Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])(C)(C)C.[CH2:20]([N:23]1[C@@H:28]([CH3:29])[CH2:27][O:26][C:25](=[O:30])[CH2:24]1)[CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([C:25]3([OH:30])[O:26][CH2:27][C@H:28]([CH3:29])[N:23]([CH2:20][CH2:21][CH3:22])[CH2:24]3)=[CH:3][CH:4]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Reactant: CCCN1CC(=O)OC[C@@H]1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN1CC(O)(c2ccc(-n3c(C)ccc3C)nc2)OC[C@@H]1C

Procedure:
5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (1.5 g 5.9 mmol) was azeotroped with toluene and dissolved in THF (20 ml). This mixture was cooled to −78 C. and t-butyllithium (1.7M in pentane, 7 ml, 11.9 mmol) was added maintaining the temperature below −70 C. The material from example 62 was dissolved in THF (20 ml) and added to the mixture immediately on completion of the t-butyllithium addition. The mixture was allowed to stir at −78° C. for 30 minutes at which time NH4Cl (10% aq, 150 ml) was added and the mixture extracted into EtOAc (200 ml), dried with magnesium sulphate, filtered and evaporated. Flash chromatography on SiO2 eluting with a stepped gradient from 25% EtOAc/pentane to 50% EtOAc/pentane gave the title compound as mixture of diastereoisomers in approximately 3.5:1 ratio as a yellow oil (480 mg).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:2])=[O:13])[S:10][CH:11]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chromium (VI) oxide (20 g), and concentrated sulfuric acid (32 g) were dissolved in water (50 mL) and when dissolution was complete, the volume was made up to 100 mL with water. 55 mL of the resulting solution was added dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (19.1 g) in acetone (200 mL) stirred at 0° C. After 2 h, the solution was diluted with water and extracted with chloroform. The organic extracts were washed with water, then extracted with aqueous sodium hydroxide. The alkaline mixture was acidified by cautious addition of concentrated hydrochloric acid then extracted with chloroform. The organic layer was then dried (Mg2SO4), filtered, and evaporated. The resulting solid was recrystallised from diethyl ether/hexane to give a colourless solid; MS (ES+) 207, 209 (MH+).
Reaction SMILES: C(O)(=O)C.O[CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[O:20]=[C:21]([CH:28]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH2:36][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[O:33])[CH2:29]1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH:18]1[C:19]2[CH:6]([CH:22]([C:21](=[O:20])[CH:28]3[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH2:36][C:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:38])=[O:33])[CH2:29]3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)C1CC(C(=O)OCCC(=O)c2ccccc2)C1
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)C1CC(C(=O)OCCC(=O)c2ccccc2)C1)C1c2ccccc2Oc2ccccc21
Reaction time: 168 h

Procedure:
Acetic acid (20 ml) was added to a stirred suspension of 9-hydroxyxanthene (3.96 g, 20 mmol) and ethyl 3-oxo-3-[3-(phenacylmethyloxycarbonyl) cyclobutyl]propanate (6.0 g, 18 mmol) in ethanol (20 ml) at room temperature. A clear solution formed and was allowed to stand for 7 days at room temperature.
Reaction SMILES: COC1C=C2C(=CC=1OC)N=CC=C2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27](Cl)=[C:26](Cl)[CH:25]=2)=[O:23])=[CH:18][CH:17]=1.B(Br)(Br)[Br:33]>ClCCl>[Br:33][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=2)=[O:23])=[CH:25][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(Cl)c(Cl)c4)cc3)c2cc1OC
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Methoxyphenyl 4-bromophenyl ketone (1.65 g) obtained in Example 122 was dissolved in dichloromethane (20 ml), a solution of 1.0 M boron tribromide in dichloromethane (23 ml) was added while cooled in ice, and the admixture was stirred at room temperature overnight. The reaction mixture was then poured into ice water and partitioned between water and chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and the solvent was removed by reduced-pressure distillation. The resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 1.34 g of the title compound (yield: 85%).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2([CH2:18][CH3:19])[CH2:17][O:16][CH2:15]2)=[CH:4][CH:3]=[C:2]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.C([Li])CCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C>C1COCC1>[CH2:18]([C:14]1([CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[S:1][C:2]([C:20]3[S:21][C:22]([B:34]4[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]4)=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[CH2:17][O:16][CH2:15]1)[CH3:19]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCC1(COCCCCCCc2ccc(-c3cccs3)s2)COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a stirred solution of 3-(6-[2,2′]bithiophenyl-5-yl-hexyloxymethyl)-3-ethyl-oxetane (6.0 g, 16.46 mmol) in anhydrous THF (100 ml) was added n-butyllithium (2.5 M in hexanes, 7.0 ml, 17.50 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.26 g, 17.5 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. NH4Cl, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, brine, and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1 to 4:1), to give 2-{5′-[6-(3-ethyl-oxetan-3-ylmethoxy)hexyl]-[2,2′]bithiophenyl-5-yl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a blue oil (4.53 g, 56%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.49 (d, J=3.6 Hz, 1H, Ar—H), 7.14 (d, J=3.6 Hz, 1H, Ar—H), 7.03 (d, J=3.6 Hz, 1H, Ar—H), 6.66 (d, J=3.6 Hz, 1H, Ar—H), 4.43 (d, J=5.8 Hz, 2H, OCH2), 4.34 (d, J=5.8 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.42 (t, J=6.6 Hz, 2H, OCH2), 2.76 (t, J=7.5 Hz, 2H, ArCH2), 1.32-1.75 (m, 22H, CH2 and CH3), 0.86 (t, J=7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 144.8 (quat.), 143.7 (quat.), 137.0 (CH), 133.7 (quat.), 124.0 (CH), 123.1 (CH), 123.0 (CH), 83.1 (quat.), 77.5 (OCH2), 72.4 (OCH2), 70.4 (OCH2), 42.4 (quat.), 31.5 (CH2), 30.5 (CH2), 29.1 (CH2), 28.4 (CH2), 27.8 (CH2) 25.8 (CH2), 24.9 (CH3), 8.3 (CH3); MS (m/e): 490 (M+, 16%) □305 (79), 223 (25), 205 (100).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[CH3:19])[CH:13]([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then 2-methyl-benzoyl chloride (4.64 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 9.47 g of brown liquid. MS: m/e 333(M++1), 332(M+), 287(M+—OCH2CH3), 197(M+—CH3C6H4CO2), 119(base), 91, 77.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccc(CN[C@H]2CCCc3ccccc32)c(Cl)c1

