Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)=[C:17]=[S:18]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
A solution of 4-[4-(1-methylethyl)-1-piperazinyl]benzenamine (1.6 g,˜6.8 mmol) (from Step B above) in N,N-dimethylformamide (25 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyidiimidazole (1.4 g, 7.7 mmol) (Aldrich) in N,N-dimethylformamide (30 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (MgSO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-(1-methylethyl)piperazine (1.8 g, quantitative yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[C:10]([O:13][C:14]1[C:23]2[C:18](=[C:19]([NH2:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:15]=1)(=[O:12])[CH3:11].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:13][C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:8])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)[CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc12
Reactant: O=C(Cl)c1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(NC(=O)c3cnccn3)cccc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Pyrazine-2-carbonyl chloride 40 (100 mg) was added to a solution of 8-amino-2-(3-(trifluoromethyl)phenyl)quinolin-4-yl acetate 39 (50 mg, 0.145 mmol) and triethylamine (0.20 mL) in dichloromethane (3 mL). The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was poured into dilute NaHCO3 (10 mL), and extracted with 3×30 mL dichloromethane. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo. The crude residue was purified by MPLC (97:3 dichloromethane:methanol) to give 41 (33 mg, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.[CH2:18]=[C:19]([CH3:21])[CH3:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]1[CH2:18][C:19]([CH3:21])([CH3:20])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[NH:8]1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1ccccc1Br
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2Br)Nc2ccc(Cl)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 4-chlorophenylamine (10.0 g, 78.4 mmol) and 2-bromobenzaldehyde (9.2 mL, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-10% ethyl acetate in petroleum ether) to afford 2-(2-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (11.0 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 350.0 & 352.0.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[N:4][N:3]=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:5]4[NH:1][N:2]=[N:3][N:4]=4)=[O:14])[CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nnn[nH]1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nnn[nH]1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1H-tetrazol-5-ylcarbamate (190 mg, 0.731 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.141 ml, 0.812 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and a crystal was collected by filtration. They were recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (72.9 mg, 27.9%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>ClCCCl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCCOCOc1c(C)cc(C=O)cc1C

