Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[N+:3]([CH2:6][CH3:7])([O-:5])=[O:4].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl>O.CS(C)=O>[N+:19]([C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[CH:6]([N+:3]([O-:5])=[O:4])[CH3:7])([O-:21])=[O:20]
Reactant: CC[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 19 °C

Procedure:
Potassium hydroxide pellets (8.42 g; 0.150 mol; 3 equiv) were crushed and placed in a 250-mL 3-necked flask equipped with a thermometer and an addition funnel. Reagent-grade DMSO (25 mL) was added and the mixture vigorously stirred. An ice-water cooling bath was then applied and when the temperature of the reaction mixture had cooled to 19° C. a mixture of nitroethane (3.95 mL; 0.055 mol; 1.1 equiv) and 4-chloro-3-nitrobenzotrifluoride (1; 7.46 mL; 0.050 mol) were added to the reaction mixture (addition funnel) over 15 min at a rate such that a temperature of 15-20° C. was maintained. After the addition was complete, the reaction mixture was cooled to 15° C. and the ice bath was replaced with a cool water bath (10-15° C.) and the reaction mixture was allowed to warm to 20° C. over 2 h, at which time GC analysis indicated >98% consumption of 1 and a ratio of 2:3 of 98:2. Toluene (25 mL) was added and the reaction mixture was cooled in ice-water. Aqueous hydrochloric acid (6 N; 15 mL; 0.090 mol) was added dropwise with vigorous stirring at such a rate that the temperature remained below 20° C. Water (40 mL) was then added and the layers were allowed to separate for 10 min. The bottom aqueous layer was decanted, and the top organic solution was used directly for the next step. An aliquot of this organic solution was analyzed by 1H NMR and indicated a 96:4 ratio of 2:3. 2: 1H NMR (CDCl3) δ 8.349 (s, 1H); 7.976 (dd, 1 H, J=1.71, 8.24 Hz); 7.788 (d, 1H, J=8.24 Hz); 6.296 (q, 1H, J=6.96 Hz); 2.036 (d, 3H, J=6.78 Hz). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15/min; 280° C., 1 min): tR 10.71 min 3: 1H NMR (CDCl3) δ 10.815 (s, 1H); 8.435 (d, 1H, J=1.77 Hz); 7.830 (dd, 1H, J=2.19, 8.79 Hz); 7.315 (d, 1H, J=8.91 Hz). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15°/min; 280° C., 1 min): tR 5.53 min.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=C)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.CC(C)=[O:25].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=[O:25])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:21][CH:22]=1
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(Cl)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(Cl)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-chlorobenzyl)-3,4-dimethyl-2-vinylbenzoate (0.17 g) in a mixed solvent of acetone (4.00 mL)-acetonitrile (4.00 mL)-water (4.00 mL) were added osmium oxide (fixed catalyst I) (0.07 g) and sodium periodate (0.58 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[CH2:22][CH3:23]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCCN1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCCN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-propylpiperidin-4-amine (14.2 mg, 0.12 mmol). The title compound was obtained as a solid (10 mg, 21% yield). MS m/z: 474.98, 476.97 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].Br[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH2:37]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)CBr
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OCC(C)C)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 1-bromo-2-methyl-propane
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[C@H:3]1[CH:17]=[CH:18][C@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:43]([NH2:45])[CH3:44]>C(Cl)Cl>[CH3:44][CH2:43][NH:45][C:14]([CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:4]1[C@@H:3](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:2]([OH:1])[CH2:6][C@@H:5]1[OH:7])=[O:15]
Reactant: CCN
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 169.6 %

