Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][S:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([NH2:73])[CH:68]=1>C(Cl)Cl>[CH3:65][S:66][C:67]1[CH:68]=[C:69]([NH:73][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: CSc1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA (0.230 mL, 1.31 mmol) and 3-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-10%) to give a white solid. 178 mg.
Reaction SMILES: Cl.C[O:3][P:4]([CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:7])[O:5]C>>[P:4]([CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12])([OH:7])([OH:5])=[O:3]
Reactant: COP(=O)(CNCC(=O)O)OC
Agent: Cl
Product: O=C(O)CNCP(=O)(O)O
Yield: 65 %

Procedure:
60 ml. of concentrated hydrochloric acid are added to 9.85 g. (0.05 moles) of N-carboxymethyl-aminomethyl-phosphonic acid dimethyl ester, and the mixture is boiled for 2 hours. The reaction mixture is concentrated to one-fourth volume under a pressure of 80 to 100 mmHg., and the oily residue is triturated with 60 ml. of methanol. The solid substance is filtered when cold, dissolved in 15 to 20 ml. of hot water; the solution is decolorized, cooled, and the product is precipitated with 45 ml. of acetone. 5.5-5.65 g. (65-67%) of N-phosphonomethyl-glycine are obtained; m.p.: 224°-225° C (with decomposition).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl[CH2:14][CH2:15][C:16]1([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1.CN(C)P(N(C)C)(N(C)C)=O.C(NC(C)C)(C)C.[Li].[Cl-].[NH4+]>C1COCC1>[C:16]12([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20][C:19]([C:22]([O:24][CH3:25])=[O:23])([CH2:18][CH2:17]1)[CH2:14][CH2:15]2
Reactant: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Agent: [Cl-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of diisopropylamine (77 mL, 0.54 mol) in anhydrous THF (500 mL) was added n-butyl lithium (210 mL, 0.53 mol, 2.5 M solution in hexane) over 20 min at −78° C. Then the mixture was stirred at 0° C. under nitrogen for 30 min. To a mixture of dimethyl 1-(2-chloroethyl)cyclohexane-1,4-dicarboxylate (116 g, 0.44 mol) and hexamethylphosphoramide (317 ml, 1.7 mol) in anhydrous THF (800 mL) was added lithium diisopropylamine (freshly prepared above) over 30 min at −40° C. The mixture was stirred for 2 h at −78° C. and then stirred overnight allowing warming to room temperature. To the reaction mixture was added saturated aqueous ammonium chloride (200 mL) and the mixture was stirred for 10 min. The solvent was removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined extracts were washed with brine (2×300 mL) and dried over sodium sulfate. Concentration under reduced pressure gave crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (58 g, 0.25 mol, 50% yield in two steps). 1H NMR (400 MHz, CDCl3) δ ppm 3.65 (s, 6H), 1.81 (s, 12H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[S:23])[CH2:8][CH2:7]1)[CH3:5].C([O-])([O-])=O.[K+].[K+]>>[NH2:1][CH2:2][CH2:3][C@@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[S:23])[CH2:8][CH2:7]1)[CH3:5]
Reactant: CC(CCN)N1CCC(N2C(=S)OC[C@H]2c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H](CCN)N1CCC(N2C(=S)OC[C@H]2c2ccccc2)CC1
Yield: 42 %

Procedure:
Using general procedure C the substrate (5.0 g, 0.012 mol) gave the desired amine. Due to the high water solubility of the compound, the mixture was neutralized with solid K2CO3 and the product was purified by column chromatography to afford (R,S)-3-[1-(3-amino-1-methyl-propyl)-piperidine-4-yl]-4-phenyl-oxazolidine-2-thione (1.6 g, 42%). 1H NMR (CDCl3) δ 0.90 (d, 3H), 0.90-1.0 (m, 1H), 1.31-1.91 (m, 8H), 2.03-2.05 (m, 1H), 2.61-2.75 (m, 6H), 4.32-4.36 (m, 2H), 4.94-4.98 (m, 1H), 5.29 (d, 1H), 7.25-7.42 (m, 5H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C[O-].[Na+].CO.[F:12][C:13]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:14][OH:15].[C:21](=O)([O:24]C)[O:22][CH3:23]>>[C:21](=[O:24])([O:15][CH2:14][C:13]([F:20])([F:12])[C:16]([F:19])([F:18])[F:17])[O:22][CH3:23]
Reactant: COC(=O)OC
Reactant: OCC(F)(F)C(F)(F)F
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)OCC(F)(F)C(F)(F)F
Yield: 55 %

