Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH:6]1[CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17]C)=[O:16].C([O-])(=O)C.CO.[OH-].[Na+]>O>[OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH:6]1[CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=[O:16]
Reactant: CCCCCC(O)C=CC1CCC2(OCCO2)C1C(CCCCC)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=CC1CCC2(OCCO2)C1C(CCCCC)C(=O)O

Procedure:
A solution of 3.85 g. of 7-(3-hydroxy-1-octenyl)-1,4-dioxaspiro[4.4]non-6-ylheptanoic acid, methyl ester, acetate in 75 ml. of methanol was treated with 75 ml. of 1N sodium hydroxide and kept at 25° for 0.5 hours. The reaction mixture was diluted with water, washed with ether, acidified with acetic acid and extracted with ether. After washing and drying, the ether extract was evaporated and the residue chromatographed on silica. Elution with 50% ethyl acetate-hexane afforded 0.94 g. of the title product, λmaxfilm 3.0 (shoulder), 3.4, 5.75, 6.85, 8.75, 9.25, 10.4 μ. NMR: 6.35 (S, 2, OH), 5.52 (M, 2, 13 and 14-H), 4.05 (M, 1, 15-H), 3.92 (S, 4, ketal) ppm.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c(-c2ccncc2)c(-c2cccc(F)c2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A suspension of 2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone (1.0 g, 3.54 mmol) in phosphorus oxychloride (15 ml) was stirred at 100° C. for 30 minutes under an atmosphere of nitrogen gas. After cooling as it was, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and 2N sodium hydroxide. The organic layer was washed with an aqueous saturated sodium bicarbonate solution twice and brine, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether, and the resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (513 mg, 48%) as a colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])(C)(C)C.[ClH:19]>CCOCC.O>[ClH:19].[NH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C#N
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: N#CC1CCCN1C(=O)CN
Reaction time: 1 h
Yield: 98 %

Procedure:
[2-(2-Cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1e (13.7 g, 54.2 mmol) was dissolved in the solvent mixture of 140 mL of ether and 40 mL of water, and 37% hydrochloride acid (90 mL) were then added dropwise to the solution. Upon completion of the addition, the reaction mixture was stirred for 1 hour in an ice-water bath, the solvent was evaporated, and ether was added to the residue to centrifuge to give 1-(2-amino-acetyl)-pyrrolidine-2-carbonitrile hydrochloride 1d (10 g, yield 98%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:26])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Sc2ccc(CCl)cc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
An oven-dried 1 L round-bottomed flask was charged with compound 7.2 (30.0 g, 90.2 mmol) and chloroform (300 mL) and the mixture was cooled to 0° C. Thionyl chloride (7.90 mL, 107 mmol) was added dropwise at 0° C., and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give 7.3 as a slightly yellow oil (33.5 g), which was used in the next step without further purification. 1H NMR (400 MHz) (CDCl3) δ 7.30-7.20 (4H, m); 7.12 (2H, d, J=8.3 Hz); 6.68 (1H, d, J=8.4 Hz); 4.65 (2H, s); 4.53 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.27 (3H, s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:23][CH2:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(O)CCC>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([CH2:24][NH:23][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:26][CH:27]=1
Reactant: NCc1ccc(N)cc1
Reactant: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Solvent: CCCCO
Product: Nc1ccc(CNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Yield: 70.3 %

Procedure:
4-Chloro-5,6-diphenylfuro[2,3-d]pyrimidine (0.10 g) and 4-(aminomethyl)aniline (0.05 g) in n-butanol (5 mL) were heated at 80° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography using a mixture of dichloromethane:methanol (40:1), to give N-(4-aminobenzyl)-5,6-diphenylfuro[2,3-d]pyrimidin-4-amine (0.09 g, 70%). 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 7.54-7.44 (m, 8H), 7.27-7.25 (m, 2H), 6.93 (d, 2H), 6.10 (d, 2H), 4.87 (t, 1H), 4.51 (d, 2H), 3.65 (brs, 2H). LC-MS (ESI) m/z 393.7 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:17]([CH3:18])[C:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:4]=2[NH:3]1.[ClH:19]>CO.CCOC(C)=O>[ClH:19].[CH3:1][N:2]1[C:17]([CH3:18])=[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]2=[N:3]1
Reactant: CC1C2=C(CCN(C(=O)OC(C)(C)C)C2)NN1C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c2c(nn1C)CCNC2
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 2,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3.0 g) in MeOH was added a solution of HCl in EtOAc (3.0 M). White solid was precipitated out after 3.0 h reaction. The resulted mixture was filtered and the residue was dried to give the title compound as a white solid (2.10 g, 91.90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 152.21 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=2)[CH:19]=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:23].[NH:24]1[CH2:28][CH2:27][C@@H:26]([C:29]([OH:31])=[O:30])[CH2:25]1.CC(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=2)[CH2:19][N:24]2[CH2:28][CH2:27][C@@H:26]([C:29]([OH:31])=[O:30])[CH2:25]2)[C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc([C@H](Nc2ccc(C)c(C=O)c2)C(F)(F)F)ccc1Cl
Reactant: O=C(O)[C@@H]1CCNC1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc([C@H](Nc2ccc(C)c(CN3CC[C@@H](C(=O)O)C3)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of aldehyde INT 33 (2.50 g, 7.32 mmol) and (R)-pyrrolidine-3-carboxylic acid (0.93 g, 8.05 mmol) in MeOH (74 mL) was added HOAc (0.42 mL, 7.32 mmol) followed by PS—CNBH3 (2.5 mmol/g, 2.93 g, 7.32 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through Celite. The filtrate was concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and water. The aqueous layers were extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH) to afford the title compound Example 21.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH:21][C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[O:32])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH2:14][CH2:13][S:12][C:11]=23)=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
3-(7-Pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine (52 mg, 0.177 mmol) was dissolved in dry DCM under nitrogen atmosphere. p-trifluoromethyl-phenylisocyanate (0.030 mL, 0.212 mmol, 1.2 eq) was added and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluant: DCM/MeOH 96:4) to give 73 mg (86%) of 1-[3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCCC2CC(c3cccc([N+](=O)[O-])c3)=NO2)CC1
Yield: 48 %

