Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)cnc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cnc(C)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylpyridine-3-carboxylate obtained in Example (171b) (113 mg, 0.4 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (64 mg, 0.37 mmol), WSC hydrochloride (211 mg, 1.1 mmol) and HOBt (49.7 mg, 0.37 mmol), to obtain 18.0 mg of the title compound as a pale yellow oily substance (11%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](Cl)(=[O:27])=[O:26])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:27])(=[O:26])[NH2:29])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(SCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: N
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Oc1ccccc1
Reaction time: 1 h

Procedure:
3-Benzylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (0.6 g) is added to concentrated aqueous ammonia (10 ml). After 1 hour, the reaction mixture is heated on a steam-bath for 15 minutes, and crude 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of 1 N hydrochloric acid until pH 2.5. The crude product is dissolved in aqueous sodium hydrogen carbonate by heating. After cooling, the precipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is redissolved in hot water (20 ml) and 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of 1 N hydrochloric acid. After cooling and collecting by filtration, and drying in vacuo at 80°C, the compound is obtained with a melting point of 235°-236°C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([NH:14][C:15]([N:4]2[C:5]([CH3:7])=[CH:6][C:2]([OH:1])=[N:3]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=C=Nc1ccccc1
Product: Cc1cc(O)nn1C(=O)Nc1ccccc1
Yield: 18.9 %

Procedure:
Reaction of 3-hydroxy-5-methylpyrazole with phenyl isocyanate was carried out in the same manner as in Referential Example 14, to give a white solid of N-phenyl-3-hydroxy-5-methylpyrazol-1-carboxamide (yield: 18.9%). mp: 232-234° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.62 (d, J=0.8 Hz, 3H), 5.72 (d, J=0.8 Hz, 1H), 7.11-7.17 (m, 1H), 7.33-7.39 (m, 2H), 7.53-7.57 (m, 2H), 8.64 (br s, 1H). (Hydroxy proton was not assigned.)
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-chlorobenzene (0.69 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.84 g, 62%).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[S:19]1[CH:15]=[CH:16][CH:17]=[C:18]1[N:3]1[CH2:4][C@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[O:1][C:2]1=[O:13]
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1cccs1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cccs1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
(S)-Spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (505 mg, 3.58 mmol), 5-bromothiophene (1.75 g, 10.74 mmol), copper (I) iodide (69 mg, 0.36 mmol) and potassium carbonate (495 mg, 3.58 mmol) were stirred at 120° C. overnight. After cooling to room temperature, the mixture was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a yellow solid (450 mg), m/zz 265 (MH+).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[S:17][CH2:16][CH2:15][CH2:14]2)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[S:17][CH2:16][CH2:15][CH2:14]2
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1SCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc2c1SCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
10 g (37.7 mmol) of the compound obtained in Step 1 above in 50 ml of dichloromethane are mixed with 50 ml of trifluoroacetic acid, and the mixture is stirred for 30 minutes at room temperature and then evaporated to dryness. The residue is taken up in ether and the solid obtained is filtered off and treated with N sodium hydroxide solution. The aqueous phase is extracted with ether and the ethereal phases are combined, dried over magnesium sulphate and concentrated to yield 4.48 g of the desired product (theory: 6.2 g).
Reaction SMILES: N1CCOCC1.C([O:10][C:11]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[C:20]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC=C)=[O:44])=[C:38]([F:49])[CH:37]=3)=[CH:32][CH:31]=2)[C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C=C.O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:15][C:13]([C:12]1[C:11]([OH:10])=[C:23]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:21][C:20]=1[CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[C:38]([F:49])[CH:37]=2)=[CH:34][CH:35]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)c(F)c3)cc2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Morpholine (0.27 ml, 3.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol) were successively added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (790 mg, 1.32 mmol) obtained in Example (11-6) in tetrahydrofuran (8 ml), and the mixture was stirred at room temperature for 1 hour. After water was poured into the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. After the residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1-0/1), it was crystallized from a mixture solvent of methylene chloride-ethyl acetate to give the title compound as a colorless powder (323 mg, yield: 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: COc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
(2-chloro-5-iodophenyl)(4-methoxyphenyl)methanone (12.0 g, 32.2 mmol) and triethyl silane (9.86 g, 84.8 mmol) were dissolved in acetonitrile (200 mL). To the resulting mixture was added boron trifluoride-diethyl etherate complex (13.7 g, 96.5 mmol) at 0° C. After the completion of dropwise addition, the mixture was warmed up to 70° C., and stirred for 3 hr. Then the mixture was cooled to room temperature. The mixture was quenched with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 10.0 g of a product in a yield of 87%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH:29](=O)[CH3:30]>>[CH2:29]([NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)[CH3:30]
Reactant: CC=O
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: CCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and acetaldehyde following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 418 (MH)+.
Reaction SMILES: [C-:1]#[N:2].[K+].[N:4]([CH:7]([CH2:12][CH2:13]I)[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6].O>CS(C)=O>[N:4]([CH:7]([CH2:12][CH2:13][C:1]#[N:2])[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6]
Reactant: [C-]#N
Reactant: COC(=O)C(CCI)N=[N+]=[N-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CCC#N)N=[N+]=[N-]
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a cold (10° C.) suspension of potassium cyanide (1.5 g, 23 mmol) in dry DMSO (25 ml) was added methyl 2-azido-4-iodobutyrate (4.0 g, 15 mmol) and the mixture stirred at 10° C. for 10 min and at room temperature for 45 min. The reaction mixture was poured into cold water (200 ml) and the solution was extracted with chloroform (4×80 ml). The chloroform extract was washed with water (4×50 ml), dried and evaporated to give a syrup (2.0 g) which on tlc (silica, 10% ether-benzene) showed a major spot of Rf 0.4 and some impurities (Rf 0, 0.67, and 1.0). The product was purified by chromatography on a silica column (20 cm×2.9 cm 1-D) using 10% ether in benzene as eluent to give 1.1 g (44%) of title compound as a syrup; ir (neat) νmax : 2100, 1745 cm-1 ; 1Hmr (CDCl3) δ: 2.17 (m, 2H, --CH2 --), 2.5 (m, 2H, CH2CN), 3.83 (s, 3H, OCH3) and 4.13 ppm (q, J=9, 6 Hz, 1H, CHN3). Anal. calcd for C6H8N4O2 : C 42.84, H 4.89, N 33.31; found: C 42.76, H 4.72, N 33.16.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[NH2:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OCCCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of diethyl(14R,18R)-14-(((9H-fluoren-9-yl)methoxy)carbonylamino)-18-(dodecyloxy)-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the deprotection completed. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1([CH3:33])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:12]1=[O:32].[CH2:34]([NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH3:35]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:36]([CH2:34][CH3:35])[CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:7])=[CH:4][C:3]=1[C:11]1([CH3:33])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:12]1=[O:32]
Reactant: COc1ccc(CN2C(=O)C(C)(c3cc(C(=O)O)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)c1ccc(Cl)c(C2(C)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1

