Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][CH:12]([C:17]([O:19]C)=[O:18])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:16][CH:14]([CH2:13][CH:12]([C:17]([OH:19])=[O:18])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC2CC(C1)CN(C(=O)OC(C)(C)C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(CC(C(=O)O)C2)C1
Temperature: 30 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
Methyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylate (1.62 g, 5.72 mmol) was dissolved in a 2:1:2 mixture of THF/water/methanol (25 mL), and lithium hydroxide monohydrate (0.721 g, 17.2 mmol) was added. The reaction mixture was stirred at 30° C. for 16 h. The volatile solvents were removed by rotary evaporation, and the residue was acidified with 2 N hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.53 g (100% crude yield) of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylic acid, as a colorless solid (1H NMR (CDCl3): δ 3.95-3.8 (m, 2H), 2.85-2.75 (m, 2H), 2.60-2.47 (m, 1H), 2.20-2.12 (m, 2H), 2.0-1.85 (m, 4H), 1.60-1.70 (m, 2H), 1.41 (s, 9H); (LC-MS (MH+): 270).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][C:19]=2[C:29]([F:32])([F:31])[F:30])[N:13]=1)=[O:10].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[C:29]([F:32])([F:30])[F:31])[N:13]=1)=[O:10]
Reactant: CCOC(=O)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)benzoate (for a preparation see Example 43)(0.773 g, 1.71 mmol) in methanol (20 ml) was added 2 M aqueous sodium hydroxide (5 ml, 10 mmol). The solution was heated to 60° C. under air for 45 min. The solvent was removed at reduced pressure and the residue dissolved in water (50 ml). The solution was acidified using 2M HCl aqueous (10 ml). The suspension was diluted with ethyl acetate (50 ml) and the phases separated. The aqueous phase was extracted with ethyl acetate (25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a white solid (0.666 g); LCMS: (System 4) MH+=426, tRET=2.48 min.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12]=[O:13].[H-].[Na+]>C1COCC1>[CH3:10][N:11]([CH:12]=[O:13])[CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: CNC=O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C=O)Cc1ccncc1
Yield: 499.4 %

