Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[NH:9][C:8]2=[O:27])=[N:4][N:3]=[N:2]1.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[Na+].BrCC1CC1>CN(C=O)C>[NH:4]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([CH2:28][CH:29]3[CH2:32][CH2:30]3)[C:8]2=[O:27])=[N:1][N:2]=[N:3]1
Reactant: O=C1N[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)C[C@H]1Cc1nnn[nH]1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@H](Cc2nnn[nH]2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Temperature: 0 °C

Procedure:
A solution of (3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 60, Step A) (65 mg, 0.162 mmol) in DMF (1.6 mL) was cooled to 0° C. and sodium tert-butoxide (31.1 mg, 0.323 mmol) was added. The reaction mixture was stirred at 0° C. for ten minutes before adding (bromomethyl)cyclopropane (78 μL, 0.808 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours, quenched with saturated ammonium chloride and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with 1M LiCl, sat. aq. NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column:
Reaction SMILES: C([BH3-])#N.[Na+].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=O)[CH2:15]2)=[CH:6]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>CO.C(O)(=O)C.O>[N:24]1([C@@H:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:5][CH:6]=3)[CH2:15]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CC(c2c[nH]c3ccccc23)c2ccccc21
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2c(c1)[C@H](c1c[nH]c3ccccc13)C[C@@H]2N1CCCCC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Sodium cyanoborohydride (61 mg; 0.97 mmol ) was added to 3-(1H-indol-3-yl)-indan-1-one (200 mg; 0.81 mmol ) and piperidine (344 mg; 4.05 mmol ) in 3 mL methanol and 0.5 mL acetic acid. The reaction mixture was stirred 30 minutes at 150° C. under microwave irradiation using the Emry Optimizer™ instrument. The reaction mixture was poured into water and made basic with 27% aqueous NaOH. The mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated in vacuo. cis-3-(3-Piperidin-1-yl-indan-1-yl)-1H-indole was obtained after flash chromatography (ethyl acetate, heptane, triethylamine, silica gel).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(N(C(C)C)CC)(C)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
0.200 g (0.93 mmol) of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine, 0.127 g (0.93 mmol) of 3-aminobenzoic acid, and 0.323 mL (1.85 mmol) of diisopropylethylamine are placed in 4 mL of tetrahydrofuran, stirred for 48 hours at ambient temperature and 48 hours at 70° C. Then the reaction mixture is combined with water and acidified with 1N hydrochloric acid. The precipitate formed is suction filtered and dried. 0.110 g of product I (39%) is obtained.
Reaction SMILES: [CH2:1]1OC(O)C[O:3][CH:2]1O.[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1.[C:31]([BH3-])#N.[Na+].C=O>CO.C(O)(=O)C>[OH:3][CH2:2][CH2:1][N:9]([CH3:31])[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])[NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: OC1COC(O)CO1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCO)c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
