Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:4]1[C@@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)NC1=O
Reactant: BrCc1ccccc1
Solvent: O
Product: CN1C[C@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1=O
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To the solution of (R)-benzyl 1-methyl-2-oxo-imidazolidine-4-carboxylate (1000 mg, 4.27 mmol) in 11 ml of DMF sodium hydride (129 mg, 5.12 mmol) was added, resulting in a slightly exothermic reaction (temperature rise to about 27° C.) and formation of a turbid solution. After stirring for 1 h at room temperature (bromomethyl)benzene (0.609 ml, 876 mg, 5.12 mmol) was added resulting again in a slightly exothermic reaction (temperature rise to about 29° C.). After stirring overnight the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed successively with a 10% citric acid solution, twice with saturated NaHCO3 solution and brine, dried over Na2SO4 and the solvent was then removed under reduced pressure. Column chromatography on silica gel using dichloromethane and dichloromethane/methanol 98/2 gave (R)-benzyl 3-benzyl-1-methyl-2-oxoimidazolidine-4-carboxylate (425 mg, 1.38 mmol, yield: 31%, ESI-MS [M+H]+=325.1), which was converted into to the corresponding carboxylate by stirring overnight at room temperature in a mixture of 2.7 ml of THF and 1.44 mL of 2N NaOH. Water was added to the reaction mixture followed by extraction with MTBE. The aqueous layer subsequently was acidified to pH 3 using 2M HCl, and extracted three times with dichloromethane. The combined organic layers were then washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as colorless oil which solidified by standing over time (245 mg, yield: 75%).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH2:30][C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.11 g, 0.20 mmol) (from Example 41 supra) in 2-propanol (15 mL) for 20 min. The mixture was heated in a microwave reactor at 140° C. for 5.5 hours. The reaction mixture was concentrated. The residue was washed with hot methanol, filtered and dried to give 4-amino-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.07 g, 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1)([O-])=O>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1
Reactant: O=c1oc(-c2c(F)cccc2F)nc2ccc([N+](=O)[O-])cc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1

Procedure:
6-Nitro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (50 mg) was dissolved in acetic acid (5 mL) under N2, PtO2 (2.5 mg) was added and the mixture was hydrogenated with H2 gas. Reaction time 2 h. The reaction mixture was filtered through Hyflo®, which was rinsed afterwards with ethyl acetate. The combined organic phases were evaporated to dryness and subsequently treated three times with toluene followed by evaporation.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:17][CH2:18][CH2:19][C:20]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=1)=[O:21]
Reactant: COC(=O)COc1ccccc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)COc1ccc(C(=O)CCCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (33.35 g) was added portionwise to a stirred cooled (<0° C.) solution of methyl phenoxyacetate (14.46 ml) and 3-chloropropionyl chloride (9.55 ml) in dichloromethane (500 ml). After the addition the ice-bath was removed and the mixture stirred for 1 hour when it was poured into ice-water (500 ml). The organic phase was separated and the aqueous portion extracted two times with dichloromethane. The combined dichloromethane extracts were washed with water, then brine and dried (MgSO4). The residue, after removal of the solvent in vacuo and trituration with ether gave methyl 4-[3-chloropropanoyl]phenoxyacetate, 22.3 g, as a solid: m.p. 89°-90° C.; NMR (d6DMSO) δ 7.95(2H,d), 7.05(2H,d), 4.92(2H,s), 3.91(2H,t), 3.71(3H,s), 3.49(2H,t); m/e 257(M+H)+ ; calculated for C12H13ClO4 : C, 56.1; H, 5.0. found: C, 55.8; H, 5.1%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)C(=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1)C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 84 %

Procedure:
Dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)methylene)malonate (424 mg, 1.2 mmol) was dissolved in 10 mL dry THF and 1.0M phenylmagnesium bromide in THF (5 mL, 5.0 mmol) was added. The reaction mixture was stirred for 12 h. The reaction was quenched with MeOH then poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC and eluting with 1:3 EtOAc/hexane. Obtained 435 mg (84% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate. MS found: (M+H)+=333.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([OH:20])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([O:20][CH2:27][C:28]#[N:29])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(O)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-benzyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.96 g) in dimethylformamide (5 ml) was added 132 mg of sodium hydride (60% in oil), and the mixture was stirred for one hour at room temperature. To the reaction mixture was added 210 μl of chloroacetonitrile, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was treated in the same manner as in Example 40 to obtain 1.0 g of a non-crystalline solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](C3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=[C:39](Cl)[O:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=[C:39]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:9]=3)[O:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC1(C)OC(c2cccc(C3CC3)c2)OC1(C)C
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 33.3 %

