Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([CH3:9])=[CH:7]1.C(=O)=O.C([Li])(C)(C)C.[CH3:24][N:25]([CH3:40])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1.[Cl-].[NH4+].Cl.C(=O)([O-])O.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:24][N:25]([CH3:40])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:27][CH2:28][C:29]([C:7]2[NH:6][C:15]3[C:10]([C:8]=2[CH3:9])=[CH:11][CH:12]=[CH:13][CH:14]=3)([OH:32])[CH2:30][CH2:31]1
Reactant: Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: C1CCOC1
Product: Cc1c(C2(O)CCC(c3cccc(F)c3)(N(C)C)CC2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
n-butyl lithium (8.39 mmol, 3.35 ml, 2.5M in hexane) was slowly added to a solution of skatole (1.00 g, 7.62 mmol) in absolute tetrahydrofuran (25 ml) in an argon atmosphere at −78° C. A colourless precipitate was formed. After 10 min the solution was heated to room temperature. Carbon dioxide was then introduced into the reaction mixture for approx. 3 min. A colourless solution was formed. After 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature ≦30° C.). The colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml). The light yellow reaction mixture was cooled to −78° C. and tert-butyl lithium (8.39 mmol, 5.59 ml, 1.5M in pentane) was added in drops. An orange solution was formed. This was stirred for 1 h at −20° C. and then cooled to −78° C. 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone [1.97 g, 8.39 mmol, in absolute tetrahydrofuran (20 ml)] was then added in drops and the resulting solution stirred for 2 h. Saturated aqueous ammonium chloride solution (50 ml) was then added in drops to the reaction mixture, stirred for 10 min, the mixture heated to 0° C. and stirred for 20 min. 2N aqueous hydrogen chloride solution (50 ml) was added thereto and stirred for 10 min (light gas development). The pH value of the milky suspension was then basified with saturated sodium hydrogencarbonate solution (50 ml) and 5N sodium hydroxide solution (20 ml). After 10 min the phases were separated. The organic phase contained a colourless solid. The phases were separated. The aqueous phase was extracted with dichloromethane/methanol 20:1 (3×50 ml). The organic solutions were combined. The volatile constituents were completely removed in a vacuum. The remaining light brown powder was extracted with methanol (5×75 ml). The residue was exclusively composed of the non-polar diastereoisomer 6b/7b (450 mg, 1.23 mmol, 16%). The extracts were concentrated until dry in a vacuum. The residue was taken up in methanol (approx. 30 ml). A light-coloured solid did not dissolve. This was separated by means of a fritted glass filter and then dried in a vacuum. 980 mg (2.67 mmol, 35%) of a colourless powder were obtained. This was composed of the two diastereoisomers.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[C:8](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>N1C=CC=CC=1>[C:8]([O:1][C@@H:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C[C@H](O)CO1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To the solution of (S)-β-Hydroxy-γ-butyrolactone (1.0 g, 9.8 mmol) in 25 mL pyridine was added dropwise BzCl (1.4 mL, 12.2 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was concentrated and coevaporated with toluene two times in vacuo. The residue was partitioned between H2O (15 mL) and EtOAc (40 mL). The organic layer was washed with water and brine, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:1) to afford 101 (1.78 g, 8.6 mmol) as a white solid, in 89% yield, which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.N1C2C(=CC=CC=2)C(C(C)C(O)=O)=[CH:33]1.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:4]([Cl:27])=[CH:5][C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH:13]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH3:33])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C(=O)O)c1c[nH]c2ccccc12
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: CC(C(=O)N=C(N)NCc1cc(Cl)c(N)c(Cl)c1)c1c[nH]c2ccccc12

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(1H-indol-3-yl)propionic acid in step 8 (A) and 3,5-dichloro-4-aminobenzylamine (preparation A) in step 8 (B), the title compound was prepared. MS (ESI) (M+H)+=404.03 1H-NMR (500 MHz, CD3OD) δ 7.55 (d, J=7.93 Hz, 1 H), 7.40 (d, J=7.93 Hz, 1 H), 7.28 (s, 1 H), 7.19 (s, 2 H), 7.12-7.17 (m, 1 H), 7.02-7.08 (m, 1 H), 4.31 (s, 2 H), 4.14 (m, 1 H), 1.63 (d, J=7.02 Hz, 3 H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]4[C:26]([C:29]#[N:30])=[CH:27][CH:28]=[C:17]34)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:33])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO.Cl[Co]Cl>[NH2:30][CH2:29][C:26]1[N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[O:21][C:14]3([CH2:15][CH2:16][N:11]([C:9]([C:8]4[CH:31]=[CH:32][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:33])[CH:7]=4)=[O:10])[CH2:12][CH2:13]3)[C:17]2=[CH:28][CH:27]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C#N)ccc23)ccc1OC(C)C
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CN)ccc23)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a solution of 1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile (255 mg, 0.572 mmol) in MeOH (15.3 mL) at 0° C. was added dichlorocobalt (149 mg, 1.14 mmol) followed by portion wise addition of NaBH4 (216. mg, 5.72 mmol). The reaction mixture was allowed to stir for 15 minutes at room temperature before it was cooled to 0° C. and acidified with 1M HCl. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc (50 mL) and aqueous saturated NaHCO3 (15 mL). The aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were dried with Na2SO4, filtered and concentrated to give (1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone (170 mg, 67%). ESI-MS m/z calc. 445.6, found 446.5 (M+1)+; Retention time: 1.45 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[N:7]=1.Cl[C:22]1[S:23][CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(OC)n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: COc1nc(-c2sccc2[N+](=O)[O-])cs1