120 mg (1.0 mmol) of glycolaldehyde dimer and 2 ml of acetic acid were added to 10 ml of a methanol solution containing 473 mg (1.55 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38. Thereafter, 754 mg (12.0 mmol) of sodium cyanoborohydride was further added thereto, and the obtained mixture was then stirred at a room temperature for 3 hours. Thereafter, 0.82 ml (10 mmol) of a 37% formalin aqueous solution was added to the reaction solution, and the obtained mixture was further stirred for 2.5 hours. Thereafter, the reaction solution was concentrated, and a saturated sodium bicarbonate aqueous solution and methylene chloride were then added to the concentrate. An organic layer was separated, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate methanol=15:30:1), so as to obtain 344 mg (61%) of 7-[(2-hydroxyethyl)methylamino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:9][C:10]([C:12]1[C:21]2[C:16](=[C:17]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>ClCCl>[CH2:43]([O:42][C:40]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][S:22]([C:17]2[C:16]3[C:21](=[C:12]([C:10](=[O:11])[NH:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]4[CH3:2])[CH:13]=[CH:14][CH:15]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:31])=[O:30])[CH2:29][CH2:28]1)=[O:41])[CH3:44]
Reactant: CCOC(=O)Cl
Reactant: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCNCC3)cccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)NC4CCCCC4C)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (2-methyl-cyclohexyl)-amide hydrochloride 48 (190 mg, 0.41 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (0.13 g, 0.18 mL, 1.28 mmol) was added followed by ethyl chloroformate (65 mg, 0.068 mL, 0.60 mmol). The reaction was stirred overnight at room temperature. The crude reaction mixture was charged to a flash column. Elution with 99:1 dichloromethane:methanol afforded H-24 (66 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3) (1:1 mixture of diastereomers) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.25 (d, 1H), 7.55 (m, 3H), 6.20 (d, 1H), 5.47 (m, 1H), 5.26 (s, 1H), 4.00 (m, 2H), 3.75 (m, 3H), 3.20 (m, 1H), 2.75 (m, 2H), 2.15 (m, 1H), 1.78 (m 3H), 1.57 (m 2H), 1.38 (m, 2H), 1.05 (m, 10H); LC/MS m/z 502 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br.Br[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCBr
Reactant: NCc1ccc(Cl)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chlorobenzylamine (1.0 mL, 8.2 mmol) was added to a solution of 2-bromo-N,N-diethylethylamine hydrobromide (2.4 g, 9.0 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (16 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated to give N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine as an oil which was used immediately without purification.
Reaction SMILES: [N+:1]([C:4]12[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2)([O-:3])=[O:2].[BH4-].[Na+].CCOCC.[ClH:22]>CO>[ClH:22].[OH:14][CH:13]1[C:4]2([N+:1]([O-:3])=[O:2])[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCCC2CCCCC12[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])C12CCCCC1CCCC2O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8a-nitrodecahydronapthalen-1-one [P. Dampawan and W. W. Zajac Jr. Synthesis, 545, 1983] (1.2 g, 6.1 mmol) in MeOH (10 ml) at 0° C., add sodium borohydride (0.09 g) and warm to RT. After 0.5 hr, add ether and 1N HCl. Dry and concentrate the organic layer. Dissolve the residue in EtOH (50 ml) and add this to Raney Nickel (1.2 g, wet weight) and place under 60 psi of H2 at 55° C. After 24 hr., filter though celite and concentrate to dryness. Dissolve the resultant oil in Et2O add dry HCl in MeOH and collect the title compound as a colorless precipitate EI MS: M+=169.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:18]=[C:19]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)[CH2:20][N:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22]1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26]([CH:23]4[CH2:24][CH2:25][N:21]([CH2:20][C:19](=[O:18])[N:29]5[CH2:30][CH2:31][N:32]([C:35]6[CH:40]=[CH:39][C:38]([C:41]7[N:42]=[CH:43][CH:44]=[CH:45][N:46]=7)=[CH:37][CH:36]=6)[CH2:33][CH2:34]5)[CH2:22]4)=[O:27])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 18 h
Yield: 24.3 %

