Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:16][CH:15]=[CH:14][CH2:13][N:12]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:11]1[C:28]([OH:30])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31][NH:32]C(C1C(COC(=O)C)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[OH:31][NH:32][C:28]([CH:11]1[CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH:15]=[CH:14][CH2:13][N:12]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:30]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COCc3ccccc3)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(COCc3ccccc3)C2C(=O)NO)cc1

Procedure:
3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide was synthesized from 3-Benzyloxymethyl-1-(4-methoxy-benzene sulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid in the same manner as the procedures used for the preparation of Acetic acid 2 -hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester: MS (M+H)+ =447, (M+NH4)+ =464.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.FC1C=C2C(N=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[O:11]=[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]1[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]1
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Yield: 34.8 %

Procedure:
Quinolin-2(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. Chromatography on silica gel with 0-5% methanol in dichloromethane gave 220 mg (35%) of product as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCNc1ccc([N+](=O)[O-])c(N)c1
Temperature: 135 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (21.6 g, 125 mmol), 2-Methoxy-ethylamine (28.1 g, 375 mmol) and anhydrous potassium carbonate (18.9 g, 137 mmol) in N,N-dimethylacetamide (40 ml) was stirred at 135° C. under nitrogen for 2 days. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 30 minutes The resulting precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford N1-(2-methoxy-ethyl)-4-nitro-benzene-1,3-diamine (16 g, 61%) as a yellow-orange powder, and used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1)[CH2:24][OH:25].C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@@H:23]([NH:22][C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[N:7]=2)[CH2:24][OH:25])=[N:27][CH:28]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: N[C@@H](CO)c1ccc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 7, 0.5 g) and (2R)-2-amino-2-(5-fluoropyridin-2-yl)ethanol hydrochloride (Intermediate 23, 0.45 g) in n-BuOH (10 mL) with diisopropylethylamine (3 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.45 g of desired product. MS (electrospray): 418 (M+1) for C18H20FN7O4. 1H NMR (300 MHz, CD3OD) δ ppm 8.50 (s, 1H) 8.20 (d, 1H) 7.60 (s, 1H) 7.45 (s, 1H) 6.30 (s, 1H) 5.70 (s, 1H) 5.45 (m, 1H), 4.60 (m, 1H) 3.90 (m, 2H) 1.30 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:7][C:8](=[O:19])[C@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[CH2:5]O.CCN(S(F)(F)F)CC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:19][C:8]([C@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])=[N:7]1)=[O:20]
Reactant: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1COC([C@@H](C)NC(=O)OC(C)(C)C)=N1
Temperature: -76 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
In a round-bottomed flask, 2-((R)-2-tert-butoxycarbonylamino-propionylamino)-3-hydroxy-propionic acid methyl ester (419 mg, 1.3 mmol) was dissolved in dichloromethane (11 ml). The solution was cooled to −76° C. and DAST (0.20 ml, 1.51 mmol) was added dropwise. The light yellow solution was stirred at −76° C. for 2 h then anhydrous potassium carbonate (269 mg, 1.95 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature, quenched with 10 ml of saturated aqueous NaHCO3 and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 339 mg (91%) of 2-((R)-1-tert-butoxycarbonylamino-ethyl)-4,5-dihydro-oxazole-4-carboxylic acid methyl ester as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]1([C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:22][CH2:23]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)COCCCl
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Product: CCOC(=O)COCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1

