Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.F[C:11]1C=CC=C(C)C=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](C)[C:20]=1[N+:29]([O-:31])=[O:30]>>[F:18][C:19]1[CH:24]=[C:23]([CH3:11])[C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1[N+](=O)[O-]
Reactant: Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of HNO3 (60 mL) and H2SO4 (80 mL), cooled in an ice bath, was added 1-fluoro-3-methyl-benzene (27.5 g, 25 mmol) at such a rate that the temperature did not rise over 35° C. The mixture was allowed to stir for 30 min at room temperature and poured into ice water (500 mL). The resulting precipitate (a mixture of the desired product and 1-fluoro-3-methyl-2,4-dinitro-benzene, approx. 7:3) was collected via filtration and purified by recrystallization from 50 mL isopropyl ether to give 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)([OH:3])=[O:2].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:11][O:18][C:19]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:4]([C:1]([OH:3])=[O:2])[CH2:5]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCCNC1
Product: O=C(O)C1CCCCN(C(=O)OCc2ccccc2)C1

Procedure:
3-Carboxyhomopiperidine (Source: U.S. Pat. No. 4,409,146) is reacted with benzoxycarbonyl chloride to give 3-(carboxy)-1-homopiperidinecarboxylic acid phenylmethyl ester. This derivative is isolated and reacted with diborane in tetrahydrofuran to give 3-(hydroxymethyl)-1-homopiperidinecarboxylic acid phenylmethyl ester. This derivative is isolated and reacted with pyridinium chlorochromate to give 3-(formyl)-1-homopiperidine carboxylic acid phenylmethyl ester. The epoxide of this derivative is prepared by reacting with trimethyl sulfoxonium iodide and sodium hydride in an aprotic solvent. This epoxide is reacted with sodium phenoxide and the reaction mixture is acidified to give 2-(1-hydroxy-2-phenoxyethyl)-1-homopiperidinecarboxylic acid phenylmethyl ester which is hydrogenated over palladium on carbon to give the free base of the title compound. The free base is then converted to the hydrochloride salt as in Example 38.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:23])/[CH:20]=[CH:21]/[CH3:22]>C1COCC1.CCOCC>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:23])/[CH:20]=[CH:21]/[CH3:22]
Reactant: C/C=C/C(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
A solution of (4S)-4-benzyl-2-oxazolidinone (1.0 g, 5.6 mmol) in anhydrous THF (20 ml) was cooled to −78° C. n-BuLi (1.6 M solution in hexanes, 3.5 ml, 5.6 mmol) was added dropwise to the cooled solution. After 30 minutes, crotonyl chloride (0.59 ml, 6.2 mmol) was added to the mixture. The reaction was stirred for 30 minutes at −78° C., then warmed slowly to room temperature. The reaction mixture was quenched by addition of 4 ml saturated aqueous ammonium chloride. The resultant reaction mixture was diluted with ether, and washed with water and brine. The organic layer was dried using anhydrous Na2SO4 and evaporated under reduced pressure. Flash chromatography on a silica gel column using ethyl acetate/hexane (1/3) as eluent provided compound 1, i.e., (4S)-3-((E)-2-butenoyl)-4-benzyl-2-oxazolidinone, (1.50 g, 87%) as a white solid. m.p.: 83° C. IR (KBr): 3027, 2922, 2539, 1772, 1682, 1351, 1209 cm−1. 1H NMR (400 MHz, CDCl3): 7.36-7.15 (m, 7H, aromatic H's, CH═CH); 4.75-4.70 (m, 1H, CHN); 4.23-4.15 (m, 2H, CH2O); 3.33 (dd, 1H, J=3.3, 13.4 Hz, CHHPh); 2.79 (dd, 1H, J=9.5, 13.4 Hz, CHHPh); 1.98 (dd, 3H, J=1.0, 6.2 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ 164.69, 153.51, 146.95, 135.28, 129.37, 128.86, 127.23, 121.74, 66.01, 55.20, 37.79, 18.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1
Reactant: C1COCCN1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)N3CCOCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (7 mg, 0.0165 mmol), 4-dimethylaminopyridine (1.0 mg, 0.0081 mmol) and morpholine (2.9 mg, 0.0333 mmol) were dissolved in methylene chloride (2 ml), WSC-HCl (9.5 mg, 0.0495 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (8.0 mg, 0.0162 mmol, 98%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O1CCOCC1.[OH-].[Na+]>O>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(C(=O)O)c1ccc(N=[N+]=[N-])cc1
Yield: 60.7 %