Procedure:
2-(3-Cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3]dioxolane (63 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (20 mg, 33%) after purification by flash chromatography on silica gel (% EtOAc in hexane=25%˜100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[C:29]#[N:30]>>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[O:32][CH3:33])[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: COc1ccc(CCl)cc1C#N
Product: COc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 5-(chloromethyl)-2-methoxybenzonitrile, the title compound was prepared using a similar method to the one described in Example 1.16, Step A & B. LCMS m/z=377.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.28-2.37 (m, 1H), 2.68 (dd, J=16.4, 8.3 Hz, 1H), 2.87-2.98 (m, 2H), 3.73-3.81 (m, 1H), 3.94 (s, 3H), 3.99-4.06 (m, 1H), 4.11-4.18 (m, 1H), 5.02 (s, 2H), 6.13 (s, 1H), 6.85 (dd, J=8.7, 2.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.64 (dd, J=8.6, 2.1 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN(C(C)C)C(C)C>CC(C)=O>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:12]([CH3:11])[O:13][CH3:14])[N:3]=1
Reactant: CNOC
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,4,6-Trichloro-1,3,5-triazine (XVIII) (30 g, 163 mmol) was dissolved in acetone (300 mL), and N,O-dimethylhydroxylamine hydrochloride (15.8 g, 163 mmol) and DIPEA (42 g, 326 mmol) were added and the mixture then stirred at 0° C. for 1 h. The solution was concentrated and the residue was treated with EtOAc (750 mL), washed with water (100 mL), and the organic layer was dried with Na2SO4. The volatiles were removed in vacuo and the residue was purified by flash column chromatography (pet ether/ethyl acetate=50/1 to 10/1) to yield the desired product, N-(4,6-dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXX), as a white solid (25 g, 73% yield). LCMS (ESI) m/z=210 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[S:8]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:13]2)=[N:7][CH:6]=1)(=[O:10])(=[O:9])[NH2:11]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(S(N)(=O)=O)cn2)C1
Temperature: 0 °C

Procedure:
6-chloropyridine-3-sulfonamide (0.32 g, 1.66 mmol) was added to a stirred solution of tert-butyl azetidin-3-ylcarbamate (0.30 g, 1.74 mmol) and DIPEA (0.9 ml, 0.65 g, 4.98 mmol) in 10 ml of ethanol and heated to reflux for 16 h. Reaction mass was cooled to 0° C. The solid formed was filtered and dried under vacuum to obtain desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][C@@H:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1.CO>C(Cl)Cl.CN(C=O)C>[N:41]12[CH2:46][CH2:45][CH:44]([CH2:43][CH2:42]1)[C@@H:39]([NH:38][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:20][CH:19]=3)=[CH:18][CH:17]=1)[CH2:40]2
Reactant: CC(=O)Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
TEA (130 μL, 1.0 mmol) is added to a suspension of the product of Step D (250 mg, 0.9 mmol) in CH2Cl2 (9 mL). Diphenylchlorophosphate (190 μL, 0.9 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. This solution is added to a solution of (R)-3-aminoquinuclidine (110 mg, 0.88 mmol) in DMF (1 mL). The resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness. The product is crystallized from CH3CN to yield the desired product (130 mg, 39%). MS for C22H25N3O3 (ESI) (M+H)+ m/z 380.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[NH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[CH2:3]1.[H-].[Na+].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[N:8]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cc[nH]c2C1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c1CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A solution of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-4-one (3.8 g, 23 mmol) in DMF (25 mL) was cooled to 0° C. and NaH (1.02 g of a 60% dispersion in mineral oil, 26 mmol) was added portionwise. The mixture was stirred for 30 min then triisopropylsilyl chloride (5.6 mL, 26 mmol) was added at 0° C. and stirring continued for 1 hr. The mixture was warmed to room temperature then extracted with ether (3×). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with isohexane: EtOAc (9:1), to give the title compound (2.9 g, 39%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.11 (6H,s), 1.14 (18H,d, J 7.5 Hz) 1.51 (3H,heptet, J=7.5 Hz), 2.34 (2H,s), 2.71 (2H,s), 6.64 (1H,d, J=3.1 Hz), 6.71 (1H,d, J=3.1 Hz). MS (ES+) 320 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:39]I>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13][I:39]
Reactant: OCCCC#Cc1cc(Cl)ccc1Cl
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1ccc(Cl)c(C#CCCCI)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
5-(2,5-Dichlorophenyl)pent-4-yn-1-ol (13.7 g, 59.8 mmol), triphenylphosphine (20.4 g, 77.8 mmol), and imidazole (5.71 g, 83.8 mmol) in a mixed solvent (100 ml acetonitrile-150 ml ether) was stirred under nitrogen at 0° C., and to this was slowly added iodine (21.3 g, 83.8 mmol). The solution was allowed to warm to room temperature and stirring was continued for 18 hours. This was chromatographed on silica gel with hexane to give the title compound (14.7 g, 72%), MS m/z 337.9 In the manner described in Example 30, above, the following alcohols in Table III were converted to the corresponding bromides:
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].Br[C:16](=[CH:18][CH3:19])[CH3:17].[Cl-].[NH4+]>O1CCCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]([OH:13])[C:16]([CH3:17])=[CH:18][CH3:19])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: CC=C(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC=C(C)C(O)c1cc(-c2ccccc2)no1

