Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][N:3]1[C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[CH2:9][CH2:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:6]3[C:4]1=[O:5]
Reactant: CONC(=O)N1c2ccccc2CCC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COn1c(=O)n2c3c(cccc31)CCC2c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of N-methoxy-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxamide (0.869 g, 3.08 mmol) in chloroform (23.2 mL) at 0° C. was with treated with [I,I-bis(trifluoroacetoxy)iodo]benzene (1.59 g, 3.69 mmol) in four portions over 20 min. The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 30 min. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate solution (40 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.576 g, 66%) as a racemic mixture. LCMS calculated for C17H17N2O2 (M+H)+: m/z=281.1. found: 281.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11]Cl>>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: COCCOCCl
Reactant: c1c[nH]nn1
Product: COCCOCn1ccnn1

Procedure:
The title compound was prepared from 1,2,3-triazole and 2-methoxyethoxymethyl chloride, by a similar method to that of Preparation 40, as a colourless oil which was characterised by 1H-NMR spectroscopy (300 MHz, CDCl3): δ=3.31(s,3H), 3.46(m,2H), 3.62(m,2H), 5.77(s,2H), 7.73(s,1H),7.75(s,1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C-:10]#[N:11].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[N:11])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C#N)nc(Cl)n1
Yield: 22.5 %

Procedure:
24.5 g of 2,4-dichloro-6-methylpyrimidine and 9.8 g of potassium cyanide were dissolved in 150 ml of CH3CN and refluxed for 8 days. The solvent was evaporated, the residue was dissolved in 150 ml of ethyl acetate and extracted twice with 50 ml H2O. The organic layer was dried over Na2SO4, the solvent was evaporated and the residue was purified on silica gel using a 4:1 mixture of benzene and methyl tert.butyl ether as eluent to give 5.2 g (24.8%) of 2-chloro-4-cyano-6-methyl pyrimidine of m.p. 57° C.
Reaction SMILES: [Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([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)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a stirred solution of benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (2.8 g, 0.0059 mol) in methylene chloride (12 ml) were added dimethylamine hydrochloride (1.44 g, 0.0176 mol), formaldehyde (0.61 g, 0.020 mol) and t-butyl alcohol (100 ml), the mixture was heated to reflux at 95° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography with a solvent gradient of 10 to 25% ethyl acetate/hexane to afford benzhydryl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (2.0 g, 69.5%) as a white foam.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:22])([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)[CH:14]=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:26])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)([CH3:22])[CH2:14][N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC1(F)CNC1
Reactant: Cc1nc(C(C)(C=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(C)(CN2CC(F)(F)C2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
To a solution of 5-cyclopropyl-N-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 128a, 0.075 g, 188 μmol) in dichloromethane (1 ml) was added 3,3-difluoroazetidine hydrochloride (26.8 mg, 207 μmol) and triethylamine (21.0 mg, 28.9 μl, 207 μmol). The reaction mixture was sonicated to completely dissolve solids and reaction mixture was then stirred at room temperature for 30 minutes, followed by addition of sodium triacetoxyborohydride (59.9 mg, 282 μmol). The reaction mixture was then stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (9.2 mg, 10%). MS (ESI, m/z): 476.5 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([NH:12][C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:15]=4[N:14]=3)[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:23]([C:21]1[CH:20]=[CH:19][C:16]2[N:17]([CH3:18])[C:13]([NH:12][C:10]3[S:11][C:7]4[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:27]=[CH:26][C:8]=4[N:9]=3)=[N:14][C:15]=2[CH:22]=1)=[O:24]
Reactant: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (33 mg) was prepared by following General Procedure F using 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benz-imidazole-5-carboxylic acid (40 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 461; and 1H NMR (DMSO-d6, 400 MHz): δ 8.36 (t, 1H), 8.14 (br, 1H), 7.94 (d, 2H), 7.66 (d, 1H), 7.59 (d, 1H), 7.44 (d, 1H), 7.25 (d, 1H), 3.61 (s, 3H), 3.45 (m, 4H), 3.27 (s, 3H), and 2.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10](Br)[CH:11]=1)[NH:8][CH:7]=[CH:6]2.C(OC(=O)C=CC1C=CC=CN=1)C.[CH2:26]([O:28][C:29](=[O:49])[CH:30]=[C:31](C1C=CC=C2C=1C(C#N)=CN2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH:30]=[C:31]([C:10]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:9]=1[NH:8][CH:7]=[CH:6]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:27]
Reactant: COc1cc(Br)c2[nH]ccc2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Agent: CCOC(=O)C=Cc1ccccn1
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2cc[nH]c12

Procedure:
3-(5-Methoxy-1H-indol-7-yl)-3-phenyl-acrylic acid ethyl ester CLXXIX was prepared from 5-methoxy-7-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]([F:21])([F:20])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:17])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-(isopropyl-methyl-amino)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M276) (0.44 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (252 mg, 72%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1.C(O)=O>O>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCN(c2cccc(C3OCCO3)n2)CC1
Solvent: O
Solvent: O=CO
Product: CC(C)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 60 °C
Yield: 81.8 %

