Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6]([CH3:8])=[N:5][N:4]([CH3:9])[C:3]1=[O:10].[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:9][N:4]1[C:3](=[O:10])[N:2]([NH:1][C:23]([C:20]2[CH:19]=[N:18][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:22][CH:21]=2)=[O:24])[CH2:7][C:6]([CH3:8])=[N:5]1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: CC1=NN(C)C(=O)N(N)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=NN(C)C(=O)N(NC(=O)c2cnc(-c3ccccc3)nc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 54.6 %

Procedure:
To a solution of 4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.219 g, 1.58 mmol) and 2-phenyl-pyrimidine-5-carboxylic acid (0.317 g, 1.58 mmol) in dry DMF (10 mL) under N2 is added DMTMM (0.46 g, 1.66 mmol). The mixture is stirred at rt for 22 h, then diluted with EtOAc (70 mL), and washed successively with saturated aqueous NaHCO3 solution (2×10 mL) and brine (10 mL). The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with heptane:EtOAc gradient to afford 2-phenyl-pyrimidine-5-carboxylic acid (2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-amide as a solid (0.28 g, 55%). MS: 325 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 2H), 8.45 (dd, J=7.7, 2.0 Hz, 2 H), 7.52-7.62 (m, 3H), 4.25 (s, 2H), 3.18 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[OH:31])=[CH:26][C:25](=[O:30])[CH2:24][CH2:23]4)[CH3:12]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[O:31][C:8](=[O:9])[CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:26][C:25](=[O:30])[CH2:24][CH2:23]4)[CH3:12]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCC1CCCC1

Procedure:
Add 3-cyclopentylpropionyl chloride (2 g.) in benzene (6 cc.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (6 cc.) at -15°. Keep the mixture at -10° for 17 hours, work up and recrystallize the product from methanol to give the title compound, m.p. 88-89°; ultraviolet absorption peak at 241 mμ (ε17,000); infrared absorption peaks at 5.80; 6.00, 6.18 μ.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)Cl>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6]
Reactant: N#CC[C@@H](CO)c1ccccc1F
Reactant: C1=COCCC1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC[C@@H](COC1CCCCO1)c1ccccc1F
Reaction time: 0.08 h

Procedure:
To a solution of β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile (210 g, 1.18 mol) in Et2O (200 ml), is added 3,4-dihydro-2H-pyran (225 ml, 2.68 mol) at ambient temperature. The mixture is stirred for 5 minutes and POCl3 (5 mL) is added dropwise. The reaction mixture is stirred for 30 minutes at ambient temperature and then refluxed for 2 hours. The resulting solution is allowed to cool and the solvent is removed in vacuo. The residue is then chromatographed (EtOAc/hexane, 1:4) to give β(R)-[[(tetrahydropyran-2-yl)oxy]methyl]-β(2- fluorophenyl)-propionitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])O.S(Cl)([Cl:28])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:28])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: O=S(Cl)Cl
Reactant: O=c1cnn(-c2ccc(C(O)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Solvent: ClC(Cl)Cl
Product: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h

Procedure:
To a stirred mixture of 16 parts of 2-[3-chloro-4-[(2.4-dichlorophenyl) hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 150 parts of trichloromethane are added dropwise, during a period of 5 minutes, 16 parts of thionyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is 10 evaporated in vacuo. Methylbenzene is added and the whole is evaporated again, yielding 2-[3-chloro-4-[chloro(2,4-dichlorophenyl) methyl]phenyl]1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[CH3:27][C:28]1[S:32][CH:31]=[N:30][C:29]=1[C:33]([NH:35][NH2:36])=O>ClCCl>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[C:33]([C:29]4[N:30]=[CH:31][S:32][C:28]=4[CH3:27])=[N:35][N:36]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1C(=O)N1CCNC(=O)C1
Reactant: Cc1scnc1C(=O)NN
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1scnc1-c1nnc2n1CCN(C(=O)c1cccc(Cl)c1C)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(3-Chloro-2-methylphenyl)carbonyl]-2-piperazinone (I131)(250 mg, 0.989 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (185 mg, 1.187 mmol) and stirring for 16 hours at RT under argon before adding 5-methyl-1,3-thiazole-4-carbohydrazide (I123) (233 mg, 1.484 mmol) and stirring for a further 3 hours. DCM was removed by evaporation and the residue was dissolved in 1-butanol (3.00 mL) before heating at 110° C. for 4 hours then cooled to RT overnight. The reaction was worked up by diluting with DCM (50 ml) and washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), the combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford a pale yellow cloudy gum as crude product. The product was purified on 50 g Isolera column, eluting with DCM (3CV) then 0-10% MeOH/DCM over 10CV. The desired fractions were isolated, the solvent evaporated and the residue was further purified by MDAP (formic acid method). The desired fraction was identified and the solvent evaporated to afford a white foam of desired product in 130 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[O:22]=[C:16]1[CH:15]([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[C:5]2=[O:7])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 82.3 %

