Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9](I)[N:4]2[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39]([NH2:42])=[N:40][CH:41]=2)O1>O1CCOCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[C:9]([C:36]4[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39]([NH2:42])=[N:40][CH:41]=4)[N:4]3[N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C

Procedure:
To a reaction mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.150 g, 0.455 mmol), 3-methoxyphenylboronic acid (0.477 mmol) and PdCl2(Ph3P)2 (0.064 g) in dioxane (3 ml), a sat. aq. solution of K2CO3 (1 mL) was added. The mixture was heated at 110° C. for 24 h in a sealed tube. The solvent was evaporated, the residue precipitated with water, and after drying the resulting gum was washed with Et2O. The residue was suspended in dioxane (3 mL), and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (1.2 eq), PdCl2(Ph3P)2 (0.2 eq) and a sat. solution of K2CO3 (1 mL) were added and heated at 100° C. for 16 h. The solvent was evaporated to dryness, and the residue was purified by automated chromatography in DCM/MeOH, 100:0 to 95:5) and then by preparative HPLC affording 5 mg of a light-yellow solid that was washed with MeOH and Et2O to obtain 2 mg of the desired product. HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=5.63 min, [M+H]+ m/z 392.1; 1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.41 (s, 1H), 7.80 (s, 1H), 7.53 (t, J=11.5 Hz, 3H), 7.24 (s, 1H), 6.74 (s, 2H), 3.88 (s, 3H), 3.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([O:25][P:26]([CH2:31][C:32](O)=[O:33])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:29]([O:28][P:26]([CH2:31][C:32]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:16][C:17]=2[CH2:22]1)=[O:33])(=[O:27])[O:25][CH2:23][CH3:24])[CH3:30]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 12A (3.00 g, 8.96 mmol) and (diethoxyphosphoryl)acetic acid (2.46 g, 12.5 mmol) were dissolved in DMF (60 mL). DIPEA (3.47 g, 26.9 mmol) and TBTU (4.32 g, 13.4 mmol) were added, and the reaction was stirred overnight at rt. Subsequently, the mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was extracted with 1 M aqueous sodium hydroxide solution, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether. The precipitate was collected by suction filtration to yield 4.31 g (94%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1.CC#N.O>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]=[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)[N:11]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc2c1
Reactant: COc1cccc(CBr)c1
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cccc(OC)c1
Product: COC(=O)c1ccc2nc(C(=O)NC3CCN(C(C)C)CC3)n(Cc3cccc(OC)c3)c2c1

Procedure:
2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid methyl ester and 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benyl)-3H-benzoimidazole-5-carboxylic acid methyl ester were prepared by a procedure according to example 5 iii) starting from 300 mg (0.87 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester and 210.2 mg (1.04 mmol) 1-bromomethyl-3-methoxy-benzene. Preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave a 1:1 mixture of both isomers described in the title. These isomers could be separated by NP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethyl amine as solvent. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=O)[CH3:2].Cl.[CH3:27][O:28][NH2:29].N1C=CC=CC=1>O1CCOCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[S:8][C:4]([C:1](=[N:29][O:28][CH3:27])[CH3:2])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:10][CH:11]=1
Reactant: CON
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CON=C(C)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1.35 g), methoxyamine hydrochloride (0.45 g) and pyridine (0.44 ml) in dioxane (17 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated, and the residue was triturated with water, filtered, washed with water and dried. The crude crystals were recrystallized from ethyl acetate to give pure crystals of 2-(4-fluorophenyl)-5-[-1-(methoxyimino)ethyl]-3-[4-(methylsulfonyl)phenyl]thiophene (0.68 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:27][NH2:28]>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:28][NH:27][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Cl)nc(-c2cccc(N)c2)c(N)c1C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 0.35 g of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(3-aminophenyl)pyridine was added 7.5 ml of hydrazine monohydrate, and the mixture was stirred at 90° C. for 30 minutes. The reaction mixture was poured into ice water (100 ml), and the mixture was adjusted to pH 6 by adding acetic acid. The resulting precipitate was collected by filtration and washed with water, followed by reprecipitation from DMSO-H2O, to give 0.23 g of the title compound as orange powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53](O)=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)c1c[nH]c(C(=O)O)c1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c[nH]c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c1Cl
Reaction time: 8 h
Yield: 8.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 4-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0065 g, 7%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm ppm 11.46 (br. s., 1H), 7.88 (br. s., 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.36-7.50 (m, 4H), 4.73 (d, 2H), 2.41 (s, 3H). LCMS: m/z 480.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=C2[C:9](=[CH:10][CH:11]=1)C=C(C(OCC)=O)C=C2.[OH:17]C1C=C2C(=CC=1)C=C(C(O)=O)C=C2.[I-].[C:32](=[O:35])([O-])[O-:33].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:9][C:10]([CH2:11][C:2]([CH2:3][C:32]([OH:33])=[O:35])=[O:1])=[O:17]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc2cc(O)ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)CC(=O)O

