Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][O:22][CH3:23].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1)[CH2:6][N:7]([C:39]1[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][O:22][CH3:23]
Reactant: Clc1ncc(Br)cn1
Reactant: CCN(CCOC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
{2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.37 g), 5-bromo-2-chloropyrimidine (2.6 g) and N-ethyldiisopropylamine (3.51 ml) are dissolved in toluene (50 ml) and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→19:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amine (4.06 g). MS (m/z): 659/661 [M+H]+
Reaction SMILES: [OH:1]S(O)(=O)=O.[CH3:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:19])[CH:16]=NO)[CH:10]=[C:11]([CH3:13])[CH:12]=1>O>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:8]=1[C:16](=[O:1])[C:15](=[O:19])[NH:14]2
Reactant: Cc1cc(C)cc(NC(=O)C=NO)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C)c2c(c1)NC(=O)C2=O
Temperature: 80 °C
Yield: 72.6 %

Procedure:
To a stirred warm (60°-70° C.) solution of concentrated H2SO4 (60 mL) and water (6 mL) was added in small portions N-(3,5-dimethylphenyl)-2-(hydroxyimino)acetamide (15.0 g, 78 mM) so that the temperature of the reaction mixture did not exceed 70° C. After the addition was completed, the reaction mixture was heated at 80° C. for 10 min and then cooled and poured onto ice. The resulting mixture was filtered and the collected solids were washed with water and dried to provide the title compound (9.93 g, 72.6%); MS(CI): 176.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21](C)[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][OH:35])=[CH:4][N:3]=1.CO.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[NH:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(-c2csc3c(CCCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-hydroxyprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (110 mg, 0.228 mmol), methanol (2 mL) and N,N-dimethylforamide (2 mL) was added sodium borohydride (26.9 mg, 0.684 mmol) under an atmosphere of nitrogen. Mixture stirred for 30 minutes at room temperature after which it was treated with 1M sodium carbonate (5 mL) and extracted with dichloromethane (3×5 mL). The organic layer was separated, dried over magnesium sulfate, and filtered, and the solvent was removed under reduced pressure. The product was purified via flash chromatography to furnish the title compound as a pale yellow powder (21.1 mg, 0.0434 mmol): LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 mm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 4.5 min, 0.8 mL/min): MH+=487 RT=3.23 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1 H), 7.99 (1 H), 7.70 (2 H), 7.60 (1 H), 7.55(1 H), 7.32-7.35 (2 H), 7.21 (1 H), 7.15 (1 H), 7.07 (1 H), 5.34 (2 H), 4.04 (3 H), 3.91 (3 H), 3.47 (2 H), 2.75 (2 H), 1.83 (4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)=O)=[CH:4][C:3]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)=[N:67][N:66]=[N:65]2)=[CH:4][C:3]=1[CH3:27]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-n2nnnc2C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from step A (840 mg, 2.171 mmol) and triphenylphosphine (1139 mg, 4.34 mmol) in THF (8.0 ml) was treated with diisopropylazodicarboxylate (0.844 ml, 4.34 mmol) and trimethylsilyl azide (0.574 ml, 4.34 mmol) at rt. The mixture was stirred at rt for 24 h, then quenched with aqueous saturated NaHCO3, and extracted with MTBE. The combined organic layers were concentrated. Purification of the resulting crude product on SiO2 (0 to 100% EtOAc, hexanes) afforded the title compound as a clear colorless oil. HPLC/MS: 412.2/414.1 (M+1); Rt=1.22 min (LC2).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CO)ccc1-2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of [2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methanol (565 mg, 1.65 mmol) in DCM (20 mL) was added Dess-Martin periodinane (1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 763 mg, 1.80 mmol). The reaction mixture was stirred at RT for 2 hours before being concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-3% MeOH in DCM) to yield the title compound as a white solid (547 mg, 98%). LCMS: RT=4.00 min, [M+H]+=341
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:29])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]C(=O)C)=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:29])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)OC(C)=O)cc3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Yield: 76.6 %