Procedure:
To a stirring, argon-purged solution of 4-picolyl chloride-HCl (15 g, 91.4 mmol) and N-methylformamide (53.4 ml, 9 14 mmol) in 300 ml of THF at room temperature was added portionwise over a 20 minute period a suspension of 80% NaH (5.48 g, 183 mmol). The reaction was quenched 18h later by the addition of ice, partitioned between methylene chloride and water, washed with water and brine, dried over MgSO4, and evaporated to dryness to afford a dark oil. Flash chromatography on silica gel provided 10.5 g (76%) of the titled compounds a pale yellow oil. TLC; silica gel (9:1 CHCl/MeOH) Rf=0.54.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13]([N:15]1[CH2:19][CH2:18][CH:17]2[N:20]([C:36](=[O:49])[CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:21][CH:22]([C:23](=[O:35])[NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:16]12)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[NH:38][CH2:37][C:36]([N:20]1[CH2:21][CH:22]([C:23](=[O:35])[NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:16]2[N:15]([C:13](=[O:14])[CH:8]([NH2:7])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:19][CH2:18][CH:17]12)=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A solution of 57 (570 mg) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 2 h, the solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The aqueous phase was back extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 58 (450 mg) which was used without further purification. Mass spectrum, m/z [586.4] (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[S:35]1[CH:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36]1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:40]([C:37]3[CH:38]=[CH:39][S:35][CH:36]=3)=[O:41])=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: O=C(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)c3ccsc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(g), by condensing tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate and thiophene-3-carboxylic acid using 1,1-carbonyldiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-thiophen-3-ylcarbonyloxy-ethyl)-phenyl]-piperidine-1-carboxylate as white crystals, MS: 572 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C([Sn](CCCC)(CCCC)C1C=CC(C(F)(F)F)=CC=1[N+]([O-])=O)CCC.FC(F)(F)S(O[C:47]1[CH2:56][CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:57][CH3:58])[CH:53]=2)[CH:48]=1)(=O)=O>>[CH3:58][O:57][C:52]1[CH:53]=[C:54]2[C:49]([CH:48]=[C:47]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:56][CH2:55]2)=[CH:50][CH:51]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitro-4-trifluoromethylbenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitro-4-trifluoromethylphenyl)tin (7.4 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 7-methoxy-3-(2-nitro-4-trifluoromethylphenyl)-1,2-dihydronaphthalene (1.5 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (1.0 g).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[Br:31][C:32]1[CH:37]=[CH:36]C(CCN)=[CH:34][CH:33]=1>>[Br:31][C:32]1[CH:37]=[CH:36][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1ccc(Br)cc1
Product: O=C(NCCc1ccc(Br)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(4-bromophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 442 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.25 (1H, s) 8.17 (1H, t, J=5.47 Hz) 8.02 (1H, d, J=5.47 Hz) 7.77 (1H, d, J=5.47 Hz) 7.46 (1H, d, J=5.47 Hz) 7.44 (2H, d, J=8.20 Hz) 7.32 (1H, d, J=3.32 Hz) 7.18 (2H, d, J=8.20 Hz) 6.80 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.42, 1.85 Hz) 3.40-3.52 (2H, m) 2.80 (2H, t, J=7.22 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[C:23]3[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH:23]3[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=C3NC(=O)NC3=O)cn2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(CC3NC(=O)NC3=O)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidin-4-ylidenemethyl)-pyrazin-2-yl]-propionamide (130 mg, 0.25 mmol) in ethanol (5 mL) was treated with 10% palladium on activated carbon (260 mg). The reaction mixture was stirred under hydrogen (65 psi) at 25° C. for 2 d. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethanol. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80%–100% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidin-4-ylmethyl)-pyrazin-2-yl]-propionamide (20 mg, 15%) as a white solid: LC-MS m/e 520 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:45]=[CH:44][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:46][C@@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:49][C@H:48]1[C:59]([OH:61])=[O:60].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[C:55]([O:54][C:52]([N:50]1[CH2:51][C@@H:47]([NH:46][C:39](=[O:40])[C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:24]3[N:23]=[C:22]([NH:21][CH2:20][C:19]4[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:45][CH:44]=4)[N:27]=[C:26]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])[N:25]=3)=[CH:43][CH:42]=2)[C@H:48]([C:59]([OH:61])=[O:60])[CH2:49]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
To a solution of 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (200 mg), trans-4-amino-1-Boc-pyrrolidine-3-carboxylic acid (72.6 mg) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (121 mg) was added iPr2NEt (0.22 mL). The mixture was stirred at room temperature for 4 hours. The mixture was purified by preparative HPLC to give trans-1-(tert-butoxycarbonyl)-4-(4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-3-carboxylic acid (32 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2Br)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 110 °C
Yield: 71.4 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (1 g, 2.1 mmol), phenylboronic acid (0.79 g, 6.4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.351 g, 0.43 mmol) and K2CO3 (0.890 g, 6.4 mmol) in dioxane (24 mL) and water (4 mL) was heated at 110° C. overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product, which was purified by column chromatography (eluting with 10-40% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.710 g racemate, 1.5 mmol, 71%) as an off-white powder. The racemic material was further separated by chiral SFC (Table 2, Method 1) to give two isomers: 3-(4(R)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 1), Rt=3.374 min., 0.281 g, 0.61 mmol, 29%) and 3-(4(S)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 1), Rt=4.333 min., 0.252 g, 26%). LC/MS (Table 1, Method 2) Rt=1.25 min.; MS m/z: 464 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18]Cl>C(O)(=O)C>[Cl:18][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7](=[O:17])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[C:11]=2[CH:1]=1
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Reactant: ClCl
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)c2ccccc12
Temperature: 38 °C

Procedure:
A mixture of 1.0 g of 5H-dibenz[b,e]azepine-6,11-dione in 50 ml of acetic acid is stirred while chlorine is bubbled into the reaction mixture until saturated. The temperature increases to 38° C. After standing, a precipitate forms and is filtered, washed with hexane and air dried to give 0.62 g of solid which is purified by chromatography to give the desired product as a solid, m.p. 289°-293° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH3:11].[N:13](OCCC(C)C)=[O:14].Cl>CC1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[OH:14])/[C:10](=[O:12])[CH3:11]
Reactant: CC(C)CCON=O
Reactant: CC(=O)Cc1ccc(F)cc1F
Agent: Cl
Solvent: CC1CCCCC1
Product: CC(=O)/C(=N/O)c1ccc(F)cc1F
Temperature: 32.5 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
A solution of 140.2 g (0.80 mol) of 1-(2,4-difluoro-phenyl)-propane-2-one in 550 g of methylcyclohexane is warmed up to 30-35° C. Over a period of 2 hours 96.6 g (0.80 mol) of isoamyl nitrite is added while a slow stream of dry hydrogen chloride is fed subsurface into the reactor. Following the end of the addition the batch is stirred for 15 minutes at 30-35° C. before the suspension is cooled to 0° C. The product is isolated by filtration and the filter cake is washed with 150 g of methylcyclohexane at 0° C.: 146.9 g of (E)-1-(2,4-difluoro-phenyl)-propane-1,2-dione 1-oxime (mp. 133-135° C.) are obtained in 89.5% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:25]>O>[ClH:25].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(CCOCCCCCBr)cc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: Fc1ccc(CCOCCCCCNCc2ccccc2)cc1
Reaction time: 3.5 h