Procedure:
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoic acid, in the racemic form, is treated with N-ethyl-3-pyridylmethylamine (document WO 01/074775, example 201a) and b)). 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoic acid, in the racemic form, is described in the document WO 01/074775, in example 101. After silica chromatography, elution being carried out with a dichloromethane/methanol 90/10 mixture, the expected compound, in the racemic form, is obtained crystallized from methanol (white powder).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene wasadded aniline (2 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N'-phenyl-urea as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:35])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid as light yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O.ClCCl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2([C:40]([N:11]3[CH2:12][CH2:13][CH2:14][C:9]([OH:15])([CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:17][CH:16]=4)[CH2:10]3)=[O:41])[CH2:39][CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: OC1(COc2ccc(C(F)(F)F)cc2)CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCC(O)(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
Into a round-bottom flask was added 3-(4-trifluoromethyl-phenoxymethyl)-piperidin-3-ol (100 mg, 0.36 mmol), dichloromethane (5 mL), diisopropylethylamine (0.190 mL, 1.08 mmol), 1-(4-chloro-phenyl)-cyclobutanecarboxylic acid (113.4 mg, 0.54 mmole), and PyBroP (0.252 g, 0.54 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate (3×10 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl acetate (4:1) to give [1-(4-Chloro-phenyl)-cyclobutyl]-[3-hydroxy-3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-methanone (18.7 mg, 11%). MH+ (468).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.C([Li])(CC)C.CON(C)[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:13]([O:12][C:11](=[O:17])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[CH2:18][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1cc(C2CC2)ccc1NC(=O)OC(C)(C)C
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1CC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (4-cyclopropyl-2-methylphenyl)carbamate (666 mg) in tetrahydrofuran (13.5 mL) was added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 5.5 mL) at −45° C., and the mixture was stirred for 30 minutes. Next, a solution of N-methoxy-N-methylbenzamide (489 mg) in tetrahydrofuran (1.4 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 35 minutes and then stirred at room temperature for 2 more hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution/water (2/1, 30 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (563 mg). 1H-NMR (CDCl3) δ ppm: 0.55-0.70 (2H, m), 0.80-1.00 (2H, m), 1.49 (9H, s), 1.75-1.90 (1H, m), 4.25 (2H, s), 6.85-7.00 (2H, m), 7.20-7.75 (5H, m), 8.00-8.15 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CO[CH:13](OC)[CH2:14][NH2:15]>>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:15][CH:14]=[CH:13]2
Reactant: COC(CN)OC
Reactant: Cc1cccc(C=O)c1Cl
Product: Cc1ccc2ccncc2c1Cl

Procedure:
8-Chloro-7-methylisoquinoline was prepared from 2-chloro-3-methylbenzaldehyde and 2,2-dimethoxyethylamine by the procedure described in Example 1.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH:9]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][N:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:22]([O:24][C:25]([N:19]1[CH2:18][CH2:17][CH:9]2[N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10]2)[CH2:21][CH2:20]1)=[O:26])[CH3:23]
Reactant: c1ccc(C2c3ccccc3CC3CCNCCN32)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC2Cc3ccccc3C(c3ccccc3)N2CC1

Procedure:
5.4 g of (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline was dissolved in 75 cc of chloroform and 30 cc of water are added. 4.3 g of chloroformic acid ethyl ester and subsequently a solution of 1.58 g of sodium hydroxide in 30 cc of water were added dropwise at a temperature of 0°-5°. The reaction mixture was stirred for another hour without cooling. The layers were then separated and the organic phase was washed twice with water. After drying with magnesium sulphate and concentration by evaporation of the filtered chloroform solution, the (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline-3-carboxylic acid ethyl ester was obtained in crude form.