Procedure:
3-(4-Fluoro-phenyl)-1H-indazol-5-ylamine (0.11 gm, 0.5 mmol) and 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (compound 12 from Step 9, 0.125 gm, 0.25 mmol) were dissolved in 4 ml of DMF. O-(7-azabenzotriazol-1-yl-)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.24 gm, 0.63 mmol) and triethylamine (0.1 ml, 0.76 mmol) were added to the reaction mixture and the mixture stirred for 18 hrs. The reaction mixture was added to bring and extracted with dichloromethane. After drying over magnesium sulfate and filtered, the mixture was evaporated and chromatographed to obtain 36.7 mg of title product.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:12][O:13][CH3:14])[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:14][O:13][CH2:12][C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[CH:11][N:10]=1
Reactant: COCc1nc(C=NNC(=S)SC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCc1ncc2cn[nH]c(=S)n12

Procedure:
A mixture of 62.4 gm. of 3-{[2-(methoxymethyl)-4-imidazolyl]methylene}dithiocarbazic acid methyl ester and 250 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p. 219.5°-223° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([O:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC=C2O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (2.42 mL, 17.1 mmol) in THF (50 mL) at 0° C. is added n-BuLi (6.84 mL, 17.1 mmol, 2.5 M in hexane) dropwise. After 40 min, 6-methoxy-1-tetralone (3.0 g, 17.1 mmol) in THF (15 mL) is added at −78° C. It is then stirred at −78° C. for 2.5 h before chloro trimethylsilane (3.2 mL, 25.7 mmol) is added. It is then warmed to RT and stirred for 18 h. Water is added and the reaction mixture is extracted with EtOAc, washed with sat. NH4Cl solution, dried with MgSO4 and concentrated to give the title compound as a yellow oil. It is used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8]([CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.N1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1S(C1SC(=O)NC1=O)(=O)=O.FC1C=C(C#CCBr)C=C(F)C=1.[Cl-:50].[NH4+]>C1COCC1>[Cl:50][C:25]1[CH:26]=[CH:27][C:22]([C:21]#[C:20][CH2:19][C:11]2([S:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)(=[O:10])=[O:9])[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:23][CH:24]=1
Reactant: Cc1cccc(S(=O)(=O)C2SC(=O)NC2=O)n1
Reactant: O=C1NC(=O)C(S(=O)(=O)c2ccc3ccccc3n2)S1
Reactant: [Cl-]
Agent: Fc1cc(F)cc(C#CCBr)c1
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
N-butyl lithium (2.5 M in hexanes, 2.77 mL, 6.93 mmol) was added to a solution of 5-(6-methyl-pyridine-2-sulfonyl)-thiazolidine-2,4-dione, [(V), from Example 90, 0.92 g, 3.38 mmol] in dry THF (30 mL) at -78° C. under a dry N2 atmosphere over a twenty minute period. A solution of [3-(4-chlorophenyl)-prop-2ynyl]-bromide [(IX), from Example 21, 3.53 g, 15.4 mmol] in dry THF (10 mL) was added over a 20 rain period. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was added to saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (2×300 mL). The extracts were washed with water, dried (brine), concentrated and purified by flash chromatography (gradient 97:3 to 93:7 CH2Cl2 : isopropanol) to provide a sticky solid which triturated with petroleum ether (90 mL): benzene (2 mL) to provide the title compound as a off-white solid (0.55 g, 39%): mp 104°-106° C.: NMR (DMSO, d 6): δ 13.1 (broad s, 1H, N H), 8.10 (t, J=7.8 Hz, 1H, py H), 7.95 (d, J=7.7 Hz, 1H, py H), 7.71 (d, J=7.7 Hz, 1H, py H), 7.45 (d, J=8.8 Hz, 2H, Ar H), 7.35 (d, J=8.7 Hz, 2H, Ar H), 3.86 (d, J=17.4 Hz, 1H, C H2), 3.72 (d, J=17.4 Hz, 1H, C H2), 2.57 (s, 3H, C H3); MS(EI): 420 (MI, 3%), 265 (12%), 263 (38%), 194 (25%), 192 (70%), 149 (40%), 93 (100%); Anal. Calc. for C18H13ClN2O4S2 : C, 51.37; H, 3.11; N, 6.66; Found: C, 50.99; H, 3.05; N, 6.58.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(N3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 342 and morpholine (200 μl) in 1,4-dioxane (1.0 ml) was stirred under nitrogen atmosphere at 100° C. for 2 days. The reaction mixture was cooled to room temperature. After dilution with ethyl acetate (40 ml), the solution was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to yield the title compound (100 mg, 89%) as an oil.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].[CH2:7]([O:23][C:24](Cl)=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CC=CC=1>C(Cl)Cl>[CH2:7]([O:23][C:24]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: C=C(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(CO)COC(=O)OCCCCCCCCCCCCCCCC
Temperature: 22 °C
Reaction time: 2.5 h

