Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N+:16]([O-])=O)([CH3:15])[CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:6]>CO>[NH2:16][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:6]
Reactant: CC(C)(CCS(=O)(=O)Oc1ccccc1)[N+](=O)[O-]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)Oc1ccccc1
Reaction time: 20 h
Yield: 96.9 %

Procedure:
13.42 g of phenyl 3-methyl-3-nitrobutane-1-sulfonate were dissolved in 40 ml of MeOH, and 2.9 g of Raney nickel which had been washed until neutral were added. Hydrogenation was carried out under a pressure of 5 bar of hydrogen at RT for 20 hours. The catalyst was then filtered off and the solvent was removed in vacuo. 11.58 g of an amorphous solid were obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:7][CH2:8][C:9]#[CH:10].[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].[OH-].[Na+]>C1COCC1>[CH2:27]([Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH2:25][CH3:26])[C:10]#[C:9][CH2:8][CH2:7][CH2:6][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CCCCOC1CCCCO1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC[Sn](C#CCCCOC1CCCCO1)(CCCC)CCCC
Temperature: 15 °C
Yield: 26 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes, 22 mL) was added dropwise to a solution of 2-(pent-4-ynyloxy)tetrahydropyran (Intermediate 25, 7.70 g) in THF (60 mL), at −60° C. The mixture was stirred and allowed to warm to 15° C. over 1 hour. It was then re-cooled to −60° C. and a solution of tributyl tin chloride (16.4 g) in THF (50 mL) was added dropwise over 30 minutes. The mixture was stirred and allowed to warm to 20° C. over 1 hour. 1M aqueous sodium hydroxide (4 mL) was cautiously added and the resultant mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give tributyl-[5-(tetrahydropyran-2-yloxy)-pent-1-ynyl]-stannane (5.44 g).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]\[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([OH:15])[CH:7]=1.S(Cl)(Cl)=O.[OH:26][CH2:27][CH2:28][NH2:29].Cl>CCCCCCCC.N1C=CC=CC=1>[OH:26][CH2:27][CH2:28][NH:29][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:7][C:8]=1[OH:15]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(O)c1
Reactant: NCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCCCC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCO)c(O)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
In 50 ml of n-octane was dissolved 2.00 g (6.9 mmol) of 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoic acid, and 5.0 ml (35 mmol) of thionyl chloride was added to the solution, followed by heating at 90° C. for 5 hours to conduct a reaction. After completion of the reaction, the reaction mixture was cooled, and n-octane was removed by evaporation. The residue was dissolved in n-octane, and a pyridine solution of 0.84 g (13.8 mmol) of 2-hydroxyethylamine was added thereto dropwise at room temperature. After the dropwise addition, the mixture was stirred for 10 minutes, poured into a 12% hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was recrystallized from an ethyl acetate/hexane mixed solvent to obtain 0.50 g (yield: 22%) of N-(2-hydroxyethyl)-4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzamide represented by the following structural formula (hereinafter referred to as compound 46) as white crystals. The analytical results are shown below. ##STR67##
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([N:6]([S:22]([CH3:21])(=[O:24])=[O:23])[S:22]([CH3:21])(=[O:24])=[O:23])=[C:4]([CH:11]2[CH2:12][CH2:13]2)[CH:3]=1
Reactant: COc1cc(N)c(C2CC2)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)c(C2CC2)cc1Cl
Temperature: 5 °C
Yield: 80 %

Procedure:
A mixture of Example 18B (1.0 equivalent) and triethylamine (2.3 equivalents) in tetrahydrofuran (0.5 M final concentration based on product from Example 18B) was cooled to 5° C. and treated dropwise with methane sulfonyl chloride (2.3 equivalents) maintaining the temperature below 20° C. After the addition was completed, the reaction mixture was warmed up to ambient temperature for 20 minutes and partitioned with water and methylene chloride. The organic layer was washed with 5% aqueous NaCl solution, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with isopropyl acetate/heptane (2:1), and the solid was collected by filtration and dried to constant mass (80% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4nc(=O)c(O)c[nH]4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (25 mg) (0.042 mmol), 8.6 mg (0.055 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 10.5 mg (0.055 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed in a high vacuum at room temperature and the residue is treated with 3 ml of water. The precipitated product is filtered off and washed in succession with water and diethyl ether. After drying in a high vacuum there are obtained 20 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl] thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(=O)(O)[O-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](Cl)[N:28]3[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]#[N:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[NH:26][C:27](=[O:3])[N:28]3[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]#[N:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2nc(Cl)n3Cc2ccccc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[nH]c(=O)n3Cc2ccccc2C#N)CC1
Temperature: 135 °C
Yield: 45.9 %

