Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:28]=[CH:29][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:35])([F:36])[F:37])=[CH:31][N:32]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(O)(c1cnc(-c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)nc1)C(F)(F)F
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (318 mg, 0.88 mmol), 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (100 mg, 0.44 mmol, Intermediate E), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (18 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (431 mg, 1.32 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.2 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3.MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (70 mg) as an off-white solid and a mixture of enantiomers.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[CH:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[NH2:23]OS(O)(=O)=O>C1COCC1.O>[NH2:23][N:9]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)=[CH:7][C:8]1=[O:10]
Reactant: NOS(=O)(=O)O
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nn1c(C2CC2)cc(-c2ccc(C(F)(F)F)cc2)cc1=O
Temperature: 23 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
To a solution of 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example C.28 step 2) (4.19 g, 15.0 mmol) in THF (225 mL) and 1M NaOH (90.0 mL, 90.0 mmol) was added dropwise a solution of hydroxylamine-O-sulfonic acid (HOSA) (95%, 5.36 g, 45.0 mmol) in H2O (60 mL) at 0° C. The reaction mixture was stirred at 23° C. for 20 h (76% conversion). Added again at 0° C. 3N NaOH (30 mL, 30.0 mmol) and then hydroxylamine-O-sulfonic acid (HOSA) (95%, 5.36 g, 45.0 mmol) and the reaction mixture was stirred at 23° C. for 3 days (88% conversion). Poured into ice water, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4. Removal of the solvent in vacuum left a residue (5.17 g) which was purified by silica gel chromatography (400 g SiO2) to give the title compound as a light yellow solid (2.81 g, 64%). MS (ISP) 295.5 [(M+H)+]; mp 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40]2.C(N(CC)CC)C>C(COC)OC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:42]3[CH:41]=[CH:40][C:39]4[C:44](=[CH:45][CH:46]=[C:37]([O:36][CH3:35])[CH:38]=4)[CH:43]=3)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (2.15 g, 4.0 mmol), 6-methoxy-2-naphthylboronic acid (1.18 g, 6.0 mmol), and triethylamine (1.2 ml, 8.0 mmol) were dissolved in dimethoxyethane (40 ml) in a thick-wall tube. The reaction mixture was purged with N2 for 15 min. Catalyst Pd(PPh3)4 (350 mg, 8%) was added, and the test tube was heated in a microwave reactor to 100° C. for 15 min. The solvent was removed under reduced pressure, and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 0.5 NH4Cl2×, brine 2×, dried over Na2SO4, and filtered through a Celite pad. The crude product was purified by column chromatography (SiO2, 10-15% ethyl acetate in hexanes) to give ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as a dry film. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.96 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 4.37 (q, J=7.1 Hz, 2H); 5.59 (q, J=7.0 Hz, 1H); 6.65 (s, 1H); 7.17 (d, J=2.6 Hz, 1H); 7.20 (dd, J=2.6, 8.9 Hz, 1H); 7.28 (d, J=8.4 Hz, 2H); 7.29 (dd, J=1.8, 8.5 Hz, 1H); 7.30 (t, J=1.9 Hz, 1H); 7.63 (d, J=1.8 Hz, 1H); 7.67 (d, J=8.9 Hz, 1H); 7.76 (d, J=8.5 Hz, 1H); 7.80 (d, J=1.9 Hz, 2H); 7.99 (d, J=8.4 Hz, 2H); MS C31H26Cl2N2O3 Cald: 544.13; Obsd: 545.15.
Reaction SMILES: [O:1]=[C:2]1[CH:9]=[C:8]2[C:4]([C:10]([O:12][CH3:13])=[O:11])([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.[CH2:14](O)C>[Pd]>[O:1]=[C:2]1[CH2:3][C:4]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9]1
Reactant: COC(=O)C12CCCC1=CC(=O)C2
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)C12CCCC1CC(=O)C2
Yield: 81 %