Procedure:
A mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (5 g), N,N-diisopropylethylamine (6.9 ml), (2-methoxyethoxy)methylchloride (4.26 ml) and 1,2-dichloroethane (65 ml) was refluxed for 5 hours. The reaction mixture was washed with water and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (8:2 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 4-[(2-methoxyethoxy)methoxy]-3,5-dimethylbenzaldehyde (6.54 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([NH:21][C@H:22]([C:26]([NH:28][CH:29]([CH:37]([OH:64])[CH:38]([NH:46][C:47](=[O:63])[C@H:48]([CH:60]([CH3:62])[CH3:61])[NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.C(Cl)Cl>[C:50]([NH:49][C@H:48]([C:47]([NH:46][CH:38]([C:37](=[O:64])[CH:29]([NH:28][C:26](=[O:27])[C@H:22]([CH:23]([CH3:25])[CH3:24])[NH:21][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:63])[CH:60]([CH3:61])[CH3:62])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
To a cold (-78° C.) solution of oxalyl chloride (93 mg, 0.73 mmol) in 11 mL of freshly distilled methylene chloride was added, with stirring, 103 μL (1.46 mmol) of DMSO. To this soltuion at -78° C. after stirring for 5 minutes was added a solution of the resultant compound of Example 70 (450 mg, 0.61 mmol) in 5.5 mL of methylene chloride/DMSO (10:1). The reaction mixture was stirred at -78° C. for ~50 min, triethylamine (426 μL, 3.0 mmol) was added and stirring was continued for 5 min at -78° C. The cold bath was removed and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with 150 mL of chloroform. The chloroform solution was washed with 100 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in -3 mL of chloroform and applied to a 1.0×45 cm column of silica gel. The column was eluted with 100 mL of chloroform and 100 mL of 0.5% methanol in chloroform to give 376 mg (84% yield) of the title compound; DCI/NH3 MS M/Z: 501 (M+ NH4)+. The 300 MHz 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH:32]=O)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:44][CH:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([C@@H:31]([CH3:32])[CH2:34][N:52]6[CH2:53][CH2:54][CH:49]([O:48][C:45]7[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][CH:44]=7)[CH2:50][CH2:51]6)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C=O)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H]([C@@H](C)CN3CCC(Oc4ccc(Cl)cc4)CC3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 33.6 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-[1-methyl-2-oxoethyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 141, 60 mg, 0.11 mmol) and 4-[(4-chlorophenyl)oxy]piperidine (Preparation 200, 25 mg, 0.1 mmol) was added dichloromethane (2 ml) and sodium triacetoxyborohydride (35 mg, 0.16 mmol), followed by triethylamine (0.02 ml, 0.17 mmol). The reaction mixture was stirred at room temperature for 17 h, before diluting with dichloromethane (5 ml) and saturated aqueous sodium hydrogen carbonate (3 ml). The reaction mixture was shaken vigorously and the layers were separated using a hydrophobic filter cartridge. The filtrate was concentrated under a stream of nitrogen and purified to give the title compound (26 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:19]2[CH2:18][CH2:17][N:16]([S:20]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][C:14]=2[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[O:11]1[C:19]2[CH2:18][CH2:17][N:16]([S:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][C:14]=2[CH:13]=[CH:12]1
Reactant: O=S(=O)(c1ccc(CO)cc1)N1CCc2occc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.27 g (33.6 mmol) of oxalyl chloride in 100 ml of dichloromethane, 4.78 ml (67.3 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To this solution, a solution of 6.580 g (22.431 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)benzyl alcohol in 50 ml of dichloromethane was added at -78° C., followed by stirring for 15 minutes. To this mixture, 18.8 ml (135 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. After the reaction mixture was washed with water, the water layer was re-extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1 to 2/1) to yield the desired product.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:11][CH:10]([OH:12])[CH:9]2[N:13]([C:16](=[O:23])[CH:17]([NH2:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:15][CH:8]12)=[O:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:33]([N:43]([CH3:49])[C@H:44]([C:46](O)=[O:47])[CH3:45])([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C)[C@H](C(O)=O)C)(OCC1C=CC=CC=1)=O>CN1C(=O)CCC1.O>[CH2:36]([O:35][C:33](=[O:34])[N:43]([CH:44]([C:46](=[O:47])[NH:22][CH:17]([C:16]([N:13]1[CH2:14][CH2:15][CH:8]2[N:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:11][CH:10]([OH:12])[CH:9]12)=[O:23])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:45])[CH3:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(N)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution containing 56 (5.10 g, 15.6 mmol) and DIPEA (3.6 mL, 20.3 mmol) in NMP (20 mL) was cooled to 0° C. In a separate flask at 0° C., Cbz-N(Me)Ala-OH (4.1 g, 17.2 mmol), HATU (6.6 g, 17.2 mmol), and DIPEA (3.6 mL, 20.3 mmol) were dissolved in NMP (80 mL). A portion of the HATU/Cbz-N(Me)Ala-OH solution (72 mL, ˜1.0 equiv) was then added to the cooled solution of 56. After 45 min, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed successively with 10% H3PO4, water, saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.0 g (82%, 2 steps) of 57 as a white foam. Mass spectrum, m/z [546.0] (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1=[O:13].C(=O)([O-])O.[Na+].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34](ON3C(=O)CCC3=O)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.CCOCC>O.O1CCCC1>[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:1][CH:2]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]3=[O:13])=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1CCCCN(CC(=O)O)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(O)CN1CCCCC(NC(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Aminohexahydro-2-oxo-1H-azepine-1-acetic acid (which can be prepared by the procedure of Thorsett, E. D. et al. J. Med. Chem. 1986, 29,251-260; 9.3 g, 50 mmol) was added to a solution of sodium hydrogen carbonate (5 g, 60 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 18.6 g, 55 mmol) in tetrahydrofuran (110 mL) was added. The solution was stirred at room temperature overnight and then ether (200 mL) was added. The layers were separated and the organic layer was back-extracted with saturated sodium hydrogen carbonate:water (1:1; 60 mL). The combined aqueous layers were acidified with 1 M HCl (110 mL). The solid was filtered off, washed with water (4×20 mL), and dried in vacuo to give 3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid (20.1 g, 98%) as a white solid, mp 118° C. (dec.)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:31]([N:30]([CH3:34])[CH3:29])=[O:32])[CH2:17][CH2:18]1)=[O:11])#[N:2]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CCC(CC(=O)NCCOc2cccc(C#N)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]-piperidine-4-carboxyamide (JP2 19-1) was dissolved in 1.6 ml of dimethylformamide, and 0.3 ml (2.06 mmol) of triethylamine and 0.16 ml (1.74 mmol) of dimethyl carbamoyl chloride were added thereto at 0° C. and stirred at room temperature for 2 hours. It was treated in an ordinary manner with ethyl acetate as the extractant to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C:5]=3[N:6]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:5]=3[N:6]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1csc(NC(=O)Cn2c3c(c4c(Br)cccc42)CCN(C(=O)OC(C)(C)C)CC3)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(NC(=O)Cn2c3c(c4c(Br)cccc42)CCNCC3)n1
Temperature: 25 °C
Reaction time: 46 h
Yield: 28 %