Procedure:
A stirred solution of 3-methylphthalic anhydride (2.96 g, 18.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (3.00 g, 18.2 mmol) and sodium acetate (1.57 g, 19.1 mmol) in acetic acid (30 mL) was heated at reflux for 23 hours. The solvent was removed in vacuo to give a solid which was stirred with water (40 mL) for 1 hour, filtered, washed with water (30 mL), and then heated with decolorizing charcoal (1 g) in acetone (2 L) at reflux temperature for 30 min. The suspension was filtered through a pad of Celite to give a clear solution. The solvent of filtrate was removed in vacuo to give 2-(2,6-dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione as a white solid (4.08 g, 82% yield); mp 290.0-292.0° C.; 1H NMR (DMSO-d6); δ2.03-2.09 (m, 1H, CHH), 2.50-2.60 (m, 2H, CH2), 2.63 (s, 3H, CH3), 2.83-2.95 (m, IH, CHH), 5.13 (dd, J=5.4,12.3 Hz, IH, NCH), 7.65-7.79 (m, 3H, Ar), 11.13 (br s, IH, NH); 13C NMR (DMSO-d6) δ17.04, 21.99, 30.93, 48.76, 121.05, 127.89, 131.63, 134.37, 136.91, 137.61, 167.04, 167.83, 169.87, 172.74; Anal Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.68; H, 4.37; N, 10.17.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[NH2:25]>CN(C=O)C>[C:13]1([C:2]2[N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]3=[N:25][C:3]=2[C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncccn1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2ccccc2)cc1

Procedure:
4.6 g 4-[bromo(phenyl)acetyl]benzaldehyde and 1.64 g pyrimidin-2-amine are stirred in 140 ml DMF at 90° C. for 4 h. The DMF is evaporated and the residue suspended in ethylacetat over night, collected by filtration.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[CH2:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[O:14][C:15]2[C:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11].Cl>O1CCOCC1.CN(C)C=O>[CH3:1][O:2][CH2:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[O:14][C:15]2[C:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11]
Reactant: CO
Reactant: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3o2)ccn1
Temperature: 50 °C
Yield: 67.1 %

Procedure:
To a stirred solution of 0.05 ml (1.24 mmol) methanol in 5 ml dioxane and 1 ml N,N-dimethylformamide at room temperature was added 27 mg (0.62 mmol) sodium hydride (55% dispersion in mineral oil), and the mixture heated at 50° C. for 1 hour. 50 mg (0.12 mmol) 2-chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide was then added, and the mixture heated at 50° C. for 20 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was acidified with 1 N aq. hydrochloric acid and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichloromethane) followed by trituration in ether afforded 32 mg (65%) 2-methoxymethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 398 (M+H+, 100).
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:17]=2)=[CH:13][CH:12]=1.Br[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[CH:37][CH:36]=1>O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=[CH:37][CH:36]=3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:32])[CH3:33])[N:17]=2)=[CH:13][CH:12]=1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)s2)n1
Reactant: Brc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)Cn1cc(-c2ccnc3ccccc23)c(-c2ccc(Cl)s2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
To a degassed solution of acetonitrile (4 mL) and water (1 mL) were added potassium carbonate (4 eq, 2.8 mmol), 3-(5-chloro-2-thienyl)-1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq, 0.7 mmol), 4-bromoquinoline (1 eq, 0.7 mmol) and 1,1′-bis(diphenylphosphinoferrocene)palladium(II)dichloride (0.1 eq, 0.07 mmol). The mixture was stirred at 130° C. in the microwave for 60 min. The solvent was evaporated and water and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 1:0 to 9:1) to afford 45 mg of 4-[3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazol-4-yl]quino line (15% yield).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Oc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(O)c3)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].O>CN(C)C=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:18])([O-:14])=[O:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([C:12]1[CH:32]=[CH:31][C:15]([C:16]([N:18]([CH2:20][C:21]2([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:24][O:23][CH2:22]2)[CH3:19])=[O:17])=[CH:14][CH:13]=1)#[N:11]>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]23[N:18]([CH3:19])[CH2:20][C:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)([CH2:22][O:23]2)[CH2:24][O:17]3)=[CH:31][CH:32]=1)#[N:11]
Reactant: CN(CC1(C2CCCCC2)COC1)C(=O)c1ccc(C#N)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CC2(C3CCCCC3)COC1(c1ccc(C#N)cc1)OC2
Reaction time: 24 h