Procedure:
This ester is prepared by the method described in Example 1.2, starting from ethyl (2-chloroethoxy)-acetate and 4-(diphenylmethylene)-piperidine. It is not isolated but used as such, without further purification, for the preparation of the corresponding acid (see Example 3.3).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2].[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:4]([CH:18]=[O:20])=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Formylation. 3-Ethyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (94 g, 0.405 mol) was stirred with glacial acetic acid (670 mL), and hexamethylenetetramine (102.6 g, 0.73 mol) was added in one portion. The mixture was heated at 95° C. for 3 h, hot water (670 mL) added, and the heating was continued for an additional 1.5 h at 100° C. The mixture was cooled to 20° C., toluene (200 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (3×150 mL), then neutralized with 5% NaHCO3 solution, and finally washed with brine (50 mL). The solvent was evaporated and the residue distilled to give 3-ethyl-2-formyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (77.9 g), bp 127°-132° C./0.5 mm, GLC purity 98%, 1H-NMR (CDCl3) δ12.87 (1H, s), 10.20 (1 H, s), 6.72 (1H, s), 2.89 (2H, q), 1.65 (4H, m), 1.44 (6H, s), 1.30 (3H, t), 1.29 (6H, s). 13C-NMR (CDCl3) δ194.3 (1C, d), 163.6 (1C, s), 156.7 (1C, s), 144.6 (1C, s), 130.8 (1C, s), 118.5 (1C, d), 115.2 (1C, s), 37.7 (1C, t), 35.5 (1C, s), 34.7 (1C, t), 34.0 (1C, s), 31.1 (2C, q), 27.7 (2C, q), 24.8 (1C, t), 16.9 (1C, q). IR (KBr) 1609 cm-1MS (m/e) 260.3 (M+, 22.6), 245.2 (100.0), 203.3 (18.2), 246.2 (17.0).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)Oc1cc(C)cc(C)c1C
Reaction time: 36 h
Yield: 87.2 %

Procedure:
To a solution of 2,3,5-trimethylphenol (20.0 g, 147 mmol) in dimethylsulfoxide (100 ml) was added methyl 2-bromoisobutyrate (52.2 g, 288 mmol) and potassium carbonate (40.0 g, 289 mmol) at room temperature. The mixture was stirred for 36 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using basic silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 30.3 g (yield 87%) of oily title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C@@H:13]([OH:41])[C@@H:14]([N:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:41])[C@@H:14]([N:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)c1cccn1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 27.8 %

Procedure:
Add 2-[2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-pyrrole-1-carboxylic acid tert-butyl ester (0.415 g, 0.74 mmol), 10% platinum on carbon (0.087 g) and methanol (15 mL) and hydrogenate at one atmosphere hydrogen gas for 1-8 h. Add filter agent and filter, concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a white foam (0.116 g, 28%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1>C(O)(=O)C>[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:11]([OH:14])=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=1
Reactant: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
65% aq. nitric acid solution (1.76 mL, 39 mmol) and fuming nitric acid (3.25 mL, 78 mmol) were added at −10° C. to a solution of 4-hydroxy-3-trifluoromethyl-benzoic acid methyl ester (4.31 g, 19.6 mmol) in acetic acid (54 mL). The ice bath was removed and the solution was stirred at room temperature for 5 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to afford 4-hydroxy-3-nitro-5-trifluoromethyl-benzoic acid methyl ester (5.16 g, 99%). Orange solid, MS (ISP)=263.9 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)(=[O:4])[CH2:2][CH3:3].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[CH2:22]=O>C(O)C>[N:16]1([CH2:3][CH:2]([CH3:22])[C:1]([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=2)=[O:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=O
Reactant: CCC(=O)c1cc(-c2ccccc2)no1
Reactant: C1CCNCC1
Solvent: CCO
Product: CC(CN1CCCCC1)C(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Added to 10 ml of ethyl alcohol were 2.0 g (10.0 mmol) of 5-propionyl-3-phenylisoxazole and 1.7 g (20.0 mmol) of piperidine, followed by the dropwise addition of 1.63 ml (20.0 mmol) of a 37% aqueous solution of formaldehyde under ice cooling. After the reaction mixture was stirred for 2 hours at room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl ether. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby the target compound, namely, 5-(2-piperidinomethylpropionyl)-3-phenylisoxazole was obtained as crystals.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[S:12](=[O:18])(=[O:17])[C:11]([CH3:20])([CH3:19])[CH2:10]2)[N:3]=1.[CH3:21][C:22]1([CH3:37])[CH2:27][CH2:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH2:23]1>>[CH3:21][C:22]1([CH3:37])[CH2:27][CH2:26][C:25]([C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[S:12](=[O:18])(=[O:17])[C:11]([CH3:20])([CH3:19])[CH2:10]3)[N:3]=2)=[CH:24][CH2:23]1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)CC(c2ccc(N)c(Br)n2)CC(C)(C)S1(=O)=O
Product: CC1(C)CC=C(c2nc(C3CC(C)(C)S(=O)(=O)C(C)(C)C3)ccc2N)CC1

