Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:25]([NH:27][C@@H:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>N1C=CC=CC=1>[C:44]1([O:43][C:41]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:25]([NH:27][C@@H:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:42])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@@H](N)CC(C)C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of H-Leu-DTrp(COOMe)-DNle-OtBu (320 mg, prepared in Example 21-(2)) in pyridine (2.3 ml) was added phenyl chloroformate at 0°-5° C. under argon atmosphere. The mixture was stirred at the same temperature for 1.5 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 10% aq. citric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel flash chromatography (Merck, Kieselgel 60) with ethyl acetate/hexane=2/1 for elution to give the product (337 mg).
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1[C:10](I)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>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.CN(C=O)C.CCN(CC)CC>[F:8][C:9]1[C:10]([C:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]
Reactant: C#CCNC(N)=O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNC(N)=O)c21

Procedure:
Using Method C above, 2-propynylurea (50 mg, 0.51 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[5-fluoro-2,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]urea. (Yield 11 mg, 16%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH:42]3[CH2:44][CH2:43]3)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:47](O)([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[CH:42]1([C:37]2[CH:36]=[C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:45])[NH:24][C:9]5[CH:10]=[C:11]([C:49]([F:52])([F:51])[F:50])[C:12]([O:48][CH2:47][C:49]([F:52])([F:51])[F:50])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)[CH:40]=[C:39]([CH3:41])[N:38]=2)[CH2:43][CH2:44]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M239) (308 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (199 mg, 79%).
Reaction SMILES: C(NC1CCCC2C=CC(OC)=CC=2C1)C1C=CC=CC=1.[C:22]1([N:28](CC2OC2)[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:32]([O:31][C:29]([NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OCc1ccccc1)N(CC1CO1)c1ccccc1
Agent: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)OCc1ccccc1
Reaction time: 24 h
Yield: 127.6 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (300 mg) and 1-[N-phenyl-N-benzyloxycarbonylamino]-2,3-epoxypropane (300 mg) in dichloromethane (5 ml) was added ytterbium(III) trifluoromethanesulfonate (66 mg) at room temperature, and the mixture was stirred at the same temperature for 24 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 4:1) to give N-[3-[N′-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-2-hydroxypropyl[-N-benzyloxycarbonylphenylamine (307 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].ClC(Cl)C.[C:16]([O:20][C:21]([NH:23][CH:24]([C@H:30]1[CH2:34][CH2:33][N:32]([C@@H](C2C=CC=CC=2)C)[C:31]1=O)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH:24]([C@@H:30]1[CH2:34][CH2:33][N:32]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:31]1)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC[C@H](C(NC(=O)OC(C)(C)C)c2ccco2)C1=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC(c1ccco1)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 74.2 %

Procedure:
In an atmosphere of nitrogen, benzyl chloroformate (761 μl, 5.31 mmol) was added dropwise to a dichloroethane solution (15 ml) of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (658 mg, 1.77 mmol) under ice-cooling and then the m was heated under refulx for 30 hours. After evaporation of the solvent under a reduced pressure, the residue was applied to a silica gel column chromatography. By eluting with chloroform to chloroform:methanol (97:3), 526 mg (74%) of the title compound was obtained as white crystals.
Reaction SMILES: [O:1]1[C:22]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=2)[NH:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH3:23][S:24]([N:4]1[C:5]2=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=[C:22]2[O:1][CH2:2][CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)OCCN3
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(S(C)(=O)=O)CCO3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 130 mg of t-butyl 3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 4 ml of dichloromethane were added 0.036 ml of methanesulfonyl chloride and 0.089 ml of diisopropylethylamine under ice-cooling, followed by stirring at room temperature for 16 hours. To the reaction mixture were added 0.036 ml of methanesulfonyl chloride and 0.089 ml of diisopropylethylamine, followed by stirring at room temperature for additional 9 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 152 mg of t-butyl 4-(methylsulfonyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a colorless solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@:19]3([C:23](O)=[O:24])[CH2:21][C@@H:20]3[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:39][C:40]1[S:41][C:42]([CH3:55])=[C:43]([CH3:54])[C:44]=1[C:45]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.C(Cl)Cl>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C:45]([C:44]2[C:43]([CH3:54])=[C:42]([CH3:55])[S:41][C:40]=2[NH:39][C:23]([C@@:19]2([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH2:21][C@@H:20]2[CH3:22])=[O:24])=[O:46])=[CH:48][CH:49]=1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: C[C@H]1C[C@]1(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(NC(=O)[C@@]2(NC(=O)OCC3c4ccccc4-c4ccccc43)C[C@@H]2C)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A round bottomed flask was charged with (1R,2S)-1-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-methylcyclopropanecarboxylic acid (408 mg, 1.209 mmol) and a stir bar. DCM (25 mL, 0.05 M) was added, followed by one drop of DMF and oxalyl chloride (97 μl, 1.109 mmol). Stirred at room temperature 1 h. A solution of triethylamine (562 μl, 4.03 mmol) and (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (268 mg, 1.008 mmol) in DCM (10 mL, 0.1 M) was added dropwise, and the solution stirred at room temperature overnight before being concentrated with celite and purified by flash chromatography to give (9H-fluoren-9-yl)methyl (1R,2S)-1-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-ylcarbamoyl)-2-methylcyclopropylcarbamate as a yellow amorphous solid (225 mg) LRMS (M+H)+: 586 m/z.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12]O)[CH:4]=1)=[O:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: O=Cc1cn(CO)c2ccccc12
Solvent: ClCCl
Product: O=Cc1cn(CCl)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.08 g of 3-formyl-1H-indole-1-ylmethanol was dissolved to 60 ml of dichloromethane. 2.5 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 3.02 g of 1-(chloromethyl)-3-formyl-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](O)=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([N:25]([O:26][CH3:27])[CH3:24])=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: C=Cc1cc(C(=O)O)c(-c2cccc(F)c2)c2ncccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a mixture of 8-(3-fluorophenyl)-5-vinylquinoline-7-carboxylic acid (66 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (32.9 mg, 0.338 mmol) in N,N-dimethylformamide (0.4 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.149 g, 0.338 mmol). After stirring at room temperature for 30 minutes, N,N-diisopropylethylamine (0.118 mL, 0.675 mmol) was added to the resulting mixture. The reaction was stirred at room temperature overnight, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resdiue was purified on silica gel, eluting 0 to 50% ethyl acetate in hexane, to give the desired product (32 mg, 42%). LCMS calculated for C20H18FN2O2 (M+H)+: m/z=337.1; Found: 337.1.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[N:8]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=2[N:32]=1.CI>O1CCCC1.O.C(OCC)C>[CH2:6]([C:7]1[N:8]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:10]=2[N:32]=1)[CH3:1]
Reactant: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(CC(C)C)c2c1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(C)c(C)c2n1CC(C)C
Temperature: -10 °C