Procedure:
Methyl 2,2,3,3,3-Pentafluoropropyl carbonate was prepared by the same manner as the example 4 except that K2CO3 (0.046 g) was used as a catalyst in stead of a 28% sodium methoxide/methanol solution (1.3 g). After 2,2,3,3,3-pentafluoropropanol and dimethyl carbonate were allowed to react, the mixture thereof was passed through a column filled with silicagel (8 g) in order to remove K2CO3, and was distilled to give methyl 2,2,3,3,3-pentafluoropropyl carbonate as a colorless liquid (yield 55 %).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]2[OH:16])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NS(=O)(=O)c2cccc(Cl)c2)[C@@H]1O

Procedure:
Following the procedure in Example 105, using (3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-chroman-6-carbonitrile and 3-chloro-benzenesulfonyl chloride as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: C([C:3]1[CH:4]=[C:5](C2CCCCS2=O)[CH:6]=[CH:7][CH:8]=1)#N.C([C:18]1[CH:19]=[C:20]([CH2:24][S:25]([CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=[O:26])[CH:21]=[CH:22][CH:23]=1)#N>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][S:25]([CH2:24][C:20]1[CH:19]=[CH:18][C:23]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:22][CH:21]=1)=[O:26]
Reactant: N#Cc1cccc(C2CCCCS2=O)c1
Reactant: N#Cc1cccc(CS(=O)CCCCCl)c1
Product: O=S(CCCCCl)Cc1ccc(-c2ccccc2)cc1

Procedure:
(±)-2-(3-cyanophenyl)tetrahydrothiopyran-1-oxide (mixture of cis/trans isomers), a colourless solid, melting point 116°-117° C., from (±)-3-cyano-1-[(4-chlorobutyl)sulphinylmethyl]benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[C:16]([F:21])[CH:15]=1>CN1CCCC1=O>[Br:13][C:14]1[CH:19]=[C:18]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[C:16]([F:21])[CH:15]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(F)cc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 2.2 ml of p-methoxybenzyl alcohol and 50 ml of N-methylpyrrolidone was added 840 mg of sodium hydride (60% oil dispersion), and the resulting mixture was stirred at room temperature for 45 minutes in a nitrogen atmosphere. To the reaction mixture was added 2 ml of 1-bromo-3,5-difluorobenzene, followed by stirring at 50° C. for 1.5 hours. The reaction mixture was poured into 50 ml of ice-diluted hydrochloric acid and extracted three times with diethyl ether-hexane (1:1 by volume. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a hexane-ethyl acetate (19:1 by volume) mixed solvent. The fraction containing the desired compound was concentrated to furnish 4.88 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:13][C:12]2[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:10][C:9]([Cl:20])=[N:8][C:7]=2[CH:6]=1)=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[Cl:20][C:9]1[N:10]=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:12]2[S:13][C:5]([C:3]3[N:21]=[C:22]([NH2:24])[S:23][CH:2]=3)=[CH:6][C:7]=2[N:8]=1
Reactant: O=C(CBr)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cs1
Temperature: 70 °C

Procedure:
To a solution of 2-bromo-1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone (1.0 eq) dissolved in EtOH was added thiourea. Reaction mixture was heated at 70° C. until completed, then extracted in dichloromethane with saturated bicarbonate solution one time. The organic layer is dried, filtered and concentrated to yield the crude intermediate. This intermediate is purified by flash chromatography to yield 4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine. MS (Q1) 413 (M+)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[C:33]([CH2:37][CH2:38][C:39](Cl)=[O:40])([O:35][CH3:36])=[O:34].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:39]([CH2:38][CH2:37][C:33]([O:35][CH3:36])=[O:34])=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 3-carbomethoxypropionyl chloride (14 mg) and N,N-diisopropylethylamine (40 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:32]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:32][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:16]([CH2:24][CH:25]([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(CN(Cc1ccncc1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1ccncc1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 97 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(pyridin-4-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-15) (3.1 g, 4.6 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (1.98 g, 97%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:36][C:37]3[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=3)[C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: Cn1ccnc1CCl
Product: Cc1ccccc1N1CN(Cc2nccn2C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=580.3 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloromethyl-1-methyl-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1C(C)C(OCC)=O.C(Cl)Cl>CCCCCC>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)Cc1c(Br)c(OC)c2ccccc2c1OC
Agent: CCOC(=O)C(C)C1=C(Br)C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)C(C)CC1=C(Br)C(=O)c2ccccc2C1=O