Procedure:
tert-Butyl 10-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.13 g, 0.24 mmol) was dissolved in CH2Cl2 (5 mL). CF3CO2H (0.5 mL, 0.74 g, 6.5 mmol) was added. The reaction mixture was stirred at rt under N2 for 46 h. The reaction mixture was partitioned between 1N NaOH (60 mL) and EtOAc (350 mL). The aqueous layer was back extracted with EtOAc (100 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was flash chromatographed (10% CH3OH/CH2Cl2 containing 0.05% 7N NH3/CH3OH) and 2-(10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide was obtained in 28% yield. 1H NMR (400 MHz, CD3OD) δ 2.33, 3.02-3.09, 3.14-3.21, 3.55-3.63, 5.16, 6.67, 6.97, 7.21, 7.30; MS (ESI+) for C18H19BrN4OS m/z 420.8 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH2:13]([N:15]([CH2:21][CH3:22])[C:16]#[C:17][CH:18]([NH2:20])[CH3:19])[CH3:14].C([OH:25])C>>[OH2:25].[CH2:13]([N:15]([CH2:21][CH3:22])[C:16]#[C:17][CH:18]([NH:20][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1)[CH3:19])[CH3:14]
Reactant: Brc1nnc(-c2ccccc2)s1
Reactant: CCO
Reactant: CCN(C#CC(C)N)CC
Product: CCN(C#CC(C)Nc1nnc(-c2ccccc2)s1)CC
Product: O

Procedure:
4 g of 2-bromo 5-phenyl-1,3,4-thiadiazole prepared as indicated in Tetrahedron, 1968, 24, 3214 was mixed with 6.98 g of 4-diethylamino butyn-2-yl amine prepared as indicated in Eur. J. Med. Chem. Chim. Ther., 1982, 17, 85-88. The mixture was reflux-heated in 100 ml of ethanol for 48 hours. The ethanol was concentrated in vacuo, and the residue was dissolved in a 4 N soda solution. It was extracted with ethyl acetate, then the organic phase was washed with water, dried on sodium sulphate and the residual oil was chromatographed on silica gel, using ethylacetate as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.CN(C=O)C>CCOCC>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(-c3ccccc3)nc2c1N
Temperature: 90 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Methyl 3-amino-5chlorothieno[3,2-b]pyridine-2-carboxylate, prepared as described in Example 6A (0.243 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.1 mmol) and triethylamine (0.20 mL) were added to 3 mL of DMF containing [1,1'-bis(diphenylphosphino)ferrocenelpalladium(II) chloride (1:1 complex with CH2Cl2) under N2. The mixture was stirred at 90° C. for 4 h. The reaction was then cooled and diluted with Et2O. The organic layer was washed with H2O, brine, dried (MgSO4), concentrated and chromatographed (2:1CH2Cl2 : hexane) to yield the title compound (140 mg, 50%): 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 3H), 6.30 (bs, 2H), 7.41-7.55 (m, 3H), 7.84 (d, J=8 Hz, 1H), 8.07-8.13 (m, 3H); MS (DCI/NH3)) m/e 285 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(C(/C=C\c2ccc(Br)cc2)SC(/C=C\c2ccc(Br)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 4-chlorobenzylsulfide. The title compound was obtained in 87% yield following oxidation. 1HNMR (CDC13) δ4.58 (2H, s), 6.72 (1H, d, JH,H=12.08), 7.15-7.68 (8H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[C:12](/[CH:14]=[CH:15]\[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:10][C:9]=2[F:19])=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C:2]1[C:3]([C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]2)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[CH:11]=[CH:10][C:9]=2[F:19])=[CH:6][CH:7]=1
Reactant: CC(C)/C=C\c1ccc(F)c(-c2ccc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCc1ccc(F)c(-c2ccc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)n2)c1
Yield: 35 %

Procedure:
Method 2 of Example 49 was followed using (S,Z)-tert-butyl 1-(3-(3-amino-6-(2-fluoro-5-(3-methylbut-1-enyl)phenyl)picolinamido)pyridin-4-yl)piperidin-3-ylcarbamate which after Boc deprotection with 25% TFA/CH2Cl2 yielded (S)-3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-fluoro-5-isopentylphenyl)picolinamide (35%). LCMS (m/z): 477.3 (MH+); LC Rt=2.91 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[C:6]([Br:12])[C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1.[CH3:25]/[C:26](/[NH2:30])=[CH:27]\[C:28]#[N:29].[CH2:31]([CH:34]1[CH2:39][C:38](=[O:40])[CH2:37][C:36](=O)[CH2:35]1)[CH2:32][CH3:33]>C(O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH:10]2[C:37]3[C:38](=[O:40])[CH2:39][CH:34]([CH2:31][CH2:32][CH3:33])[CH2:35][C:36]=3[NH:30][C:26]([CH3:25])=[C:27]2[C:28]#[N:29])[CH:7]=[C:6]([Br:12])[C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Reactant: COC(=O)c1cc(C=O)cc(Br)c1OCc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc([N+](=O)[O-])c2)c(C(=O)OC)c1
Temperature: 80 °C

Procedure:
A mixture of 3-bromo-5-formyl-2-(3-nitro-benzyloxy)-benzoic acid methyl ester (788 mg), 3-aminocrotonitrile (165 mg) and 5-propylcyclohexane-1,3-dione (308 mg) in ethanol (5 ml) was heated at 80° C. for 17 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Method B).