Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[N:35]([CH:38]([CH3:40])[CH3:39])=[C:36]=[O:37].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(COC(=O)NCC)CC1>ClCCl>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][O:1][C:36](=[O:37])[NH:35][CH:38]([CH3:40])[CH3:39])[CH2:4][CH2:5]1
Reactant: CC(C)N=C=O
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)CC2)c1OC
Agent: CCNC(=O)OCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(COC(=O)NC(C)C)CC2)c1OC

Procedure:
To a stirring solution of 4-[2-(1-Hydroxymethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 177) (200 mg, 0.543 mmol) in dichloromethane (20 mL), were added triethylamine (164 mg, 1.623 mmol) and 2-isocyanatopropane (184 mg, 2.164 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 179 to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:52]1([N:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53]1>CN(C=O)C>[CH:52]1([N:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]([C:7]([C:6]3[C:5]([O:4][C:3]4[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=4[Cl:1])=[N:13][CH:12]=[CH:11][CH:10]=3)=[O:9])[CH2:57][CH2:56]2)[CH2:54][CH2:53]1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
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: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (70 mg, 0.25 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1.4 mL) was added N-ethyldiisopropylamine (96 mg, 126 μL, 0.74 mmol, 3.0 equiv; [CAS RN 7087-68-5]) and HATU (112 mg, 0.30 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt. After 15 min, 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (52 mg, 0.30 mmol, 1.2 equiv) was added and stirring at rt continued over night. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 38 mg (35%) of the title compound. MS (ISP): 440.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=S)=[C:4]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:3]=1[S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29].CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[C:4]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[C:3]=1[S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
To a solution of N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl)thiourea (270 mg, 0.45 mmol) in dichloromethane (10 mL) at 0° C., methanesulfonyl chloride (0.07 mL, 0.9 mmol) and triethylamine (0.13 mL, 0.9 mmol) were added. 4-Dimethylaminopyridine was added as a catalyst. The reaction mixture was stirred at 0° C. for 1 hour, then it was partitioned between dichloromethane and water. The combined organic phase was dried and concentrated to give the desired product (270 mg, crude). 1H NMR (CDCl3) δ 0.47 (s, 6H), 1.05 (s, 9H), 2.9 (s, 6H), 7.08 (d, 1H), 7.12 (d, 1H), 7.2 (t, 1H), 7.31 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]([OH:8])=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=1
Reactant: Oc1ccc(Cl)cc1CCc1ccccn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)cc(CCc2ccccn2)c1O
Reaction time: 2.5 h
Yield: 82.1 %

Procedure:
To a solution of 12.5 g (54.56 mmol) 4-chloro-2-[2-(pyridin-2-yl)ethyl]phenol in 80 ml acetic acid is added portionwise to a nitrating mixture of 70% nitric acid (8.59 g, 136.39 mmol) in 20 ml acetic acid at 5-10° C. The reaction mixture is left to stir at this temperature for 2.5 hours. The pH of the reaction mixture is then adjusted to pH 5.5-6.0 (pH meter) by the addition of a saturated solution of sodium carbonate. The resulting reaction mixture is then extracted with EtOAc (3×300 ml). Concentration of the organic extracts in vacuo yielded a brown oil. This oil is purified by flash chromatography (SiO2, 30% EtOAc in hexane) to give the title compound as a yellow solid, (12.48 g, 82%), m.p. 97-100° C. δH (250 MHz, CDCl3), 11.1 (bs, 1H), 8.57-8.55 (m, 1H), 7.94 (d, J=2.6 Hz, 1H), 7.60 (dt, J=7.7,1.7 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.17-7.11 (m, 2H), 3.21-3.08 (m, 4H).
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH3:11])([O-:8])=[O:7].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH:19]([OH:20])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH3:11])=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(C(O)c1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.6 %

