Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15](=O)[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH3-]C#[N:28].[Na+].C([O-])(=O)C.[NH4+]>CO>[NH2:28][CH:15]1[C:14]2[C:13]([C:23]([OH:25])=[O:24])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1
Reactant: [BH3-]C#N
Reactant: O=C1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21

Procedure:
A mixture of Example 103B (20 mg, 0.055 mmol), NaCNBH3 (17.2 mg, 0.275 mmol), and ammonium acetate (42 mg, 0.55 mmol) in methanol (5 mL) was heated to reflux overnight and concentrated. The concentrate was purified by reverse-phase HPLC to provide the desired product. MS (ESI) m/e 363 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.4 (br s, 2H), 7.66 (m, 2H), 7.36 (m, 2H), 7.25 (d, 1H), 7.14 (d, 1H), 4.42 (br s, 1H), 2.65 (m, 2H), 2.06 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[CH:10][CH2:11][C:5]2=[N:4][N:3]=1.C[O-:25].[Na+]>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:7]2[N:6]3[C:2](=[O:25])[NH:3][N:4]=[C:5]3[CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]=2[CH:19]=1
Reactant: Fc1ccccc1C1=CCc2nnc(Br)n2-c2ccc(Cl)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2

Procedure:
3.9 g of 1-bromo-8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine are suspended in 90 ml of methanol and treated with 1.62 of g of sodium methylate. The mixture is heated to boiling under reflux for 20 hours and then evaporated. The residue, which contains predominantly 8-chloro-6-(2-fluorophenyl)-1-methoxy-4H-s-triazolo[4,3-a][1]benzazepine, is heated to boiling under reflux for 4.5 hours in 100 ml of 48% hydrobromic acid. The mixture is diluted with water, made weakly alkaline with sodium carbonate and extracted with methylene chloride. The methylene chloride solution is evaporated and the residue is chromatographed on 120 g of aluminium oxide (activity grade III). Impurities are separated by elution with benzene/chloroform (9:1 to 1:4). By elution with chloroform which contains 1% to 10% methanol and two-fold recrystallization of the resulting material from benzene there is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 223°-225°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([NH:17][CH:15]([CH3:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1cccc(CC(C)N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cccc(CC(C)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (131 g, 1.15 M) was added during 30 min to a solution of 2-(3-methoxyphenyl)-1-methylethylamine (189.7 g, 1.15 M) and triethylamine (116.7 g, 1.15 M) in benzene (2 l) with cooling to maintain an internal temperature of 20°-30°. The reaction was stirred at room temperature for 2 hr. The benzene solution was filtered from the triethylamine hydrochloride. The filter cake was washed with benzene (500 ml) and the combined filtrates were washed with 1 N. HCl (2×250 ml) and water (2×250 ml). The solution was dried over magnesium sulfate and then evaporated to give the sulfonamide as a thick oil. Wt=292 g.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[F:1][CH:2]([F:5])[CH2:3][O:4][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 2,2-difluoro-ethanol (6 g, 73.12 mmol) and mesyl chloride (6.26 ml, 80.43 mmol)) in DCM (40 ml) was added triethylamine (12.66 ml, 87.74 mmol) dropwise at 0° C. After the addition was completed, the mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was then washed two times with water and with brine and dried with Na2SO4. Evaporation of the solvent yielded the title compound as yellow liquid (10.7 g, 92%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([CH:23]=[O:24])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH:21]([CH3:22])[CH2:23][OH:24])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(CO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 83.3 %

Procedure:
The procedure of Example 1 was repeated except that 110 mg of 1α,3β-bis(t-butyldimethylsilyloxy)pregna-5,7-diene-20-carbaldehyde was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 92 mg of 1α,3β-bis(t-butyldimethylsilyloxy)-20-methylpregna-5,7-dien-21-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:26][N:27]2[C:31]([CH3:32])=[CH:30][N:29]=[CH:28]2)=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:26][N:27]2[C:31]([CH3:32])=[CH:30][N:29]=[CH:28]2)=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=C(Cn2cncc2C)c2ccc(F)cc2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cncn1CC(=Cc1ccc(C(=O)O)c(-c2ccccc2)c1)c1ccc(F)cc1