Procedure:
Under an atmosphere of nitrogen 250 mL methylenechloride were added to 12.34 g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW=402.54; 26.1 mmol; 1 equivalents) and the solution was cooled to −10° C. At this temperature 5.1 g of triethylamine (MW=101.19; 50.4 mmol; 1.9 equivalents) and 5.8 g of pivalic acid chloride (MW=120.58; 48.1 mmol; 1.8 equivalents) were added. The reaction mixture was stirred for two hours. Then a solution of 2.3 g ethylamine (MW=45.08; 2.0 equivalents) in 10 mL of methylene chloride was added. After stirring the reaction mixture for two hours at −10° C., the mixture was warmed to room temperature. The reaction was quenched by adding 250 mL of water and adjusting the pH to 2.0 with 1M aqueous hydrochloric acid. After separation of the layers, the organic layers was washed with 250 mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 18.4 g of bimatoprost crude (yield: 95%; as determined by NMR). Bimatoprost crude was purified as described below.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:38][C:39]([F:48])([F:47])[CH2:40][CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].O>ClCCl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:43]([CH2:42][CH2:41][CH2:40][C:39]([F:48])([F:47])[F:38])(=[O:45])=[O:44])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)CCCC(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic piperidin-1-ylamide, from Ex 2, Step 1 (0.49 g, 1.20 mmol) was dissolved in dichloromethane (20 ml), cooled to 0° C. and triethylamine (0.67 ml, 4.8 mmol) added followed by 4,4,4-trifluorobutane-1-sulfonyl chloride (prepared as described in WO00/010968) (0.38 g, 1.80 mmol). The reaction mixture was stirred at room temperature for 3 hrs. TLC showed remaining starting material and another portion of triethylamine and 4,4,4-trifluorobutane-1-sulfonyl chloride was added and the reaction mixture stirred overnight. Water was added, the product extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Flash chromatography (hexane:EtOAc 1:3-EtOAc) followed by recrystallization (hexane:EtOAc) afforded 0.45 g (61%) of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11](COS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:26](=O)([O-])[O-].[K+].[K+].[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.O>C(#N)C>[C:41]([O:40][C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:11]2[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=3)[C:10]=2[CH3:26])[CH2:34][CH2:33]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxy methyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) in acetonitrile (1 mL) were added potassium carbonate (56.3 mg, 0.41 mmol) and tert-butyl 1-piperazine-carboxylate (60.7 mg, 0.33 mmol), and the mixture was stirred at 80° C. for 2 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, water was added. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol (40/1)] to yield the title compound as a yellow oil (115 mg, 92.4%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[N+:32]([O-])=O)[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.[Fe]>[NH2:32][C:7]1[CH:8]=[C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 78.2 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (300 mg, 0.626 mmo) was taken in 30 ml of Toluene:Water (1:1) and to it added Fe powder (203 mg, 3.62 mmol), Ammonium formate (228 mg, 3.62 mmol). The reaction mixture was refluxed for 3 h and then filtered through celite. The toluene was distilled off under reduced pressure and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 220 mg of ethyl 2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate. 1H NMR (CDCl3): δ 7.40-7.20 (m, 5H), 6.90 (s 1H), 4.50 (bs, 2H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (450, M+1,100%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:24][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)CN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)(C)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and neo-pentylamine (336 mg, 3.85 mmol) suspended in 1-butanol (10 ml) were heated at 100° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 1N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (88 mg, yield 74%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:31])[N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH:20]=[C:19]([Cl:32])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[ClH:32].[Cl:32][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[O:31]
Reactant: CCCN(CCC)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Product: Cl
Reaction time: 18 h
Yield: 171.1 %