Procedure:
A solution of ethyl 6-hydroxyl-2-naphthate (49, 89 mg, 0.42 mmole) (6-hydroxy-2-naphthoic acid was obtained from TCI America and converted to the ester using standard esterification methods) and iodide (2, 177 mg, 0.42 mmole) in dimethylforamide (1 ml) was stirred with potassium carbonate (174 mg) for 14 hours. The reaction mixture was worked up with water (30 ml) and ethyl acetate (100 ml). The organic layer was washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column (hexane ethyl acetate, 4:1) to provide the triacetate of 3 (120 mg, 55%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:4].Cl.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:19]([CH2:18][CH2:17][CH2:16][C:15]#[C:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][OH:1])=[O:7])=[O:21]
Reactant: CN
Reactant: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Agent: Cl
Product: CNC(=O)CCCC#Cc1cccc(C(=O)NC(C)CO)c1
Yield: 52.8 %

Procedure:
6-[3-(2-Hydroxy-1-methyl-ethylcarbamoyl)phenyl]-hex-5-ynoic acid (4)(0.400 g, 1.37 mmol) was reacted using method C with methylamine hydrochloride (0.609 g) to give 3-(5-methylcarbamoyl-pent-1-ynyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (22) (0.221 g, 0.724 mmol; 53% yield).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=O>>[SH:6][C:3]1[N:2]([CH3:1])[C:9]([C:8]([F:13])([F:12])[F:7])=[N:5][N:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=S)NN
Product: Cn1c(S)nnc1C(F)(F)F
Reaction time: 8 h

Procedure:
In a 500-ml flask, 100 g (0.95 mole) 4-methylthiosemicarbazide and 155 g [100 ml (1.36 mole)] trifluoroacetic acid were combined, refluxed 3 hours, and then allowed to stand overnight. Since the reaction mixture solidified overnight, it was heated to solution and then added to ice. The precipitated solid was filtered, washed with water and air-dried. The solid was dissolved in hot benzene and the water was separated. The benzene solution was concentrated cooled, and filtered to give the product as crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][N:15]2[CH2:16][CH2:17][O:13][C:14]2=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NCCO1
Reactant: CC(C)(C)c1ccc(SCl)cc1
Product: CC(C)(C)c1ccc(SN2CCOC2=O)cc1

Procedure:
Analogously to Example 4, 2.7 g of 3-(4-tert.-butylphenylthio)-oxazolidin-2-one were obtained as colourless crystals with a melting point of 76° to 81° C. from 4-tert.-butylphenylsulphenyl chloride and oxazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>C1COCC1>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[S:3][C:4]=2[CH:10]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccc(Br)cc2s1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2ccc(Br)cc2s1
Yield: 74 %

