Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=[O:7])C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH2:23][CH2:22][CH2:21]2.[OH-].[Na+].C>O>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:25]3[N:24]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc2c(c1)CCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c3c(c1)c(=O)c(C(=O)O)cn3CCC2
Temperature: 220 °C

Procedure:
Diethyl ethoxymethylenemalonate (43.2 g., 0.20 mole) and 6-methoxytetrahydroquinoline (32.6 g., 0.20 mole) are mixed and heated at 125°-130° C. for three hours. Polyphosphoric acid (200 g.) is added, and the mixture is heated gradually to 220° C. then maintained at 220° C. for one hour. The mixture containing the product ester of Formula III is poured into about 600 ml. of water, then made basic with 40 percent sodium hydroxide solution and heated on a steam bath for two hours. The solution is treated with decolorizing charcoal, filtered and acidified. The solid product is isolated by filtration, washed with water and ethanol, then recrystallized from N,N-dimethylformamide to give 6,7-dihydro-9-methoxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 253°-257° C.
Reaction SMILES: [CH2:1]([C@H:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7]C)=[O:6])[CH:2]=[CH2:3].S(=O)(=O)(O)O>P([O-])([O-])([O-])=O>[CH2:1]([C@H:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CC[C@H](CCCCCC)C(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Product: C=CC[C@H](CCCCCC)C(=O)O
Temperature: 40 °C
Reaction time: 77 h
Yield: 65.1 %

Procedure:
In a flask, there were placed 50 ml of 100 mM phosphate buffer (pH 6.0), 6 g of Novozyme CALB L (product of Novozyms) and 2 g of methyl (S)-2-allyloctanoate (60% ee) prepared in Example 31. After tight closure, the flask was shaken at 40° C. for 77 hours. To the mixture was added 0.35 ml of a 55% (w/w) aqueous solution of sulfuric acid, and the resulting mixture was extracted with two 100-ml portions of ethyl acetate. The organic phases were combined, and the product was transferred to 100 ml of a 0.3 M aqueous solution of sodium carbonate. Furthermore, 5 ml of a 55% (w/w) aqueous solution of sulfuric acid was added to that aqueous phase, followed by extraction with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water, and the solvent was then distilled off to give 1.21 g of (S)-2-allyloctanoic acid (99% ee). The organic phase remaining after the transfer of the reaction product to the 100 ml portion of the 0.3 M aqueous solution of sodium carbonate was washed with 50 ml of water, and the solvent was then distilled off to give 0.63 g of methyl (R)-2-allyloctanoate (14% ee).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[NH:37][C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[N:37]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: CC1NC(=O)N(COCc2ccccc2)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)cc2)CC1
Yield: 64.6 %

Procedure:
Using (4-bromophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (320 mg) described in Preparation Example 185 and 3-benzyloxymethyl-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 206 and by the reaction and treatment in the same manner as in Example 536, the title compound (286 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O:13][C:14](=O)[C:15]([C:28]#[N:29])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=1)C>>[C:28]([C:15]1[C:14](=[O:13])[O:9][C:5]2[C:6]([C:16]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=1)=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)#[N:29]
Reactant: CN(C)c1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cc(Br)c(OC)c(OC)c1
Product: COc1cc(-c2c(C#N)c(=O)oc3cc(N(C)C)ccc23)cc(Br)c1OC
Yield: 0.5 %

Procedure:
The title compound was prepared from 3-dimethylaminophenol and 3-(3-bromo-4,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.5% yield. 1H NMR (CDCl3): 7.21-7.18 (m, 2H), 6.98 (d, J=1.8 Hz, 1H), 6.62 (dd, J=2.4, 9 Hz, 1H), 6.53 (d, J=2.7 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.15 (s, 6H).
Reaction SMILES: C[Li].[OH:3][C:4]1[C:9]2[C:10](=[O:24])[C:11]3[C:16]([C:17]4([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.Cl.[C:26](=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[OH:3][C:4]1[C:9]2[C:10]([OH:24])([CH3:26])[C:11]3[C:16]([C:17]4([CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: O=C([O-])[O-]
Reactant: CN1CCC2(CC1)c1ccccc1C(=O)c1c(O)cccc12
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN1CCC2(CC1)c1ccccc1C(C)(O)c1c(O)cccc12
Reaction time: 1 h