Procedure:
A mixture of 1-[6-(1,3-dioxolan-2-yl)pyridin-2-yl]-4-isopropylpiperazine (8, 0.31 g, 1.1 mmol), formic acid (2.50 g, 50 mmol) and water (0.5 mL) was heated at 60° C. for 5 h. After this time, the mixture was concentrated and the residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to afford the title compound (0.21 g, 82%) as a yellow oil; ESI MS m/z 234 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][O:16]C(=O)C)[C:6]=2[N:7]=1>[NH4+].[OH-]>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OCCCCn1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: [NH4+]
Agent: [OH-]
Product: Nc1nc2c(sc(=O)n2CCCCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-Amino-3-(4-acetoxybutyl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (230 mg, 771 izmol) and conc. NH4OH (10 mL) was placed in a pressure bottle and stirred at ambient temperature for 18 h. The solution was evaporated under vacuum and the residual solid was stirred with H2O (10 mL). The solid was collected by filtration, crystallized from a MeOH:H2O mixture and dried in vacuum at 80° C. for 3 d; 120 mg (468 μmol, 61%), mp 258°-260° C. Ir (KBr): ν 3305 and 3189 (OH, NH, NH2), and 1650 broad (C=O, C=N) cm-1. Uv, λ max (nm), (ε×10-3): pH 1, 302 (9.83),250 (8.47), 222 (30.3); H2O, 302 (9.70), 250 (8.37), 222 (30.4); pH 11, 292 (7.71), 250 (7.47), 224 (9.62). 1H nmr (DMSO-d6): δ1.35-1.42 (m, 2 H, CH2), 1.60-1.68 (m, 2 H, CH2), 3.38 (m, 2 H, OCH2), 3.76 (t, 2 H, NCH2), 4.40 (t, 1 H, OH), 6.89 (brs, 2 H, NH2), and 11.06 (br s, 1 H, NH). Anal. Calc'd for C9H12N4O3S (256.28): C, 42.18; H, 4.72; N, 21.86. Found: 42.05; H, 4.67; N, 21.72.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[O:4][N:3]=1.[CH3:17]OC(OC)N(C)C.[CH3:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH2:26]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH:17]=[C:7]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:30][CH:29]=1)[CH3:25]
Reactant: Cc1cc(CC(=O)Nc2ccccc2)on1
Reactant: CCOc1ccc(N)cc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOc1ccc(NC=C(C(=O)Nc2ccccc2)c2cc(C)no2)cc1

Procedure:
A solution of 3-methyl-N-phenyl-5-isoxazoleacetamide (10 mmol) and N,N-dimethyl-formamide dimethyl acetal (1.80 g, 2.0 mL, 15 mmol) in 20 mL of toluene was stirred at 80° C. for 24 h. The reaction was conc. to dryness. The residue was dissolved in 5 mL of toluene and treated with neat p-phenetidine (10 mmol). After heating at reflux for 2 h, the reaction was evaporated to dryness. Purification by column chromatography (2% MeOH/CH2Cl2) afforded the title compound as a light yellow solid, mp 114-115° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]4)[CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:3][CH:2]=1.CN(C(O[N:37]1N=N[C:39]2C=CC=N[C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)C>CN(C)C=O.C(OCC)(=O)C>[CH2:38]([NH:37][C:26]([C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:9](=[O:10])[NH:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:16]=1)=[CH:25][CH:24]=2)=[O:28])[CH3:39]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NCc1ccncc1)c1cc(-c2ccc3[nH]c(C(=O)O)cc3c2)ccn1
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cc2cc(-c3ccnc(C(=O)NCc4ccncc4)c3)ccc2[nH]1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a mixture of 5-{2-[(Pyridin-4-ylmethyl)-carbamoyl]-pyridin-4-yl}-1H-indole-2-carboxylic acid (40 mg, 0.1 mmol) in N,N dimethylformamide (1 ml) is added HATU (49 mg, 0.13 mmol) followed by N,N-diisopropylethylamine (0.025 ml. 0.12 mmol). The reaction is stirred for ½ hour. The ethylamine (64 uL, 0.13 mmol) is added and the reaction mixture stirred for 24 hours. The reaction mixture is diluted with ethyl acetate and is washed 3× with water, 1× with sodium carbonate and 1× with brine. The organic layer dried over Na2SO4, filtered, and is evaporated in vacuo. The crude product is purified by reverse phase HPLC to give the title compound 8 mg, 19%, LC/MS ESI m/z (M+H)+=400.4.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][CH:15]([N+:22]([O-:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[N+:22]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC1CCC(c1ccccc1)[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])C(CCC1CCCN1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 230 mg (0.688 mmol) 2-(3-nitro-3-phenyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 3.5 ml methanol were added 860 ul (0.3.44 mmol) of a 4M HCl solution in dioxane. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo. The residue was dissolved in water. The mixture was basified with a saturated sodium bicarbonate solution and extracted 6 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 96 mg (y: 59.6%) of the title compound as a white solid. MS (m/e): 235.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.O1CCC[CH2:19]1.[H-].[Na+].IC>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:19])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: CN(C)C(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.24g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 6ml of dry tetrahydrofuran (THF) was added 0.045g of 60% sodium hydride (in mineral oil) at room temperature, followed by stirring for 30 minutes. A solution of 0.16g of iodomethane in lml of THF was added to the reaction mixture and allowed to react for 3 days. After adding 0.lml of acetic acid, the mixture was filtered to remove insoluble materials and the filtrate was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to obtain 0.17g of 1-(6-chloro-3-pyridylmethyl)-1,3,3-trimethyl-2-nitroguanidine (Compound No. 14) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH2:20]O)[N:17]([CH2:22][C:23]4[S:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)[C:16](=[O:32])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:33]([N:35](CC)[CH2:36]C)C.CS(Cl)(=O)=O.CNC>O1CCOCC1.ClCCl>[CH3:33][N:35]([CH2:20][C:18]1[N:17]([CH2:22][C:23]2[S:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[C:16](=[O:32])[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[N:19]=1)[CH3:36]
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(CO)n1Cc1ccc(C(F)(F)F)s1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)Cc1nc(N2CCN(c3ccc(F)cc3)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 9.9 %