Procedure:
To a solution of 2-amino-6-bromobenzothiazole (10 g, 43.65 mmol) and triethylamine (12.2 mL, 87.3 mmol) and N,N-dimethylaminopyridine (269 mg) in THF (100 mL) is added acetyl chloride (4.7 mL). After stirring for 17 hours water (100 mL) is added and the mixture is extracted twice with EtOAc (75 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford N-(6-bromo-benzothiazol-2-yl)-acetamide (8.79 g, 74%) as a solid.
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4](O)[C@H:2]1O.I([O-])(=O)(=O)=O.[Na+].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[C:22]1[CH:23]=[N:24][O:25][C:26]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([C:36]3[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH:37]=3)[CH:34]=2)[NH:29][CH:28]=1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>O.CO>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[C:22]1[CH:23]=[N:24][O:25][C:26]=1[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[C:33]([C:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:2][CH2:1][O:7][CH2:6][CH2:4]4)[CH2:38][CH:37]=3)[CH:34]=2)[NH:29][CH:28]=1
Reactant: NC1CC=C(c2cnc3[nH]cc(-c4oncc4-c4cccc(F)c4F)c3c2)CC1
Reactant: O[C@@H]1COC[C@@H]1O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: Fc1cccc(-c2cnoc2-c2c[nH]c3ncc(C4=CCC(N5CCOCC5)CC4)cc23)c1F
Yield: 36 %

Procedure:
A solution of 1,4-anhydroerythritol (208 mg, 2 mmol) in water was treated with sodium periodate (400 mg, 4 mmol)for 12 h, transferred to a solution of 4-{3-[4-(2,3-difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo [2,3-b]pyridin-5-yl}-cyclohex-3-enylamine (50 mg, 0.12 mmol) in methanol (5 ml). The resulting solution was treated with sodium cyanoborohydride. After the reaction was completed, TFA was added, and the mixture was concentrated and purified by HPLC to give the morpholine product (20 mg) in 36% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:48]>>[Cl:48][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:24]3[CH2:23][CH2:22][N:21]([CH2:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[C:17]([F:16])([F:31])[F:32])[CH2:26][CH2:25]3)[O:9][N:8]=2)=[CH:2][CH:3]=1
Reactant: ClCCl
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(-c3ccc(Cl)cc3)no2)CC1
Yield: 94.4 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (10.4, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26.7 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.5 hr and followed the same processes as in Example 1 to obtain 18.4 mg (94.4%) of the target compound.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([C:10]([CH:12]=O)=[O:11])=[CH:5][C:4]=1[Cl:14].[CH3:15][C:16]([NH2:29])([CH3:28])[CH2:17][NH:18][C:19](=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[ClH:9].[ClH:9].[NH2:2][C:3]1[C:4]([Cl:14])=[CH:5][C:6]([CH:10]([OH:11])[CH2:12][NH:29][C:16]([CH3:28])([CH3:15])[CH2:17][NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(N)CNC(=O)Cc1ccccc1
Reactant: Nc1c(Cl)cc(C(=O)C=O)cc1Cl
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)Cc1ccccc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 130.4 %

Procedure:
A mixture of 4-amino-3,5-dichlorophenylglyoxal hydrate (1.18 g.) and 1,1-dimethyl-2-(2-phenylacetamido)ethylamine (1.03 g.) in methanol (20 ml.) was stirred at room temperature for 16 hours. The mixture was then filtered and the filtrate stirred vigorously during the dropwise addition of a solution of sodium borohydride (500 mg.) in water (2 ml.). After stirring for 2 hours, the mixture was acidified with concentrated hydrochloric acid to pH 2-3, and then evaporated. The solid residue was suspended in water (50 ml.) and the suspension obtained was extracted with ether (100 ml). The aqueous phase was basified to pH 12-13 by addition of aqueous ammonia solution (density 0.88), and extracted with ether (2×100 ml.). The combined extracts were dried (MgSO4) and evaporated. The resultant oil was dissolved in propan-2-ol (5 ml.) and an ethereal solution of hydrogen chloride was added to bring the pH to 2-3. Further addition of an excess of dry ether gave a precipitate (1.05 g., 43%) of 1-(4-amino-3,5-di-chlorophenyl)-2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]-ethanol dihydrochloride (Example 1), m.p. 105°-8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
5-Bromoindole (1.4 gm, 7.14 mmol) was dissolved in dry THF (50 ml) and cooled to 0° C., which was followed by the addition of NaH (0.34 g, 14.28 mmol) portion wise. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was again cooled to 0° C. and triisopropylsilyl chloride (1.78 g, 9.28 mmol) was added drop wise. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was evaporated under reduced pressure and triturated with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over Na2SO4 and evaporated. The compound was purified by flash column chromatography using pure hexanes to afford colorless oily product 47 (1.90 g, 76%). 1H NMR (400 MHz, CDCl3) δ 1.13 (d, 18H, J=8.0 Hz), 1.63-1.71 (m, 3H), 6.56 (d, 1H, J=3.2 Hz), 7.20-7.25 (m, 2H), 7.37 (d, 1H, J=8.8 Hz), 7.74 (d, 1H, J=2.0 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:10][CH:9]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[CH:10][CH:9]=1)[CH3:22]
Reactant: CCNCC
Reactant: BrCCCCCCc1ccc(CCCCCCBr)cc1
Solvent: CCO
Product: CCN(CC)CCCCCCc1ccc(CCCCCCN(CC)CC)cc1
Yield: 91.6 %

