Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[NH:13][C:9]=2[CH:8]=[CH:7][N:6]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: CCCCCCCCI
Reactant: COc1nccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCn1c(C)cc2c(OC)nccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (98 mg, 2.5 mmol, 60% in mineral oil) in THF (10 mL), 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 3 (280 mg, 1.72 mmol) in THF (3 mL) was added. The mixture was stirred at room temperature for 30 min, and then 1-iodooctane (0.41 mL, 2.2 mmol) was added, stirring was continued for 18 h. The reaction mixture was quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 10% EtOAc in hexanes to 20% EtOAc in hexanes) gave product 8 as a yellow oil. Yield: 231 mg (49%).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH:29]([OH:41])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:44])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:47])[CH2:22][C:23]([CH3:46])([CH3:45])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@H:29]([OH:41])[C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)=[C:27]([CH:42]([CH3:43])[CH3:44])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:47])[CH2:22][C:23]([CH3:45])([CH3:46])[O:24]3)=[CH:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
140 μl (800 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 4.45 mg (30 μmol) of (1R,2S)-1-aminoindan-2-ol in 5 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 100 mg (200 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 24A) in 5 ml of tetrahydrofuran is then slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the diastereomerically pure target compounds.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([CH:24]=O)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:8]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([CH2:24][NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: Cc1cc(N)no1
Reactant: CCN(CC1CCC1)c1nc2ccccc2cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC1CCC1)c1nc2ccccc2cc1CNc1cc(C)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
5-Methyl-isoxazol-3-ylamine (0.098 g, 1 mmol) was added to a solution of 2-(cyclobutylmethyl-ethyl-amino)-quinoline-3-carbaldehyde (0.268 g, 1 mmol) in anhydrous methanol (5 mL) and acetic acid (0.15 mL) under nitrogen. After being stirred for 15 minutes at ambient temperature, sodium cyanoborohydride (0.19 g, 3 mmol) was added slowly, and the reaction mixture was stirred overnight. Afterwards, the solvent was evaporated in vacuo, and water (30 mL) and ethyl acetate (30 mL) were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 1-5% methanol in dichloromethane, to afford the title compound (0.150 g, yield: 43%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([Cl:35])=[CH:37][CH:38]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) and 4-chlorobenzoyl chloride (0.15 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (31 mg) which was characterized by its mass spectrum: MS m/z (%): 497 ([M+H]+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.COCCOC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:20][CH2:21]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: COCCN1CCNCC1
Reactant: C=C1CCN(c2ccc(Br)cc2)C1=O
Solvent: O
Solvent: COCCOC
Product: COCCN1CCN(CC2CCN(c3ccc(Br)cc3)C2=O)CC1
Yield: 92.7 %

Procedure:
1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 1.00 g of 4-(2-methoxyethyl)piperazine were mixed with 5 ml of ethylene glycol dimethyl ether. The mixture was refluxed for 6.5 hours and then cooled. Thereto was added water. The mixture was subjected to extraction with ethyl acetate twice. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain 1.91 g of 1-(4-bromophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[SH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](O)=[O:9].S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:4][CH2:3][CH2:2][CH2:1][O:5][C:8](=[O:9])[CH:7]([SH:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: O=C(O)C(S)c1ccccc1
Reactant: OCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCCCOC(=O)C(S)c1ccccc1)C(S)c1ccccc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
1,3-Propanediol (9.50 g, 0.125 mol), a 55:45 mixture of the respective 4- and 3- isomers of mercaptophenylacetic acid (45.00 g, 0.268 mol), concentrated sulfuric acid (0.2 mL), and toluene (200 mL) were combined in a round-bottom flask equipped with a magnetic stirring bar, a water separator, and a condenser. During 6 h of heating under reflux with stirring, the solid organic acid isomers disappeared, and 4.46 mL (0.248 mol) of water was collected by the water separator. The mixture was allowed to cool to room temperature, washed in succession with 20 mL of saturated NaHCO3 solution and two 50-mL portions of brine, then dried over anhydrous MgSO4 and freed of solvent on a rotary evaporator. Dissolution of the residue in 400 mL of dichloromethane, followed by treatment at the boiling point with a small amount of decolorizing carbon, hot filtration, and rotary evaporation to remove solvent, gave 46.4 g (yield, 99%) of 1,3-propanediol bis(mercaptophenylacetate) as a viscous pale yellow oil that was shown by NMR analyses to contain the 4- and 3-isomers in a ratio of ca. 55:45, respectively: 1H NMR (in CDCl3 w/TMS, ppm): 1.91-1.96 (m, 2H, CH2CH2CH2); 3.44 (s, 4-isomer SH) and 3.47 (s, 3-isomer SH), 2H in toto; 3.53-3.63 (m, 4H, CH2C═O); 4.10-4.14 (m, 4H, CH2O); 7.03-7.44 (m, 8H, aromatic CH); {1H}13C NMR (in CDCl3 w/TMS, ppm): 28.14 (CH2CH2CH2); 40.99 (4-isomer CH2C═O) and 41.31 (3-isomer CH2C═O); 61.64 (CH2O); 126.80-132.36 (at least 9 peaks, aromatic C); 171.20 (3-isomer C═O) and 171.41 (4-isomer C═O).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]4[N:31]=[N:32][NH:33][N:22]=4)=[CH:19][CH:18]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(Nc3ccc(C#N)cc3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Nc3ccc(-c4nn[nH]n4)cc3)c2)ccc(C(C)=O)c1O
Yield: 28.5 %

