Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([C:16](=O)[C@H:17]([NH:25][CH:26]=O)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.B(F)(F)F.CCOCC.B.C1COCC1.Cl>C1COCC1>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([NH:25][CH3:26])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=CN[C@H](Cc1ccccn1)C(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 16.6 %

Procedure:
To a solution of (1R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]-2-oxo-1-(pyridin-2-ylmethyl)ethylformamide (710 mg.; 1.9 mmol, from Example 19) in THF (10 mL) was added BF3.Et2O (0.47 mL; 3.8 mmol). The reaction mixture was heated to reflux, and treated, at reflux, with a 1M solution of BH3.THF in THF (19 mL; 19 mmol). Stirring was continued at reflux for 16 hours. The mixture was cooled to ambient temperature, cautiously treated with 5N aqueous HCl (20 mL), and heated to reflux for 4 hours. The mixture was cooled to ambient temperature and concentrated in vacuo to remove THF. The aqueous residue was washed with ether, and the ether layer discarded. The aqueous layer was rendered basic with 6N NaOH, and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo to afford the title compound as a white solid (110 mg.; 17%). MS (+) ESI [M+H]+ @ m/z 350.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:33][C:30]([CH2:34][NH2:35])([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:35][CH2:34][C:30]23[CH2:33][N:26]([CH2:32][CH2:31]2)[CH2:27][CH2:28][CH2:29]3)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC12CCCN(CC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CC1)C2
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A suspension of 4-amino-5-chloro-2-methoxybenzoic acid (1.72 g, 8.5 mmol) in anhydrous tetrahydrofuan (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.0 mmol), stirred for one hour, then degassed under a stream of nitrogen for 10 minutes. A solution of 1-azabicyclo[3.2.1]octane-5-methanamine (1.27 g, 9.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added, and stirring was continued at room temperature for 18 hours and at 50° C. for one hour. The mixture was concentrated in vacuo and partitioned between toluene (100 mL) containing a little 2-propanol and saturated sodium carbonate (50 mL). The organic layer was separated and the organic solution was dried (Na2SO4), concentrated in vacuo, and triturated from cold ether. Recrystallization from acetonitrile (2 crops) afforded 1.92 g (70%) of colorless crystals; mp 185°-187° C.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:3]([OH:46])=[O:2]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5cccc([N+](=O)[O-])c5)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.3 %

Procedure:
To 41 mg of (S)-3-methyl-2-(4′-{[3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid methyl ester dissolved in 0.5 mL of THF was added 2 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 29 mg of (S)-3-methyl-2-(4′-{[3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid, obtained as pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 2.2 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.3 (dd, J=7.3, 0.8 Hz, 1 H) 7.6 (dd, J=8.3, 7.3 Hz, 1 H) 7.8 (m, 8 H) 8.0 (d, J=8.8 Hz, 3 H) 8.1 (d, J=9.3 Hz, 1 H) 8.3 (t, J=1.9 Hz, 1 H) 8.3 (m, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(OCC)(=O)C.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1OCC(F)(F)F
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(F)ccc1OCC(F)(F)F
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 90.1 %

Procedure:
A mixture of 0.66 g of Compound 5A and 0.07 g of Raney-Nickel in 20 mL of ethyl acetate was stirred for 14 hours at 20-25° C. The organic layer was separated and the mixture extracted with 2×40 mL of ethyl acetate. The combined organic layers were washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness in vacuo to afford 0.52 g (90.6%) of Compound 5B as an orange oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:2]=[CH2:3].[BH4-].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:6]=1[CH2:7][OH:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C=CCOc1ccc(Br)cc1CO
Yield: 96.3 %