Procedure:
Compound 68b was prepared from 67b (0.258 g, 0.678 mmol) as described above for 68a to give 0.064 g (0.18 mmol, 27%) of the product as a yellow solid following flash chromatography (3:1 CH2Cl2:hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:23][CH3:24])=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:5][CH:4]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:46]([N:50](CC(C)C)CC(C)C)C(C)C.C(OC(Cl)=O)C(C)C.CNCCCC>CC(C)=O.O.C(Cl)Cl.C(O)(C)C>[CH3:46][NH:50][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:23][CH3:24]
Reactant: CCC(C(=CCCCCCCCCCCO)c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CC(C)CN(CC(C)C)CC(C)C
Agent: O=[Cr](=O)=O
Agent: CC(C)COC(=O)Cl
Agent: CCCCNC
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CCC(C(=CCCCCCCCCCC(=O)NC)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a cooled solution of alcohol 3 (710 mg, 1.56 mmol) in acetone (17 ml) was added Jones' reagent (8N-chromic acid solution, 0.77 ml). After 30 minutes, isopropanol (5 ml) was added and the mixture was poured in water and extracted three times with ethyl acetate. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated to dryness. The crude 12,13-Bis (4-methoxyphenyl)-11-pantadecenoic acid was used in the next step without purification. To its solution in anhydrous methylene chloride (4 ml) at -10° C. was added, under stirring, triisobutylamine (470 μl, 1.96 mmol) and isobutylchloroformate (280 μl, 2.1 mmol). After 40 minutes, N-methylbutylamine (1.5 ml) was added and the mixture was stirred at room temperature during 1 hour. Methylene chloride (50 ml) was added. The organic solution was washed with 1N HCl, saturated sodium bicarbonate solution and water (3X), dried on magnesium sulfate and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 50 g). Elution with a mixture of hexane-ethyl acetate (4:1 v/v) gave N-butyl, N-methyl-12,13-Bis (4-methoxyphenyl)-11-pentadecenoic amide (4), (549 mg, 68%) colorless oil; IR νmax (neat), 1640, 1600 cm-1 ; UV γmax (log ε)=230, (4.39) nm; 1H-NMR (δ, CDCl3), 0.85-0.98 (6H, m, 2--CH2CH3), 2.27 (2H, t, J=7.1 Hz, CH2CON), 2.91 and 2.96 (3H, 2s, --NCH3), 3.25-3.36 (3H, m, --NCH2 and CH3CH2CH--), 3.77 and 3.78 (6H, 2s, OCH3), 5.50 (1H, J=7.1 Hz, --C=CH--) and 6.69-7.01 (8H, m, H--Ar) ppm; MS m/e=521 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([N:13]2[CH:17]=[C:16]([C:18](OC)=[O:19])[CH:15]=[N:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>O1CCCC1>[CH:7]1([N:13]2[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[N:14]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(C2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnn(C2CCCCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
Under a nitrogen atmosphere, 0.57 g of lithium aluminum hydride was suspended in 100 ml of dry tetrahydrofuran, and a solution of 3.01 g of methyl 1-cyclohexyl-1H-pyrazole-4-carboxylate in 40 ml of tetrahydrofuran was added dropwise thereto over 15 minutes with stirring at 0° C. After completion of the addition, the mixture was stirred at room temperature for 7 hours and then cooled to 0° C. Thereto 10 ml of a 1 mol/L aqueous saturated sodium hydroxide solution was added dropwise. Produced precipitates were filtered and then washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.68 g of (cyclohexyl-1H-pyrazol-4-yl)methanol.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:9]=[C:10]([OH:28])[C:11]2[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:14]=[N:15][C:16]=2[CH:17]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCCCCC.C(OCC)(=O)C>[C:29]([O:28][C:10]1[CH:9]=[C:8]([CH3:7])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[N:14]=[N:15]2)(=[O:31])[CH3:30]
Reactant: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C)cc2nnc(-c3cccc(C(F)(F)F)c3)cc12
Yield: 36 %