Procedure:
Sodium acetate (0.168 g) and sodium bicarbonate (0.100 g) were added to a solution of 4-[8-chloro-9-(2-cyanobenzyl)-9H-purin-6-yl]-piperazine-1-carboxylic acid t-butyl ester (0.100 g) in dimethylsulfoxide (3 mL). This was then heated at 135° C. for 45 hours. The reaction solution was filtered, and then directly loaded onto a column for purification by reverse phase high performance liquid chromatography to give the title compound (0.044 g).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Br[CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]=1[CH3:39].[Cl-].[NH4+]>CCOCC.CCCCCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH:8]([CH:28]=[CH:29][CH:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[C:31]3[CH3:39])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(CCBr)c2ccccc2C1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2ccccc2C1C=CC1c2cc(C(C)(C)C)ccc2-c2ccc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
To a 100 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel, 2,7-di-t-butylfluorene (1.18 g, 4.22 mmol) and dehydrated ether (30 ml) were introduced. To the flask was dropwise added a hexane solution of n-butyllithium (1.67 mol/l, 2.8 ml, 4.64 mmol) at 0° C. over a period of 1 hour, followed by stirring at room temperature for 7 hours. The reaction liquid became red orange transparent. Then, the liquid was cooled to −78° C. (a yellow orange slurry), to which a solution of 3-(2-bromoethyl)-2-methylindene (1 g, 4.22 mmol) in dehydrated ether (10 ml) was dropwise added over a period of 30 minutes. Then, the temperature of the system was allowed to spontaneously rise to room temperature, followed by stirring for 15 hours. The reaction mixture gradually became a yellow slurry. The resulting yellow slurry was poured into 200 ml of a saturated ammonium chloride aqueous solution to separate an ether phase. The aqueous phase was extracted with ether (100 ml×2), and a combined organic phase was dried over anhydrous magnesium sulfate, Then, the solvent was distilled off, and the resulting white yellow powder was reslurried with hexane (100 ml) and filtrated to obtain 1.70 g (yield: 93%) of an aimed product of a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](O)(=[O:13])C.C1N2CN3CN(C2)CN1C3>O>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH:11]=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc2cc[nH]c2n1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2nc(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
6-Chloro-1H-pyrrolo[2,3-b]pyridine (0.041 g, 0.27 mmol) was successively added with acetic acid (0.1 mL), water (0.2 mL), and hexamethylenetetramine (0.053 g, 0.28 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and the precipitated solid was collected by filtration to obtain 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.031 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[C:7]1=[O:14].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)=[C:8]([I:13])[C:7]1=[O:14]
Reactant: O=c1c(I)c(O)ccn1Cc1cccc(F)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c(I)c(OCc2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin-2(1H)-one (0.5 g, 1.44 mmol) in DMF (5 mL) was added K2CO3 (0.199 g, 1.44 mmol) followed by the addition of 4-fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction mixture stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. 1H-NMR (CD30), 400 MHz) δ7.75 (d, 1H, J=7.6 Hz), 7.49 (q, 2H), 7.34 (q, 1H), 7.11 (m, 5H), 6.40 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 454.0098 (M+H calculated for C19H15NO2F2I requires 454.0110).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)OC)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 2) and methyl bromoacetate. 1H-NMR (CDCl3) δ: 8.08 (1H, d, J=1.8 Hz), 7.42 (1H, d, J=8.8 Hz), 7.22 (1H, dd, J=8.8, 1.8 Hz), 5.17 (2H, br s), 4.40 (2H, q, J=7.3 Hz), 3.88 (3H, s), 1.40 (3H, t, J=7.3 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11][OH:12])=[CH:6][CH:7]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
In analogy to example 22, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and (3-methylsulfonylphenyl)boronic acid was prepared the title compound as a mixture of E and Z isomers (2:1) as a white foam, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[OH:32][C:33]1([C:40]2[S:44][CH:43]=[N:42][CH:41]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:36]3[CH2:35][CH2:34][C:33]([OH:32])([C:40]4[S:44][CH:43]=[N:42][CH:41]=4)[CH2:38][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH2:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH2:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (296 mg, 75%).
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]>O1CCOCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])[CH2:26][CH2:25]3)[CH2:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1cc(C2=CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Product: COc1cc(C2=CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A solution of methyl vinyl sulfone (201 mg, 1.89 mmol) and 1-{4-[3-(methyloxy)-4-nitrophenyl]-3-cyclohexen-1-yl}piperazine (200 mg, 0.63 mmol) was stirred in dioxane (6 mL) under N2. The reaction was then heated to 95° C. and stirred for approximately 3 h. The reaction was then cooled to rt and concentrated under vacuum. The residue was taken up in DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step G (222 mg, 0.52 mmol, 83%) as a light yellow solid. MS (ESI): 424 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:11]=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1Br
Reaction time: 1.5 h