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitropropane (0.9mL, 10mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes 4-nitrobenzaldehyde (0.75 mL, 5 mmol) in CH2Cl2 (4 mL) was added and the mixture allowed to warm up to room temperature (~30 min). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5mmol) and extracted with Et2O (3×75 mL). The combined Et2O fractions were washed with dilute hydrochloric acid (2 M, 75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatrography [Si2, hexane:Et2O, 3:1 v/v] gave 1-(4-nitrophenyl)-2-nitro-butan-1-ol (0.86 g, 72%) Erythro:threo ratio 7:1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>C(#N)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:26])[CH2:2][CH2:3]1
Reactant: CCc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: CCc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of Step 3 intermediate (3.89 g, 10.72 mmol) was added N-iodosuccinimide (2.69 g, 11.79 mmol) in acetonitrile at room temperature. The reaction temperature was then raised to 60° C. and stirred for 4 h. The reaction mixture was then cooled to room temperature, diluted with water and stirred for 20 min. The filtered solid was washed with water and dried to afford 5.19 g of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.33 (m, 2H), 0.54-0.56 (d, J=7.2 Hz, 2H), 1.22 (br s, 1H), 3.77-3.81 (m, 5H), 7.06-7.14 (m, 2H), 7.27-7.29 (d, J=7.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.57 (s, 1H), 7.96 (d, J=3.9 Hz, 1H), 8.18 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 481.45 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH2:6])[CH2:4]O.[OH-].[Na+].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>COC(C)(C)C>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([N:6]2[CH2:4][C@H:3]2[CH2:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCC(N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC[C@@H]1CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
R-(-)-2-amino-1-butanol (99.96 g, 105 mL) and tert-butyl methyl ether (TBME) (277 g, 366 mL) are combined under a nitrogen atmosphere. This mixture is stirred for several minutes and 10 N aqueous sodium hydroxide (449 mL) is added over a period of about 10 minutes. The reaction mixture is cooled to below 10° C. and a solution of p-toluene sulfonyl chloride (TsCl) (464 g) in TBME (711 g) is added over a period of about 50 minutes, maintaining the temperature of the reaction mixture at or below 32° C. After the addition is complete, the mixture is stirred for about 30 minutes at 40° C., and water (900 mL) is added while cooling the mixture to 25° C. The layers are separated and the organic layer washed sequentially with water (150 g) and 25% aqueous sodium chloride solution (300 g). Toluene (450 g) is added to the organic layer, and the mixture distilled under reduced pressure, maintaining the temperature of the mixture at or below 45° C., until the water content of the mixture is below about 0.1%. The resulting solution is used, without further treatment, for the preparation described in Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.8 g, 18 mmol) was dissolved in 150 mL dry diethyl ether under Ar, and the resulting solution was cooled in an ice water bath, while dry pyridine (8.6 mL, 106 mmol) was added, followed by the dropwise addition of oxalyl chloride (4.6 mL, 53 mmol). A precipitate formed immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. 100 mL of diethyl ether were then added, and the solids wwere removed by filitration washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 50 mL dry DCM under Ar, cooled to 0° C., added 6 mL pyridine followed by 4-bromo-2-fluoroaniline (3.4 g, 17.7 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (3.2 g, 47%) APCI (AP−): 385.1, 387.1 (M−H)−.
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:17]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CF)c1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
2-Fluoroacetophenone (2.0 mg, 14.5 mmol) was dissolved in DMF (50 mL), phenol (1.4 g, 14.5 mmol) and potassium carbonate (2.0 g, 14.5 mmol) were added thereto, and then the mixture was stirred at 120° C. for 7 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 85:15) to give the title compound (2.0 g, yield 65%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27][OH:28]>>[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27][O:28][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(Cl)cc1Cl
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)cc3Cl)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 2,4-dichlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(2,4-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=509 (M++1); Rt=5.07 min; 1H-NMR 400 MHz (CDCl3): δ 5.60 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.21 (m, 6H), 7.38-7.42 (m, 1H), 7.60 (d, J=9 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:20]OC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Cl:20][C:14]1[C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:13]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)COc1ccc(CCO)cc1OCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(Cl)c(CCO)cc1OCC
Reaction time: 0.25 h

Procedure:
To a stirred solution of ethyl 2-[2-ethoxy-4-(2-hydroxyethyl)phenoxy]acetate (1.15 g) in dichloromethane (4.3 ml) was added tert-butyl hypochlorite (478 μl) at room temperature, and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of sodium sulfite (542 mg) in water (5 ml), and the resulting mixture was stirred for 10 minutes at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave ethyl 2-[5-chloro-2-ethoxy-4-(2-hydroxyethyl)phenoxy]acetate (1.28 g).
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10]([CH3:13])(=O)=O)[CH2:6]1.BrC[C:17]1[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[F:22].O>CN(C)C=O>[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10][CH2:13][C:17]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]=2[F:22])[CH2:6]1
Reactant: Fc1c(CBr)c(C(F)(F)F)nn1-c1ccccc1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Reaction time: 2 h
Yield: 37.4 %

