Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([O:15][C:16]([C:18]1[CH:48]=[CH:47][C:21]([CH2:22][C:23]([CH2:36][CH2:37][C:38]2([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:40][CH2:39]2)(C(OCC=C)=O)[C:24]([O:26]CC=C)=[O:25])=[CH:20][CH:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:15][C:16]([C:18]1[CH:48]=[CH:47][C:21]([CH2:22][CH:23]([CH2:36][CH2:37][C:38]2([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:40][CH2:39]2)[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)=[O:17])([CH3:13])([CH3:12])[CH3:14]
Reactant: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: CCOC(=O)CC1(CCC(Cc2ccc(C(=O)OC(C)(C)C)cc2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
At room temperature, a solution of 7.42 ml (53.56 mmol) of triethylamine and 1.53 ml (40 mmol) of formic acid in 25 ml of dioxane is added to a solution of 8.58 g (16.2 mmol) of diallyl [4-(tert-butoxycarbonyl)benzyl]{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}malonate, 298 mg (1.14 mmol) of triphenylphosphine and 73 mg (0.33 mmol) of palladium acetate in 75 ml of dioxane. The reaction mixture is then stirred at 100° C. for 2 hours. After complete conversion, the reaction solution is cooled and the solvent is removed under reduced pressure. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid (pH 4-5), and the organic phase is separated off. The aqueous phase is extracted three more times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated under reduced pressure. The crude product obtained is purified by flash chromatography on silica gel (700 g; mobile phase: petroleum ether/ethyl acetate 1:1). This gives 4.9 g (74.6% of theory) of a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:17][CH:16]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH:6]([OH:7])[CH2:8][N:23]2[CH2:24][CH2:25][C:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([CH3:14])=[CH:28][CH:27]=3)([OH:26])[CH2:21][CH2:22]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CC2CO2)cc1F
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Solvent: CO
Product: COc1ccc(CC(O)CN2CCC(O)(Cc3ccc(C)cc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
(RS)-2-(3-Fluoro-4-methoxy-benzyl)-oxirane (0.48 g, 2.6 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (0.65 g, 3.2 mmol) were dissolved in MeOH (3 ml) and stirred at room temperature for 16 hours. Solvent was evaporated and residue was chromatographed over silica gel (CH2Cl2MeOH 19:1) to provide (RS)-1-[3-(3-Fluoro-4-methoxy-phenyl)-2-hydroxy-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol (0.82 g, 81%) as a yellow oil MS: m/e=388.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:32]4[CH:31]=[C:30]([Br:29])[CH:34]=[N:33]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(Br)cn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-1H-pyrazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].C1C=CC=CC=1>O>[CH2:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
Indole (1.17 g, 0.01 mol) was added to a mixture of benzyl chloride (1.90 g, 0.015 mol), 50% aqueous sodium hydroxide solution (5 ml), benzene (10 ml) and 0.5 mmol of compound 1. The mixture was stirred at 60°-70° C. for 5 hours, then cooled to room temperature and diluted with water (10 ml). The organic layer was separated, washed with diluted hydrochloric acid, water and dried over anhydrous magnesium sulphate. The solvent and excess of benzyl chloride were removed under vacuo and the residue was chromatographed on silica gel using n-hexane to give the N-benzylindole (70%), m.p.: 43°-45° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=O)=[CH:7][CH:6]=1)=[O:4].Cl.[OH:28][NH2:29]>C(O)C.C(OCC)(=O)C.ClCCCl.[O-2].[Mn+4].[O-2]>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[O:28][N:29]=2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NO
Reactant: CCCCCOc1ccc(C(=O)C=Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: CCO
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)on2)cc1
Yield: 23.6 %