Procedure:
First, 0.42 g of 1,4-bis(6-bromohexyl)benzene and 0.44 g of diethylamine were dissolved in 5 ml of absolute ethanol, and the mixture was refluxed for 2 hours. After removing the solvent under a reduced pressure and adding chloroform, the mixture was evaporated under a reduced pressure. The residue was acidified with 1N hydrochloric acid, washed with chloroform, alkalized with 10% sodium hydroxide, subjected to salting out, and extracted with total 80 ml of chloroform. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 0.37 g of the title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:26][N:27]([Ti:29](N(C)C)(N(C)C)N(C)C)[CH3:28]>C1(C)C=CC=CC=1>[CH3:16][N-:17][CH3:18].[CH3:26][N-:27][CH3:28].[Ti+2:29].[CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CN(C)[Ti](N(C)C)(N(C)C)N(C)C
Agent: CC1=C(C)C(c2ccccc2CNc2cc(C)cc(C)c2)C(C)=C1C
Solvent: Cc1ccccc1
Product: C[N-]C
Product: [Ti+2]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(3,5-dimethylphenyl)amine (4.0 mmol) in toluene (18.4 mL) was added dropwise a solution of tetrakis(dimethylamino)titanium (4.0 mmol) in toluene (12.2 mL) at −78° C. The mixture was stirred at room temperature for 1 hr and then at 100° C. for 5 hrs to give a red solution. The solvent was distilled off under reduced pressure to synthesize N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(3,5-dimethylphenyl)amine titanium bis(dimethylamide) (2.08 g, yield 100%) as a red solid.
Reaction SMILES: [C-:1]#[N:2].[K+].C(Cl)Cl.[CH2:7]([O:14][C:15]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O.CCOCC>[C:33]([N:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:15]=2[O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:20]1[C:1]#[N:2])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc(COc2cc(OCc3ccccc3)c3ccncc3c2)cc1
Reactant: O=C(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: N#CC1c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2C=CN1C(=O)c1ccccc1
Yield: 87.6 %

Procedure:
A solution of 3 g of potassium cyanide in 15 ml of water is added to 25 ml of a methylene chloride solution containing 3.3 g of 5,7-dibenzyloxyisoquinoline. 6.4 g of benzoyl chloride are added to the mixture at 0° C for 2 hours under stirring. After the mixture is allowed to stand at room temperature, the methylene chloride layer is separated therefrom. The methylene chloride solution separated is washed with an aqueous 1% sodium hydroxide solution and water, respectively. The methylene chloride solution is then dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 10 ml of ether, and this solution is poured onto a silica gel column. The column is eluted with a mixture of ether and hexane. The eluate is evaporated to remove solvent, and the crystalline residue thus obtained is recrystallized from ethanol. 4 g of 2-benzoyl-1-cyano-5,7-dibenzyloxy-1,2-dihydroisoquinoline are thereby obtained. Yield: 64% M.p. 123° - 125° C.