Procedure:
9.3 g of sodium hydrosulfide hydrate (purity: 70%, 116.3 mmoles) was added to a solution of 18.7 g (105.7 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline (present compound No. 2-1) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. The reaction system was ice-cooled. Thereto was added a solution of 30.3 g (93.8 mmoles) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 13.11 g (yield: 37.4%) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20](=[CH2:22])[CH3:21])[CH3:15].Cl>>[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20]([C:10]1[CH:11]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])([CH3:22])[CH3:21])[CH3:15]
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
34.45 g (258.91 mmol) of aluminum trichloride is introduced into 354.35 g (237.02 mmol) of 4-bromoanisole. 38.95 g (172.19 mmol) of 2-hydroxy-4-methylene-2-(trifluoromethyl)pentanoic acid ethyl ester is added in drops to this mixture within one hour. After stirring overnight at room temperature, the batch is added to ice water and made acidic with 10% hydrochloric acid. After being extracted three times with ethyl acetate, the combined organic extracts are washed with 1N hydrochloric acid and brine. After drying on magnesium sulfate, the solvent is spun off. Most of the excess 4-bromoanisole is distilled off (10 mbar; bath temperature 110° C.). After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 36.87 g (51.8%) of the desired compound is obtained.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[CH3:25][C:21]1[N:20]=[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Cc1cccc(Cl)n1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-chloro-6-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10](O)=[O:11])[CH2:7][CH2:6][S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.O.[NH2:17][NH2:18]>C(O)C>[N:17]1[NH:18][C:10](=[O:11])[CH2:9][CH:8]2[CH2:7][CH2:6][S:5][C:4]3[S:13][CH:14]=[CH:15][C:3]=3[C:2]=12
Reactant: NN
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Solvent: CCO
Solvent: O
Product: O=C1CC2CCSc3sccc3C2=NN1
Yield: 71.2 %

Procedure:
A suspension of 2.0 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 0.6 g of hydrazine hydrate in 20 ml of ethanol is refluxed under heating for 5 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from a mixed solvent of chloroform and ethanol to give 1.4 g of 4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 215°-217° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([S:29]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36]C[C@H](CO)O3)=[CH:34][CH:33]=2)(=[O:31])=[O:30])C=CC=CC=1>>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]3[C:13]([CH2:16][CH2:17][C@@H:18]([CH2:19][O:20][S:29]([C:32]4[CH:41]=[CH:40][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[O:21]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CC[C@@H](O)CO)c(Br)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@@H](CO)CC2
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCc3ccc(S(=O)(=O)c4ccccc4)cc3O2)cc1

Procedure:
Toluene-4-sulfonic acid (S)-7-benzenesulfonyl-chroman-2-ylmethyl ester was prepared following the procedure described for the corresponding (R) enantiomer in step 9 of Example 6, but substituting ((S)-7-benzenesulfonyl-chroman-2-yl)-methanol for ((R)-7-benzenesulfonyl-chroman-2-yl)-methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br)([O-:33])=[O:32].P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1,3-oxazolidin-2-one (0.20 g) in DMF (5 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.030 g) and the mixture stirred under nitrogen at 20° C. for 15 min. 3-nitrobenzylbromide (0.11 g) was added, and the mixture stirred at 20° C. for a further 3 h. Phosphate buffer (20 ml, pH6.5) was added and the mixture was stirred for 5 min before extracting with EtOAc (3×20 ml). The organic layer was washed with water (3×20 ml), dried over Na2SO4 and filtered. Solvent evaporation gave the crude product which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (7:3) followed by solvent evaporation in vacuo gave the title compound (0.10 g). LCMS RT=3.61 min, ES+ve 529 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.05 g, 20 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) in DMF (50 mL) at −40° C. under N2, was added NaH (60% in mineral oil, 880 mg, 22 mmol). The mixture was stirred at rt for 15 min, then cooled to −40° C. To this solution was added (2-(chloromethoxy)ethyl)trimethylsilane (3.67 g, 22 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed twice with 10% LiCl, and dried over MgSO4. The title compound was purified by flash column chromatography (silica gel, eluding with hexane, followed by Et2O) to give the desired product (5.6 g, quantitiatve yield) as an oil. LC/MS(ESI+) m/z 283 (M+H)+.