Procedure:
4-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]butanal (25.2 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.312 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 18.3 mg (44.6%) of the target compound was obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>CC(C)=O.CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[OH:23][C@@H:11]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH2:31][CH2:32][CH2:33][C:34]#[N:35])[CH:14]=2)[N:19]=[CH:20][CH:21]=1)[C@@H:10]1[N:5]2[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]2)[CH2:9]1
Reactant: N#CCCCBr
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC#N)cc12
Yield: 94.3 %

Procedure:
To a solution of 400 mg (1.2 mmol) of 6-hydroxycinchonane (1) in 25 ml of anhydrous acetone (dried and distilled over potassium carbonate) and 5 ml of anhydrous dimethylformamide was added 267 mg (1.93 mmol) of anhydrous potassium carbonate followed by 129 ml (0.87 mmol) of 4-bromobutyronitrile and a catalytic amount (3 mg) of 18-crown-6. The reaction mixture was heated to reflux for 18 h, cooled and filtered. The filtrate was concentrated under reduced pressure and redissolved in 200 ml of chloroform. The organic layer was washed with 2×50 ml of 5% aqueous sodium hydroxide, washed with brine, dried using anhydrous magnesium sulfate and yielded 310 mg (0.82 mmol, 66%) of (9S)-4-[(9-hydroxycinchonan-6'-yl)oxy]butanenitrile (2) as pale yellow solids. MS, IR and NMR data confirmed the identity of the compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[F:16][C:17]([F:37])([F:36])[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)=[O:19]>C1COCC1.CCOCC>[F:37][C:17]([F:16])([F:36])[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1)[OH:19]
Reactant: COc1ncc(Br)cc1C
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 5-bromo-3-methyl-2-methoxypyridine (1.56 mmol) in 2 mL THF was added dropwise n-butyllithium (1.71 mmol from a 2.5 M solution in hexanes). The mixture was stirred for 30 minutes and then 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (1.39 mmol) in 3 mL THF was added. After 30 minutes, the mixture was diluted with ether and quenched with aqueous ammonium chloride. The organic layer was washed with brine and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by Combiflash chromatography using ethyl acetate-hexane. The product-rich fractions were concentrated in vacuo to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[CH2:3][CH2:4][OH:5].[CH:9]([C:11]1[C:19]2[C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=[N:15][C:14]=2[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:12]=1)=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH:6]1([CH:2]([NH:1][CH2:9][C:11]2[C:19]3[C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=[N:15][C:14]=3[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:12]=2)[CH2:3][CH2:4][OH:5])[CH2:8][CH2:7]1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: NC(CCO)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccnc2c1c(CNC(CCO)C1CC1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
3-Amino-3-cyclopropylpropan-1-ol (30 mg, 0.26 mmol) was added to a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (39.6 mg, 0.13 mmol) in MeOH (3 mL) with AcOH (2 drops). After stirring for 90 min at rt, sodium cyanoborohydride (33 mg, 0.53 mmol) was added, and the reaction was stirred for an additional 3 h. The mixture was quenched with sat. NaHCO3 solution and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo to give 50 mg of crude 1-tert-butyl 4-methyl 3-((1-cyclopropyl-3-hydroxypropylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate as a yellow oil which was used without further purification. [M+H] found 404.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([CH3:34])[C@H:28]2[CH2:29][C@@H:24]1[CH2:25][CH2:26][C@H:27]2[CH2:30][C:31](O)=[O:32]>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:31](=[O:32])[CH2:30][C@@H:27]2[CH2:26][CH2:25][C@H:24]3[CH2:29][C@@H:28]2[C:23]3([CH3:22])[CH3:34])[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)C[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid (Eigenmann, G. W.; Arnold, R. T. JACS 1959, 81, 3440-2) were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.36-8.28 (m, 1H), 8.10 (d, J=7.8, 1H), 7.98 (dd, J=11.1, 4.1, 1H), 7.90 (t, J=7.1, 1H), 7.40 (s, 1H), 4.45 (d, J=5.7, 2H), 2.41-2.29 (m, 3H), 2.07-1.80 (m, 5H), 1.64-1.47 (m, 1H), 1.43-1.29 (m, 10H), 1.21 (s, 3H), 1.07 (s, 3H), 0.91 (d, J=9.5, 1H). MS (ESI+) M/Z 472 (M+NH4)+.
Reaction SMILES: [OH-].[K+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[O:19].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:8]([N:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:4][CH2:5][CH2:6]1)=[O:19])[CH3:21]
Reactant: CCO
Reactant: O=c1oc2ccc([N+](=O)[O-])cc2n1CCCCl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Potassium hydroxide (2.19 g, 33.2 mmol) was dissolved in Ethanol (150 mL) and 3-(3-Chloro-propyl)-5-nitro-3H-benzoxazol-2-one (8.11 g, 31.6 mmol) was added. After 2 h, the mixture was concentrated in vacuo, and the solids redissolved in N,N-Dimethylformamide (150 mL). The mixture was heated to 80° C. for 2 h. The mixture was cooled and diluted with 500 mL EtOAc and washed with water (4×50 mL). The aq. washes were back extracted with 100 mL EtOAc. The combined organics were washed with water (50 mL) and brine (100 mL), dried over sodium sulfate and conc. in vacuo to give orange solids, which were triturated in 10% Ether:Hexane (100 mL) overnight. The orange solids were collected and washed with hexane to furnish 2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (6.45 g, 77%). 1H-NMR (DMSO): 8.19 (s, 1H), 8.02 (d, 1H, J=8.9 Hz), 7.19 (d, 1H, J=8.9 Hz), 4.25 (m, 2H), 4.15 (m, 2H), 3.76 (m, 2H), 2.05 (m, 2H), 1.19 (m, 3H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C2c2cccc(Cl)c2F)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2(C#N)C(CC(C)(C)C)NC(C(=O)O)C2c2cccc(Cl)c2F)ccc1Cl
Yield: 85 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 100b (2.0 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.88 g, 85%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[CH2:13][C:14]([O:16][CH3:17])=[O:15].O.O.O.C([O-])(=O)C.[Na+]>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(C(F)(F)F)c1