Procedure:
Butyllithium (0.5 mL of 2.5M in hexanes) was added to a cooled (-78°C.) solution of 2,6,7-trimethyl-1-(2-methylpropyl)-N4,N4 -bis(phenylmethyl)-1H-imidazo[4,5-c]pyridin-4-amine (0.5 g, 1.2 mmole) in tetrahydrofuran (30 mL). The reaction mixture was allowed to warm to -10° C. then it was cooled to -78° C. and combined with methyl iodide (0.23 mL, 3.6 mmole). The reaction mixture was allowed to warm to ambient temperature then diluted with water and diethyl ether. Theether layer was separated, washed with ammonium chloride solution, dried over magnesium sulfate and then concentrated to provide 0.5 g of the desired product.
Reaction SMILES: FC(F)(F)[CH:3]([C:8]([F:11])([F:10])[CH3:9])[C:4]([F:7])([F:6])[CH3:5].CC(=O)CC(=O)C>>[F:6][C:4]([F:7])([CH2:3][C:8]([F:11])([F:10])[CH3:9])[CH3:5]
Reactant: CC(F)(F)C(C(C)(F)F)C(F)(F)F
Solvent: CC(=O)CC(C)=O
Product: CC(F)(F)CC(C)(F)F

Procedure:
As another example, the 3-trifluoromethyl-2,2,4,4-tetrafluoropentane may be prepared by fluorinating commercially available 2,4-pentanedione to form 2,2,4,4-tetrafluoropentane which may then be dehydrohalogenated to form 2,4,4-trifluoro-2-pentene. The 2,4,4-trifluoro-2-pentene may then be reacted with CF3 to form 3-trifluoromethyl-2,2,4,4-tetrafluoropentane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8].[N-:36]=[N+:37]=[N-:38].[Na+]>O.C(O)(C)C.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[NH:38][N:37]=[N:36][N:27]=3)[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(C#N)ccc12
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(-c3nnn[nH]3)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 617 from (1R,3S,5R)-2-[2-(3-acetyl-6-cyano-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Example 616 (100.0 mg, 0.203 mmol), sodium azide (66.0 mg, 1.014 mmol) and zinc bromide (228.0 mg, 1.014 mmol) in water (2 mL) and isopropanol (1 mL). White solid. MS (LC/MS): 536.0 [M+H]+; tR (HPLC conditions k): 3.21 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]/[CH:12]=[C:13]2/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][C:22]/2=3)[CH2:6][CH2:5]1.C(Cl)Cl>O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]/[CH:12]=[C:13]2\[C:14]3[C:19]([S:20][C:21]4[CH:26]=[CH:25][C:24]([S:27]([N:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])=[CH:23][C:22]\2=4)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:6][CH2:5]1
Reactant: CN1CCN(CC/C=C2/c3ccccc3Sc3ccc(S(=O)(=O)N(C)C)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(CC/C=C2\c3ccccc3Sc3ccc(S(=O)(=O)N(C)C)cc32)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
5N aqueous sodium hydroxide was added to a suspension of thiothixene.2H3PO4 (63.96 g., 100 mmoles, ca. 85% trans/ 15% cis) in water (750 ml.)/methylene chloride (750 ml.) until the aqueous phase was strongly basic. The phases were separated and the aqueous phase extracted with an additional 200 ml. portion of methylene chloride. The combined methylene chloride extract was dried (Na2SO4), filtered and evaporated in vacuo to a light brown oil (ca. 45 g., ca. 100% yield, ca. 85% trans/15% cis). The oil was dissolved in warm acetonitrile (100 ml.) and the solution cooled to room temperature. Some solids, probably trans-thiothixene, formed upon cooling. Potassium t-butoxide (1.1 g., 9.8 mmoles) was added and the mixture stirred overnight at room temperature. Analysis of the reaction mixture, which contained solids, showed a ca. 85% cis/ 15% trans ratio of isomers. Water (10 ml.) was then added and the reaction mixture stirred briefly at room temperature. The tan cis-thiothixene solids were then filtered, washed with acetonitrile, and dried (35.0 g., 78.9% yield, 5% trans, m.p. 143°-145° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:13]2[CH:14]=[N:15][N:16](C(OCC)C)[CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Cl.O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:13]2[CH:17]=[N:16][NH:15][CH:14]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cn[nH]c1
Yield: 75.6 %