Procedure:
The title compound was prepared from 2-bromo-6-(2,2,6,6-tetramethyl-1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-pyridin-3-ylamine (as prepared in the previous step) and 4,4-dimethyl-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane according to the procedure of Example 15, step (f). Mass spectrum (APCI, m/z): Calcd. for C22H34N2O2S, 391.2 (M+H), found 391.3.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:12][C:13]([CH3:38])=[CH:14][CH2:15][CH2:16][C:17]([CH3:37])=[CH:18][CH2:19][CH2:20][C:21]([CH3:36])=[CH:22][CH:23]=[C:24]([CH:33]([CH3:35])[CH3:34])[CH:25]([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:26]#[N:27]>O1CCCC1>[CH3:34][CH:33]([C:24]1[C:25]([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([C:26]#[N:27])[CH2:12][C:13]([CH3:38])=[CH:14][CH2:15][CH2:16][C:17]([CH3:37])=[CH:18][CH2:19][CH2:20][C:21]([CH3:36])=[CH:22][CH:23]=1)[CH3:35].[CH3:35][CH:33]([C:24]1[C:25](=[O:28])[CH2:26][C:13]([CH3:38])=[CH:14][CH2:15][CH2:16][C:17]([CH3:37])=[CH:18][CH2:19][CH2:20][C:21]([CH3:36])=[CH:22][CH:23]=1)[CH3:34]
Reactant: CC(=CCCC(C)=CCCC(C)=CC=C(C(C)C)C(C#N)O[Si](C)(C)C)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=CC=C(C(C)C)C(=O)CC(C)=CCCC(C)=CCC1
Product: CC1=CC=C(C(C)C)C(C#N)(O[Si](C)(C)C)CC(C)=CCCC(C)=CCC1
Reaction time: 0.33 h
Yield: 83 %
Yield: 16 %

Procedure:
A solution of lithium bis(trimethylsilyl) amide (5.0 mmol, 0.25 M) in dry tetrahydrofuran (20 ml) is stirred under argon atmosphere on an oil bath at 40° C. and thereto is dropwise added a solution of the cyanohydrin trimethylsilyl ether which is 15-chloro-3-(1-methylethyl)-6,10,14-tri-methyl-2-trimethylsiloxy-3,5,9,13-pentadecatetraenenitrile (378 mg, 0.895 mmol) prepared in Reference Example 5 in dry tetrahydrofuran (15 ml) over 50 minutes. After stirring the mixture at this temperature for 20 minutes, the reaction is quenched by adding a saturated aqueous ammonium chloride solution while stirring on an ice-water bath. After removing tetrahydrofuran by distillation under reduced pressure, the organic layer is extracted with ether. The obtained extract is purified by silica gel column chromatography (n-hexane/ethyl acetate =60:1) to give 2-(1-methylethyl)-5,9,13-trimethyl-1-trimethylsiloxy -2,4,8,12-cyclotetradecatetraene-1-carbonitrile (288 mg, 83%) and 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraene-1-on (42.9 mg, 16%).
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19]C(=O)C)[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C>O>[CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH2:19])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N)c1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture containing 6.30 g of N-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide, a 10% sodium hydroxide aqueous solution, 300 ml of ethanol and 200 ml of water was stirred at room temperature for 4 hours and then at 50° C. for 3 hours. The solvent was distilled off to approximately a half volume, and the residue was adjusted to a pH of 2 with 10% hydrochloric acid. The crystals precipitated were collected, and were dried under reduced pressure to give 5.22 g of N-1-butanesulfonyl-3-amino-4-nitrobenzamide.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:22][CH2:21][C@@H:20]([OH:23])[C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=[C:11]2[CH2:10]1>CO.[Pd]>[NH2:17][C:15]1[CH:16]=[C:11]2[CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:22][CH2:21][C@@H:20]([OH:23])[C:12]2=[N:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Reaction time: 4 h

Procedure:
The mixture of Pd/C (37 mg, 0.035 mmol) and (6R,9R)-6-(2,3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (300 mg, 0.937 mmol) in methanol (10 mL) was hydrogenated under H2 (balloon) for 4 h. LCMS showed the reaction was over. The reaction was filtered through a celite plug. The filtrate was concentrated to give the crude product. MS (ESI)[M+H+]=291.29; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84 (br. s., 1H) 7.02 (br. s., 3H) 6.79 (br. s., 1H) 5.90 (br. s., 1H) 4.74 (d, J=10.32 Hz, 1H) 3.87 (br. s., 2H) 3.06 (t, J=12.34 Hz, 1H) 2.86 (br. s., 1H) 2.62 (d, J=13.85 Hz, 1H) 2.26 (d, J=12.34 Hz, 1 H) 1.96-2.12 (m, 3H) 1.52 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([F:11])[C:5]2=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cnc2[nH]c(Cl)nc(Cl)c1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)nc(Cl)nc32)cc1
Reaction time: 24 h

Procedure:
A solution of 2,4-dichloro-5-fluoro-1H-pyrrolo[2,3-d]pyrimidine (1.65 g, 8.01 mmol, crude material from abovefl) in dichloromethane (100 ml) was treated with DIPEA (2.80 ml, 16.02 mmol) and p-toluenesulfonylchoride (1.756 g, 9.21 mmol) and stirred for 24 hours. The mixture was poured into saturated sodium bicarbonate/DCM and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography (10% EtOAc/Hex). The chromatographic residue (still containing multiple impurities) was further purified with a 65% isocratic MeCN mobile phase on a Luna C18 5 um, 21×150mm column, 20 mL/min, UV @275 nm. The final purity of 2,4-dichloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine was estimated at 99.5% at 254 nm using the same method (1.128 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=2.20 Hz, 1H), 7.96 (d, J=8.24 Hz, 2H), 7.47 (d, J=8.79 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)[O:6][CH:7]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:24][C:7]1[O:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: ClCc1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Solvent: ClC(Cl)Cl
Product: ClCc1nc(-c2ccc(Cn3cnc4ccccc43)cc2)oc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of 1-{4-[4-(chloromethyl)-1,3-oxazol-2-yl]benzyl}-1H-benzimidazole (0.40 g, 1.24 mmol) in dry chloroform was treated with N-bromosuccinimide (NBS) (0.24 g, 1.36 mmol), stirred at room temperature for 1 h and concentrated in vacuo. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. This residue was purified by column chromatography (silica, CH2Cl2:MeOH 98:2) to afford the title compound in 56% yield, identified by NMR and mass spectral analyses. 1H NMR (300 MHz, DMSO-d6): 8.43 (s, 1H), 7.93 (m, 2H), 7.59-7.76 (m, 1H), 7.47-7.53 (m, 1H), 7.45 (m, 2H), 7.10-7.31 (m, 2H), 5.60 (s, 2H), 4.65 (s, 2H). LCMS (ESI+) 402, 404 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[F:16][C:17]1[C:22]([F:23])=[C:21](O)[CH:20]=[CH:19][C:18]=1/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28]>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:21]2[CH:20]=[CH:19][C:18](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[C:17]([F:16])[C:22]=2[F:23])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(F)c1F
Reactant: OCc1c(Cl)nsc1-c1ccc(Cl)cc1
Product: O=C(O)/C=C/c1ccc(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 135 following Step 8 and 9 by coupling of (3-chloro-5-(4-chlorophenyl)isothiazol-4-yl)methanol and (E)-ethyl 3-(2,3-difluoro-4-hydroxyphenyl)acrylate then hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=12.5 Hz, 1H), 7.48 (s, 2H), 7.28 (s, 2H), 6.52 (d, J=11.5 Hz, 1H), 5.04 (s, 2H).