Procedure:
Methyl 5-oxo-1,2,3,3a,4,5-hexahydropentalene-3a-carboxylate (2.5 g, 12.8 mmol) in ethanol (25 mL) was purged with nitrogen for about 10 minutes with stirring. Palladium on carbon (0.043 g, 20 mol %) was added and the reaction vessel was purged with nitrogen for about 10 minutes. The flow of nitrogen was stopped and the flask was flushed with hydrogen. The reaction mixture was stirred overnight under an atmosphere of hydrogen. The flask was flushed with nitrogen for about 20 minutes. The reaction mixture was passed through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 25% ethyl acetate/heptane) to afford ethyl 2-oxooctahydropentalene-3a-carboxylate (2.04 g, 10.4 mmol, 81%).
Reaction SMILES: [CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25][CH3:26])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25]([CH3:26])=[O:38])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (0.22 mmol) of the compound from Example 94 were introduced into 6 ml of dichloromethane at 0° C., 56.1 mg (0.23 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. Methanol was added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 43.6 mg (52% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:28]CC[CH2:25]4)=[CH:17][CH:16]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CN(C)CCOC1C=CC(NC(N)=S)=CC=1>C(Cl)Cl.CO>[CH3:25][N:24]([CH3:28])[CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[S:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Agent: CN(C)CCOc1ccc(NC(N)=S)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3ccc(OCCN(C)C)cc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 3 for [5-(4-methoxy-phenyl)-thiazol-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using [4-(2-dimethylamino-ethoxy)-phenyl]-thiourea. Title compound: ES-MS: 370.0 [M+H]+; single peak at tR=6.13 min (System 1); Rf=0.13 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cnc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (500 mg, 2.43 mmol) in DCM at −78° C., DIBAL-H (2.67 mL, 2.67 mmol) was added dropwise and stirred for 3 h at −78° C. The mixture was allowed to warm up to 0° C. then water (0.12 mL) was added dropwise to the mixture followed by aq. NaOH (15%, 0.12 mL). H2O (0.3 mL) was added then the mixture was warmed up to room temperature and stirred for 15 min and the organic layer collected, dried over MgSO4 and filtered with the filtrate concentrated to give the desired product with was used without further purification (280 mg, Yield 65%). LCMS (m/z): 176.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20].O=S(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(Cl)cc1C(=O)OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of methyl 5-chloro-2-ethylbenzoate (5.12 g, 25.77 mmol) in concentrated H2SO4 (31 ml, 587 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (2.15 ml, 33.51 mmol) and concentrated H2SO4 (2 ml, 37.52 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5 to 0° C. for 1 hour before being poured onto ice (500 ml) and this was extracted with EtOAc (3×100 ml). The combined organic phases was washed with deionized water (100 ml) and then brine (100 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. LCMS and NMR showed ˜30% hydrolysis of the ester. The crude material was dissolved in Methanol (30 ml) and cooled to 0° C. under nitrogen where SOCl2 (2.25 ml, 30.93 mmol) was added slowly. The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure to give 6.18 g (98.4%) of methyl 5-chloro-2-ethyl-3-nitrobenzoate as an orange oil. Product contained 1:1 mixture of 3-nitro:6-nitro isomers along with some ethyl ester which was suitable for use without any further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Ca+2].[Br-:21].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:21][C:10]1[C:11]([CH2:13][OH:14])=[CH:12][C:3]([N:2]([CH3:1])[CH3:15])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CO)cc1N(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(CO)cc1N(C)C
Yield: 83.5 %

Procedure:
After dissolving methyl 2-(dimethylamino)-4-(hydroxymethyl)benzoate (1.023 g, 4.9 mmol) in a methylene chloride (15 ml) and methanol (6 ml) mixed solvent, calcium carbonate (2 g) was added, the mixture was stirred, and then benzyltrimethylammonium tribromide (2.100 g, 5.4 mmol) was gradually added and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was filtered and the solvent was distilled off under reduced pressure. Water was added to the residue, extraction was performed with ethyl acetate and the ethyl acetate layer was washed with water and brine. The aqueous layer was then extracted with a methylene chloride and methanol mixed solvent, combined with the ethyl acetate layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.179 g) as a white solid. (84% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: CCOC(=O)c1cn2cc(Br)ccc2n1
Yield: 72.9 %

Procedure:
15.00 g of 2-amino-5-bromopyridine (3), 16.99 g of ethyl 3-bromo-2-oxopropanoate were dissolved in ethanol (100 mL), and the solution is heated at reflux for 8 hours. The reaction mixture was concentrated, and saturated aqueous NaHCO3 was added to the residue. The resulting precipitate was isolated by filtration, and washed with water to afford 17.01 g of the titled compound as colorless powder (yield: 73%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[C:16]4[C:21]([CH:22]=[C:23]5[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:29][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]2
Reactant: c1ccc2c(-c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Yield: 81.8 %

Procedure:
In a flask were placed 35 g of 9,9′-bianthryl, 18.0 g of N-bromosuccinimide and 500 mL of carbon tetrachloride, and the mixture was stirred overnight. The reaction mixture was filtered, the filtrate was passed through a column filled with alumina. Carbon tetrachloride was evaporated from the solution under a reduced pressure, and then the residue was recrystallized from petroleum ether, to give 35 g(yield: 80%) of 10-bromo-9,9′-bianthryl. Then, in a 100 mL three-necked flask were placed 18.3 g of 10-bromo-9,9′-bianthryl, 10 g of diphenylamine, 8.5 g of potassium carbonate, 0.2 g of copper powder and 50 mL of nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 15 g(yield: 60%) of 10-diphenylamino-9,9′-bianthryl.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)/[C:5](=[CH:13]/[C:14]([OH:16])=O)/[CH2:4]1)[CH3:2].[Cl:17]CCl>>[CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)/[C:5](=[CH:13]/[C:14]([Cl:17])=[O:16])/[CH2:4]1)[CH3:2]
Reactant: CCC1C/C(=C\C(=O)O)c2cc(F)ccc21
Reactant: ClCCl
Product: CCC1C/C(=C\C(=O)Cl)c2cc(F)ccc21

Procedure:
This compound was prepared in an analogous manner to Example 18h with replacement of (E)-2-(6-fluoro-3-methyl- 1 -indanylidene)acetic acid with (E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetic acid (5.7 g. 25.88 mmol). The product residue was dissolved in dichloromethane and used without purification in Example 26.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.C[N:20](C=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:20])=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(-n2cccn2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)c1cccc(-n2cccn2)c1
Yield: 80 %

Procedure:
To a suspension of 3-(1H-pyrazol-1-yl)-benzoic acid [see WO 00/21951] (104 g, 0.55 mol) in anhydrous benzene (500 ml) was added thionyl chloride (85 g, 0.715 mol) and DMF (0.5 ml). The mixture was heated at reflux for 3 hours, then evaporated under reduced pressure. The residue was dissolved in anhydrous THF (100 ml) and evaporated. The residue was dissolved in anhydrous acetone (600 ml), and treated with ammonium acetate (77 g, 1 mol). The mixture was heated at reflux for 12 hours, solvent was evaporated and the residue treated with cold water (2000 ml). The resulting precipitate was filtered, washed with cold water (200 ml) and recrystallised from absolute ethanol (600 ml) to give 3-(1H-pyrazol-1-yl)benzamide (82 g, 80%). A solution of this material (82 g, 0.44 mol) in THF was added dropwise to a solution of LiAlH4 (25 g, 0.66 mol) in anhydrous THF (800 ml). The mixture was heated at reflux for 4 hours, cooled and quenched by the sequential addition of water (25 ml), 15% aqueous NaOH (25 ml), and water (50 ml). The inorganic by-products were filtered off and washed several times with diethyl ether (overall volume 1000 ml). The combined filtrates were dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (400 ml), the solution was treated with activated carbon (10 g), and the mixture was refluxed for 40 minutes, then filtered and evaporated. The residue was treated with 1N HCl in ether (1000 ml), and the precipitate formed was filtered, washed with ether and dried to give the title compound (53 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH:10]([Cl:12])[CH3:11])Cl)=[CH:4][CH:3]=1.F[C:21]1[CH:26]=CC([Si](C2C=CC(F)=CC=2)(CCCl)Cl)=C[CH:22]=1.C([Mg]Br)C=C>O1CCCC1.[Cl-].[NH4+].O>[CH2:26]([Si:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]([Cl:12])[CH3:11])[CH:21]=[CH2:22]
Reactant: Fc1ccc([Si](Cl)(CCCl)c2ccc(F)cc2)cc1
Reactant: CC(Cl)[Si](Cl)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[Si](c1ccc(F)cc1)(c1ccc(F)cc1)C(C)Cl