Procedure:
To a suspension of 0.95 g of 2-acetamido-4-hydroxy-6-[2-(4-acetoxycarbonylphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 50 mL of water was added 1N aqueous sodium hydroxide until a homogenous solution was obtained. Acidification with acetic acid resulted in the formation of a yellow precipitate which was collected by filtration. The filter cake was washed sequentially with water, methanol, acetone and ether. The residual solid was recrystallized from DMF to give 0.65 g (77%) of the title compound, which can be alternatively named as 2-acetamido-6-(4-carboxystyryl)-5-deaza-4(3H)-pteridinone, as a microcrystalline yellow solid, mp >300° C.; NMR (TFA-d1) delta 2.5 (s, 3H), 6.85, 7.32 (AB q, 2H, J=12 Hz), 7.45, 8.18 (AB q, 4H, J=9 Hz), 8.65 (s, 1H), 9.02 (s, 1H); IR (Nujol) 3300-2200 (br), 1685, 1655, 1630, 1600, 1565 cm-1 . MS: Calc'd. for C18H14N4O4 : 350. Found: m/e 350 (base), 308.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1.[ClH:16]>O.[Cu]>[Cl:16][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1
Reactant: Nc1nc2cc(F)ccc2s1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2sc(Cl)nc2c1
Yield: 49 %

Procedure:
A solution of 242 g (3.5 mol) of sodium nitrite in 440 ml of water is added dropwise with stirring to a mixture, cooled to -10° C., of 147 g (0.87 mol) of 2-amino-5-fluoro-benzothiazole, 1700 ml of conc. hydrochloric acid and 20 g of copper power and the reaction mixture is stirred at 0° C. for 60 minutes and at 50° C. for a further 60 minutes. It is then extracted with chloroform and the solvent is carefully removed by distillation from the organic phase in a water-jet vacuum. 80 g (49% of theory) of 2-chloro-5-fluoro-benzothiazole are obtained as a crystalline residue of melting point 69° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]1[CH:11]=[C:12]([CH:21]=[O:22])[N:13]2[C:17]3[CH2:18][CH2:19][CH2:20][C:16]=3[S:15][C:14]=12>C1COCC1>[C:4]1([CH2:3][CH2:2][CH:21]([C:12]2[N:13]3[C:14]([S:15][C:16]4[CH2:20][CH2:19][CH2:18][C:17]=43)=[N:10][CH:11]=2)[OH:22])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cnc2sc3c(n12)CCC3
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)c1cnc2sc3c(n12)CCC3