Procedure:
To a pyridine solution (2 mL) of 7-methyl-3-(3-trifluoromethylphenyl)cinnolin-5-ol (60 mg, 0.2 mmol) obtained in Example 70 was added acetic anhydride (3 mL), followed by reaction at room temperature over night. The reaction liquid was concentrated under reduced pressure, followed by adding distilled water (1 mL), extraction with ethyl acetate and purification of residue obtained after concentration of an organic layer under reduced pressure, with HPLC column chromatography (hexane/ethyl acetate=3/1) to obtain an objective compound (25 mg, 36%) as pale yellow solid.
Reaction SMILES: [Br:1]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]([CH2:40]O)=[CH:27]2.CCOCC.CCCCCC>C(#N)C>[Br:1][CH2:40][C:28]1[CH:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:30][C:31]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:23][CH3:22])=[CH:33][CH:32]=2
Reactant: COc1ccc2c(c1)C=C(CO)C(c1ccccc1)O2
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc2c(c1)C=C(CBr)C(c1ccccc1)O2
Reaction time: 0.25 h

Procedure:
4.79 g (8.95 mmol) of dibromotriphenylphosphorane are added to a solution of 2.4 g (8.95 mmol) of the alcohol obtained in Step A in 80 ml of acetonitrile. After 15 minutes of stirring under argon, the solvent is evaporated in vacuo; the residue obtained is then taken up in an ether/hexane mixture (1/1). The solid formed is filtered off; the filtrate is then concentrated under reduced pressure to yield the brominated compound of the title in the form of a chestnut-brown syrup.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[O:14][CH2:15][CH2:16]2)=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[O:14][CH2:15][CH2:16]2
Reactant: [H][H]
Reactant: O=C(N[C@@H]1C(=O)N2CCO[C@H]12)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N2CCO[C@H]12

Procedure:
(5R,6S)-6-benzyloxycarbonylamino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one (950 mg, 3.624 mmole) was hydrogenated with 3 g of 10% palladium on activated carbon in ethyl acetate (80 ml) at 50 psi hydrogen pressure at room temperature for 6 hrs. after removal of catalyst by filtration, deprotected (5R,6S)-6-amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one in ethyl acetate was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH2:13].[O-]S([O-])(=O)=O.[Mg+2].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CC#N>[C:17]([O:16][C:14]([NH:12][N:13]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NN=C1CCC(C(C)(C)C)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of 4-tert-butylcyclohexanone (3.95 g, 25.6 mmol) in CH2Cl2 (50 mL) was added tert-butyl hydrazinecarboxylate (3.83 g, 25.6 mmol). A 1:1 mixture of MgSO4/Na2SO4 was added to the reaction to make a slurry and the reaction was stirred vigorously. After 18 h, the reaction was diluted with CH3CN and filtered. The solvent was removed from the filtrate under reduced pressure to give 6.78 g of N′-(4-tert-butyl-cyclohexylidene)-hydrazinecarboxylic acid tert-butyl ester as a white foam. This material was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 2.93 (d, J=15 Hz, 1H), 2.30 (d, J=13 Hz, 1H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.43 (s, 9H), 1.25 (m, 1H), 1.13 (m, 1H), 1.03 (m, 1H), 0.85 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl-].[C:11]([O:15][C:16](=[O:19])[CH2:17][Zn+])([CH3:14])([CH3:13])[CH3:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:5]([C:4]1[CH:3]=[C:2]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cccc(C#N)c1
Yield: 85.9 %

Procedure:
Combined 3-bromobenzonitrile (1500 mg, 8.24 mmol), 0.5 M (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (24.72 mL, 12.36 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (324 mg, 0.824 mmol) and Pd(dba)2 (237 mg, 0.412 mmol) in THF (25 mL) and heated at 100° in an oil bath for 14 h. The reaction solution was concentrated onto Celite® and chromatographed on a 120 g silica gel column eluted with 0 to 50% EtOAc in hexanes to give the title compound (1.537 g, 86% yield) as a yellow oil. MS m/z 218 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ ppm 1.45 (s, 9H) 3.56 (s, 2H) 7.40-7.46 (m, 1H) 7.49-7.54 (m, 1H) 7.54-7.59 (m, 2H).