Procedure:
2-Methoxy-4-(3-nitrothiophen-2-yl)thiazole was prepared from 2-methoxy-4-(tributylstannyl)thiazole (1.0 g, 2.47 mmol) and 2-chloro-3-nitrothiophene (0.404 g, 2.47 mmol) according to protocol E. Retention time (min)=2.516, method [1], MS (ESI) 242.9 (M+H).
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]Cl)=[C:8]([C:14]([Cl:17])([Cl:16])[Cl:15])[CH:7]=1)([O-:5])=[O:4]>C(OCC)C>[CH3:1][NH:2][S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[C:14]([Cl:17])([Cl:16])[Cl:15]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CN
Solvent: CCOCC
Product: CNSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
At 0° C., 10 liters of methylamine is passed into a solution of 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 200 ml of diethyl ether. After the mixture has been stirred for 6 hours at 25° C., it is poured onto ice water, and the aqueous phase is separated and evaporated to dryness. There is obtained 51 g (85% of theory) of N-methyl-4-nitro-2-trichloromethylphenylsulfenamide as an oil (nD20 :1.6610).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([Cl:20])[C:5]=1[O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 85.6 %

Procedure:
To a solution of phenol 185 (2.29 g, 6.23 mmol) in DMF (30 mL) were added tert-butyldimethylsilyl chloride (1M in THF, 9.35 mL, 9.35 mmol), imidazole (1.3 g, 18.7 mmol) and catalytic DMAP. The mixture was stirred at 50° C. for 15 hours. The mixture was extracted with EtOAc/aq. 50% NaCl solution (100 mL/500 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 186 (2.57 g, 86%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[C:23]([O:26][CH2:27][C:28]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][Si](C(C)(C)C)(C)C)=[CH:42][C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:31])(=[O:25])[CH3:24]>O1CCCC1>[C:23]([O:26][CH2:27][C:28]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:31])(=[O:25])[CH3:24]
Reactant: COc1ccc(COC(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccc2COC(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(COC(=O)c2cc(CO)ccc2COC(C)=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Tetrabutylammonium fluoride (1N tetrahydrofuran solution; 9.9 ml, 9.9 mmol) and acetic acid (592.9 mg, 9.87 mmol) were added to a solution of 4-methoxybenzyl 2-(acetoxymethyl)-5-[(tert-butyldimethylsilyl)oxymethyl]benzoate (905 mg, 1.97 mmol) obtained from Example 1-(8) in tetrahydrofuran (5 ml). The mixture was stirred at 50° C. for 1 hour, and then the solvent was distilled off under reduced pressure. The oily residue was subjected to chromatography on a silica gel (25 g) column (eluent; ethyl acetate:hexane=1:1) to give the title compound (500.1 mg, 74% yield) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.[OH-:22].[Na+]>>[Cl:1][C:2]1[NH:7][C:6](=[O:22])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)[nH]c(=O)n2)CC1
Yield: 101.1 %

Procedure:
tert-Butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (14.9 g, 44.5 mmol) synthesized in Reference Synthesis Example 5 and 1 M sodium hydroxide aqueous solution (111 mL, 111 mmol) were used to obtain the title compound (14.2 g, quantitative) by synthesis in a similar manner to Reference Synthesis Example 2.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH3:13]>CO.[Pd]>[NH2:13][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: N
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (3.0 g, 17.65 mmol) was dissolved in 150 mL methanol saturated with ammonia at 0° C., and to the solution was added wet 10% Pd/C catalyst (4.0 g). The mixture was stirred at room temperature under hydrogen (1 atm) for about 36 h. Then the catalyst was then removed by filtration and the filtrate was concentrated to give the crude product, which was purified by chromatography on silica gel to give 2.0 g of the desired product. MS (ESI): 172 (MH+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.O>C(Cl)Cl>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of dry methylene chloride, under nitrogen, and 7.0 ml of triethylamine is added 1.43 g of 6-chloro-pyridine-3-carbonyl chloride. The reaction mixture is stirred at room temperature for 16 hours and poured into 100 ml of water. The organic layer is separated, washed with 2% HCl, water, saturated NaHCO3, and dried (Na2SO4). The solvent is evaporated An vacuo to give a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 1.76 g of the desired product as a yellowish crystalline solid. M+H=324.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2F)(=[O:18])=[O:17])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][CH2:40][NH2:41]>C(#N)C>[CH2:1]([O:3][C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:41][CH2:40][CH2:39][CH:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH3:33])(=[O:18])=[O:17])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CN1CCCC1CCN
Reactant: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2NCCC2CCCN2C)c1C(=O)O

