Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[C:8]([C:12]1[CH:13]=[C:14]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])([CH3:10])[CH3:9].C1(C)C(C)=CC=CC=1>O>[C:19]([C:16]1[CH:15]=[C:14]([CH2:23][CH2:24][C:25]([NH:27][N:28]2[C:1](=[O:7])[CH:2]=[CH:3][C:4]2=[O:6])=[O:26])[CH:13]=[C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:17]=1[OH:18])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1cc(CCC(=O)NN2C(=O)C=CC2=O)cc(C(C)(C)C)c1O
Yield: 86.5 %

Procedure:
A mixture of maleic anhydride (4.9 g, 50.0 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (15.2 g, 50.0 mmol) and 250 ml of xylene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water. The solvent was then removed on a rotary evaporator. The residual mass was extracted with 100 ml of tetrahydrofuran and the extract was added to 500 ml of hexane to precipitate the product. The product was collected by filtration and air dried. 16.1 g of a solid material was obtained having a melting range of 90°-94° C.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1([CH2:37][CH2:38][CH2:39][OH:40])[CH2:16][CH2:15][CH2:14][CH:13]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[Cl:28])[C:24]([O:29]CC2C=CC=CC=2)=[N:23][CH:22]=[CH:21]3)[CH2:12][CH2:11][CH2:10]1)(C)(C)C>>[NH2:8][C:9]1([CH2:37][CH2:38][CH2:39][OH:40])[CH2:16][CH2:15][CH2:14][CH:13]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[Cl:28])[C:24](=[O:29])[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Agent: Cl
Product: NC1(CCCO)CCCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CCC1
Yield: 83.7 %

Procedure:
168 mg of 6-[5-amino-5-(3-hydroxy-propyl)-cyclooctyloxy]-7-chloro-2H-isoquinolin-1-one (60) were synthesized as diastereomeric mixture as hydrochloride from 300 mg (0.53 mmol) of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (59) using the standard deprotection procedure described for the synthesis of 6-(cis-4-amino-4-cyclopropyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one (41). Rt=2.07 min, 2.12 min (Method H). Detected mass: 379.2 (M+H+).
Reaction SMILES: C(OC(C(O[C:21]([C:24]([O:30][C:31]([C:34]([C:37]([F:40])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([C:26]([F:29])([F:28])[F:27])[F:25])([F:23])[F:22])(C(F)(F)F)F)=O)(C(F)(F)F)(C(F)(F)F)F.C(OC(C([O:59][C:60]([C:63]([O:69]C(C(C(F)(F)F)(F)F)(F)F)([C:65]([F:68])([F:67])[F:66])[F:64])([F:62])F)(C(F)(F)F)F)=O)(C(F)(F)F)C(F)(F)F.[F-].[Na+].[F-].[K+]>>[F:62][C:60]([C:63]([O:69][C:21]([C:24]([O:30][C:31]([C:34]([C:37]([F:38])([F:39])[F:40])([F:35])[F:36])([F:32])[F:33])([C:26]([F:29])([F:28])[F:27])[F:25])([F:23])[F:22])([C:65]([F:68])([F:67])[F:66])[F:64])=[O:59]
Reactant: O=C(OC(F)(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Product: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F

Procedure:
A reaction was carried out in the same manner as in Example 1-3, except that the mixture (2.1 g) was changed to a mixture of (CF3)2CFOCOCF(CF3)OCF2CF(CF3)OCF2CF2CF3 and (CF3)2CHOCOCF(CF3)OCF2CF(CF3)OCF2CF2CF3 in a ratio of 8:2 (mass ratio) (hereinafter this mixture will be referred to as the fluorinated ester mixture, 10.0 g), and the NaF powder (0.02 g) was changed to KF powder (0.03 g). After cooling, a liquid sample (7.9 g) and a gas sample (1.9 g) were recovered. They were respectively analyzed by GC-MS, whereby it was confirmed that in the gas sample, the above-identified compound was the main product, and in the liquid sample, FCOCF(CF3)OCF2CF(CF3)OCF2CF2CF3 was the main product. The yield of the above-identified compound as calculated by GC in the same manner as in Example 1-3, was 95.2%. Further, from the liquid sample, FCOCF(CF3)OCF2CF(CF3)OCF2CF2CF3 (5.9 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 552.8 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19]C(C)(C)C)=[O:18])[CH:13]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].FC(F)(F)C(O)=O>ClCCl>[F:24][C:2]([F:1])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CC(C)(C)OC(=O)c1ccc2nc(C(F)(F)C(F)(F)F)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2nc(C(F)(F)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
To a solution of tert-butyl 2-pentafluoroethylquinoline-6-carboxylate (165 mg, 0.475 mmol) in dichloromethane (5 mL), cooled to 0° C., was added trifluoroacetic acid (2 mL, 26 mmol) and the reaction mixture allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, 2-pentafluoroethylquinoline-6-carboxylic acid (140 mg, 100%). 1H NMR (400 MHz, CDCl3+2drops CD3OD) δ 7.79 (1H, d), 8.26 (1H, d), 8.39 (1H, dd), 8.47 (1H, d), 8.67 (1H, d). LCMS: Retention time: 1.49 min. MS (ESI) m/z 292 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].O.N>C(O)=O>[NH2:28][C:22]1([C:20]([NH:19][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=3)=[CH:9][CH:10]=2)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3cccc(C#N)c3)cc2)CCOCC1
Agent: N
Solvent: O
Solvent: O=CO
Product: N#Cc1cccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)c1
Temperature: 36 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