Procedure:
A solution of 20 g (63 mmol) of a 1:1 mixture of bis(4-fluorophenyl)-1-chloroethyl(chloro)silane and bis(4-fluorophenyl)-2-chloroethyl(chloro)silane in 100 ml of tetrahydrofuran is treated dropwise with 71 ml (71 mmol) of 1.0 molar allyl magnesium bromide in tetrahydrofuran. The mixture is refluxed two hours, cooled, and diluted with saturated aqueous ammonium chloride and water. The aqueous phase is separated and extracted with ether, and the combined organic phases are washed with water and brine, dried over sodium sulfate, and evaporated to give the title compounds as a 1:1 mixture.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:53][CH2:54][CH2:55][O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CCOC(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:53][CH2:54][CH2:55][O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: BrCCCOCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(OCCCOCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 90.8 %

Procedure:
To a 0.5 L stirred round bottom, purged with nitrogen, charge in order: [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-(4-hydroxybenzoyl)-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (13.58 mmol), acetonitrile (250 mL), and potassium carbonate (67.92 mmol). To this stirred solution, at room temperature, add 3-bromopropoxymethylbenzene (27.2 mmol) and heat at 60° C. for 16 hours under nitrogen. Dilute with EtOAc (200 mL) and filter. Concentrate the filtrate and purify by flash chromatography (330 g silica gel) eluting with 2-40% EtOAc/chloroform. Concentrate the product containing fractions to give the title compound (9.0 g. 90.79%): mass spectrum (m/z): 730.4 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][N:37]([C:2]2[C:3]([F:19])=[CH:4][C:5]3[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]([CH:12]4[CH2:14][CH2:13]4)[C:10]=3[N:11]=2)[CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7, with 113 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.4 mmol), 230 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-piperidin-4-yl ester benzyl ester (MW: 571.60, 0.4 mmol), 161 mg triethylamine (MW: 101.19, 1.6 mmol) and 87 mg trimethylchlorsilan (MW: 108.64, 0.8 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 25 mg, 7.6%. MS: 819 (M+H)+, 817.8, Method ESI+, ESI−.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:11])=[CH2:10])=[CH:5][C:4]=1[CH3:12]>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([Cl:1])([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH3:12]
Reactant: Cl
Reactant: C=C(C)c1ccc(C)c(C)c1
Product: Cc1ccc(C(C)(C)Cl)cc1C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
A 0.25 l flask with a stirrer following the wall and a gas inlet tube was filled with hydrogen chloride gas. 73 g of 1,2-dimethyl-4-isopropenylbenzene were then added drop-wise at -5° to -10° C. with vigorous stirring in the course of 30 minutes, hydrogen chloride being re-added. The absorption of gas was complete 5 minutes after the end of the dropwise addition. Hydrogen chloride was stripped off from the reaction product under reduced pressure (35° C./0.8 mbar) and 89.6 g (98.2% of theory) of 1,2-dimethyl-4-(α-chloroisopropyl)benzene were obtained, m.p.: -20° to -19° C., decomposition at >50° C./1 mbar with elimination of HCl.