Procedure:
A solution of 2-allyloxy-5-bromobenzaldehyde (5.27 g, 21.9 mM) was treated with sodium borohydride, (0.415 g, 10.9 mM). The reaction was stirred at ambient temperature for 21/2 hours, water was added and the solvent removed at reduced pressure. The residue was acidified to pH 1 and extracted with ethyl acetate twice. The organic layers were combined, dried (MgSO4) and evaporated to give 2-allyloxy-5-bromobenzyl alcohol (5.12 g, 96%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>>[CH3:23][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cc(C)cc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (99 mg, 0.53 mmol) and 1-iodo-3,5-dimethylbenzene (0.08 mL, 0.55 mmol) according to the general procedure IC to give 128 mg (83%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.59 (EtOAc:hexanes, 2:5); 1HNMR (CDCl3) δ 7.21-7.19 (m, 2H), 7.07-7.05 (m, 2H), 6.90-6.89 (m, 2H), 6.78-6.77 (m, 1H), 2.72-2.67 (t, 2H, J=7.8 Hz), 2.42-2.37 (t, 2H, J=7.8 Hz), 2.05 (s, 6H); 13CNMR (CDCl3) δ 173.1, 140.7, 137.8, 131.7, 130.1, 129.2, 128.3, 122.9, 121.4, 89.4, 88.6, 51.6, 35.4, 30.8, 21.1; ESI-MS m/z 315.1 (MNa+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-:20])[C:10]=2[CH:11]=1
Reactant: Brc1cnc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a stirred solution of 3-bromo-1,5-naphthyridine (C-2) (35.6 g, 170 mmol, 1.0 eq) in dichloromethane (300 mL) at 0° C. was added m-chloroperbenzoic acid (35.27 g, 204 mmol, 1.2 eq) in portions. The resulting mixture was stirred for 1 h at RT. The reaction was complete based on TLC analysis. The reaction mixture was washed with saturated Na2SO3 solution and saturated NaHCO3 solution sequentially, and then washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1-5% MeOH-DCM) to afford the desired product 3-bromo-1,5-naphthyridine-5-oxide (C-3) (28.35 g, 74% yield). 1H NMR (300 MHz, CDCl3-d6) δ: 9.21 (s, 1H), 9.01 (s, 1H), 8.52 (d, J=6.3 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.53 (m, 1H); ESI-MS m/z: 208.10 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[C:10]([N+:12]([O-])=O)[CH3:11])[C:6]([O:15][CH3:16])=[CH:5][C:4]=1[CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Li].[H-].[OH-].[Na+]>C1COCC1.C(OCC)C.O>[CH3:16][O:15][C:6]1[CH:5]=[C:4]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH:10]([NH2:12])[CH3:11]
Reactant: COCOCCc1cc(OC)c(C=C(C)[N+](=O)[O-])cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOCCc1cc(OC)c(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution (ice bath) of 1,4-Dimethoxy-2-(2-methoxymethoxy-ethyl)-5-(2-nitropropenyl)-benzene (0.83 g, 2.67 mmol) in 10 mL of dry THF was added dropwise a solution of 1 M LAH in THF (10.67 mL, 10.67 mmol). The reaction mixture was allowed to warm to room temperature and stir overnight. The excess lithium aluninLm hydride was decomposed by careful addition of 0.4 mL of water, 0.4 mL of 15% NaOH, and 1.2 mL of water. The reaction mixture was diluted with 50 mL of ethyl ether. The heterogeneous solution was stirred for 5 min and then filtered and the precipitate was washed with ethyl ether. The combined filtrates were dried (MgSO4) and concentrated under reduced pressure to give a solid. MS (m/z) 284 (M+1)+. 1HNMR(CDCl3): δ ppm 1.03 (d, 3H), 2.46 (m, 1H), 2.65 (m, 2H), 2.83 (m, 2H), 3.25 (m, 3H), 3.65-3.75 (m, 9H), 4.56 (s, 2H), 6.59 (s, 1H), 6.66 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)C(=O)Cl
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (Preparative Example 27, 0.020 g, 0.042 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added isobutyryl chloride (0.0054 mL, 0.052 mmol) and DIEA (0.026 mL, 0.15 mmol). After stirring from 0° C. to room temperature for 16 hours, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 0.020 g (88%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobuty ramide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.9, 2.4 Hz), 7.40 (d, 1H, J=2.1 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.15 (t, 1H, J=9.0 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.31 (m, 1H), 3.62 (m, 8H), 3.49 (m, 2H), 3.27 (t, 2H, J=6.9 Hz), 2.98 (m, 7H), 2.10 (m, 4H), 1.38 (dd, 1H, J=6.6, 2.7 Hz), 1.19 (d, 6H, J=6.6 Hz). MS-ESI: 544.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33]([O:35]CC)=[O:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.[OH-].[Na+].Cl>C1COCC1>[OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (30 mg, 55 μmol) in THF (1 mL) was added 1 N NaOH aqueous solution (1 mL). The resulting mixture was stirred at rt for 3 h. The reaction mixture was acidified with 1N HCl solution (1.5 mL). The mixture was extracted with CH2Cl2 (4×5 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid. It was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15](OCC)=[O:16])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nn(-c2cccc(OC)c2)cc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(-n2cc(C)c(C=O)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A solution (5 mL) of ethyl 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate (1.9 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (20 mL) of lithium aluminum hydride (0.29 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (0.76 mL), 1N aqueous sodium hydroxide solution (3.8 mL) and water (0.76 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (0.99 g) of 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-methanol as a pale-yellow oil. This was dissolved in toluene (15 mL), manganese dioxide (0.32 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The filtrate was concentrated under reduced pressure to give the title object compound (0.84 g, 54%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)C.Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=3)[CH2:4][C:3]([C:2]([F:18])([F:17])[F:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CS(=O)(=O)c1ccc(/C=C/C(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N2N=C(C(F)(F)F)CC2c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 32 %