(S)-tert-butyl 4-(1-cyano-2-(3′-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 8, step (ii), 282 mg) in formic acid (1.5 mL) was stirred at room temperature for 5 h, warmed at 36° C. for 30 mins then stirred at room temperature overnight. Water was added and the cooled solution was made basic with 0.880 ammonia and then extracted (×3) with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and the solvent was evaporated to yield an oil which was purified by chromatography on silica using 80% ethyl acetate in isohexane as eluent and then crystallised from isopropanol to yield a solid. The solid was washed with diethyl ether and dried to afford the titled compound (89 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][S:69]([C:72]2[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=2)(=[O:71])=[O:70])=[CH:61][CH:60]=1)[C:45]([N:47]1[CH2:52][CH2:51][CH:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH2:48]1)=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:58][C:59]5[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][S:69]([C:72]6[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=6)(=[O:71])=[O:70])=[CH:61][CH:60]=5)[C:45]([N:47]5[CH2:48][CH2:49][CH:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:51][CH2:52]5)=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)N=[N+]=[N-])CC1
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)n2cc(COc3ccc4nc(S(=O)(=O)NC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)sc4c3)nn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (91 mg, 0.159 mmol) and the tosylate 145 (87 mg, 0.159 mmol) in THF (1 mL) was added copper(I) iodide (3 mg, 0.0159 mmol) then diisopropylethylamine (30 μL, 0.175 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatography on silica gel using hexanes/ethyl acetate on a Biotage purification system yielding the desired product as a white, crystalline solid (145 mg, 82%).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:20]1>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:30][C:29]([CH2:28][C:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[NH:19][CH:20]=4)=[N:31][C:11]=3[C:10]=2[CH:13]=1
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Product: O=C1Cc2cnc(Cc3c[nH]c4ccccc34)nc2-c2cc(F)ccc2N1
Yield: 87 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 87%.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[O:9]=[C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][N:4]1[CH2:3][C:2]([N:14]1[CH2:19][CH2:18][N:17]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][CH2:15]1)=[O:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cn1sc2ccccc2c1=O)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Compound 10 (100 mg, 0.36 mmol) was treated with benzyl chloroformate (75 mg, 0.44 mmol) and DIEA (140 mg, 1.10 mmol) in anhydrous CH2Cl2 (5 mL) and DMF (1 mL) at room temperature for 4 h. CH2Cl2 and DMF were removed in reduced pressure. The mixture was washed successively with 1 M HCl(aq) and saturated NaHCO3(aq.). The organic phase was dried over MgSO4, filtered, concentrated, and the title compound was obtained after purification on a thin-layer silica-gel plate (20 cm×20 cm×2 mm) using CH2Cl2/MeOH (9:1) as the developing solution. C21H21N3O4S; white solid; mp 138-142° C.; IR vmax (neat) 2923, 2854, 1700, 1655, 1428, 1354, 1286, 1227, 1125, 1075, 1027, 984, 861, 741 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J=8.0 Hz), 7.60 (1H, t, J=7.2 Hz), 7.53 (1H, d, J=8.0 Hz), 7.36 (6H, m), 5.12 (2H, s), 4.69 (2H, s), 3.62 (8H, m); 13C NMR (100 MHz, CDCl3) δ 165.1, 154.8, 141.1, 136.1, 132.1, 128.5, 128.1, 127.9, 126.7 (2×), 126.3 (2×), 125.4, 123.2, 120.2, 67.6, 45.2, 44.9, 43.6 (2×), 42.0; ESI-HRMS calcd for C21H21N3O4NaS: 434.1150. found: m/z 434.1149 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.N1CCCCC1>C(O)C>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
A stirred solution of 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (81 mg, 0.79 mmol), 5-fluoro-1,3-dihydro-indol-2-one (44 mg, 0.79 mmol) in 0.48 ml of ethanol was added dropwise with anhydrous piperidine (0.06 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure, washed with anhydrous ethanol (0.2 ml×5) and purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (24 mg, 7.4%) as a brown solid
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O.O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4](=[CH:3][CH2:2][N:21]2[C:20](=[O:22])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:27])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(=CCBr)CC1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
A solution of 5.775 g (19.900 mM) of tert-butyl 4-(2-bromoethylidene)piperidine-1-carboxylate and 4.05 g (21.9 mM) of potassium phthalimide in 100 ml of N,N-dimethylformamide was stirred at 100° C. for 1 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over anhydrous magnesium sulfate (MgSO4) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([CH:36]1[CH2:40][O:39][C:38](=[O:41])[N:37]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1