Procedure:
Methyl lithium in ether (5 ml., 1.5M) is added dropwise with stirring under nitrogen to 4-hydroxy-1'-methyl-10-oxo-9,10-dihydroanthracene-9-spiro-4'-piperidine (0.7 g.) in dry ether (25 ml.) and the mixture is stirred for 1 hour then diluted with water, acidified (2N hydrochloric acid), basified with sodium carbonate, and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with brine, dried (MgSO4), evaporated, and the residue is recrystallised from ethanol to give 4,10-dihydroxy-1',10-dimethyl-9,10-dihydroanthracene-9-spiro-4'-piperidine, m.p. 151°-154°C.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].[NH2-].[Li+]>CCCCCCC>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:10][CH:7]2[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4][C:3]([CH2:1][CH3:2])([CH3:14])[CH:8]2[CH3:9])=[O:24])=[CH:27][CH:28]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCC
Product: CCC1(C)CC(OC(=O)c2ccc(C(C)(C)C)cc2)C(C)C(C)(CC)N1
Yield: 104.2 %

Procedure:
15.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) and 16.0 g of methyl p-t-butylbenzoate were dissolved in 500 ml of heptane. 1.5 g of lithium amide were then added to the solution and the mixture was refluxed by heating in a flask equipped with a Dean-Stark separator. 1.5 g of methanol were first removed and this was followed by 200 ml of heptane, which distilled off over a period of 3 hours. After cooling the reaction mixture, it was washed with water and dried over magnesium sulphate; the solvent was then removed by evaporation under reduced pressure. The residue was distilled under reduced pressure, giving 28.2 g of the title compound as a colourless liquid (bp 176° - 178° C/0.008 mmHg).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1.O.[NH2:22][NH2:23]>CCO>[NH:22]([C:8]([C:6]1[S:7][C:3]([S:2][CH3:1])=[C:4]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=1)=[NH:9])[NH2:23]
Reactant: CSc1sc(C#N)cc1-c1nc(-c2ccccc2)cs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=N)NN)cc1-c1nc(-c2ccccc2)cs1
Yield: 45 %

Procedure:
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile (100 mg, 0.32 mmol) as prepared in previous step was dissolved in EtOH (10 mL). To this solution hydrazine monohydrate (10 eq) was added and the mixture was heated at reflux for 3 h. The EtOH solution was concentrated down to 1 mL and water (2 mL) was added to this solution. This resulted in the formation of a white solid. The solid was collected by filtration washed with a small amount of water and dried under vacuum to give 50 mg (45%) of hydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methanimine. 1H-NMR (CD3OD/CDCl3; 300 MHz) δ2.69 (s, 3H), 7.35-7.43 (m, 1H), 7.44-7.49 (m, 2H), 7.52 (s, 1H), 7.96-7.99 (m, 2), 8.10 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C15H14N4S3, 347.04 (M+H), found 347.1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>C(O)C>[CH:16]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:6](=[CH:5][CH2:4][CH2:3][N:2]([CH2:23][CH2:22][C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH3:1])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CNCCC=C1c2ccccc2C=Cc2ccccc21
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN(C)CCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 2.61 g of 5-[3-(methylamino)propylidene]-5H-dibenzo[a,d]cycloheptene, 1.20 g of ethyl acrylate, and 13 ml of ethanol was refluxed for 2 hours. After reaction was completed, the solvent was removed by distillation and the residue was purified by column chromatography on aluminum oxide [n-hexane-diethyl ether (1:1)] to give 3.22 g of slightly yellow viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17].[C:23](Cl)(=[O:25])[CH3:24]>O1CCCC1>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17])(=[O:25])[CH3:24]
Reactant: COC(=O)NC(=S)Nc1cc(Sc2ccccc2)ccc1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)NC(=S)Nc1cc(Sc2ccccc2)ccc1NC(C)=O
Reaction time: 2 h

Procedure:
0.7 G. of 2-amino-1-(3-methoxycarbonyl-2-thioureido)-5- phenylthiobenzene, as prepared according to Example XI, is dissolved in 20 ml. tetrahydrofuran and treated with 1.5 ml. of acetyl chloride. The mixture is stripped after two hours and the residue recrystallized from methanol, yielding 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-5-phenylthiobenzene.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][NH:8][C:9](=[O:30])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:27]=[O:28])=[CH:16][C:15]=2[F:29])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:30])[CH:10]([C:14]2[C:15]([F:29])=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][OH:28])=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:31][CH:32]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2CO)cc1F
Yield: 82.2 %

Procedure:
To a suspension of (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-formyl-biphenyl-4-yl)-2-ethoxy-acetamide (500 mg) in EtOH (1.2 ml) at 0° C. was added sodium borohydride (91 mg). After 5 min the ice bath was removed. Ice water was added and the mixture was extracted with EtOAc. The organic phase was dried, filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:2=>EtOAc) to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxymethyl-biphenyl-4-yl)-2-ethoxy-acetamide (413 mg). Colorless solid. MS 437.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=O)[CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([NH2:46])[C:42]([NH2:45])=[CH:43][CH:44]=1>C(Cl)Cl>[NH2:45][C:42]1[CH:43]=[CH:44][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:40][C:41]=1[NH:46][C:11]([CH2:10][CH:8]1[CH2:7][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:5])[CH2:9]1)=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: CON(C)C(=O)C1CC(CC(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(CC(=O)Nc2cc(C(F)(F)F)ccc2N)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
TEA (1.49 ml, 10.70 mmol) was added to a suspension of 2-{3-[methoxy(methyl)carbamoyl]cyclobutyl}acetic acid, EDC.HCl 1.18 g, 6.20 mmol), HOBt.xH2O (0.77 g, 5.69 mmol) in DCM (20 ml) at 0° C. and stirred for 5 min before the addition of 4-(trifluoromethyl)benzene-1,2-diamine (1.04 g, 10.34 mmol). This was stirred for a further 20 min at 0° C. then allowed to warm to RT. The reaction was monitored by LC MS, after 2 hours the reaction mixture was washed with 1N HCl (50 ml) then sat. NaHCO3 (50 ml). This was dried over Na2SO4, filtered and evaporated to dryness. Purification by silica gel column chromatography, eluting with EtOAc gave the desired product (0.83 g, 44%) as a beige solid; MS (ESI+) for C16H20N3O3 m/z 360.00 [M+H]+; HPLC purirty 90% (ret. time, 1.64 min); 1H NMR (500 MHz, MeOD) δH ppm 2.02-2.16 (2H, m), 2.31-2.68 (4H, m), 2.69-2.88 (1H, m), 3.18 (3H, d, J=4.41 Hz), 3.36-3.59 (1H, m), 3.65-3.76 (3H, m), 6.81-6.97 (1H, m), 7.02-7.27 (1H, m), 7.28-7.48 (1H, m).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:17]1N2CN3CN(C2)CN1C3.C(OCC)(=O)C>C(O)(=O)C>[N:1]1[CH:2]=[C:3]2[N:4]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=13)[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17]2
Reactant: CCOC(=O)CSc1cccc2nccn12
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a solution of ethyl (imidazo[1,2-a]pyridin-5-ylthio)acetate (11.8 g) in acetic acid (120 ml) was added hexamethylenetetramine (14.0 g) and the mixture was reacted at 90° C. for 10 hours. After this reaction mixture was allowed to cool, ethyl acetate (360 ml) was added and the mixture was washed with water. The organic layer was neutralized with 30% aqueous solution of sodium hydroxide under ice-cooling and washed again with water. The organic layer was concentrated and n-hexane (100 ml) was added to the crystalline residue, followed by 1 hour of stirring at room temperature. The crystals were collected by filtration and dried to provide the title compound (9.6 g, 78%).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][N:35]=[C:36]=[O:37]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:36]([NH:35][CH3:34])=[O:37])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN=C=O
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CNC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound obtained in Example 26 (28.8 mg) and methyl isocyanate (6.8 mg) were reacted and treated in the same manner as in the method described in Example 31 to obtain the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32].O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([NH:30][C:31](=[O:33])[CH3:32])([CH3:29])[CH3:28])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)N)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(C)(C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.4 %