Procedure:
2,4-Dichlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)=O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)OC
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 100 °C
Yield: 56.6 %

Procedure:
In a three-neck flask (capicity 100 ml) equipped with a mechanical stirrer and reflux condenser, 20 ml of dimethylformamide, 10.0 g (0.054 mol) of syringaldehyde and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 100° C. To this mixture was added 8.00 ml (0.094 mol) of dimethyl sulfite. The mixture was maintained at about 100° C. for eight hours and then cooled to 25° C. and quenched with 500 ml water. The mixture was extracted with 100 ml of methylene chloride. The extracts were washed with water and concentrated in vacuo to give 4.0 g of 3, 4, 5-trimethoxybenzaldehyde.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Nc1ccnn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(Cn2nccc2NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-5-amine (2.09 g) in acetic acid (20 mL) was added tetrahydro-4H-pyran-4-one (1.25 g), and the mixture was stirred at room temperature for 30 min. After stirring, sodium triacetoxyborohydride (3.90 g) was added at room temperature, and the mixture was stirred overnight. Acetic acid was evaporated under reduced pressure and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (3.00 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C.O>[F:13][CH:12]([F:14])[C:5]1[C:4]([C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:2]([N:1]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([C:8]([F:10])([F:11])[F:9])[N:6]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N)c1C1CCC1
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(-n2cccc2)c1C1CCC1

Procedure:
A solution of 1.62 g (5 mmol) of methyl 5-amino-2-(difluoromethyl)-4-cyclobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate (example A-2 of U.S. Pat. No. 5,114,465) and 0.8 g (6 mmol) of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid as heated at 70° C. for 2.5 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (3×100ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% EtOAc in hexane) to give the product, mp 70-71° C.
Reaction SMILES: [H-].[Na+].[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@H:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:11]([CH2:32][OH:33])[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1.CO>CN(C=O)C>[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:11]([CH2:32][O:33][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO)[C@H]2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](COCc3ccc(Cl)cc3)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A suspension of sodium hydride (71 mg, 1.8 mmol) in dry DMF (5 mL) was cooled to 0° C., and a solution of methyl 2-azido-4-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (33) (680 mg, 1.5 mmol) in dry DMF (5 mL) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and 4-chlorobenzyl chloride (295 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 4.5 hours, cooled at 0° C. and dry methanol (1 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, then xylene (10 mL) was co-evaporated from the residue. The residue was treated with hexane (10 mL) and filtered to give methyl 2-azido-4-O-benzyl-6-O-(4-chlorobenzyl)-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (34) (620 mg, 71%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=3)[C:18]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[O:19])(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1.O1C=[CH:36][C:35](C2SC(S(Cl)(=O)=O)=CC=2)=N1>>[CH2:35]([O:26][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][CH:32]=[C:15]([NH:14][S:11]([C:9]3[S:10][C:6]([C:3]4[CH:4]=[CH:5][O:1][N:2]=4)=[CH:7][CH:8]=3)(=[O:13])=[O:12])[CH:16]=2)=[CH:22][CH:23]=1)[CH3:36]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4ccon4)s3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4ccon4)s3)c2)cc1

Procedure:
4-[3-(5-Isoxazol-3-yl-thiophene-2-sulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=468.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-isoxazol-3-yl-thiophene-2-sulfonyl chloride and yielded 4-[3-(5-isoxazol-3-yl-thiophene-2-sulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Cl)cc23)cc1