Procedure:
1-{5-Chloro-3-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-2-methoxy-4-methylphenyl}ethanone (0.22 g, 0.65 mmol) was treated with 1.0 M hydrogen chloride in water (3.9 mL, 3.9 mmol) in tetrahydrofuran (4 mL) overnight. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered, concentrated and purified on silica gel (eluting with 0-60% of ethyl acetate in hexane) to afford the desired product (0.13 g, 75%). LCMS calculated for C13H14ClN2O2 (M+H)+: m/z=265.1. found: 265.0.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:28]#[N:29])[CH2:26][CH2:27]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C2(C#N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclopropyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (86.5 mg, 0.430 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclopropanecarbonitrile (80.0 mg, 0.430 mmol) prepared according to scheme 10, Et3N (131 mg, 1.29 mmol, 0.180 mL) and HATU (163 mg, 0.430 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Synergi Polar (5μ) 21.2×50 mm, Mobile phase: A=water (0.05% TFA) B=MeCN, (23.0 mg, 0.0623 mmol, 14%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.35 (dd, J=7.81, 5.47 Hz, 2H) 1.49 (d, J=7.03 Hz, 3H) 1.68 (dd, J=7.42, 5.08 Hz, 2H) 5.00-5.13 (m, 3H) 6.65 (d, J=7.42 Hz, 1H) 7.22 (d, J=8.59 Hz, 2H) 7.29 (d, J=8.20 Hz, 2H) 7.33 (d, J=7.81 Hz, 1H) 7.59 (d, J=7.62 Hz, 1H) 7.96-8.06 (m, 2H); MS [M+H], calcd: 370.0. found: 370.0.
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH:15]=[CH:14]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:20]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=[O:8])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1C=Cc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
A suspension of 8-diphenylphosphinoyl-2-methyl-1,2-dihydroquinoline (5) (11 g, 32 mmol) and Pd/C (1.1 g, 10 wt %) in MeOH (40 mL) was stirred under H2 at 145 psi pressure for 16 hours. The mixture was then diluted with EtOAc (200 mL) and filtered over celite (−25 mL). The filtrate was then evaporated to give compound 6 as a yellow oil (11.2 g, quantitative). 1H NMR (400.13 MHz, CDCl3) δ 7.7-7.6 (m, 4H, Ph-H), 7.6-7.5 (m, 2H, Ph-H), 7.5-7.4 (m, 4H, Ph-H), 7.03 (d, 1H, J=7.2 Hz, C5—H), 6.87 (bs, 1H, N1—H), 6.58 (dd, 1H, J=14.0, 7.2 Hz, C7—H), 6.39 (ddd, 1H, J=10.4, 7.2, 2.8 Hz, C6—H), 3.5-3.4 (m, 1H, C2—H), 2.8-2.7 (m, 2H, C4—H), 1.9-1.8 (m, 1H, C3a—H), 1.6-1.4 (m, 1H, C3b—H), 1.13 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.9, 132.0 (d, J=11.1 Hz), 131.5, 131.0 (d, J=10.1 Hz), 130.7 (d, J=10.1 Hz), 130.6 (d, J=10.1 Hz), 130.4 (d, J=6.1 Hz), 130.3 (d, J=6.1H), 130.1 (d, J=11.1 Hz), 127.0 (d, J=13.1 Hz), 126.9 (d, J=12.1 Hz), 120.4 (d, J=8.1 Hz), 112.5 (d, J=14.1 Hz), 107.9, 106.9, 45.4, 27.4, 25.5, 20.9 ppm; 31P NMR (161.97 MHz, CDCl3) δ 36.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][C:21](=[CH:24][C:25]#[N:26])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([CH2:24][C:25]#[N:26])[CH2:22][CH2:23]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CC[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexylidene)acetonitrile (100 mg, 0.26 mmol) and 10% Pd/C (100 mg) in EtOAc (2 mL) was stirred under H2 balloon at room temperature for 4 h. LCMS showed the most of s.m was consumed. The mixture was filtered and the filterate was concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-87 (13 mg, 13.7%) as a white solid.