Procedure:
A mixture of 10 g of 2-(4-azidophenyl)-3-methylbutanoic acid, benzyl ester, 25 ml of dioxane, 10 ml of water and 5.2 g of 50% sodium hydroxide was stirred and boiled under reflux for 30 hours. Most of the dioxane was evaporated in vacuum, and the oily residue diluted with water and butyl chloride, and acidified with 4 N HCl. The butyl chloride solution was washed with water (2 times) and saturated brine, dried (MgSO4), and evaporated to a residual oily solid. Stirring with hexane provided 4.3 g of 2-(4-azidophenyl)-3-methylbutanoic acid as a yellowish solid, m.p. 95°-97°. The infrared spectrum shows absorption peaks at 2120 cm-1 (azide) and 1715 cm-1 (carboxylic acid carbonyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:5][C:4]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=2[O:2][CH3:1])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 77.2 %

Procedure:
Using 2,5-dimethoxyaniline (2.53 g, 16.5 mmol) and 4-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.50 g (77.2%) of the title compound in the form of orange needle crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([N+:22]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H]>[Pd].COCCO>[NH2:22][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:7]([C:6]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:4]([NH2:1])[CH:5]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1)c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cc(C(=O)c2ccc(Oc3ccccc3)c(N)c2)ccc1Oc1ccccc1
Yield: 86.6 %

Procedure:
To a reaction apparatus equipped with a thermometer, reflux condenser and stirrer, 60 g (0.131 mol) of 3,3'-dinitro-4,4'-diphenoxybenzophenone, 150 g of methyl cellosolve and 3.0 g of 5%-Pd/C (50% moisture content) were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 45 g (86% yield) of 3,3'-diamino-4,4'-diphenoxybenzophenone as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc(Cl)cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-chlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(317/319); MS (ESI) m/z [M−H]−(315/317); Anal. calcd for C17H17ClN2O2: C, 64.46; H, 5.41; N, 8.84. Found: C, 63.40; H, 5.46; N, 7.97.
Reaction SMILES: NCCN1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>C(O)C>[OH:34][C@@H:32]([CH3:33])[CH2:31][N:30]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: C[C@H](O)CN
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](O)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C

Procedure:
A mixture of 5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A, Step 3) (200 mg 0.59 mmol), triethylamine (82 μl, 0.59 mmol) and (S)-1-aminopropan-2-ol (44.6 mg 0.59 mmol) in ethanol (2 ml) was heated under microwave radiation for 1 hour. The reaction mixture was filtered and the residue rinsed with ethanol to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.Cl.O>C1C=CC=CC=1>[CH2:16]([O:15][C:9](=[O:14])[CH:10]=[C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)[CH3:13])[CH3:17]
Reactant: Nc1cccc(I)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1cccc(I)c1
Reaction time: 4 h