Procedure:
In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-(4-methylsulphonylphenyl)-3-butene-2-one (prepared according to the method E-1) (1.83 g, 6.58 mmoles) and 4-methylphenylhydrazine chlorohydrate (1.04 g, 6.58 mmoles) are dissolved in 50 ml de ethanol. A few drops of hydrochloric acid are added, and the mixture refluxed under an inert atmosphere for 4 days. The mixture is cooled and the product crystallised. The solution is filtered and the product recrystallised from ethanol. 4,5-dihydro-1-(4-methylphenyl]-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole (0.8 g, yield: 32%) is obtained in the form of a solid with a melting point of 140-3° C.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.C(O)(=O)C.N[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][CH2:25][OH:26])[C:16]=1[F:27]>C(Cl)(Cl)Cl.C(O)C>[F:27][C:16]1[C:17]([CH2:24][CH2:25][OH:26])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][CH:15]=1
Reactant: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccc(F)c1CCO
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 46.1 %

Procedure:
While cooling on ice, 6.52 g (94.5 mmol) of sodium nitrite was added to 45 ml of concentrated sulfuric acid through 30 minutes. Then, 180 ml of acetic acid solution containing 14.5 g (72.9 mmol) of the compound (124) obtained in Reference Example 6 was dropped to the solution through 1.5 hours below 20° C. The solution was stirred for 20 minutes. The solution was dropped to 300 ml ethanol suspension containing 40.9 g (285.8 mmol) of cuprous oxide. The reaction solution was heated at 50° C. and was stirred for 20 minutes. The solution was added to 1.0 1 of ice/water, and 1.0 l of chloroform was added to the solution. The insoluble matter was filtered off, and the organic layer was separated. After drying over magnesium sulfate, the solvent was removed by distillation, and the residue was separated by column chromatography (silica gel 500 g, eluent solvent; chloroform) to obtain 6.22 g of the subject compound (185) in a 46% yield.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1>CO>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C@H:15]3[C@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C@:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2cccc(-c3nnn[nH]3)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(-c3nnn[nH]3)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (690 mg) was resolved on a Berger SFC machine under 100 bar, 30° C. with 10% of methanol on an O.D. column gave two separated peaks. