Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[NH:17][CH3:18])([O-])=O.C(O)(=O)C>[Fe].C(O)C>[CH3:18][NH:17][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([C:10]([F:11])([F:13])[F:12])=[CH:7][C:6]=1[NH2:14]
Reactant: CNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(N)cc(C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80.1 %

Procedure:
To a mixture of (2,6-dinitro-4-trifluoromethyl-phenyl)-methyl-amine (5.0 g), acetic acid (11 mL), ethanol (100 ml), and ice (20 g), iron powder (6.4 g) was added under ice-cooling. The reaction mixture was stirred at 0° C. for 3.5 hours, and filtered through Celite®. The resulting filtrate was concentrated under reduced pressure, and diluted with 1N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 3.1 g of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine. N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH:8][CH3:9])=[CH:5][CH:4]=1.C1CCN2C(=[N:16]CCC2)CC1.O>CN1C(=O)CCC1>[NH:16]1[C:5]2[C:6](=[CH:7][N:8]=[CH:9][CH:4]=2)[CH:10]=[CH:11][C:3]1=[O:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CNCc1ccc(OC)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1ccc2cnccc2[nH]1
Yield: 173.7 %

Procedure:
A solution of Example A18 (22 g, 65.7 mmol), (4-methoxy-benzyl)-methyl-amine (14.9 g, 98.5 mmol) and DBU (15 g, 98.5 mmol) in NMP (120 mL) was heated at 160° C. for 5 h. The mixture was poured into 200 mL of water while stirring and the resulting solids were collected by filtration, washed with water, dried and then washed with Et2O to give 3-(5-amino-2,4-difluoro-phenyl)-1-ethyl-7-[4-methoxy-benzyl)-methyl-amino]-1H-[1,6]naphthyridin-2-one (25 g, yield 85% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.51 (s, 1H), 7.80 (s, 1H), 7.19-7.17 (d, J=8.7 Hz, 2H), 7.06 (t, J=10.2 Hz, 1H), 6.90-6.81 (m, 3H), 6.32 (s, 1H), 5.02 (s, 2H), 4.86 (s, 2H), 4.19 (q, J=6.9 Hz, 2H), 3.72 (s, 3H), 3.14 (s, 3H), 1.14 (t, J=6.9 Hz, 3H); MS (ESI): m/z 451.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[F:7][CH2:8][C:9]1([C:14]#[N:15])CC(=C)[CH2:10]1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[F:7][CH2:8][C:9]1([C:14]#[N:15])[CH2:5][C:6](=[O:1])[CH2:10]1
Reactant: C1COCCO1
Reactant: C=C1CC(C#N)(CF)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: N#CC1(CF)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of water (2 mL, 0.1 mol) and 1,4-dioxane (6 mL, 0.08 mol), 1-(fluoromethyl)-3-methylenecyclobutanecarbonitrile (0.256 g, 0.00204 mol), and 0.2 M of osmium tetraoxide in water (0.04 mL) was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (0.919 g, 0.00430 mol) was added in portions over a period of 30 min. The mixture was stirred overnight. The mixture was extracted with EtOAc and combined organic layers were dried over MgSO4. After removal of the solvents, the crude product was used directly in next step.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.Cl.[S:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20]>>[S:19]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH:5]([C:6]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][CH:7]=3)[CH2:4][C:3]([C:2]([F:17])([F:16])[F:1])=[N:30]2)=[CH:27][CH:28]=1)(=[O:22])(=[O:21])[NH2:20]
Reactant: O=C(/C=C/c1c[nH]c2ccccc12)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(N2N=C(C(F)(F)F)CC2c2c[nH]c3ccccc23)cc1
Yield: 82 %

Procedure:
A solution of trans-1,1,1-trifluoro-4-(3-indolyl)-3-buten-2-one (5 mmol) and 4-sulfamylphenyl hydrazine hydrochloride (6 mmol) was subjected to Procedure 3. The title compound was obtained in 82% yield, m.p. 138-140° C.; C, H analysis (C16H14SO2N4F3):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:6][S:7][C:8](=[O:10])[CH3:9])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:6][S:7][C:8](=[O:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(CSC(C)=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)=O)c1ccc(N)cc1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 2-(4-(benzyloxycarbonylamino)phenyl)-3-(acetylthio)-propanoic acid ethyl ester (0.2 g, 0.54 mmol) in 5 mL of methylene chloride was added 5 mL of trifluoroacetic acid. After 0.5 hours, the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography through silica gel (1/1 hexanes/ethyl acetate) to afford 2-(4-aminophenyl)-3-(acetylthio)propanoic acid ethyl ester (0.12 g, 85%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12](I)=[C:8]3[CH:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25]>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:25]#[C:24][C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)=[C:8]3[CH:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)n3ncc(I)c3c2)cc1
Product: Nc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)cc23)cn1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-iodo-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine (example C.28 step 7) (204 mg, 0.48 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (101 mg, 0.85 mmol) according to general procedure II. Obtained as a yellow solid (40 mg, 20%). MS (ISP) 419.1 [(M+H)+].
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=2)[CH2:4][CH2:3]1.[NH2:17][C@@H:18]([CH3:34])[CH2:19][N:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[CH:26]=2)=[N:21]1>>[Cl:33][C:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][N:20]([CH2:19][C@@H:18]([NH:17][C:14]([C:12]3[N:13]=[C:9]([CH2:8][N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)[S:10][CH:11]=3)=[O:16])[CH3:34])[N:21]=2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(CN2CCOCC2)n1
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CN2CCOCC2)n1
Yield: 68.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(morpholinomethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(morpholinomethyl)thiazole-4-carboxylic acid hydrochloride (260 mg, 0.982 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (218 mg, 0.818 mmol). The product was purified by washing the organic phase with 1M HCl, 1M Na2CO3, brine and water. Yield 68.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.23 (d, 3H), 2.50 (t, 4H; overlap with DMSO), 3.61 (t, 4H), 3.85 (d, 2H), 4.32 (dd, 1H), 4.40 (dd, 1H), 4.43-4.50 (m, 1H), 6.96 (d, 1H), 7.84 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.02 (dd, 1H), 8.16 (s, 1H), 8.46 (d, 1H). m/z [471.0+1].
Reaction SMILES: [C:1]([N:11]1[CH2:31][CH2:30][C:14]2[N:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][C:21]=3[C:13]=2[CH2:12]1)(OCC1C=CC=CC=1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:43][CH2:42]C(O)[O:40]2)=[CH:35][CH:34]=1>>[CH:37]1[C:36]([CH:39]([OH:40])[CH2:43][CH2:42][CH2:1][N:11]2[CH2:12][C:13]3[C:21]4[CH:20]=[C:19]([F:22])[CH:18]=[CH:17][C:16]=4[N:15]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:14]=3[CH2:30][CH2:31]2)=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Reactant: OC1CCC(c2ccc(F)cc2)O1
Product: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1

Procedure:
A process of claim 6 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst in the presence of substantially one molar equivalent of 2-(p-fluorophenyl)-5-hydroxytetrahydrofuran, at 0°-75° C. in a reaction-inert solvent to form flutroline.
Reaction SMILES: C(O[CH:4]=[C:5]([C:9](=O)[CH3:10])[C:6](=[O:8])[CH3:7])C.[F:12][C:13]([F:18])([F:17])[CH2:14][NH:15][NH2:16].Cl>CO>[CH3:10][C:9]1[N:15]([CH2:14][C:13]([F:18])([F:17])[F:12])[N:16]=[CH:4][C:5]=1[C:6](=[O:8])[CH3:7]
Reactant: NNCC(F)(F)F
Reactant: CCOC=C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)c1cnn(CC(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 3-(ethoxymethylene)pentane-2,4-dione (Perkin 1. 2000, 1455-1460, 1.95 g, 12.5 mmol) in MeOH (33 ml) was added a solution of 2,2,2-trifluoroethylhydrazine (1.54 g, 13.5 mmol) and conc.HCl (2.6 ml) in MeOH (10 ml) (pre-cooled at 0° C.) dropwise at −15° C. The resulting mixture was then stirred for 24 h at rt. After removal of the solvent at rt, the residue was basified with 2N NaOH aq, and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give the crude product as a single regioisomer (1.41 g, 51% yield). 1H NMR (300 MHz, CDCl3) δ 2.46 (3H, s), 2.62 (3H, s), 4.66 (1H, d, J=6.0 Hz), 4.72 (1H, d, J=9.0 Hz), 7.92 (1H, s). MS (ESI) m/z 207 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 72 %

Procedure:
Following the general methods as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and N-methyl-4-(trifluoromethoxy)aniline, the title compound was isolated as a yellow solid in 72% yield (99% purity by HPLC).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][C@@H:7]([C:9]([F:12])([F:11])[F:10])[CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[CH:26][C:27]([C:31]#[N:32])=[N:28]2)=[CH:23][CH:22]=1>CC#N.O>[Cl:33][C:25]1[C:24]2[C:29](=[CH:30][C:21]([CH2:20][N:5]3[CH2:6][C@H:7]([C:9]([F:10])([F:12])[F:11])[O:8][C@H:3]([CH3:2])[CH2:4]3)=[CH:22][CH:23]=2)[N:28]=[C:27]([C:31]#[N:32])[CH:26]=1
Reactant: C[C@@H]1CNC[C@H](C(F)(F)F)O1
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(Cc2ccc3c(Cl)cc(C#N)nc3c2)C[C@H](C(F)(F)F)O1
Temperature: 60 °C
Yield: 96 %

Procedure:
(2R,6R)-2-Methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6, 500 mg, 2.432 mmol) and K2CO3 (739 mg, 5.35 mmol) were combined in CH3CN (10 ml) at rt. To this was added 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 753 mg, 2.68 mmol) all at once as a solid then the mixture was heated to 60° C. overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were filtered through a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (50 g, 0-10% EtOAc/hexanes, 15 minute gradient) to afford 4-chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-7, 859, 96%) as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=8.7 Hz, 1H); 8.11 (s, 1H); 7.83 (dd, J=8.6, 1.6 Hz, 1H); 7.78 (s, 1H); 4.09-4.01 (m, 1H); 3.79 (m, 3H); 2.90 (d, J=10.9 Hz, 1H); 2.73 (d, J=11.4 Hz, 1H); 2.28-2.17 (m, 1H); 2.03-1.92 (m, 1H); 1.20 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)=[O:15].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][N:18]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Benzyloxycarbonyl chloride (10.2 mL, 71.5 mmol) was added to a solution of 1-benzyl-4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3-carboxylic acid methyl ester (14.0 g, 35.8 mmol) in dichloromethane (200 mL), and the mixture was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 13.9 g (89%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[C:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])[C:2]#[CH:3]
Reactant: OCCCCCCCc1ccccc1
Reactant: C#CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCCCCc1ccccc1

Procedure:
A mixture of 1 g of ethyl propiolate, 2.94 g of 7-phenylheptanol and 0.01 g of p-toluenesulfonic acid in 30 ml of benzene was refluxed for twelve hours. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 7-phenylheptyl propiolate (compound 3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.N1CCCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CCCc2ccc(Br)cc21
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2cccnc2)CCc2ccc(Br)cc21
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 7-bromo-1-tetralone (11.25 g), pyridin-3-carboxaldehyde (5.35 g), acetic acid (5 ml) and piperidine (6 ml) was heated on a stream bath for 6 hours and then allowed to stand for 18 hours. The volatile material was evaporated and the residue was dissolved in ethyl acetate. The solution was extracted several times with dilute hydrochloric acid and the combined extracts were made just alkaline with dilute sodium hydroxide solution. The solid was filtered off, washed with water and crystallised from methanol to give 7-bromo-2-(3-pyridylmethylene)-1-tetralone (12.8 g), m.p. 124°-125°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([C:30]([F:31])([F:32])[F:33])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:29])[CH3:28]
Reactant: O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Yield: 81.4 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(3-fluorophenyl)methyl]-1-indanol (98% trans, 2% cis) and 1.07 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.52 g of trans-3-[(3-fluorophenyl)-methyl]-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC[N:17](CC)CC.ClC(OCC)=O.N.O>C1COCC1>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of 4-bromo-5-chloro-2-nitrobenzoic acid (1.3 g, 4.63 mmol), Et3N (1.4 g, 13.9 mmol) in THF (20 mL) at 0° C., ethyl chloroformate (1.5 g, 13.9 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. Then NH3.H2O (4 mL) was added and stirred for 0.5 h. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (900 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][N:7]=1.[Cl:14]C1C(Cl)=CC=CN=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[C:11]([Cl:14])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Clc1cccnc1Cl
Reactant: COC(=O)CSc1ccc(Cl)cn1
Product: COC(=O)CSc1ncccc1Cl
Yield: 52 %

Procedure:
was synthesized according to the procedure used for compound 14. Starting with 2,3-dichloropyridine (17, 2.09 g, 14.0 mmol) the target 18 was obtained as a colorless oil (1.6 g, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2cnn(C3CCNCC3)c2c1
Reaction time: 1 h

Procedure:
To tert-butyl 4-(6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate prepared as in STEP 1 above (998 mg, 3.10 mmol) in DCM (20 mL) at 0° C. was added TFA (10 mL). The resulting mixture was then stirred for 1 hour. The solvent was removed in vacuo. To the resulting residue was added 0.5N NaOH (15 mL), followed repeated extraction with CHCl3. The organic layer was dried with MgSO4 and filtered to yield 6-fluoro-1-(piperidin-4-yl)-1H-indazole.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.C([BH3-])#[N:18].[Na+].C([O-])(=O)C.[NH4+]>CO>[NH2:18][CH:8]1[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH:3]1[O:2][CH3:1]
Reactant: [BH3-]C#N
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC1CN(C(=O)OC(C)(C)C)CCC1N
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 3-(methyloxy)-4-oxo-1-piperidinecarboxylate D18 (2.9 g) in MeOH (100 ml), was added sodium cyanoborohydride (7.9 g, 126 mmol) and ammonium acetate (9.7 g, 126 mmol) at R.T. The reaction mixture was stirred for 4 hours. The resulting mixture was concentrated in vacuo, dissolved in water, basified with sodium hydroxide to pH10 and extracted with DCM. The organic layer was dried over anhydrous MgSO4, concentrated in vacuo to get the desired product D19 in 2.85 g. LCMS [MH+] 231@0.83 min (5 min run)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][C:3]=1[OH:20].[CH3:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][O:28][C:29](=[O:34])[CH2:30][C:31](O)=[O:32])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29]([CH2:30][C:31]([O:20][C:3]2[CH:4]=[C:5]([C:8]3[N:9]=[C:10]4[N:14]([CH:15]=3)[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[S:11]4)[CH:6]=[CH:7][C:2]=2[Cl:1])=[O:32])=[O:34])=[CH:35][CH:36]=1
Reactant: Oc1cc(-c2cn3c(n2)sc2ccccc23)ccc1Cl
Reactant: COc1ccc(COC(=O)CC(=O)O)cc1
Product: COc1ccc(COC(=O)CC(=O)Oc2cc(-c3cn4c(n3)sc3ccccc34)ccc2Cl)cc1
Yield: 45.3 %

Procedure:
By following the same procedure as in Example 2 using 1.9 g of 2-(4-chloro-3-hydroxyphenyl)imidazo[2,1-b]benzothiazole and 2.7 g of malonic acid mono-p-methoxybenzyl ester, 1.05 g of 2-(3-carboxyacetoxy-4-chloro)phenylimidazo[2,1-b]benzothiazole.hydrochloride was obtained through 2-[3-(p-methoxybenzyloxycarbonylacetoxy)-4-chlorophenyl]imidazo[2,1-b]benzothiazole (yield of 1.45 g, melting point of 113°-115° C.).
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]1[C:16]([Cl:17])=[CH:15][NH:14][N:13]=1)([O-])=O.O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]1[C:16]([Cl:17])=[CH:15][NH:14][N:13]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1-c1n[nH]cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(Cl)cc1-c1n[nH]cc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
14.6 g (0.05 mol) of 3-(2-nitro-3,5-dichlorophenyl)-4-chloropyrazole, in solution in 200 ml of acetic acid, are introduced into a 500 ml, three-necked, round-bottomed flask. The solution is brought to 50° C. and 8.4 g (0.15 mol) of iron powder are introduced in portions. The reaction mixture is then kept stirring at 70° C. for 5 hours. After cooling, the reaction mixture is poured into 800 ml of water, filtered on sintered glass, rinsed with water and dried to lead to the production of a white solid (yield: 90%, M.p.: decomposition at 300° C.) of 3-(2-amino-3,5-dichlorophenyl)-4-chloropyrazole.
Reaction SMILES: C[C@@:2]([OH:14])([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](N)=[O:4].[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[NH2:13][C@@H:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:2]([OH:14])[C:3]([O:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:4]
Reactant: C[C@](O)(C(N)=O)[C@@H](N)c1ccccc1
Reactant: CC(C)CO
Product: CC(C)COC(=O)[C@H](O)[C@@H](N)c1ccccc1

Procedure:
To a mixture of crude (2R, 3S)-2-hydroxy-3-amine-3-phenylpropionamide (CVII, EXAMPLE 6, 180 mg, 1 mmol) in isobutyl alcohol (2.5 ml) is bubbled anhydrous hydrogen chloride gas until saturated allowing the temperature to rise. The reaction mixture is then heated to 100° overnight. The resulting solution is evaporated to dryness under house vacuum at 50°. The residue is dissolved in water (5 ml), and the aqueous is neutralized with saturated potassium carbonate solution to pH >9. The basic aqueous is extracted with ethyl acetate (15 ml×3). The combined organic phase is dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue is purified by flash chromatography (methanol/dichloromethane, 1/5) to give the title compound, NMR (300 MHz, CDCl3) 7.44-7.28, 4.34, 4.30, 4.00, 1.95 and 0.95 δ; CMR (300 MHz, CDCl3) 173.5, 142.3, 128.5, 127.5, 126.7, 75.0, 71.8, 58.0, 27.6 and 18.9 δ; MS (m/z) 238 (M+ +1), 165, 136, 118, 107, 106, 104, 91, 79, 77 and 57; HRMS (m/z) calculated for C13H19N1O3 +H1 =238.1443, observed=238.1441.