Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)C3)ccc1-2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(N)CC4)C3)ccc1-2
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a suspension of (1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester (225 mg, 0.41 mmol) in MeOH (3.1 mL) was added 4N HCl/dioxan (1.0 mL, 4.1 mmol) and the reaction mixture was stirred for 18 hours. The resulting solid was filtered off and washed with diethyl ether before being partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-8% 2N NH3/MeOH in DCM). The resulting solid was suspended in ether and collected by filtration to give 425 as a white solid (108 mg, 59%). LCMS: RT=7.96 min, [M+H]+=451. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1H, d, J=8.20 Hz), 8.02 (1H, s), 7.20 (1H, dd, J=8.22, 1.81 Hz), 7.05 (1H, s), 5.86-5.78 (1H, m), 4.59 (2H, t, J=9.01 Hz), 4.40 (2H, t, J=5.07 Hz), 4.20 (2H, d, J=7.67 Hz), 3.85 (1H, t, J=7.50 Hz), 3.44 (2H, t, J=5.08 Hz), 2.18 (2H, s), 1.58 (6H, d, J=6.59 Hz), 1.09-1.06 (2H, m), 0.70 (2H, q, J=3.28 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@H:14]([N:22](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@H:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Reaction time: 0.03 h

Procedure:
Dissolve 2-(R)-(2-(R)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (610 mg, 1.2 mmol) in methanol (13 mL). Add 20% palladium hydroxide on carbon (157 mg, 0.19 mmol). Bubble hydrogen gas through the mixture and stir under 1 atmosphere of hydrogen gas overnight. Bubble nitrogen through the mixture for 2 min, filter through a filtering agent, wash with methanol and concentrate to give the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:11][C@H:10]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 99 %

Procedure:
Following method 2, tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1M solution) was reduced yielding tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, (>99%). LCMS (m/z): 423.2 (MH+); LC Rt=3.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:17][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of methyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (3 g) in dry dimethyl-formamide (20 ml) was added potassium carbonate (6.1 g) followed by benzyl bromide (1.44 ml) and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml), the organic layers were combined and washed with water (2×100 ml), 1M hydrochloric acid (1×100 ml), brine (2×100 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give methyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (2.8 g). δ (360 MHz, DMSO-d6) 3.95 (3H, s, OCH3), 5.48 (2H, s, CH2), 7.35 (1H, d, p-ArH), 7.38 (2H, t, m-ArH), 7.46 (2H, d, o-ArH), 7.59 (1H, s, 3-H), 7.83 (1H, d, 6-H) and 8.11 (1H, d, 8-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:22]([C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=O)=[CH:10][C:9]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[C:22]([C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)[C:11]2=[CH:10][C:9]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1
Reactant: Cn1ccnc1C(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1ccnc1-c1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 0.094 g (0.18 mmol) of the product of Step B and 0.027 g (0.18 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 2 mL DMF was placed in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. The reaction vessel was sealed, placed in the microwave reactor and heated at 150° C. for 5 min. After the reaction vessel had cooled again to room temperature, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–75% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 504.2 (M+1), 506.0 (M+3); Rt=3.39 min.
Reaction SMILES: [CH:1]1[C:13]2[CH:12](CCCC(O)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[C:1]1([CH2:25][CH2:21][CH2:22][CH2:23][OH:24])[C:13]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCC1c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Agent: B
Product: OCCCCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of the acid material 6 (3.50 g; 13.90 mmol) in 30 mL of THF was cooled to 0° C. and treated with 13.90 mL of a 1.0M solution of borane in THF (13.90 mmol). The resulting mixture was stirred overnight, then quenched with saturated ammonium chloride (30 mL). The product was extracted into ethyl acetate, and the organic phase was washed successively with 3% HCl, saturated sodium bicarbonate, and brine. Removal of the solvent furnished the alcohol (2.90 g; 88%), which crystallized to a waxy solid on standing and did not require further purification. 1H NMR (CDCl3): δ 1.22 (m, 2H); 1.49 (m, 2H); 1.98 (m, 2H); 3.50 (t, 2H); 3.95 (t, 1H); 7.33 (m, 4H); 7.49 (d, 2H, J=7.3); 7.73 (d, 2H, J=7.3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]Cl)[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=C1CC(CCl)CN1Cc1ccccc1
Solvent: CN(C)C=O
Product: CCN(CC)CC1CC(=O)N(Cc2ccccc2)C1