Procedure:
To a solution of 2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 3, 121 mg, 0.27 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.02 ml, 0.3 mmol). The reaction mixture was stirred at room temperature for 7 h. To the reaction mixture was added water (5 ml) and the aqueous mixture was extracted with dichloromethane (30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2/methanol (10/1) to afford 76 mg (57%) of the title compound as white amorphous.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[N:9]1[C:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[N:18][N:19]=[C:8]1[C:7](=[O:27])[NH:6]2)#[N:2].[OH-].[Na+].Cl>>[C:22]([CH2:21][CH2:20][C:17]1[N:9]2[C:10]3[C:5]([NH:6][C:7](=[O:27])[C:8]2=[N:19][N:18]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:12]([C:13]([F:15])([F:16])[F:14])[CH:11]=3)([OH:24])=[O:23]
Reactant: CCOC(=O)CCc1nnc2c(=O)[nH]c3cc(C#N)c(C(F)(F)F)cc3n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc2[nH]c(=O)c3nnc(CCC(=O)O)n3c2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A mixture of 0.5 g (~1.3 mmol) of 7-cyano-1-(2-ethoxycarbonylethyl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 25 ml of 1N sodium hydroxide was stirred at 25° C. for 2 h. The solution was cooled in an ice bath and acidified with 4N hydrochloric acid to pH=2. The precipitate was filtered off to give 0.29 g (~63%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:12]=12)C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][NH:2][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:19][C:12]=12
Reactant: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cncc2c1ccn2COCC[Si](C)(C)C
Yield: 76.4 %

Procedure:
A solution of tert-butyl methyl((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)carbamate (232 mg, 0.593 mmol) in DCM (20 mL) and TFA (10 mL) was stirred at RT for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to afford 132 mg (76.4%) of N-methyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine as a yellow solid. MS (ESI): m/z=292.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:4]1[C:3](=[O:10])[C:2]([Br:1])=[CH:7][N:6]=[C:5]1[S:8][CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSc1ncc(Br)c(=O)[nH]1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
5-bromo-2-(methylthio)pyrimidin-4(3H)-one (3.63 g, 16.4 mmol) was suspended in THF (80 ml) and CaH2 powder (1.29, 32.3 mmol) and benzyl bromide (2.6 ml, 22 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (65 C-70 C) and stirred overnight. After 15.5 hours, more benzyl bromide (0.7 ml, 6 mmol) was added, and the temperature of the oil bath was raised to 87 C to achieve reflux. After 19 more hours, the reaction was cooled to 0 C and quenched cautiously with ice water first, and then with water (40 ml). The reaction was warmed to room temperature and stirred as more water (40 ml) and then brine (30 ml) were added. The reaction was extracted with a DCM/MeOH mixture, and the organic extractions were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was filtered through silica gel (˜3 inches, DCM) to afford the desired 3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one (642 mg, 2.06 mmol, 90% purity, 11% yield). MS (ESI pos. ion) m/z: 311 (MH+), 313 (MH+). Calc'd exact mass for C12H11BrN2OS: 310, 312. 1HNMR (400 MHz, CDCl3): 8.09 (s, 1H), 7.42-7.29 (m, 5H), 5.34 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CC(NC1CCN(Cc3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one (10 g, 56.7 mmol) and 1-benzyl-piperidin-4-ylamine (12.7 mL, 62.4 mmol) in dichloroethane (50 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (30 g, 141.8 mmol, 3.5 eq.) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice more with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford a dark oil. This material was used directly in Step 2.
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[C:11]([O:13][CH2:14][O:15][CH3:16])=[CH:12][C:5]=2[O:4][C:3]1([CH3:21])[CH3:20].[OH-].[Na+].O>O1CCOCC1>[O:8]1[CH:7]2[CH:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:6]=12
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])[C@@H](O)[C@H](Br)C(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCOc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of (±)-trans-3-bromo-7-methoxymethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-benzopyran-4-ol (550 mg, 1.52 mmol) in dioxane (5.5 mL), 1 mol/L aqueous sodium hydroxide solution (1.82 mL, 1.82 mmol) was added at room temperature, and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, water was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium thiosulfate solution and then with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=4/1) and the aimed product was obtained (yield: 78%).