Procedure:
The Grignard reagent generated during 18 hours, from (2-bromoethyl)benzene (2.2 g) an Mg (0.291 g) in THF (70 mL) was treated with solid 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxaldehyde (FIG. E-6) (0.58 g) and reacted for 1.5 hours. The supernate solution was decanted into cold 5% ammonium chloride solution and precipitated 6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-7) (0.80 g) was filtered. Crystallization from acetonitrile solution gave pure 6,7-Dihydro-α-(2-phenylethyl)-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-7), m.p. 117-118°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(C(C)C)C(C)C)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:9])([F:21])[F:22])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)s1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1C(F)(F)F
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a stirred suspension of 1-(5-bromo-2-thienyl)-methanamine (0.5 g) in dichloromethane (8 mL) were added 2-(trifluoromethyl)-benzenesulfonyl chloride (0.67 g) and N-ethyl-diisopropylamine (0.37 g) at 0° C. After stirring for 10 min, the ice bath was removed and the mixture was stirred for 40 min. The reaction mixture was diluted with dichloromethane and washed with 0.5 M HCl and with water. The organic phase was dried (MgSO4), filtered and concentrated. The residue was suspended in cyclohexane. The solid was collected by filtration and dried to give N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (0.596 g) as a colorless solid. MS: 417.1 ([M+NH4]+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(N(CC)CC)C.C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([N:36]1[CH2:35][CH2:34][N:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)[CH2:38][CH2:37]1)=[O:22])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2CCN(C(=O)[C@H](Cc3ccc([N+](=O)[O-])cc3)NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
9.00 g of N-(tert-butoxycarbonyl)-p-nitrophenylalanine was dissolved in 120 ml of tetrahydrofuran, 100 ml of methylene chloride and 100 ml of chloroform, and to the solution were sequentially added 7.68 g of N-(p-methoxyphenyl) piperazine dihydrochloride and 4.44 g of N-hydroxybenzotriazole monohydrate as well as 20 ml of triethylamine and 6 g of DCC, and the mixture was stirred at a room temperature for 18 hours. The reaction mixture was concentrated to one third of the original volume under a reduced pressure, and after adding 200 ml of 2.5% potassium carbonate aqueous solution, extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure to crystallize a product, which was washed with methanol to obtain 10.75 g of the title compound as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=2)[CH:6]=[C:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2ccc(I)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(I)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
A solution of ethyl 6-iodoindole-2-carboxylate (7.0 g, 22 mmol) in DMF (25 mL) was added dropwise over 15 min to a stirred suspension of sodium hydride (60%, 1.36 g, 34 mmol) in DMF (50 mL) at 0° C. under Ar. The reaction was stirred at 0° C. for 45 min then chloroacetonitrile (2.85 mL, 45 mmol) was added in one portion. The reaction was then heated to 75° C. and stirred for one h. After allowing to cool to room temperature the mixture was poured into water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (1×200 ml), dried (magnesium sulfate), filtered and the solvent removed under vacuum to give the product (1.8 g, 23%). IR νmax (Nujol)/cm−1 2924, 2854, 1895, 1703, 1601, 1527, 1464, 1446, 1426, 1398, 1377, 1366, 1334, 1308, 1261, 1204, 1148, 1135, 1119, 1103, 1048, 1024, 989, 949, 904, 894, 871, 842, 833, 800, 786, 762, 736, 654, 612, 584 and 471; NMR δH (400 MHz; CDCl3) 7.79 (1H, s), 7.51 (1H, d, J 8.6 Hz), 7.42 (1H, d, J 8.6 Hz), 7.32 (1H, s), 5.54 (2H, s), 4.37 (2H, q, J 7 Hz), 1.39 (3H, t, J 7 Hz).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][NH:20][CH2:21][CH2:22][OH:23].N1C=CN=C1>CN(C)C=O>[O:23]([CH2:22][CH2:21][NH:20][CH3:19])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CNCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 5.5 h
Yield: 38.5 %

Procedure:
Under nitrogen atmosphere, an N,N-dimethylformamide (33 ml) solution of tert-butylchlorodiphenylsilane (8.78 g, 32.0 mmol) was dropwise added at room temperature to an N,N-dimethylformamide (100 ml) solution of N-methylethanolamine (2.00 g, 26.6 mmol) and imidazole (2.72 g, 39.9 mmol), and stirred for 5.5 hours. The solvent was evaporated away under reduced pressure, then the residue was dissolved in ethyl acetate, and the solution was washed with saturated sodium hydrogencarbonate water, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (3.21 g, 39%) as a pale yellow oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:2]
Reactant: COC(=O)CCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCCCC#N
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
7.5 g (154 mmol) of sodium cyanide was added to 80 mL of dimethyl sulfoxide, and dissolved therein under heat at 90° C. 25.0 g (128 mmol) of methyl 5-bromovalerate was dropwise added to the solution at an inner temperature of 130° C. or lower, and stirred at 100° C. for 2 hours. After cooled to room temperature, 50 mL of water was added to this, which was then extracted with 60 mL of ethyl acetate. The organic layer was dried with magnesium sulfate, and the solvent was evaporated away under reduced pressure to give 18.0 g (yield 99%) of methyl 5-cyanovalerate.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[O:28]C>>[CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][N:22]=[C:21]4[OH:28])[C:6]=2[CH:5]2[CH2:4][CH2:3][N:2]1[CH2:16][CH2:15]2
Reactant: COc1ncnc2ccc(Br)cc12
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: Oc1ncnc2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc12

