Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N-:13]=[C:14]=[O:15].[K+]>O.C(O)(=O)C>[NH:1]([C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:14]([NH2:13])=[O:15]
Reactant: [N-]=C=O
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(/C=C/C(=O)O)cc1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
A stirred solution of (E)-3-(4-aminophenyl)acrylic acid (1.0 g, 5.0 mmol) and potassium isocyanate (2.0 g, 5 equiv.) in a mixture of water and acetic acid (50 mL) was heated at 100° C. for 12 hours. After cooling, a white solid precipitated out. Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0.82 g, 80%) as a white solid. MP>350° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:35]=1)[CH2:5][N:6]([CH:30]1[CH2:32][CH2:31]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:8].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:6]([CH:30]2[CH2:32][CH2:31]2)[C:7]([C@H:9]2[C@H:14]([C:15]3[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH:33]=[C:34]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:35]=1
Reactant: COCCCc1cc(Br)cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(Br)cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a CH2Cl2 solution (0.05 M) of trans-tert-butyl 3-{[[3-bromo-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]carbonyl}-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 1.5 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+, M+H): 516.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]([S:11][CH3:12])=[N:5][O:6][C:7]([NH:9][CH3:10])=[O:8].[S:15](Cl)(Cl)=[O:16].[CH:19]1([NH:24][P:25](=[S:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[CH3:14][N:2]([CH3:1])[C:3](=[O:13])[C:4]([S:11][CH3:12])=[N:5][O:6][C:7]([NH:9][CH2:10][S:15]([N:24]([P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[S:32])[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:16])=[O:8]
Reactant: CNC(=O)ON=C(SC)C(=O)N(C)C
Reactant: O=S(Cl)Cl
Reactant: CCOP(=S)(NC1CCCC1)OCC
Solvent: c1ccncc1
Product: CCOP(=S)(OCC)N(C1CCCC1)S(=O)CNC(=O)ON=C(SC)C(=O)N(C)C

Procedure:
Methyl 2-(dimethylamino)-N-[[[[[(diethoxyphosphinothioyl)cyclopentylamino]sulfinyl]methylamino]carbonyl]oxy]-2-oxoethanimidothioate was prepared by the procedure employed in Example 21, by reacting methyl 2-(dimethylamino)-N-[[(methylamino)carbonyl]oxy]-2-oxoethanimidothioate (3.29 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole), and O,O-diethyl cyclopentylphosphoramidothioate (3.56 g, 0.015 mole) in pyridine (10 ml). Column chromatography afforded 2.5 g of an oil of the formula below, nD24 : 1.5322. ##STR43##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
m-Nitroaniline, 10.0 g (0.072 mole), is dissolved in 150 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoyl chloride, 12.9 g (0.073 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20° C. There is obtained N-(3-nitrophenyl) nonanamide (M.P. 63.0°-63.5° C.). Analysis shows 9.88% nitrogen as against a calculated value of 10.06% for C15H21N2O3.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:14]=[CH:13][C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>>[C:3]([C:5]([C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:14]=[CH:13][C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Yield: 92.7 %

Procedure:
Sodium hydride (65.5%, 665 mg), ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetate (5.7 g) and methyl iodide (3.55 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionate (5.5 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12.C1C=C(Cl)C=C(C(OO)=[O:29])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:29])[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12
Reactant: CSc1nc2ccc(Cc3cnc4sccn34)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole (350 mg, 1.1 mmol) in DCM (20 mL) was added m-CPBA (240 mg, 1.4 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na2S2O3 (20 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole as a yellow solid (310 mg, 85%). 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 1H), 7.82 (d, J=0.9 Hz, 1H), 7.43 (dd, J=1.5, 8.4 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J=4.5 Hz, 1H), 6.75 (dd, J=0.9, 4.5 Hz, 1H), 4.32 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](Br)=[CH:6][C:5]=1[SiH:15]([CH3:17])[CH3:16])[CH:2]=[CH2:3].C([Li])(C)(C)C.CN([CH:26]=[O:27])C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:26]=[O:27])=[CH:6][C:5]=1[SiH:15]([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCc1c([SiH](C)C)cc(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1c([SiH](C)C)cc(C=O)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution 1-allyldimethylsilyl-4-bromo-naphthalene (1 Scheme 26, 3.0 g, 10 mmol) in dry THF (150 mL) at −78° C. was added t-butyllithium (6.0 mL, 1.7 M solution in pentane, 10.2 mmol) over a period of 10 min. After 30 min stirring at −78° C., anhydrous DMF (1.5 mL, 20 mmol) was added dropwise. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (5 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (50 mL) and brine (10 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:20 ethyl acetate/hexanes) to afford a colorless oil (2.1 g, 88%); 1H NMR (300 MHz, CDCl3) δ 0.53 (s, 6 H), 2.03 (d, J=7.80 Hz, 2 H), 4.88-4.97 (2 H), 5.79 (m, 1 H), 7.60-7.70 (2 H), 7.84 (d, J=7.50 Hz, 1 H), 7.89 (d, J=6.90 Hz, 1 H), 8.20 (d, J=8.10 Hz, 1 H), 9.35 (d, J=8.10 Hz, 1 H), 10.39 (s, 1 H); 13C NMR (75 MHz, CDCl3) −1.7 (2C), 24.2, 114.5, 126.1, 126.9, 128.6, 128.7, 132.9, 134.3, 135.4, 137.6, 146.8, 194.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[C:10]=2[N:11]=1.[Cl:24][C:25]1[C:30]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])(=[O:34])=[O:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:24][C:25]1[C:30]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])(=[O:34])=[O:33])=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=4)[C:10]=3[N:11]=2)=[CH:27][N:26]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: FC(F)(F)Oc1ccc(Nc2ncnc3ccc(Cl)nc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(Nc4ccc(OC(F)(F)F)cc4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A mixture of 6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 23) (0.050 g, 0.147 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.070 g, 0.161 mmol), PdCl2(dppf)-CH2Cl2Adduct (5.99 mg, 7.34 μmol) and 1 N aq. sodium bicarbonate (0.294 ml, 0.294 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(4-(trifluoromethoxy)phenylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.049 g, 55%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][C:18]=2[O:25]CC2C=CC=CC=2)=[C:12]([F:33])[CH:11]=1)[CH2:6][CH2:7][CH2:8][NH2:9])(=[O:4])=[O:3].O1CCCC1>CO>[CH3:1][S:2]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][C:18]=2[OH:25])=[C:12]([F:33])[CH:11]=1)[CH2:6][CH2:7][CH2:8][NH2:9])(=[O:3])=[O:4]
Reactant: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(O)c1
Yield: 68.8 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for N-Methanesulfonyl-N1-[4-(2-benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (90 mg, 0.19 mmol) and tetrahydrofurane for methanol (15 mL), the title compound (50 mg, 68%) was obtained as a brown liquid, after purification on silica gel (dichloromethane/ethyl acetate: 8/2)
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[CH2:23]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1)[CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:23]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:22][C@H:11]([C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)[C@@H:10]2[CH2:9][C@@H:8]3[CH2:7][CH2:6][N:5]2[CH2:4][C@@H:3]3[CH:2]=[CH2:1])=[O:33])[CH2:28][CH2:27]1)[CH2:24][CH3:25]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](OC(=O)C1CCC(CCC)CC1)c1ccnc2ccccc12