Procedure:
Using the general procedure for formation of tetrazole (Et3NHCl method) of Example 1 using 4-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrile (380 mg, 0.949 mmol), sodium azide (308 mg, 4.74 mmol), and triethylamine hydrochloride (653 mg, 4.74 mmol) to yield the title product as a white solid (120 mg, 29%): 1H NMR (DMSO-d6) δ 0.785 (t, 3H), 1.44 (sextuplet, 2H), 2.52 (s, 3H), 2.55 (t, 2H), 5.20 (s, 2H), 6.68 (d, 1H), 6.97 (d, 1H), 7.04 (d, 1H), 7.15 (d, 2H), 7.24 (s, 1H), 7.29 (t, 1H), 7.76 (d, 1H), 7.82 (d, 2H), 8.69 (s, 1H), 12.80 (s, 1H); MS (esi negative) m/z (rel intensity) 442 (100).
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])[CH:25]([CH3:28])[C:26](=[O:27])[C@H:22]12)=[O:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(C1C=CC=CC=1)C(NC1C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)C(C)C(O)[C@H]12)=O)=O)C1C=CC=CC=1.OC1[C@@H]2C(NC(=O)C(C(OCC3C=CC4C(=CC=CC=4)C=3)=O)C3C=CC=CC=3)C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)C1C>>[CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])=[O:30])[CH:25]([CH3:28])[CH:26]([OH:27])[C@H:22]12)=[O:19])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Agent: CC1C(O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccc4ccccc4c3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Agent: CC1C(O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Product: CC1C(O)[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C

Procedure:
By the same method, the other 4-oxocarbapenam esters of Example 53 are converted to the corresponding pivaloyloxymethyl 6-(2-benzyloxycarbonyl-2-phenylacetamido)-1-hydroxy-2-methylcarbapenam-3-carboxylate and pivaloyloxymethyl 1-hydroxy-2-methyl-6-[2-(2-naphthylmethoxycarbonyl)-2-phenylacetamido]-carbapenam-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(=O)(O)[O-].[Na+].O>[N:14]1([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: Clc1nc2cccc3c2n1CCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1cc2c3c(c1)nc(N1CCOCC1)n3CCC2
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo [4,5,1-ij]quinoline (2.50 g) in morpholine (15 ml) was heated under reflux, under nitrogen, with stirring. After one hr, the solution was diluted with sodium bicarbonate solution (100 ml) and water (100 ml). The aqueous solution was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by high performance liquid chromatography (silica gel; ethyl acetate). The appropriate fractions were collected and concentrated. The residue was crystallized from ether to give 2.1 g (67%) of product, mp 93°-94° C.
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.Br[CH2:18][C:19]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[O:20]>>[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:18]=1[C:19]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cc(C)ccn2)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-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 5 1) and 2-bromoacetyl4-methylpyridine hydrobromide (F. H. Case et al., J. Am. Chem. Soc., 1956, 78, 5842).
Reaction SMILES: CC#N.[F:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.[Br:19]N1C(=O)CCC1=O.CCOC(C)=O>[Al]>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)=[N:12][CH:13]=1
Reactant: COc1ccnc(-c2cccc(F)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cccc(F)c2)ncc1Br
Temperature: 55 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
A MeCN (22 mL) solution of 2-(3-fluorophenyl)-4-methoxypyridine (2.21 g, 10.88 mmol) and N-bromosuccinimide (2.129 g, 11.96 mmol) in a 40-mL vial was wrapped in aluminum foil and stirred at 55° C. overnight. 22 h later, the reaction was cooled to rt, quenched with 1:1 sat. aq. NaHCO3:sat. aq. Na2S2O3 and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil. Column chromatography (50 g Snap Ultra column, 15% to 100% EtOAc/hept) afforded 5-bromo-2-(3-fluorophenyl)-4-methoxypyridine (0.420 g, 1.489 mmol, 13.69% yield) as a white amorphous solid. m/z (ESI) 282.0 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:12]=1[NH2:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:13][C:12]1[C:11]([F:10])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1c(F)cc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCBr)Nc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
6-Bromohexanoyl chloride (234 mg, 1.1 mmols) was gradualy added dropwise to a chloroform (3 ml) solution of 2,4,6-trifluoroaniline (147 mg, 1.0 mmol) and triethylamine (11 mg, 1.1 mmols) cooling in ice bath, and stirred for 1 hour at room temperature. The reaction mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with 1N-HCl, an aqueous saturated solution of sodium hydrogencarbonate, water, and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the resulting solid was recrystallized from hexan-ether, and 6-bromo-N-(2,4,6-trifluorophenyl)hexan amide 283 mg(yield 87%) was obtained as colorless needle-like crystals. Potassium carbonate (45 mg, 0.33 mmols) and 18-crown-6 (8 mg, 0.03 mmols) were added to DMF (2 ml) solution of the resulting anilide (97 mg, 0.3 mmols) and 2-mercaprbenzoxzole (45 mg, 0.3 mmol), and stirred for 1.5 hours at 80° C. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. And the resulting crystals were recrystallized from hexane-ether, and colorless needle-like crystals 106 mg (yield: 90%) of the intended product as crystals.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][CH:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.O>CN(C1C=CN=CC=1)C.ClCCl>[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:21]([NH:18][CH:14]([CH:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1)=[O:22]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C(N)CCc1ccc2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)C(=O)NC(CCc1ccc2c(c1)OCCCO2)C(C)C
Reaction time: 8 h