Procedure:
A mixture of 47.79 g 3-iodoaniline, 27.7 ml ethyl acetoacetate and 0.13 ml 37% hydrochlorid acid in 65 ml benzene is boiled under a reflux condenser fitted with a water separator. After 4 h. 4 ml of water have been collected. The solvent is removed at reduced pressure and the residual oil dried in vacuo 3-(3-iodo-phenylamino)-but-2-enoic acid ethyl ester is obtained as a light brown oil. MS (ISP): 332.1 (M+H)+.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([CH2:10]P(=O)(OCC)OCC)#[N:9].[Br:19][C:20]1[C:28]2[O:29][CH2:30][CH2:31][C:27]=2[C:26]2[C:25](=O)[CH2:24][CH2:23][C:22]=2[CH:21]=1>O>[Br:19][C:20]1[C:28]2[O:29][CH2:30][CH2:31][C:27]=2[C:26]2/[C:25](=[CH:10]/[C:8]#[N:9])/[CH2:24][CH2:23][C:22]=2[CH:21]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCc2cc(Br)c3c(c21)CCO3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#C/C=C1\CCc2cc(Br)c3c(c21)CCO3
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
60% Sodium hydride (0.17 g, 4.35 mmols) was added to a tetrahydrofuran (20 ml) solution of diethyl cyanomethylphosphonate (0.77 g, 4.35 mmols) while cooling with ice, and the mixture was stirred for 20 minutes. To this was added a tetrahydrofuran (10 ml) solution of 4-bromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (1.00 g, 3.95 mmols), and the mixture was stirred at room temperature further for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (hexane/ethyl acetate=from 85/15 to 8/2) and then recrystallized from ethyl acetate/isopropyl ether to obtain 0.47 g (yield: 43%) of the target compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH:19]=O)[C:9](=[O:21])[CH:8]=1)(=[O:5])=[O:4].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][N:35]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:46]2[CH2:47][CH2:48][CH:43]([N:35]([CH2:34][C:31]3[N:30]=[CH:29][C:28]4[O:27][CH2:26][CH2:25][O:24][C:33]=4[CH:32]=3)[C:36]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:42])[CH2:44][CH2:45]2)[C:9](=[O:21])[CH:8]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(OS(=O)(=O)C(F)(F)F)c2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccc(F)cc32)CC1
Reaction time: 18 h

Procedure:
The crude 7-fluoro-2-oxo-1-(2-oxoethyl)-1,2-dihydro-4-quinolinyl trifluoromethanesulfonate (5.6 g, 15.9 mmol assumed 100% from previous step) was dissolved in THF (50 ml) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (5.60 g, 15.9 mmol) added followed by sodium sulphate (˜15 g). After 2 h sodium triacetoxyborohydride (12.3 g, 58 mmol) was added portionwise over 1 h and the solution stirred for 18 h. The solution was diluted with ethyl acetate and washed with sodium bicarbonate solution, dried and concentrated. Chromatography (70 g silica SPE, eluting with ethyl acetate) provided product (4.88 g) contaminated with an impurity. Further chromatography (70 g silica SPE gradient elution with 2:1 ethyl acetate/hexane to ethyl acetate to ethyl acetate/10% methanol) provided the title compound as a clear oil (2.81 g, 26%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[C:20]([F:26])[CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:20]([F:26])[CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)c(F)c1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CN2CCCC2)c(F)c1