Procedure:
Boron trifluoride etherate (37.2 μl) was added to a stirred solution of 3-[N-(4-cyanobenzoyl)-N-methylaminomethyl]-3-cyclohexyloxetane (281 mg) in dichloromethane (3 ml) at -70° C. under nitrogen. After stirring overnight a further portion of boron trifluoride etherate (110 μl) was added. After stirring for a further 24 hours the reaction mixture was poured into dichloromethane (20 ml, saturated with ammonia). Filtration and evaporation of the filtrate gave 1-(4-cyanophenyl)-4-cyclohexyl-7-methyl-2,6-dioxa-7-aza-bicyclo[2,2,2]octane as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:11]([NH:18][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-methoxybenzaldehyde (5 g, 35 mmol) and benzylamine (3.8 g, 35 mmol) were added to sodium triacetoxyborohydride (10.4 g, 49 mmol) in dichloroethane (125 mL). The reaction was stirred at ambient temperature 2 hours, then concentrated. The mixture was diluted with dichloromethane (200 mL), washed with saturated aqueous sodium hydrogen carbonate (200 mL), brine (200 mL) and dried over magnesium sulfate. The crude amine was concentrated and purified by silica gel chromatography (70% ethyl acetate in hexanes) To afford N-benzyl-1-(4-methoxyphenyl)methanamine as an oil. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.59 (s, 2H), 3.64 (s, 2H), 3.71 (s, 3H), 6.86 (d, J=8.8 Hz, 2H), 7.28 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCCCN
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Product: CCCCNc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 11.15 g of butylamine are added. The reaction mixture is refluxed for 2 hours and then evaporated to dryness. The residue is taken up in 100 ml of water. After 1 hour's stirring the precipitate is filtered off on sintered glass and is then recrystallized from 80 ml of 6/4 water/acetonitrile. 8.75 g of 2-amino-4-butylamino-6-chloropyrimidine are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](C2C=CC=CC=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2-[2-({4-[(E)-2-(2,4-Difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole was prepared according to the method of Example 135 Step 2 using 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (Step 1) in place of (S)-1-(2-iodophenyl)ethanol and Intermediate 2 in place of Intermediate 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH3:32])[C:26](=[O:31])[CH2:27][NH:28][C:29](=[O:30])[C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1>C(OC(O)C)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH3:32])[C:26](=[O:31])[CH2:27][NH:28][C:29](=[O:30])[C:23]=2[CH:22]=1)[CH3:14]
Reactant: CN1C(=O)CNC(=O)c2cc(N)ccc21
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)C(=O)NCC(=O)N4C)c2cc1OCC
Yield: 99.8 %

Procedure:
A mixture of 0.5 g (1.8 mmol) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 0.35 g (1.8 mmol) of 7-amino-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, and 0.21 g of pyridine hydrochloride was refluxed in ethoxyethanol for 5 hr. The solvent was removed at reduced pressure. The residue was stirred with ammonium hydroxide and the insoluble material was collected to give 0.8 g of title compound as a a tan solid. crystals: mass spectrum (electrospray, m/e): M+H 446.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.[Zn].[Cu]Cl>[CH2:18]([O:17][C:15](=[O:16])[CH:14]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH3:19]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC(=O)CBr
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCc2cc(OC)ccc21

Procedure:
To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under argon atmosphere and refluxed for 15 min; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring for 12 h at rt; TLC showed the presence of desired product. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35° C.). After 4 h, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol) was added dropwise. An exotherm was observed (internal temperature increased to 35° C.). When the stirred mixture was cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated under reduced pressure to a volume of about 2 L. The liquid was then poured into HCl (1 N aqueous solution, cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2×1 L, 1×500 mL). The combined extracts were washed with water (1 L), brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark red oil which solidified gradually (438.3 g; theoretical yield=432 g). 1H NMR (CDCl3): 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1 H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m,2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (CI) m/z 233 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(OCC)(=O)C>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([NH:24][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[O:12])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: Nc1cnc2ccccc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(trifluoromethyl)phenyl]propanoic acid XII (0.93 g, 2.79 mmol) and 3-aminoquinoline XIII (0.45 g, 3.10 mmol) in ethyl acetate (30 mL) was added DMT-MM (1.0 g, 3.63 mmol). After being stirred at r.t. overnight, the reaction was washed with water, 1 N HCl, aq. sat. NaHCO3, water and dried over Na2SO4. The solvent was removed under reduced pressure to afford tert-butyl N-[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamate (1.19 g, 2.59 mmol, 93% yield). 1H NMR (DMSO-d6) 1.31 (s, 9H), 2.95-3.15 (m, 1H), 3.22-3.27 (m, 1H), 4.46-4.52 (m, 1H), 7.36 (d, J=8 Hz, 1H), 7.62-7.68 (m, 4H), 7.67 (t, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 8.13 (t, J=7 Hz, 2H), 8.99 (d, J=2 Hz, 1H), 9.24 (d, J=2 Hz, 1H), 11.18 (s, 1H); ESIMS found for C24H24N3O3F3 m/z 460 (M+H).