylamine (2M in THF; 60 mL) was added, and the reaction mixture was further stirred for overnight at room temperature. The mixture was acidified with conc. HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 followed by concentrating in vacuo. The residue was washed hexane-ethyl acetate (1:1) to give a light brown powder. The powder was dissolved in THF-MeOH-4N-NaOH (6:1:1, 80 mL), and the mixture was heated at 70° C. for 30 min. After cooling to room temperature, the mixture was acidified with conc. HCl and concentrated in vacuo. The residue was washed with water and AcOEt to give the title compound (4.61 g) as light brown powder.