Procedure:
To a solution of dimethyl 2-bromoterephthalate (1.04 g) in methanol (10 mL) was added 1 N sodium hydroxide (5.71 mL) at room temperature. After stirring for 1.5 hour, the reaction was quenched by adding 1 N hydrochloric acid (7 mL). White crystals were formed. Water (10 mL) was added to aid crystalyzation. The crystals were collected by filtration, washed with water, and dried in the air. 3-Bromo-4-(methoxycarbonyl)benzoic acid was obtained as white crystals (532 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl.N>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A mixture of N-benzoyl 2-methyl-4-nitroaniline (2.93 g, 11.4 mmol) and tin (II) chloride (12.9 g, 57.2 mmol) were heated in ethyl acetate (100 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature and concentrated aqueous ammonia (20 ml) was added. The reaction was filtered, the solid material was washed with ethyl acetate (3×30 ml) and then the combined organic layers were evaporated in vacuo. Drying of the resultant solid in vacuo, yielded N-benzoyl 2-methyl-4-aminoaniline (1.03 g, 40% yield) as a white crystalline solid:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1>ClC(Cl)C.C(N)C1C=CC=CC=1.C(O)C>[CH2:6]([NH:7][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH:10]=1)[C:5]1[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: NCc1ccccc1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@H](CNCc1ccccc1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, benzylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=88%, [M+H]+=393.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.[CH3:26][C:27](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([Mg]Br)C.C(OCC)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Agent: CC[Mg]Br
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a stirred suspension of [10-chloro-1-(3,5-dichloropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]methanol (376 mg, 0.946 mmol) in acetonitrile (10 mL) was added Dess-Martin reagent (481 mg, 1.14 mmol) at room temperature. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and a solution of ethyl magnesium bromide in diethyl ether (3.0 M, 568 μL, 1.70 mmol) was added at −78° C. After 30 min, the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (301 mg, 0.707 mmol, 75%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH2:13][CH3:14])[C:4]=1N)[CH3:2].Cl.N([O-])=O.[Na+].[PH2](O)=O>O>[CH2:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH2:13][CH3:14])[CH:4]=1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CCc1cc(CC)cc([N+](=O)[O-])c1
Reaction time: 24 h

Procedure:
A solution of 19.4 parts of 2,6-diethyl-4-nitroaniline in 40 parts by volume of concentrated hydrochloric acid is diluted with 80 parts of water and added to 100 parts of ice. A solution of 7 parts of sodium nitrite in 15 parts of water is added and the filtered diazonium solution treated with 150 parts by volume of 50% hypophosphorous acid and kept cold for 24 hours. The 3,5-diethylnitrobenzene which separates is extracted with ether and distilled, b.p. 190°/20mm.