Procedure:
The title compound was prepared from (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid and (S)-(−)-4-benzyl-2-oxazolidinone following the same procedure as for the synthesis of compound 39a.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([Cl:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[C:11]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([OH:18])[CH:12]=[C:13]([Cl:17])[C:14](=[O:16])[CH:15]=1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C=C1Cl
Yield: 92 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.59 g (3.33 mmol) of 2,5-dichloro-p-benzoquinone in 6.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate, and the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.81 g of the desired product (yield 92%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[CH:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1)C(=O)OC(C)(C)C)[CH3:2].C(=O)(O)[O-].[Na+]>>[CH2:1]([NH:3][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]=[CH:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:26][CH:25]=3)[N:20]=2)=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from tert-butyl ethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate (CB64), neutralized with aqueous sodium bicarbonate, and isolated as an orange solid (0.167 g, 98%, 80% pure): 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.17-8.06 (m, 2H), 7.87-7.63 (m, 2H), 7.37 (dt, J=8.0, 1.0 Hz, 2H), 7.34-7.28 (m, 2H), 3.21 (s, 2H), 3.14-2.97 (m, 4H), 1.84 (s, 1H), 0.87 (ddd, J=12.0, 8.9, 6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.04; ESIMS m/z 377 ([M+H]+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].[CH3:30]O>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 98 mg (0.257 mmol) of methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and 2.0 ml of 1.0 M of aqueous lithium hydroxide in 6 ml of methanol/tetrahydrofuram (1:1) mixture was stirred at 50° C. for 3 hours. The mixture was concentrated and acidified to pH 3 by careful addition of 1 N aqueous hydrogen chloride. The precipitate was collected and dried in high vacuum for 18 hours to give 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid. Yield 58 mg. M/z 368.2, calc 367.16
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:16]2[CH2:15]1)=[O:13].[Br:27]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[Br:27][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:9])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][C:21]=1[C:23]([F:26])([F:24])[F:25]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(C(F)(F)F)c2Br)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.181 g, 0.455 mmol, Example 2) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and treated with N-bromosuccinimide (NBS, 0.097 g, 0.546 mmol). The solution was stirred at room temperature for 16 hr. The mixture was poured onto water (100 ml) containing 1% sodium sulfite (w/w) and extracted into ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to afford crude product (0.323 g). The crude product was purified by mass-directed automated preparative HPLC to afford 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.135 g, 0.283 mmol, 62.2% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:40]([CH3:42])[CH3:41])[C:10]([NH:12][C@@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:27]=1)[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[NH:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:43]([C:45]1[CH:53]=[C:52]2[C:48]([CH2:49][CH2:50][C@H:51]2O)=[CH:47][CH:46]=1)=[CH2:44].C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:43]([C:45]1[CH:53]=[C:52]2[C:48]([CH2:49][CH2:50][C@H:51]2[O:23][C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:40]([CH3:42])[CH3:41])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH:27]=3)[NH:17]2)=[O:24])=[CH:47][CH:46]=1)=[CH2:44]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O)N1
Reactant: C=Cc1ccc2c(c1)[C@H](O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)[C@H](OC(=O)[C@@H]1CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (658 mg, 1.086 mmol) 2f, prepared as described earlier, (R)-6-vinyl-indan-1-ol (208.7 mg, 1.303 mmol) and 4-dimethylaminopyridine (132.7 mg, 1.086 mmol) in anhydrous dichloromethane (20 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (340.6 mg, 1.738 mmol). After overnight stirring at room temperature the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (762 mg, 95%) as a white solid. 1H NMR (300 MHz, CDCl3) δ0.13-0.22 (m, 6H), 0.86-0.99 (m, 15H), 1.47 (s, 10H), 1.72-1.91 (m, 3H), 1.99-2.20 (m, 2H), 2.43-2.60 (m, 2H), 2.66-2.78 (m, 1H), 2.81-3.01 (m, 3H), 3.04-3.17 (m, 1H), 3.91-4.01 (m, 1H), 4.33 (br d, J=12.7 Hz, 1H), 5.03-5.11 (m, 1H), 5.22-5.33 (m, 1H), 5.70-5.82 (m, 2H), 6.21 (dd, J=3.6, 6.9 Hz, 1H), 6.49 (d, J=8.5 Hz, 1H), 6.57-6.65 (m, 2H), 6.68-6.74 (m, 1H), 6.75-6.85 (m, 2H), 6.92 (app t, J=7.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.48 (s, 1H). LCMS (m/z) 771.4 [M+Na], Tr=6.05 min.