Procedure:
A solution of 1-(4-Methoxycarbonylphenyl)-3-(4-n-pentyloxyphenyl)-1-propen-3-one (4.0 g) and hydroxyamine hydrochloride (3.93 g) in ethanol (40 ml) was refluxed for 4 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water (×2), brine and dried over magnesium sulfate. The solvents were removed under reduced pressure to give crude oxime. To a solution of crude oxime in 1,2-dichloroethane (20 ml) was added activated-manganese(IV) oxide (10.0 g). The reaction mixture was refluxed for 2 hours and filtered. The residue was washed with dichloromethane. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile. The solid was collected by filtration and dried to give Methyl 4-[3-(4-n-pentyloxyphenyl)isoxazol-5-yl]benzoate (0.98 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc(N)c2ncccc2c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1C
Yield: 8.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5,6-dimethylquinolin-8-amine (Intermediate 55) (60 mg, 0.38 mmol), benzenesulfonyl chloride (72 mg, 0.41 mmol) and DMAP (cat.) gave the title compound (10 mg, 10%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]#[N:28]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[N:22]([CH3:21])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: Cn1cccc1C#N
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
5-(3,3-Dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 1-methyl-2-cyanopyrrole according to the same coupling procedure as described in example 2. MS (ES) m/z 265.1. HRMS: calcd for C17H16N2O+H+, 265.13354; found (ESI, [M+H]+), 265.1332.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]2[C:10](=[CH:11][S:12][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]1=2.[CH:21]([N-]C(C)C)(C)C.[Li+].C(O[CH2:33][CH3:34])(=O)C>O1CCCC1.IC>[CH3:1][CH2:2][N:3]1[C:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]2[C:10](=[CH:11][S:12][C:13]=2[CH3:21])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]1=2.[CH3:1][CH2:2][N:3]1[C:4]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[C:14](=[C:33]([CH3:34])[S:12][C:11]=2[CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]1=2
Reactant: CCN1c2ncccc2-c2cscc2-c2cccnc21
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(C)=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCN1c2ncccc2-c2c(C)sc(C)c2-c2cccnc21
Product: CCN1c2ncccc2-c2csc(C)c2-c2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-ethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.025 g) in tetrahydrofuran (2 mL) cooled to -78° C. was added lithium diisopropylamide (1.5M in cyclohexane, 0.1 mL). After 10 minutes, iodomethane (2 drops) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was dissolved in tetrahydrofuran (2 mL) cooled to -78° C., and lithium diisopropylamide (1.5M in cyclohexane, 0.1 mL) was added. After 10 minutes, iodomethane (0.05 mL) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by HPLC to give 8-ethyl-1-methyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.010 g) mp 106-108° C. and 8-ethyl-1,3-dimethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.003 g) mp 176-178° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[S:8][C:9]=1[CH3:10])=O.[C:17]1([NH:23][C:24]([NH2:26])=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[BrH:1].[CH3:10][C:9]1[S:8][C:7]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[C:3]1[N:26]=[C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:25][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(=O)CBr
Product: Br
Product: Cc1sc(C(=O)OC(C)C)cc1-c1csc(Nc2ccccc2)n1
Yield: 86.7 %

Procedure:
Isopropyl 4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (64 mg, 0.21 mmol) was allowed to react with phenylthiourea (32.1 mg) as described in Example 154, step (a) to give 80 mg (87% yield) of isopropyl 5-methyl-4- [2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C18H18N2O2S2, 358.5 (M+H), found 359.2.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[N:30]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[C:31]=[O:32]>C(Cl)Cl>[CH:33]1([NH:30][C:31]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C=NC1CCCC1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.100 g, 0.361 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0754 mL, 0.433 mmol), and isocyanatocyclopentane (0.0421 g, 0.379 mmol) in DCM (4 mL) was stirred at RT for 24 h. The mixture was concentrated and purified by ISCO (20% EtOAc/hexanes) to give the white solid. MS (ESI, positive ion) m/z: 389 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([S:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([S:27]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=1)=[O:9])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(S(=O)C(Cn2ccnc2)c2ccccc2OC)cc1
Reaction time: 0.5 h

Procedure:
5 ml of dry methylene chloride containing 304 mg of 3-chloroperbenzoic acid were added to 368 mg of methyl 4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 9) in 7 ml of dry methylene chloride, and the resulting mixture was stirred at 0°-5° C. for 30 minutes. At the end of this time, chloroform was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 10:1 volume mixture of ethyl acetate and methanol, to give 263 mg of the title compound as colorless crystals, melting at 113°-115° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[C:24]([O-:27])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][C:24]([O:27][CH2:21][C:20]([OH:23])=[O:22])=[CH:13][CH:12]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: O=C([O-])[O-]
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: CC(=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(OCC(=O)O)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 19.5 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), tert-butyl[4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenoxy]acetate (0.067 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes at 250° C. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0038 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H].[ClH:20]>[Pd]>[ClH:20].[ClH:20].[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1
Agent: [Pd]
Agent: Cl
Product: N=C(Nc1cccc(N)c1)N1CCCC1

Procedure:
A sample of the product of step (a), 17 g, was dissolved in 200 ml of 1 M hydrochloric acid. The mixture was then hydrogenated with 1 g of 5% Pd/C. When hydrogen uptake had stopped the catalyst was filtered off. The solvent was evaporated in vacuum, and the residue dissolved in isopropanol, evaporated in vacuum again and the residue dissolved in 100 ml of methanol. To this mix was added 200 ml of toluene. This was then concentrated on a steam bath until the volume had decreased to approximately 175 ml. The crystals that precipitated were filtered to give N-(3-aminophenyl)-1-pyrrolidinecarboximidamide dihydrochloride, m.p. 250-251° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH2:14][C:15]1[N:19]=[CH:18][O:17][N:16]=1.O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH2:14][C:15]1[N:19]=[CH:18][O:17][N:16]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1SCc1ncon1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccccc1SCc1ncon1