Procedure:
50 mg of (±)-1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methylpentan-3-ylamine was mixed with of (±)-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (25 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (53 mg), and DMAP (33 mg) in dichloromethane (5 ml) and stirred overnight. Water (5 ml) was added, and the reaction mixture was extracted with ethyl acetate (5 ml three times). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica (20% ethyl acetate in hexane) yielded a resin: MS (m+1)=435.6.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.O1CCCC1.C[Si](C)(C)[C:35](F)([F:37])[F:36].[I-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23]4([C:35]([F:37])([F:36])[CH2:26]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH2:2]1
Reactant: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 115 °C
Yield: 79 %

Procedure:
To a 10 mL microwave tube charged with tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate (0.475 g, 1.27 mmol) and tetrahydrofuran (4 mL) was added trimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide (0.42 g, 2.79 mmol). The reaction mixture was heated at 115° C. for 1 hour. After cooling to ambient temperature, additional trimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide (0.42 mg, 2.79 mmol) were added. The reaction was heated at 115° C. for another 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.426 g, 79%) as a colorless oil: MS (ES+) m/z 369.1 (M−55).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH2:8]([N:10]([CH3:40])[C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:13][CH:12]=1)[CH3:9].CNC>>[CH2:38]([S:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:14]4[CH:15]=[N:16][C:11]([N:10]5[CH2:40][CH2:3][O:4][CH2:9][CH2:8]5)=[CH:12][CH:13]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:30][CH2:31]1)(=[O:37])=[O:36])[CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Agent: CNC
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N5CCOCC5)nc4)cc23)CC1
Yield: 69.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford 40.1 mg of the title compound (69.5%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])([CH3:27])[CH3:26]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:31]3[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[C@H:29]([CH3:34])[CH2:30]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CC(C)N1CCNC[C@H]1C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C(C)C)[C@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-isopropyl-2-methylpiperazine. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.93 (br. s., 3H) 1.01 (br. s., 2H) 1.16 (br. s., 5H) 2.43 (s, 1H) 2.47 (s, 3H) 2.61 (d, J=12.20 Hz, 1H) 2.75-2.98 (m, 1H) 3.07 (br. s., 1H) 3.29 (br. s., 2H) 4.39 (br. s., 1H) 7.47-7.62 (m, 3H) 7.68 (s, 1H) 7.95-8.11 (m, 2H) 8.44 (s, 1H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:19])[CH2:13][C:14](OCC)=[O:15])=[C:8]([CH:20]=[CH2:21])[CH:7]=1)=[O:4].[BH4-].[Li+].O.Cl>O1CCCC1>[CH3:22][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:19])[CH2:13][CH2:14][OH:15])=[C:8]([CH:20]=[CH2:21])[CH:7]=1
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CCO
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of ethyl 3-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-hydroxy-propionate (5.28 g, 17.2 mmol) obtained in step (d) of Example 192 in tetrahydrofuran (50 ml) was added lithium tetrahydroborate (544 mg, 25.0 mmol) at −20° C. with stirring, and the reaction temperature was raised gradually to ambient temperature over one hour under a nitrogen atmosphere. To the reaction mixture were added successively water (20 ml) and 1N hydrochloric acid (20 ml), and the resulting mixture was extracted with ethyl acetate (40 ml×2). The organic layer was dried over anhydrous sodium sulfate, filtered; and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using mixed solvents of hexane and ethyl acetate (1:1-0:1) and ethyl acetate and methanol (5:1) successively as the eluents to afford the title compound (4.44 g, yield: 97%) as a colorless oil.