Procedure:
A solution of [2-(3-chloro-5-dipropylcarbamoyl-phenoxy)-ethyl]-pyridin-4-yl-carbamic acid tert-butyl ester (0.085 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was triturated with ethereal hydrogen chloride to give the title compound (0.063 g) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2-(2-methoxyethoxy)ethanol (200 mg, 1.67 mmol, 1 equiv.), triethylamine (232 μL, 1.67 mmol, 1.0 equiv.) and tosyl chloride (317 mg, 1.67 mmol, 1 equiv.) in methylene chloride (5 mL, 0.29 M) was stirred at room temperature for 50 hours. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (10 g, hexanes/EtOAc 9:1 to 1:1) to afford (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate as a colorless oil (260 mg, 457 mg theoretical, 56.9%). LC-MS m/z 275 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:21])C.C(O)(=O)C.IC1C=CC=CC=1.II.CO>C(Cl)Cl>[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[O:21][CH3:19])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: II
Solvent: Ic1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of (S)-(−)-N-benzyloxycarbonylproline (10 g, 40 mmol) in CH2Cl2 (500 mL) was added iodobenzene diacetate (26 g, 80 mmol, 2.0 equiv) and iodine (5.2 g, 20 mmol, 0.50 equiv). The resulting mixture was stirred at rt for 5 h. Methanol (20 mL) was added and the reaction mixture was stirred at rt for 1.5 h. The reaction was then quenched by the addition of 10% Na2S2O3 (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with 10% Na2S2O3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product (28 g) as a yellow oil. Purification by flash chromatography (silica gel, 10-30% EtOAc/hexane) provided the expected product (9.41 g, 77%) as a yellow oil along with the corresponding hydroxy product (8.85 g, 11%) as a white solid: mp 44-46° C. The hydroxy product could subsequently be quantitatively recycled to the desired methoxy compound by treatment with pyridinium p-toluene sulfonate (PPTS) in MeOH at rt for 20 h. Data for step 1 compound: HPLC (Phenominex 4.6×50 mm) retention time 2.94 min; LC/MS m/z 236 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 5.15-5.29 (m, 3H), 3.52 (td, 1H, J=8.8, 1.3 Hz), 3.32-3.48 (m, 3H), 3.26 (s, 1H), 1.99-2.15 (m, 1H), 1.84-1.98 (m, 2H), 1.67-1.82 (m, 1H). Data for compound 3: LC/MS m/z 222 [M+H]+; 1 H NMR (CDCl3, 400 MHz) δ 7.30-7.40 (m, 5H), 5.47-5.55 (m, 1H), 5.15 (s, 2H), 3.55-3.65 (m, 1H), 3.30-3.42 (m, 1H), 1.78-2.02 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:28][CH:29]=2)[CH2:12][CH2:13][CH3:14])[CH2:9][O:10][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][CH:33]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CO)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(COCc1ccc(OC(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The major diastereomer of methyl N-(4-{1-[1-(4-chlorophenyl)-2-hydroxyethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 86, Step C, 80 mg, 0.19 mmol), 1-(bromomethyl)-4-(trifluoromethoxy)benzene (97 mg, 0.38 mmol) and Ag2O (87 mg, 0.38 mmol) in DCM (20 mL) was refluxed overnight. After cooling to room temperature, the mixture was filtered, then the filtrate was concentrated. The resulting residue was purified by PTLC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8 Hz, 2H); 7.22-7.31 (m, 6H); 7.05-7.12 (m, 4H); 6.90 (t, J=5.4 Hz, 1H); 4.10-4.24 (m, 2H); 332-3.77 (m, 5H); 3.22-3.29 (m, 2H); 2.94-2.98 (m, 2H); 2.67 (t, J=53 Hz, 2H); 1.32-1.44 (m, 2H); 0.88-0.94 (m, 2H); 0.65 (1, J=7.2 Hz, 3H). MS (M+H)+ 592.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C@@H:28]1[CH2:30][C@H:29]1[C:31]([NH:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:32]>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31]([C@@H:29]2[CH2:30][C@H:28]2[CH3:27])=[O:32])=[CH:41][CH:40]=1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 79 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.94 g, 2.2 mmol) with a solution of (±)-trans-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamine (0.899 g, 4.403 mmol) in anhydrous toluene (22 mL) and anhydrous dioxane (5.8 mL). Purify by chromatography on silica gel to afford (±)-trans-7-chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.834 g, 79%) as an orange oil.
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:11]=[C:10]([NH:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:5]=2[N:4]=1.N1([C:46](N2C=CN=C2)=[O:47])C=CN=C1.C(N(CC)CC)C.O>O1CCCC1>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:11]=[C:10]([NH:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]4[CH2:30][C:31]([CH3:34])([CH3:32])[O:33][C:46]4=[O:47])[CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:5]=2[N:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOC[C@@H]4C)nc(NC[C@H]4CC[C@H](NCC(C)(C)O)CC4)n3)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(C(F)F)n(-c3cc(N4CCOC[C@@H]4C)nc(NC[C@H]4CC[C@H](N5CC(C)(C)OC5=O)CC4)n3)c2c1
Reaction time: 3 h

Procedure:
1-({trans-4-[({4-[2-(Difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}amino)methyl]cyclohexyl}amino)-2-methylpropan-2-ol (100 mg) was dissolved in tetrahydrofuran (2 mL), and di-1H-imidazol-1-ylmethanone (131 mg) and triethylamine (50 μL) were added thereto, followed by stirring for 3 hours while heating and refluxing. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=60:40) to obtain 3-{trans-4-[({4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}amino)methyl]cyclohexyl}-5,5-dimethyl-1,3-oxazolidin-2-one (100 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=O)[C:5](F)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][C:14]([NH2:16])=[NH:15]>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:15]=[C:14]([NH:13][CH3:12])[N:16]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: CNC(=N)N
Agent: Cl
Solvent: CC#N
Product: CNc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Yield: 23.9 %

Procedure:
Treat a solution of 5-bromo-2-fluoropyridine-3-carboxaldehyde (0.50 g, 2.451 mmol) and 1-methylguanidine hydrochloride (0.322 g, 2.94 mmol) in acetonitrile (20 mL) with TEA (0.947 mL, 7.35 mmol) and heat to 180° C. in the microwave for 15 min. Concentrate the mixture to dryness, treat the residue with DCM and wash with H2O, then brine. Dry the organic layer over Na2SO4, concentrate to dryness and purify via silica gel chromatography (20-100% EtOAc/Hexanes) to afford the title compound (140 mg, 24% yield). MS (m/z): 241.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.5 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.17 g, 4.65 mmol) obtained in Example 19, step 2 and 4-(4-fluorophenyl)piperidine (1.0 g, 5.58 mmol), the title compound (1.18 g, 62%) was obtained.