Procedure:
Product from step F (1.54 g; 3.6 mmol) was heated at reflux in methanol (20 ml) and NaOH 2N, (4.5 ml) for 4 hours. Methanol was then evaporated and the solution acidified to pH 6.5. The resulting solid was filtered and dried to give 4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-2-phenyl-benzoic acid as a yellow powder (1.4 g; 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)[CH:3]=1.[ClH:18].C(=O)([O-])O.[Na+].O1CCO[CH2:26][CH2:25]1>CN(C)C=O.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[NH:17])[S:16][CH2:25][CH3:26])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2ccc(NC(N)=S)cc2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCSC(=N)Nc1ccc(-c2cc(C)ccn2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a suspension of N-(4-(4-methylpyridin-2-yl)phenyl)thiourea (186 mg) in N,N-dimethylformamide(4 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.383 ml) and iodoethane (0.306 ml), and the mixture was stirred at 50° C. for 2.5 hours. After cooling, the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and recrystallized from ethanol-ethyl acetate to give N-(4-(4-methylpyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (162 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([F:10])[C:5]=2[CH:6]=[O:7])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cc(F)c2C=O)C1
Reaction time: 18 h
Yield: 15.2 %

Procedure:
To a solution of the title compound of Step A (270 mg, 1.5 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (270 mg, 1.5 mmol) in dry DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 22 mg, 1.5 mmol). After 18 h, H2O and EtOAc were added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried and concentrated. The crude residue was purified by RP HPLC to provide the title compound (75 mg, 15%). MS (ESI): mass calcd. for C15H17ClFNO4, 329.1; m/z found, 274.0 [M+H-56]+. 1H NMR (CDCl3): 10.4 (s, 1H), 6.84 (dd, J=10.0, 1.6 Hz, 1H), 6.39 (dd, J=1.4, 1.3 Hz, 1H), 5.00-4.92 (m, 1H), 4.38 (dd, J=9.9, 6.3 Hz, 2H), 4.08 (dd, J=10.7, 4.0 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1F>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(Br)c(OCC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A solution of cyclopropyl carbinol (0.269 mL, 3.40 mmol) in tetrahydrofuran (6.9 mL) at 0° C. was treated with sodium hydride (0.0860 g, 3.40 mmol) and stirred at RT for 30 min. The reaction mixture was cooled to 0° C., treated with 4-bromo-3-fluoro-2-nitroaniline (0.400 g, 1.70 mmol) [Combi-Blocks, AN-2785] and stirred at RT for 15 h. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (50 mL) and water (40 mL). The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated to give crude oil. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (0.365 g, 75%). LCMS calculated for C10H12BrN2O3 (M+H)+: m/z=287.1. found: 286.8.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:6]([CH:9]=3)[CH2:7][NH2:8])=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: NCc1cc(I)ccc1OCCN1CCCC1
Product: NCc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 5-iodo-2-(2-pyrrolidin-1-ylethoxy)benzylamine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 28 mg (11% of theoretical); C26H26ClN3O (M=431.957); calc.: molpeak (M+H)+: 432/434 (Cl); found: molpeak (M+H)+: 432/434 (Cl); HPLC-MS: 3.90 minutes (method B).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:33])[C:30]([OH:32])=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:33][C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[C:30]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:32]
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)O
Reactant: C1COCCN1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N1CCOCC1
Yield: 34 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (300 mg, 0.68 mmol) was reacted with morpholine to give the title compound as a white solid (120 mg, 34%); NMR spectrum 1.58 (d, 3H), 3.67-3.58 (m, 8H), 5.77 (s, 2H), 5.88 (q, 1H), 6.95 (d, 1H), 7.29 (m, 2H), 7.35 (d, 1H), 7.75-7.67 (m, 3H), 7.83 (m, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 11.12 (s, 1H); Mass spectrum MH+ 510.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C1COCC1.[CH2:12]([C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:12]([C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
Triphenyl methylphosphonium bromide (13.1 g, 0.037 mol) was suspended in toluene (150 mL) and was treated with 1M potassium tert-butoxide in THF (28.8 mL, 0.8 equivalents) at 25° C. for 16 hrs. This solution was added dropwise to a suspension of Example 4C in toluene (100 mL) at −78° C. over 15 min. After 1.5 h, the mixture was warmed to 25° C. and partitioned between saturated ammonium chloride (100 mL) and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvents were evaporated. The oil was redissolved in ether:hexanes (10 mL, 1:1) and filtered to remove triphenylphosphine oxide. The filtrate was evaporated and the crude residue was purified using ethyl acetate:hexanes (1:6) to give 2.4 g (49%) of the title compound.
Reaction SMILES: [C:1]([O:11]C)(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][NH2:22])[CH:18]=[CH:19][CH:20]=1>CO>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[C:1](=[O:11])[C:2]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:3][NH:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: NNc1cccc(Cl)c1
Reactant: C=C(C(=O)OC)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(Cl)c1
Yield: 79.9 %