Procedure:
4-Benzyloxy-1-[2-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared as example 1.1b from 105 mg (0.24 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 16h) and 0.06 mL (0.73 mmol) pyrrolidine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>ClCCl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][O:15][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred of 1-(4-trifluoromethyl-phenyl)-cyclopentyl]-methanol (239) (15 g, 61.47 mmol) in dichloromethane (200 mL) was added Et3N (17.1 mL, 123 mmol) followed by mesyl chloride (5.7 mL, 73.77 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched by the addition of water. The reaction mixture was diluted with dichloromethane. The organic part was washed with water, separated, dried over Na2SO4 and finally concentrated. The crude product was purified by 100-200 silica column chromatography using 10% ethyl acetate in hexane as the eluent to give methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240) (14 g, 70.6%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[ClH:16].CO>C(Cl)Cl.CO>[ClH:16].[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)ethylamine (10.0 g, 66.2 mmol) in dry CH2Cl2 (100 mL) at −78° C. was added a 1 M solution of BBr3 in CH2Cl2 (200 mL, 3 eq.) and the solution was allowed to slowly warm to RT. After stirring for 3 h at RT the resulting precipitate was filtered off, washed with CH2Cl2 (200 mL) and dried. The off-white solid was dissolved in cold H2O (50 mL) and the insoluble material was filtered off. The acidic filtrate (pH 1.2) was made basic (pH 13.0) with 10 N NaOH and the resulting yellow solution was extracted with ether (100 mL) and the organic layer was discarded. The aqueous layer was re-acidified with conc. HCl to pH 1.5 and then made alkaline (pH 9-10) with conc. NH4OH. The aqueous layer was then extracted with n-butanol (2×150 mL), dried (K2CO3) and concentrated to dryness to afford a viscous oil. The oily residue was then dissolved in MeOH (10 mL) and a solution of saturated HCl/MeOH was added. The solution was concentrated to small volume and ether was added to give a precipitate. The ether was decanted off to afford the desired compound as an off white solid (6.5 g, 57%). 1H NMR (D2O) 2.79 (t, 2H, J=7.2 Hz), 3.08 (t, 2H, J=7.2 Hz), 6.60-6.78 (m, 3H), 7.11 (t, 1H, J=7.7 Hz).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH3:6])[NH:12][CH:11]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: COc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc2[nH]cc(C=O)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Add phosphorus oxychloride (1.1 eq.) with vigorous stirring to DMF (cooled in an ice bath). After the addition is complete, allow to stir in the ice bath for ˜10 minutes, then add a solution of 4-methoxy-1H-indole (5 g) in anhydrous DMF with vigorous stirring. Allow to stir at 0° C. After 1 hour, warm to room temperature. After 16 hours, carefully add 4 eq. of 2N NaOH with vigorous stirring. Heat to about 80° C. and then cool. Pour the reaction mixture into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry in a vacuum oven at room temperature to give the title compound. Acidify the filtrate and extract with EtOAc. Combine the organic layers and wash with 50% brine. Collect the organic layer, dry (MgSO4) filter, and remove the solvent to give the title compound as a light purple solid. Total yield of the title compound is 5.44 g: MS (ES+): m/z 175 (M+H)+, 160 (M-CH3)+; (ES−): m/z 174 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Clc1ncccn1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1ncccn1
Temperature: 150 °C

Procedure:
A solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (43 mg, 0.16 mmol) and 2-chloropyrimidine (56 mg, 0.49 mmol) in N,N-dimethylformamide (1.0 mL) was sealed in a microwave vial and heated by a Smith Synthesizer microwave at 150° C. for 15 minutes. The mixture was diluted with ethyl acetate (10 mL) and washed with water (2×10 mL). The organic phase was concentrated and purified by flash column chromatography on silica (20% to 50% gradient of ethyl acetate/hexanes) to provide 6-bromo-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine. The amine was diluted with diethyl ether (3 mL) and hydrogen chloride (1.0 M in diethyl ether) was added. The suspension was concentrated, diluted with acetonitrile and water, frozen and lyophilized to provide 6-bromo-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (16 mg, 26%) as a yellow solid. 1H-NMR (DMSO-d6): δ 10.94 (s, 1H), 8.44-8.39 (m, 2H), 8.03-7.96 (m, 1H), 7.55 (s, 1H), 7.23 (d, 1H), 7.12 (d, 1H), 6.72 (t, 1H), 5.37-5.32 (m, 1H), 2.63-2.59 (m, 2H), 2.09-1.95 (m, 2H), 1.87-1.75 (m, 2H); MS m/z (M−1) 341, 343.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:30])[CH:17]([NH:18][C:19](=[O:29])[C:20](=[N:27][OH:28])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1.[N+](=[CH2:33])=[N-]>O1CCOCC1.C(OCC)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:15])[Cl:14])=[O:9])[N:5]2[C:16](=[O:30])[CH:17]([NH:18][C:19](=[O:29])[C:20](=[N:27][O:28][CH3:33])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2S1
Reactant: C=[N+]=[N-]
Agent: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2S1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (125 mg.) in dioxane (5 ml.) was added dropwise 0.1 M solution of diazomethane in diethyl ether till the starting compound disappeared. After the reaction mixture was concentrated, the residue was pulverized in diethyl ether, collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-amino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (110 mg.), mp 128° to 149° C. (dec.).