Procedure:
A solution of 4,6-dichloro-3-nitroquinoline (Compound of Preparation E, 4.0 g, 16.46 mmol) and 2-(4-aminophenyl)-2-methylpropanenitrile (2.63 g, 16.46 mmol) in acetic acid (350 ml) was stirred for 2 hours. Water was added and the yellow precipitate was filtered off, washed with water and saturated aqueous NaHCO3. The yellow solid was dried to obtain the title compound. Yield: 5 g (83%); 1H NMR (DMSO-d6, 300 MHz): δ 10.074 (s, 1H), 9.062 (s, 1H,), 8.552-8.558 (d, 1H, J=1.8 Hz), 7.995-8.025 (d, 1H, J=9 Hz), 7.875-7.912 (t, 1H), 7.437-7.466 (d, 2H, J=8.4 Hz), 7.100-7.128 (d, 2H, J=8.4 Hz), 1.664 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:29])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:28][O:27]4)[CH2:21][CH2:20]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:30][NH2:31]>>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([OH:29])[CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH:26]([OH:27])[CH2:28][NH:31][CH3:30])[CH2:23][CH2:24]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: OC(CN1CCN(CC2CO2)CC1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: CN
Product: CNCC(O)CN1CCN(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To (±)-1-(3,6-dibromo-carbazol-9-yl)-3-(4-oxiranylmethyl-piperazin-1-yl)-propan-2-ol (0.110 g, 0.21 mmol) is added methyl amine (3 mL, 2M in MeOH). The resulting mixture was stirred for 16 hr at rt. Concentration in vacuo, flash chromatography on a 2×14 cm2 column of SiO2 using (ACN:(aqueous NH4OH-25%)) (5:1) as eluting solvent gives the title compound as a white foam in a 90% yield. M.p.: 65-75° C. Slow addition of HCl (1 mL, 1M in Et2O) into a solution of the above compound in DCM (2 mL) gives the hydrochloride salt of the title compound (0.39 g) as a white solid in a 35% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=1>C1COCC1.O.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>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
Reactant: Fc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.95 mol) in THF (4 L), was added portionwise a solution of potassium carbonate (807 g, 5.85 mol) in water (1.6 L), followed by 2-bromo-3-fluoropyridine (361 g, 2.05 mol) and the mixture degassed with argon. To this mixture was added tetrakis(triphenylphosphine)palladium (56.4 g, 48.8 mmol) and the mixture heated at reflux for 5 h. The mixture was cooled to room temperature and the organic layer separated and washed with brine (1 L). This organic solution containing the title compound was used directly in the next reaction (Preparation 27A).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1C=[C:12]2[CH2:14][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[C:1]([O:5][C:6]([CH:8]1[O:20][CH:12]2[CH2:14][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1C=C2CCC1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1OC2CCC1C2
Reaction time: 24 h

Procedure:
Bicyclo[2.2.1]heptan-3-ene-2-carboxylic acid tert-butyl ester (1.94 g) is dissolved in CH2Cl2 (20 mL). m-Chloroperoxybenzoic acid (2.7 g, 70%) was added and the mixture was stirred 24 hrs. When bicyclo[2.2.1]heptan-3-ene-2-carboxylic acid tert-butyl ester disappeared, Na2CO3(sat.) (20 mL) was added then stirred for an additional 2 hrs. The reaction mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed till the pH=7 then evaporated to dryness to obtain the 3-oxa-bicyclo[2.2.1]heptan-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]([Br:5])=[N:3][OH:4].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:4][N:3]=[C:2]([Br:5])[Br:1])=[O:12])=[CH:9][CH:8]=1
Reactant: ON=C(Br)Br
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(ON=C(Br)Br)c1ccc(Cl)cc1
Yield: 0.1 %

Procedure:
A mixture of 3 g (14.78 mole) of dibromoformaldoxime and 2.71 g (15.5 mole) of 4-chlorobenzoyl chloride in methylene chloride (40 ml) is treated with dry pyridine (1.26 g, 16 mole) After workup as in Step B of Example 1 there is obtained 4.4 g (80% theory) of 4-chlorobenzoyldibromoformaldoxime, m.p.=93°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH2:36]OS(C)(=O)=O)[CH:33]=[CH:32][N:31]=1.CC1C=C(CO)C=CN=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: Cc1cc(COS(C)(=O)=O)ccn1
Agent: Cc1cc(CO)ccn1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccnc(C)c3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with methanesulfonic acid 2-methyl-pyridin-4-ylmethyl ester (prepared by mesylation of the commercially available (2-methyl-pyridin-4-yl)-methanol) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 130 °C
Yield: 101.4 %

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)phenol (1 g, 5.55 mmol), 2-fluoro-5-formylbenzonitrile (0.828 g, 5.55 mmol) and K2CO3 (0.921 g, 6.66 mmol) in DMF (10 mL) was heated with a microwave condition at 130° C. for 2 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.74 g, 101% yield) as a brown oil. LCMS: rt=3.38 min, [M+H+]=310