Procedure:
A mixture of 10.5 grams of the atropic acid, methyl ester, 9.1 grams 3-chlorophenylhydrazine hydrochloride, and 200 ml. methanol was refluxed overnight. The reaction product mixture was washed up in the usual manner to yield 11 grams of crude 1-(3-chlorophenyl)-4-phenyl-3-pyrazolin-5-one. A sample recrystallized from methanol had a melting point of about 211°-212° C.
Reaction SMILES: [CH:1]1[N:9]2[C:5](=[N:6][C:7]3[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:8]=32)[CH:4]=[CH:3][CH:2]=1.[BrH:15].[Br:16]C1C(=O)C2N3N=CN=C3SC=2CC1>>[BrH:16].[Br:15][CH:11]1[C:10](=[O:14])[C:8]2[N:9]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=[N:6][C:7]=2[CH2:13][CH2:12]1
Reactant: O=C1CCCc2nc3ccccn3c21
Reactant: O=C1c2c(sc3ncnn23)CCC1Br
Agent: Br
Product: O=C1c2c(nc3ccccn23)CCC1Br

Procedure:
6,7-Dihydropyrido[1,2-a]benzimidazole-9 (8H)-one prepared in the above (A) was subjected to bromination in the similar manner to that of Example 1, Route 1(C) to give 8-bromo-6,7-dihydropyrido[1,2-a]benzimidazole-9(8H)-one hydrobromide. The resulting compound (17.4 g) and thiourea (6.0 g) were dissolved into absolute ethanol (200 ml), and the solution was heated to reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled and filtered to give solids (10.6 g), which are dihydrobromide of the desired compound. The dihydrobromide was neutralized with 2N-potassium hydroxide in an aqueous system and recrystallized with a mixture of DMF and ethanol to give the titled compound (7.1 g, 56%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[C:12]([CH3:19])[C:11]([O:10][CH3:9])=[CH:16][C:15]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OC)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(OC)cc1C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
A suspension of 17.52 g of aluminium chloride in a mixture of 100 ml of CCl4 and 100 ml of DCM is cooled to +4° C. under nitrogen, and 10.4 g of acetyl chloride are added dropwise, followed by a solution of 20 g of 2,5-dimethoxytoluene in 20 ml of DCM. After stirring for 4 hours at +4° C., the reaction medium is poured onto ice to which a few ml of concentrated HCl have been added and the mixture is left stirring for 30 minutes. The phases are separated by settling, the aqueous phase is extracted with DCM and the combined organic phases are washed with aqueous 5% NaCO3 solution, dried over MgSO4 and evaporated. The product crystallizes, and is triturated from 150 ml of heptane, filtered off and then washed with heptane to give 21.03 g of the expected compound: m.p.=75-77° C.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.C(OCC)(=O)C.CCCCCC.P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OCC)C>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: [C-]#N
Reactant: Nc1ccc2nc(Cl)sc2c1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(N)cc2s1
Temperature: 135 °C
Yield: 53.6 %