Procedure:
Example 10 was performed as Example 1 except for substitution of 2.7 g of cinchonidine, 1.5 g of 4-n-Propyl-cyclohexanecarboxylic acid, 2.1 g of N,N′-Dicyclohexyl carbodimide (DCC), 1.2 g of N,N-(dimethyl amino)-pyridine (DMAP) and 80 ml of dichloromethane into a round-bottom flask. After filtering and condensing, the residue was subjected to recrystallization from methanol, giving (R)-1-(4-quinolyl)-1-[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 4-propyl-1-cyclohexanecarboxylate, as a white solid with a chemical purity 91.31%. The optical properties of the resulting compound were tested as in Example 1. The compound exhibited a specific rotation [α] of +5.52 and a helical pitch P of 3.1 μm, with helical twisting power of 32.2 μm−1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CN(C=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CO2)c2cccnc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
In 20 ml of dried DMF was dissolved 1 g of 5-hydroxyquinoline, and 0.28 g of sodium hydride (60% content) was then added thereto, followed by heating with stirring at 50° C. for 30 minutes. Afterward, 1.92 g of epichlorohydrin was further added to the reaction liquid and the latter was then heated with stirring at 90° C. for 3 hours, and the solvent was distilled off under reduced pressure. Water was then added to the residue, and the liquid was extracted with chloroform. The chloroform extract was then decolored and purified with active carbon, then was dried with anhydrous sodium sulfate, and was distilled off. The residue was then purified through a silica gel column chromatograph by the use of an effluent solvent of chloroform:methanol=100:1, so that 0.88 g of 5-(2,3-epoxypropoxy)quinoline was obtained in an oily state.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)CCC>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-tributylstannyl pyridine as in Example 39 to afford 0.055 g (32%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C28H21NO4F3Cl 528.1190, found 528.1194.
Reaction SMILES: CS(C)=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][C:19]=2[N:20]=1.C(N(CC)CC)C.Cl>ClCCl>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=[O:28])=[CH:21][C:19]=2[N:20]=1
Reactant: OCCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Oxalyl chloride[(COCl)2] (0.88 g) was added dropwise to a solution of dimethyl sulfoxide (DMSO) (1.0 g) in dichloromethane (30 ml) at −30° C. To the mixture was added 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]-propanol (2.0 g). The mixture was stirred for 30 minutes at the same temperature. To the mixture was added triethyl amine (3.19 g). The mixture was stirred for 30 minutes, warmed to 0° C. and poured into 2N HCl. The organic layer was separated, washed with water and dried over magnesium sulfate (MgSO4). The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:2, v/v), 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (1.54 g, 77%) was obtained. Recrystallization from ether-isopropyl ether gave colorless needles. Melting point: 81-82° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]=3[CH3:24])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2].[OH-].[Na+].C1COCC1.CO>O>[CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[CH3:24])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3CC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoate (5.0 g, 11.8 mmol, prepared using B from Example #2, Step A with ethyl hydrazine oxalate, C with 4-bromo-2-methylbenzaldehyde (Asta Tech) and 2-mercaptoacetic, D with borane-THF complex, E with PdCl2(dppf), TEA, DMF and EtOH), NaOH (0.95 g, 23.6 mmol), THF (30 mL), MeOH (30 mL) and water (15 mL) was stirred at rt for about 3 h. The organic volatiles were removed under reduced pressure. The aqueous layer was adjusted to about pH 6 by the addition of 1N aqueous HCl. The precipitate was collected by filtration and dried under reduced pressure to afford 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoic acid (4.5 g, 11.4 mmol, 96%) as a white solid. LC-MS (Table 1, Method 1) Rt=1.15 min, m/z 395 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N[C@H:11]([C:16](O)=O)[C@H:12](CC)C.N[C@H](C(O)=O)CCSC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]1[CH:6]=[CH:16][CH:11]=[CH:12][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
F Leu: L Ile: I Met: M
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu][C:25]#[N:26]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:23])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([C:25]#[N:26])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 170 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
(Method 1) 3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper (I) cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml), followed by stirring at 170° C. for 17 hr. The reaction mixture was suspended in ethyl acetate (500 mL) and distilled water (200 mL). The insoluble matters were removed by Celite filtration and washed twice with ethyl acetate (300 mL×2). The organic layer was washed once with an aqueous solution of disodium EDTA (200 mL) and twice with saturated brine (200 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (6.58 g, 73%).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([N:35]1[C@H:39]([CH:40]=O)[CH2:38][O:37]C1(C)C)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:35][C@H:39]([CH2:40][NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)[CH2:38][OH:37]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: Br
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC[C@@H](N)CO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester. The protecting group is cleaved off by means of a 4N HCl/dioxane solution: The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness. The product is converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: CC1C=C([CH2+]=NC(C(O)=O)C(C)C)C=CC=1.[NH2:17][CH:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20].C(=O)([O-])O.[Na+].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH:17][CH:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:39])[CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)C(N)C(=O)O
Agent: Cc1cccc([CH2+]=NC(C(=O)O)C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(NC(=O)NC(C(=O)O)C(C)C)c1

Procedure:
(RS)-N-(3-Methylphenylcarbamo-yl)valine may be prepared in a manner similar to that described in Example 35 for the preparation of (RS)-N-(3-methylphenylcarbamoyl)phenylglycine, but starting with (RS)-valine (4.7 g), sodium hydrogen carbonate (3.36 g) and 3-methylphenyl isocyanate (5.14 cc). (RS)-N-(3-Methylphenylcarbamoyl)valine (6.6 g), m.p. 170° C., is thereby obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH2:10].C[C:12]#[N:13]>Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:12]([NH2:13])=[O:10])=[CH:2]1
Reactant: O
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC#N
Agent: Cl
Product: NC(=O)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
CSI (0.578 mL, 6.63 mmol) was added dropwise to a solution of indole (777 mg, 6.63 mmol) in dry CH3CN (125 mL) at 0° C., and the mixture stirred at 0° C. for 1 h. Water (10 mL) was added, with HCl (1 drop, conc. aq), and the mixture heated to 100° C. for 2 h with stirring, then stirred at RT for 2.5 h, then refrigerated over the weekend. The reaction mixture was then evaporated to dryness, recrystallized from aqueous acetonitrile, filtered, and dried under vacuum overnight to provide 1H-indole-3-carboxylic acid amide (700 mg, 66% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=O)=O.[I-:18].[Na+].O>CC(C)=O>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][CH2:6][I:18]
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CCI)cc1OC
Yield: 92.6 %

Procedure:
To a flask was added 21.2 g (0.078 mole) of 2-(3,4-dimethoxyphenyl)ethyl methanesulfonate and 44.65 g (0.3 mole) of sodium iodide in 420 ml of acetone. The solution was refluxed for 2 hr, poured into water, washed with brine, dried over MgSO4, and evaporated to give 21.1 g of a yellow oil. The oil was recrystallized in MeOH to give 17.1 g of product, mp 43°-46° C.