Procedure:
A solution of Example 385I (120 mg, 0.33 mmol), triethylamine (0.24 mL) and N-methyl-2-(2′-aminoethyl)pyrrolidine (217 mg, 1.7 mmol) in acetonitrile (3 mL) was heated to 120° C. in a sealed vial for 2 days, concentrated, and purified using a reverse phase HPLC, giving the desired product, 79 mg, 50.3%. 1H NMR (DMSO-d6) δ 1.08 (t, 3H), 1.28 (t, 3H), 1.60-1.70 (m, 1H), 1.80-2.00 (m, 3H), 2.12-2.30 (m, 2H), 2.53 (q, 2H), 2.68 (s, 3H), 2.90-3.04 (m, 1H), 3.20-3.32 (m, 3H), 3.50-3.60 (m, 1H), 3.90 (q, 2H), 5.98 (br s, 1H), 6.60 (d, 1H), 6.68 (t, 1H), 6.85 (d, 1H), 7.15 (d, 1H), 7.40 (t, 1H), 7.58 (d, 1H), 9.68 (s, 1H), 10.48 (br s, 1H); MS (ESI(+)) m/e 476 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: Brc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-bromo-3-iodobenzene (15.3 g, 54.0 mmol), phenylacetylene (5 g, 49.0 mmol), tetrakis(triphenylphosphine)palladium (2.8 g, 2.4 mmol) and copper(I) iodide (0.46 g, 2.4 mmol) were dissolved in dry toluene and diisopropylamine (35 mL, 196 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and the organic layer was dried in vacuo to give the title compound as a residue that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[N:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: BrCc1ccncc1
Agent: Br
Product: O=C(c1ccc(OCc2ccncc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-(bromomethyl)pyridine hydrobromide. MS (ES+) 366.2
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.152 mmol) and 2-methoxy-5-methylaniline (28 mg, 0.231 mmol) similar to example 180 and was isolated as a solid (43 mg, 81%). 1H NMR (CDCl3): 9.73 (m, 1H), 8.44–8.41 (m, 1H), 7.81–7.75 (m, 1H), 7.46 (s, 1H), 7.34–7.28 (m, 2H), 7.23 (t, J=8.1 Hz, 1H), 7.09–7.06 (m, 1H), 7.00–6.97 (m, 1H), 6.55 (d, J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32](Cl)[C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=1)[CH3:21]>CN(C)C=O.O>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]([CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH:32]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=1)[CH3:21]
Reactant: Cc1ccc(S)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(C)cc1
Temperature: 25 °C

Procedure:
ρ-Thiocresol (0.43 g) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.14 g) in dry N, N-dimethylformamide (23 mL,) under N2. The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate (1.31 g) in dry N,N-dimethylformamide (16 mL) and the mixture was then left stirring at room temperature for a further 12 hrs. The reaction mixture was diluted with water (375 mL) before extracting with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with water (3×100 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using 60% hexane in ethyl acetate as eluent to afford the title compound which solidified on standing, mp 88.6°-90.1° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]([Br:17])([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[CH3:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1ccc(S(C)(=O)=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Mixture of 2-(4-Methanesulfonyl-phenyl)-propionic acid methyl ester (0.939 g, 0.3.88 mmol), N-bromosuccinimide (0.69 g, 3.88 mmol) and catalytic amount of benzoyl peroxide (0.01 g) in carbon tetrachloride (75 ml) was refluxed for 1 hour under nitrogen atmosphere, RM was cooled to room temperature and poured onto water (50 ml) under stirring, layer separated, organic layer was washed with water (2×25 ml). Removal of solvent gave the 2-Bromo-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.22 g) as white solid which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 3.08 (s, 3H), 3.82 (s, 3H), 7.78 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:13]=1/[CH:22]=[CH:23]/[N+:24]([O-])=O.Cl>O1CCCC1.O>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][NH2:24]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])c(Cl)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCN)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To tetrahydrofuran (THF) (60 mL) was added lithium aluminum hydride (1.822 g, 48.0 mmol) at 0° C. and aluminium chloride (6.40 g, 48.0 mmol) in tetrahydrofuran (THF) (80 mL) was added via syringe. The solution of (E)-2-chloro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (5.85 g, 24 mmol) in tetrahydrofuran (THF) (100 mL) was added via addition funnel over 40 min. Stirred at rt for 16 h. Water (8 ml) was added dropwise followed by 5N hydrochloric acid (60 ml). The mixture was washed with ether (2×200 mL) and the aqueous phase was made basic with 6N sodium hydroxide. The aqueous layer was extracted with ether (3×200 mL). Dried over magnesium sulfate, evaporated to give 2-(2-chloro-3,4-dimethoxyphenyl)ethanamine (2.85 g, 13.21 mmol, 55.1% yield). LCMS (M+H)+: 216.0