Procedure:
14 g (0.06 mol) of crude 1-benzyl-4-chloromethyl-pyrrolidin-2-one, prepared as in Example 1a), 10 g of diethylamine and 50 ml of dimethylformamide are stirred or shaken for 2 hours at 150° C. in the autoclave. The mixture is evaporated to dryness in vacuo and the residue is taken up in methylene chloride then washed first with water and finally the title compound is extracted twice with 25 ml of 2N HCl. The aqueous phase is removed, made alkaline with sodium hydroxide solution and the organic base is extracted with methylene chloride. The methylene chloride phase is concentrated by evaporation and the residue is distilled in vacuo.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O: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][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27].[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43].O1CCCC1.Cl>N1C=CC=CC=1>[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42]([NH:2][C:3]1[CH:8]=[C:7]([O: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][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27])(=[O:44])=[O:43]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(O)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g of 2-amino-4-hexadecyloxy-5-methylphenol hydrochloride and 18 g of 4-(2-methoxyethoxy)nitrobenzene-3-sulfonyl chloride prepared as described in Step (a) above were added to a mixture of 100 ml of tetrahydrofuran and 10 ml of pyridine and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of 300 ml of ice water and 50 ml of concentrated hydrochloric acid with stirring. The crystals thus-precipitated were recovered with filtration, washed with water, air-dried and recrystallized from 100 ml of acetonitrile. Yield: 35 g. Melting Point: 85.5° to 86° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]([N:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[NH:30][C:29]2=[O:36])[O:4]1.N1C(C)=CC=CC=1C.[C:45]([S:49][S:50][CH2:51][CH:52]([NH:66][C:67](=[O:73])[O:68][CH2:69][CH:70]([CH3:72])[CH3:71])[C:53]([NH:55][CH:56]1[CH2:61][CH2:60][N:59]([P:62](Cl)([Cl:64])=[O:63])[CH2:58][CH2:57]1)=[O:54])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:45]([S:49][S:50][CH2:51][CH:52]([NH:66][C:67](=[O:73])[O:68][CH2:69][CH:70]([CH3:71])[CH3:72])[C:53]([NH:55][CH:56]1[CH2:57][CH2:58][N:59]([P:62]([Cl:64])([O:1][CH2:2][C@H:3]2[O:4][C@@H:5]([N:28]3[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[NH:30][C:29]3=[O:36])[CH2:6][N:7]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:8]2)=[O:63])[CH2:60][CH2:61]1)=[O:54])([CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1cn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(P(=O)(Cl)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](COP(=O)(Cl)N3CCC(NC(=O)C(CSSC(C)(C)C)NC(=O)OCC(C)C)CC3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (moT(Tr)) (5.576 g, 10.98 mmol) in DCM (100 ml) at 0° C., was added lutidine (1.92 ml, 16.47 mmol) and DMAP (669 mg, 5.5 mmol), followed by the addition of the compound from Example 62 (6.13 g, 12.08 mmol). The reaction was left stirring at RT for 18 h. The title compound was obtained after ISCO purification (50% EtAc/Hexane).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11](Br)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([S:26]([N:29]1[C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[NH2:41])(=[O:28])=[O:27])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:23]([S:26]([N:29]1[C:33]2[CH:34]=[C:35]([C:11]3[N:10]=[C:9]([CH3:22])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[NH2:41])(=[O:27])=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Reactant: Cc1nc(Br)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
To a solution of 1-(benzyl)-4-(bromo)-5-(2,4-difluorophenyl)-2-(methyl)-imidazole (1.12 g, 3.08 mmol) in 8 mL DME, add 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (2.62 g, 9.25 mmol). Add sodium carbonate (0.98 g, 9.25 mmol) dissolved in 1 mL of water and trans-dichlorobis(triphenylphosphine) palladium (II) (0.65 g, 0.93 mmol). Heat the mixture to 100° C. with stirring under nitrogen. After 3 hours, cool the solution and filter over a pad of Celite® and sodium sulfate. Purify the residue by radial chromatography eluting with 3% methanol in CH2Cl2 with a gradient to 10% methanol. Perform a second purification by radial chromatography eluting with 4% methanol in CH2Cl2 with a gradient to 6% methanol to yield 390 mg (24%) of the title compound as a yellow solid. MS(ES+): m/z=522.0 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1.[OH:21]S(O)(=O)=O>O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]([NH2:17])=[O:21])=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: N#Cc1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Yield: 86 %