Procedure:
To a dichloromethane solution (1.5 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-6-(hydroxymethyl)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (10.0 mg, 21.3 μmol) synthesized in Synthesis Example 458b, triethylamine (6.0 μL, 42.6 μmol) and methanesulfonyl chloride (2.4 μL, 32.0 μmol) were added and the resultant mixture was stirred at room temperature for 1 hour and 30 minutes. The volume of the reaction solution was divided in half. To one of the divided reaction solution, dimethylamine (20 μL) and 1,4-dioxane (4.0 mL) were added and the resultant mixture was stirred at 90° C. for 20 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.05 mg, yield: 20%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]3[C:11]([CH2:12][C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:34])[CH3:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=43)=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]3[C:11]([C:12](=[CH:45][C:38]4[C:39]5[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=5)[NH:36][CH:37]=4)[C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:33])[CH3:34])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=43)=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Yield: 57.3 %

Procedure:
Following the procedure described for Example 1(A), Step A, 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (Preparation 12) (244 mg, 0.522 mmol) was condensed over 48 hours with 1H-indole-3-carbaldehyde (105 mg, 0.723 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (EtOAc to 5% MeOH in EtOAc to 10% MeOH in EtOAc) yielded 177.9 mg of 2-[1-(3-hydroxy-phenyl)-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ 8.23 (d, 1H), 7.90 (s, 1H), 6.90-7.63 (m, 16H), 4.95 (m, 1H), 3.68-4.50 (m, 3H), 1.11 (m, 6H); MS 595.3 (M+1), 593.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([OH:12])=[C:4]([O:13][CH3:14])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[O:12][C:9]([CH2:11][OH:20])([CH3:10])[CH2:8][C:6]=2[CH:7]=1
Reactant: C=C(C)Cc1cc(Cl)cc(OC)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Cl)cc2c1OC(C)(CO)C2
Yield: 74.4 %

Procedure:
Treatment of 4-chloro-2-methoxyphenol (15.00 g, 0.10 mol) with sodium hydride (4.4 g, 0.11 mol, 60 wt. %) and 3-chloro-2-methylpropene (12.00 g, 0.12 mol) generally according to the procedure described for Intermediate 13 provided 19.3 g (91%) of 4-chloro-2-methoxy-1-[(2-methylprop-2-enyl)oxy]benzene as a colorless oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 afforded 15.5 g (78%) of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol as a pale yellow oil. Treatment of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol (10.00 g, 0.047 mol) with 3-chloroperoxybenzoic acid (20.00 g, 0.089 mol, 77%) followed by potassium carbonate (20.00 g, 0.145 mol) generally according to the Procedure described for Intermediate 9 provided 8.00 g (74%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a light yellow oil. Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (10.8 g, 0.047 mol) with p-toluenesulfonyl chloride (13.5 g, 0.071 mol), diisopropylethylamine (12.15 g, 0.094 mol), and 4-(dimethylamino)pyridine (0.35 g, 2.83 mmol) generally according to the procedure described for Intermediate 45 gave 13.8 g (76%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 113-115° C.; Anal. calcd. for C18H19ClO5S: C, 56.47; H, 5.00. Found: C, 55.82; H, 4.94.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=O)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[ClH:24].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Product: CCCCc1ccc(-c2nc(C3CCN(C(C)C)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-butylbenzoyl chloride.
Reaction SMILES: C([N:8]1[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:14]=2)[CH2:9]1)(OC(C)(C)C)=O.[ClH:29]>CCOC(C)=O>[ClH:29].[C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)[C@@H]1Cc2ccc(-c3ccccc3)cc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1Cc2ccc(-c3ccccc3)cc2CN1

Procedure:
The Boc-amine from Step 3 (48 mg) was deprotected using 75 mL EtOAc saturated with HCl. Removal of the solvent in vacuo gave the title compound as a white solid.