Procedure:
Potassium cyanide (1.29 g, 19.7 mmol) was added to dimethyl sulfoxide (DMSO, 150 mL). After argon substitution, the mixture was refluxed overnight at 135° C. with stirring. The temperature was lowered to 120° C., and Compound 3 (1.02 g, 5.55 mmol) dissolved in DMSO (20 mL) was added. After disappearance of the starting materials was confirmed by thin layer chromatography (developing solvent: ethyl acetate/n-hexane=2/1), the reaction mixture was poured into a mixed solution of 1.0 mol/L potassium dihydrogenphosphate solution (100 mL) and diethyl ether, (150 mL), and the diethyl ether layer was separated. The aqueous layer was extracted 5 times with ethyl acetate, the organic layer was mixed with the diethyl ether layer, and this organic solvent layer was washed twice with purified water and twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/4 to 1/2) to obtain Compound 4 as yellow solid (521 mg, 54% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:12])=[CH:5][N:6]=[CH:7]2.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>O1CCOCC1.CCCCCCC.[Pt](=O)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]([CH3:12])[CH2:5][NH:6][CH2:7]2
Reactant: Cc1cncc2cccc(Br)c12
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2c1C(C)CNC2
Reaction time: 6 h
Yield: 125.1 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.319 g, 0.450 mmol), 5-bromo-4-methylisoquinoline (Frontier Scientific, Logan, Utah, 1.000 g, 4.50 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, San Diego, Calif., 0.990 g, 4.50 mmol), and potassium phosphate (3.82 g, 18.01 mmol) in 10 mL dioxane 5 mL water was heated to 80° C. for overnight. The reaction mixture was diluted with heptane, and the organics were separated then concentrated. The resulting residue was dissolved in 10 mL MeOH, was treated with platinum(IV) oxide (0.102 g, 0.450 mmol) and TFA (0.694 ml, 9.01 mmol) and was placed under 45 psi (4559.6 kpa) H2 overnight. LC/MS showed incomplete reaction, so an additional portion of platinum(IV) oxide (0.102 g, 0.450 mmol) and TFA (0.694 ml, 9.01 mmol) were added, and the reaction mixture was placed under 45 psi (4559.6 kpa) H2 for an additional 6 hours. The reaction mixture was then filtered through diatomaceous earth. The filtrate was poured into saturated NaHCO3 solution and extracted with EtOAc. The organics were dried over MgSO4 and concentrated yielding racemic 5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline (1.810 g, 5.63 mmol). [M+H]+=322.2
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:39][CH:40]1[CH2:42][CH2:41]1>CN(C)C=O.O>[CH:40]1([CH2:39][N:15]2[C:16]([CH3:29])=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14]2)[CH2:42][CH2:41]1
Reactant: BrCC1CC1
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Reaction time: 72 h
Yield: 60 %

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g), cesium carbonate (0.20 g) and a catalytic amount of sodium iodide in N,N-dimethylformamide (1 mL) was added bromomethylcyclopropane (0.050 g) at 50° C., and the mixture was stirred for 3 days. Water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.034 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCCC(Oc2ccc(N)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(OC2CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-methyl-3-piperidyloxy)phenylamine (1 equivalent) was dissolved in CH2Cl2 and a catalytic amount of DMAP was added. Acetic anhydride (1.3 equivalents) was added slowly, and the solution was stirred at room temperature overnight. The reaction was then quenched with water and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo, to yield N-[4-(1-methyl-3-piperidyloxy)phenyl]acetamide as a yellow oil. LC/MS (m/z) 249.3 (MH+), Rt 1.24 minutes.