Procedure:
A solution of 144 (100 mg, 0.35 mmol) in a mixture of cone. H2SO4 (1.8 mL) and water (0.2 mL) was heated at 65° C. for 1 h, then cooled and neutralized with saturated aqueous KHCO3. The precipitate was collected, washed with water, and dissolved in warm EtOAc. The solution was filtered through a column on silica gel and then concentrated and diluted with iPr2O to give 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-7 carboxamide (145) (92 mg, 86%) as a red solid: mp (EtOAc/iPr2O)>300° C.; 1H NMR [(CD3)2SO] δ 8.61 (d, J=1.3 Hz, 1H), 8.09, 7.39 (2 br s, 2H), 7.95 (dd, J=8.8, 1.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.66 (s, 1H), 6.54 (s, 1H), 426-4.18 (m, 1H), 3.91 (dd, J=11.0, 3.8 Hz, 1H), 3.86 (td, J=9.9, 2.3 Hz, 1H), 3.78 (dd, J=11.0, 8.5 Hz, 1H), 3.72 (dd, J=10.3, 2.6 Hz, 1H). Anal. (C14H12ClN3O3) C, H, N.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
2-Methyl-6-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (333 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (399 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.5, 281.2 1H NMR (400 MHz, CD3OD) d ppm 2.42 (s, 3H) 2.45 (td, J=5.74, 1.04 Hz, 2H) 2.56 (td, J=5.80, 1.15 Hz, 2H) 3.51-3.58 (m, 2H) 3.61-3.67 (m, 2H) 6.44 (s, 1H) 6.64 (d, J=8.24 Hz, 1H) 6.91-6.97 (m, 2H) 6.99 (d, J=7.19 Hz, 1H) 7.07 (d, J=7.65 Hz, 1H) 7.29-7.40 (m, 2H) 7.63-7.74 (m, 1H) 7.90 (ddd, J=8.38, 2.53, 1.39 Hz, 1H) 8.16 (dd, J=4.79, 1.40 Hz, 1H) 8.58 (d, J=2.31 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COc1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(CO)ccc1OC
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzylalcohol (0.80 g, 7.79 mmol.), allyl bromide (0.45 ml, 5.9 mmol.), acetonitrile (20 ml), and potassium carbonate (1.08 g, 7.8 mmol.) was reluxed for 18 hours, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to give the product as a yellow oil (1.14 g, 57%). 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 1H), 3.79 (s, 3H), 4.52-4.54 (m, 4H), 5.2 (d, 1H, J=12 Hz), 5.32 (d, 1H, J=17.25 Hz), 6.0 (m, 1H), 6.77 (s, 2H), 6.85 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 56.3, 65.6, 70.3, 111.2, 113.6, 118.4, 119.7, 133.7, 134.4, 147.8, 149.9.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:32]([N:31]([CH3:30])[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6])[CH3:33]
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: CCNC
Product: CCN(C)c1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)ccn1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and N-methylethylamine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.25 (m, 2 H), 7.84 (m, 1H), 7.56 (m, 2H), 7.45 (d, 1H), 7.17 (s, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 4.31 (t, 2 H), 3.62 (m, 4H), 3.06 (s, 3H), 2.88 (t, 2H), 2.57 (t, 4H), 1.10 (t, 3H). MS: 435.2 (M+1).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[O:39][CH3:40]
Reactant: COc1ccc(N)cc1O
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (50 mg, 0.3593 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 74% yield (0.115 g, 0.1965 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1.[BH4-].[Na+]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:10][CH2:9][CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Cc1cn(CCCN)c(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cn(CCCNC(C)c2ccc(Cl)cc2)c(-c2ccccc2)n1

Procedure:
A mixture of 3-(4-methyl-2-phenylimidazol-1-yl)propyl-amine (5.3 g) and 4'-chloroacetophenone (3.8 g) was heated at 120°-125° C. for 7 hours. On cooling, the oil was dissolved in absolute alcohol (70 ml) and, after the addition of sodium borohydride (7.0 g), the mixture was boiled under reflux for 16 hours. Work-up as described in Example 3 gave an oil which was distilled at 185°-205° C. (0.06 mmHg). The main fraction was redistilled to give N-[1-(4-chlorophenyl)ethyl]-3-(4-methyl-2-phenyl-imidazol-1-yl)propylamine, b.p. 205° C. (0.04 mmHg). Glc indicated the presence of 14% of N-[1-(4-chlorophenyl)-ethyl]-3(5-methyl-2-phenylimidazol-1-yl)propylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:22][N:23]=[C:24]=[S:25]>C(O)C>[CH3:22][NH:23][C:24]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[CH:14]=1)=[O:19])=[S:25]
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NNC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2c1
Yield: 93.7 %

Procedure:
A mixture of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide (0.60 g, 2.01 mmol), methyl isothiocyanate (97%, 0.21 g, 2.82 mmol) and ethanol (15 mL) was tightly sealed in a vial, and the microwave was irradiated at 100° C. for 30 min. After cooling, the precipitate was collected by filtration, and washed with ethanol to give the title compound (0.70 g, yield 94%) as colorless crystals.