Procedure:
Methanesulphonyl chloride (1.39 g) was added dropwise to a cooled solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (3.1 g) in pyridine (12 ml). The reaction mixture was then poured into water (75 ml) the so formed solid removed by filtration and crystallised from ethanol to give 3-(2-methylsulphonamidophenylthiomethyl)-1,2,4-oxadiazole, m.p. 106°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=C[CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32]C(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.BrC1C=NC=C(C=1)C(O)=O.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:31]=[N:32][CH:29]=[C:4]([CH:3]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: O=C(O)c1cncc(Br)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cncc(Br)c3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.10 g, 033 mmol), 5-bromonicotinic acid (0.073 g, 0.36 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (0.14 g, 0.36 mmol) and triethylamine (0.10 mL, 0.72 mmol) in N,N-dimethylformamide (5 mL) gave 5-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)nicotinamide (0.15 g) as a white solid. MS m/z 489, 491 (M+1, M+3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2].C([Li])CCC.[B:24](OC)([O:27]C)[O:25]C.Cl>C(OCC)(=O)C.C1COCC1.CCCCCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([B:24]([OH:27])[OH:25])=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 131.8 %

Procedure:
The compound (3) (10.0 g) and THF (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyllithium (1.57 M in a n-hexane solution; 22.4 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture obtained was stirred for another 2 hours. Subsequently, trimethyl borate (4.0 g) in a THF (50 ml) solution was added dropwise thereto in the temperature range of −74° C. to −65° C., and the mixture was stirred for another 8 hours while allowing the temperature to come to 25° C. Then, the reaction mixture was poured into a vessel containing 1N-hydrochloric acid (100 ml) and ice-water (500 ml), and mixed. Ethyl acetate (300 ml) was added thereto and the mixture was allowed to be separated into organic and aqueous phases, and then an extractive operation was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, giving 11.7 g of 4-ethoxy-2,3-difluoro-1,1′-biphenyl-4′-boronic acid (6). The yield based on the compound (3) was 81.1%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].OS(O)(=O)=O>CC(O)=O.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:28][C:26]2[S:27][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccc([N+](=O)[O-])s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 96 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with 5-nitrothiophene-2-carboxaldehyde (0.123 g, 0.78 mmol) in a mixture of HOAc (1 mL) and concentrated H2SO4 (0.100 mL) at room temperature overnight. The reaction was diluted with water, and the resulting precipitate was collected, washed well with water, and dried in vacuo at 60° C. to afford 0.296 g (80%) of the title compound as a brown powder, mp>240° C.: APCI-MS m/e 396.1 (M++1).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(N(CC)CC)C.[C:28](#[N:31])[CH:29]=[CH2:30]>C(O)C>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([CH2:30][CH2:29][C:28]#[N:31])[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: C=CC#N
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CCC#N)CC3
Yield: 94.7 %

Procedure:
To a mixture of 1.5 g of (-)-1-(morphinan-3-yl)ethanone, 2.3 g of triethylamine and 35 ml of absolute ethanol, was added 0.35 g of acrylonitrile. After the mixture had been heated at reflux for 16 hours the solvent and excess of reagents were removed under reduced pressure to give 1.7 g (94%) of crude (-)-3-acetyl-17-morphinanpropanenitrile. For analysis, a sample of this compound was distilled, bp 220°-230° (0.05 mm), [α]25D-65.5° (c 1.03, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1.Cl>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:8]2([CH3:9])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:25](=[O:26])[O:10]2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 1-(2-aminophenyl)-ethanone (8.00 g, 59.20 mmol) in THF (200 mL) at 0° C. was slowly added 4-chlorophenyl magnesium bromide (1.0 M, 178 mL, 178 mmol) in ether. The reaction was allowed to warm to room temperature. After 3 hours, the reaction mixture was quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The crude solid was taken up in THF (200 mL) and CDI (10.56 g, 65.10 mmol) was added. The reaction solution was stirred overnight at room temperature, poured into 1N HCl, and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and trituration with ether gave 4-(4-chlorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a tan solid (5.19 g, 32%). 1H NMR (DMSO-d6): δ 10.30 (s, 1H), 7.46 (m, 3H), 7.36 (td, J=7.7, 1.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.15 (t, J=7.6 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 1.94 (s, 3H); MS (ESI) m/z [M+H]+=(274/276); MS (ESI) m/z [M−H]−=(272/274); Anal. calcd for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C, 65.38; H, 4.58; N, 5.00.