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (127 mg, 0.6 mmol; Example 187A) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the major product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.96-2.20 (m, 4H) 2.90-2.97 (m, 1H) 3.08-3.29 (m, 4H) 4.36 (s, 2H) 7.07-7.13 (m, 3H) 7.39-7.46 (m, 1H) 7.75-7.82 (m, 1H) 7.87-7.94 (m, 1H) 8.13 (d, J=2 Hz, 1H) 8.18 (s, 1H); MS (DCI/NH3) m/z 357 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:13]#[N:14].C1C=C(O[C:23](OC2N=CC=CC=2)=[S:24])N=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:13]([C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([N:1]=[C:23]=[S:24])[C:3]=2[CH3:15])[N:8]=[CH:7][CH:6]=1)#[N:14]
Reactant: Cc1cc(N)c(C)c2c(C#N)ccnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1cc(N=C=S)c(C)c2c(C#N)ccnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-amino-4-cyano-5,8-dimethylquinoline (2.0 g, 10.15 mmol), di-2-pyridyl thionocarbonate (2.52 g, 10.86 mmol), dimethylaminopyridine (0.266 g, 2.18 mmol) and methylene chloride (62 mL) is stirred at room temperature for 1.5 hours. Evaporation affords a residue which is purified by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using methylene chloride as eluent, to give 4-cyano-5,8-dimethyl-6-isothiocyanatoquinoline.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([F:28])([F:27])[F:26])=[CH:14][C:13]=2[N+:29]([O-])=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.CC(O)=O.[Fe]>[CH:1]1([CH:7]=[CH:8][C:9]2[NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=[CH:22][C:23]=4[F:24])=[CH:14][C:13]=3[N:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C=CC1CCCCC1)Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1cccc(C(F)(F)F)c1-c1ccc2[nH]c(C=CC3CCCCC3)nc2c1
Temperature: 25 °C

Procedure:
To a solution of 3-cyclohexyl-N-(6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-acrylamide (135 mg, 0.309 mmol, prepared as in STEP B above) in EtOH (4 mL) and HOAc (2 mL) was added Fe powder (86.3 mg, 1.54 mmol). The resulting mixture was heated at reflux overnight. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated. The residue was dissolved in DCM with heating and sonication. The DCM layer was washed with 10 mL saturated aqueous NaHCO3, separated, dried over Na2SO4 and concentrated. The residue obtained was purified on silica (EtOAc/hexane, 0:100 to 100:0, v/v) to yield 2-(2-Cyclohexyl-vinyl)-5-(2-fluoro-6-trifluoromethyl-phenyl)-1H-benzimidazole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][CH2:2][CH2:3][NH:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1ccc(NCCO)cc1C(F)(F)F
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCNc2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Prepared as described in Example 1C from 4-[(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.6 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.85 (s, 4H), 6.76 (dd, J=8.7, 1.7 Hz, 1H), 5.66 (bs, 1H), 4.15 (t, J=4.7, 2H), 3.78 (s, 3H), 3.59 (t, J=4.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(Nc2nc(Cl)ncc2F)cc1C(F)(F)F

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5fluoropyrimidine and 4-methyl-3-trifluoromethylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-methyl-3-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.10 (d, 1H, J=3.0 Hz), 7.85-7.78 (m, 2H), 7.33 (d, 1H, J=9.3 Hz), 6.96 (bs, 1H), 2.48 (d, 3H, J=1.2 Hz); 19F NMR (282 MHz, CDCl3): −17641, −44541 ; LCMS: purity: 97%; MS (m/e): 306 (MH+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]=1[CH2:36][C:37](O)=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]=1[CH2:36][C:37]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:38])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a solution (20 ml) of 4-benzylpiperidine (423 mg) and 2,4-dibenzyloxyphenylacetic acid (700 mg) in N,N-dimethylformamide are added triethylamine (0.56 ml) and diethyl cyanophosphate (393 mg) and the mixture is stirred at room temperature for 15 minutes. Water is added and stirring carried out for 10 minutes, followed by extraction of the product with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is subjected to purification by silica gel column chromatography. 1-(2,4-Dibenzyloxyphenylacetyl)-4-benzylpiperidine (1.0 g) in the colorless oily form is obtained from a fraction eluted with dichloromethane-ethyl acetate mixture (8:1).