Procedure:
2-Methylenepropane-1,3-diol (5.0 g), hexadecyloxycarbonylchloride (17.4 g) and pyridine (4.4 g) was dissolved in methylene chloride (60 ml). The mixture was stirred for 2.5 hours at 22° C. The mixture was purified through a column of silica gel 60 (70-230 mesh, 30 g), eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®-System 500A using a PrepPAK®-500-SILICA cartridge with ether/chloroform/pentane 1:1:3 as eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:25])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([Br:21])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:22]([NH2:24])=[O:23])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]([C:28]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.O1CCCC1>[Br:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[C:3]([CH3:25])=[C:2]([NH:1][CH2:26][C:28]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:29]=5[C:30]([OH:32])=[O:31])[CH:7]=[CH:6][CH:5]=4)=[CH:9][N:10]=[C:11]([C:22](=[O:23])[NH2:24])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(Br)ccc3c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CNc2cccc(-c3cnc(C(N)=O)c4[nH]c5cc(Br)ccc5c34)c2C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 163.1 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxamide (0.184 g, 0.466 mmol), 2-formyl-5-methoxybenzoic acid (0.210 g, 1.164 mmol), sodium triacetoxyborohydride (0.296 g, 1.397 mmol), and acetic acid (0.067 mL, 1.164 mmol) in dichloromethane (14 mL) and tetrahydrofuran (14 mL) was stirred at room temperature for 16 hr. The reaction was quenched with water (30 mL) and the mixture was extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 ml) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the crude desired product (0.425 g, 0.760 mmol, 163% yield) as a beige solid. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:20]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[C:43]([NH:50][CH2:51][CH2:52][NH2:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:32](=[O:34])[NH:53][CH2:52][CH2:51][NH:50][C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[N:23]=3)[CH:20]=2)[CH:12]=[N:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2ccc3nc(N)nn3c2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2ccc3nc(NC(=O)NCCNC(=O)OC(C)(C)C)nn3c2)c1
Temperature: 35 °C

Procedure:
5-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-pyridine-3-sulfonic acid tert-butylamide (50 mg, 0.14 mmol) was suspended in tetrahydrofuran:pyridine (30 mL, 5:1) and cooled to 0° C. Triphosgene (41 mg, 0.14 mmol) was added in one portion and the reaction mixture heated at 35° C. for 2 hours. After this time the solvent was decanted and the resultant semi-solid dissolved in DMF:pyridine (1 mL, 10:1), N-Boc-ethylenediamine (50 mg, 0.32 mmol) was added in one portion and the reaction mixture heated for 18 hours at 65° C. The desired product was isolated as a white solid, directly from the reaction mixture, by preparative HPLC (35 mg)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[CH:4][N:3]=1.[C:14]([C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>O.C1(C)C=CC=CC=1>[C:14]([C@@H:18]1[CH2:19][CH2:20][C@H:21]([NH:24][C:2]2[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[CH:4][N:3]=2)[CH2:22][CH2:23]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)Cc1cc(Cl)ncn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)ncn1

Procedure:
1.80 g (9 mmol) of ethyl (4-chloropyrimidin-6-yl)acetate, 1.40 g (9 mmol) of cis-4-tert-butylcyclohexylamine and 1.82 g (18 mmol) of triethylamine were heated at 80° to 90° C. for 8 hours. After cooling, the mixture was taken up in water/toluene and the organic phase was dried and concentrated. Purification was carried out by chromatography on silica gel (ethyl acetate) to give 1.85 g (64.4% of theory) of a colorless resin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=3[N+:27]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCC[CH2:33]1.COC(OC)OC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=4[N:27]=[CH:33]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1C=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1C=O
Temperature: 25 °C

Procedure:
To a suspension of 0.100 g (0.23 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-4-methoxy-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.46b), 3 mL of saturated ammonium chloride solution and 3 mL of tetrahydrofuran was added 0.100 g of zinc powder. The mixture was stirred room temperature until the organic layer became straw yellow in color (1 hour). The mixture was filtered, and the filtrate was partitioned between 30 mL of saturated ammonium chloride solution and 30 mL of tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a red solid. The solid was stirred at room temperature with 5 mL of glacial acetic acid and 0.05 mL of trimethylorthoformate for 1 hour and then concentrated under reduced pressure. The residue was partitioned between 50 mL of ethyl acetate and 50 ml, of potassium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.053 g of 4-(3-chloro-phenyl)-2-(6-formyl-5-methoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.46a) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][CH2:7][C:8](Br)=[O:9]>ClCl.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[O:9])[CH2:7][Br:6])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CCNCC
Agent: ClCl
Solvent: ClCCl
Product: CCN(CC)C(=O)CBr
Reaction time: 2 h

Procedure:
N,N-diethylbromoacetamide was prepared as follows: Diethylamine (1.54 mL, 14.9 mmol) and TEA (2.49 mL, 17.9 mmol) were dissolved in 75 mL CH2 Cl2, then bromoacetyl bromide (1.29 mL, 14.9 mmol) was added dropwise. After 2 h, the reaction was diluted with CH2Cl2, washed with water (2×), and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 45% EtOAc/hexanes) provided N,N-diethylbromoacetamide as a lachrymatory yellow oil.