Procedure:
To a solution of 5.0 g (28.9 mmol) of 3-phenyl-isoxazole-5-aldehyde in 40 ml of tetrahydrofuran, was added dropwise at -30° C. a solution of 1.5 g of metallic magnesium and 10.1 g (74.8 mmol) of 2-bromo-2-butene in 80 ml of tetrahydrofuran. After they were reacted at the same temperature for 30 minutes, the temperature of the reaction mixture was allowed to rise to room temperature and a saturated aqueous solution of ammonium chloride was added to terminate the reaction. Water was added, followed by extraction with ethyl ether. The organic layer was successively washed with water and saturated saline and then dried over anhydrous sodium sulfate. After ethyl ether was distilled off, the residue was purified by chromatography on a silica gel column (eluent: 9:1 hexane/ethyl acetate) so that 3-phenyl-5-(1-hydroxy-2-methyl-2-butenyl)isoxazole was obtained as oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C.Br[C:54]1[CH:55]=[C:56]2[C:60](=[CH:61][CH:62]=1)[NH:59][CH:58]=[C:57]2[CH2:63][C@H:64]1[CH2:68][CH2:67][CH2:66][N:65]1[CH3:69]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:69][N:65]1[CH2:66][CH2:67][CH2:68][C@@H:64]1[CH2:63][C:57]1[C:56]2[C:60](=[CH:61][CH:62]=[C:54]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)[CH:55]=2)[NH:59][CH:58]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(C)(=O)=O)cc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc12

Procedure:
A mixture of 4-methylsulphonylphenyltri-n-butylstannane (see Preparation 15) (680 mg, 1.53 mmol) tri-o-tolyphosphine (120 mg, 0,394 mmol), palladium (II) acetate (15 mg, 0.067 mmol), triethylamine (0.40 ml, 2.87 mmol) and 5-bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (400 mg, 1.36 mmol) (see Preparation 36) in anhydrous acetonitrile (5 ml) was heated under reflux, under nitrogen, for 18 hours. The reaction mixture was then evaporated under reduced pressure and dichloromethane (25 ml) was added. The resultant solution was washed with aqueous sodium carbonate, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/diethylamine (98:2) to afford, after combination and evaporation of the appropriate fractions, the title compound as a white foam, (189 mg). Found: C,68.17; H,6.81; N,7.53; C21H24N2O2S.1/20 CH2Cl2 requires: C,67.83; H,6.51; N,7.52%.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:27])[C@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Cl:26][C:21]1[CH:20]=[C:19]([C@@H:15]([CH2:14][OH:27])[CH2:16][CH:17]=[CH2:18])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: C=CC[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](CO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
4(S)-Benzyl-3-(2(S)-(3,4-dichlorophenyl)pent-4-en-1-oyl)oxazolidin-2-one (30.32 g) (see Bioorganic and Medicinal Chemistry Letters, 3, 319, (1993)) was dissolved in anhydrous tetrahydrofuran (400 ml), cooled in an ice-bath and lithium aluminium hydride (5.7 g) carefully added in two portions (exothermic reaction). The mixture was stirred at 0° C. for 20 minutes and then stirred at room temperature for 1 hour before being cooled to 0° C. Water (6 ml) was carefully added followed by 2N aqueous sodium hydroxide solution (6 ml) and further water (12 ml). The mixture was stirred vigourously for 40 minutes and the resulting precipitate removed by filtration and washed with diethyl ether. The filtrate was collected and the organic and aqueous phases separated. The solvent was then removed from the organic phase under reduced pressure to give a yellow oil which was chromatographed on silica gel eluting with a solvent gradient of 4:1 changing to 4:0, by volume, dichloromethane:hexane to give 4(S)-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (11.74 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.C(=O)(O)[O-].[Na+].[I-].[Na+].[ClH:45]>C(O)CCC>[ClH:45].[ClH:45].[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOc1ccc2ccccc2c1
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Product: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCN(CCOc3ccc4ccccc4c3)CC2)cc1

Procedure:
A mixture of 4.20 g (0.010 mol) of 4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine, 2.90 g (0.012 mol) of 2-(2-bromoethoxy)naphthalene, 8.1 g (0.096 mol) of sodium bicarbonate, and a trace of sodium iodide in 400 mL of 1-butanol was heated at reflux for 16 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo to give a gum. This was subjected to flash column chromatography (silica gel, eluted with CH2Cl2 and 1-2% MeOH in CH2Cl2) to give the free base. This was converted to the HCl salt, and the salt was recrystallized from diethyl ether/MeOH to give 3.05 g (54.1%) as a white crystalline solid: mp 210°-215° C.