Procedure:
1-[2-[(5-Bromopentyl)oxy]ethyl]-4-fluorobenzene (7.95 g) was added dropwise over 10 min to benzylamine (24 ml) at 125° under nitrogen. The reaction mixture was stirred for 3.5 h at 120° and the hot reaction mixture was poured into 2N aqueous hydrochloric acid (170 ml) and water (220 ml). After stirring for 15 min the precipitate was collected by filtration to give the title compound as a white solid (7.41 g) m.p. 112°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:13]=2[F:12])/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(F)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(F)c1F)c1ccc(Cl)cc1F
Yield: 89.7 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 2,3-difluorobenzaldehyde (Aldrich) (4.5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (6.3 g, 29 mmol) in methanol (135 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)-acrylonitrile as a white powder (6.85 g, 88%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][C:6]1[CH:7]=[C:8]([CH:16](Br)[C:17]([CH3:19])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[S:3][C:16]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:14])[CH3:15])=[C:6]([Br:5])[CH:7]=2)=[C:17]([CH3:19])[N:4]=1
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1ccc(OC(C)C)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)sc1-c1ccc(OC(C)C)c(Br)c1
Temperature: 40 °C
Yield: 66.4 %

Procedure:
Thiourea (65 mg, 0.857 in mol) was added to 1-(3-bromo-4-isopropoxyphenyl)-1-bromo acetone (200 mg, 0.571 mmol) in 0.5 mL of methanol and the mixture was heated to 40° C. The mixture was then heated to 80° C. And 1.0 mL of methanol was added to facilitate stirring. After refluxing 3 h, the reaction was transferred to a separatory funnel with 50 mL of ethyl acetate and 30 mL of saturate aqueous sodium bicarbonate, the layers were separated, and the organic layer was washed with 30 mL of brine. Drying over sodium sulfate and evaporation gave the crude product. Purification by flash chromatography, eluting with 30-50% ethyl acetate in hexane, gave 124 mg of the title compound as a white solid. Mass spectrum (NH3/CI): m/z=327 (M+1).
Reaction SMILES: [S:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[SH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=S)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(S)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To a solution of crude tert-butyl 4-thioxopiperidine-1-carboxylate (2 g, 9.30 mmol, 1.00 equiv) in ethanol (20 mL) contained in a 100-mL 3-necked round-bottom flask under nitrogen was added sodium borohydride (570 mg, 15.00 mmol, 1.50 equiv) in several portions. The resulting solution was stirred at 80° C. for 2 h. The reaction mixture was then quenched by the addition of 30 mL of water after it was cooled to room temperature with a water bath. The solution was extracted with 3×30 mL of ether and the organic layers combined. The combined organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.34 g of crude tert-butyl 4-mercaptopiperidine-1-carboxylate as yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)[CH2:3]OS(C)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH2:3][CH:2]([CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)[OH:1])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)COS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)CN=[N+]=[N-])C2
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
2-(1-Hydroxy-2-methanesulfonyloxyethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.66 g, 4.90 mmol) was dissolved in dimethylformamide (50 ml). Sodium azide (1.91 g, 29.4 mmol) was added to the mixture, and the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was condensed under reduced pressure, and the residue was extracted from chloroform-water. The organic phase was dried over sodium sulfate, and condensed under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent=chloroform: methanol=10:1) to obtain 1.19 g of the title compound as pale yellow powdery crystals (85.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH2:5]O.P(Br)(Br)[Br:16]>C1COCC1>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH2:5][Br:16]
Reactant: COc1cc(C)c(OC)c(CO)c1C
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COc1cc(C)c(OC)c(CBr)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 208.4 %

Procedure:
To a solution of 2,5-dimethoxy-3,6-dimethylbenzyl alcohol (23.6 g, 0.12 mol) in THF (250 ml) was added dropwise phosphorus tribromide (5.7 ml, 0.06 mol) at 0° C., the mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (250 ml), and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 32.4 g of 2,5-dimethoxy-3,6-dimethylbenzyl bromide. The resultant bromide was dissolved in acetonitrile (50 ml) and added dropwise to a solution of sodium cyanide (7.35 g, 150 mmol) in water (75 ml) and acetonitrile (75 ml), and the mixture was stirred at room temperature for 3 days. The organic layer was separated, washed with saturated brine, and dried over magnesium sulfate. It was purified by silica gel chromatography with a small amount of silica gel and eluted with ethyl acetate, and the solvent was removed under reduced pressure. The residue was suspended in hexane, and crystals were filtered to obtain 23.5 g of the title compound.