Procedure:
3-Trifluoromethylaniline (80.5 g), methyl chloroacetate (44 ml) and sodium acetate trihydrate (114 g) were treated according to the method of Intermediate 1 to give a solid (84 g), a sample of which (ca. 1 g) was purified by FCC eluting with System A (1:1) to give a solid which was recrystallised from System A to give the title compound, m.p. 60°-63°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:27][CH3:28])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:30]#[N:31].O.N>CN(C)C=O>[C:30]([C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:27][CH3:28])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1)#[N:31]
Reactant: CCc1nc(-c2cccc(Br)c2)c(-c2ccnc(NC(=O)OC(C)(C)C)c2)s1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(-c2cccc(C#N)c2)c(-c2ccnc(N)c2)s1
Temperature: 150 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
To a solution of 4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole (0.5 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added copper cyanide (0.25 g, 1.6 mmol), and the mixture was stirred for 20 hours at 150° C. under argon atmosphere. Into the reaction mixture was poured ammonia water, and the deposit was removed, then, extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to obtain a crystal. This crystal was washed with hexane-ethyl acetate to obtain a title compound (0.19 g, yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:29]#[N:30])=[O:5]
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: N#CC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
2-Fluorobenzoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.2 mL of 2-fluorobenzoyl chloride (97%, Aldrich) (10 mmol), 26 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.55 mL of trimethylsilyl cyanide (12 mmol) were placed in a 100-mL round bottom flask. To this solution 0.25 mL of tin (IV) chloride (2.1 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from yellow to dark brown. The reaction mixture was stirred for 2 hr at room temperature, then quenched with 75 mL of ice-cold water, and finally extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield a dark brown oil which was purified by Kugelrohr vacuum distillation to yield 0.711 g (47%) of 2-fluorobenzoyl cyanide as a colorless oil: IR (CH2Cl2) (partial) 2225, 1695, 1670, 1610, 1489, 1484, 1457 cm-1.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][C:18]=1[O:26][CH3:27])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H][H]>[C].[Pd].CO>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:9]1([CH2:8][CH2:7][C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[NH:24])[NH2:25])=[CH:19][C:18]=2[O:26][CH3:27])=[O:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COc1cc(C(=N)N)ccc1OC(=O)C=Cc1ccccc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1cc(C(=N)N)ccc1OC(=O)CCc1ccccc1
Yield: 74.6 %

Procedure:
To 100 ml of methanol, were added 2.0 g of 4-amidino-2-methoxyphenyl cinnamate methanesulfonate and 0.5 g of a 10% palladium-carbon. Hydrogen was fed to the mixture which was stirred vigorously to facilitate absorption. The reaction mixture was freed from the insolubles by filtration and from the solvent by distillation. The residue was recrystallized from ethanol to obtain 1.5 g of the same 4-amidino-2-methoxyphenyl 3-phenylpropionate methanesulfonate.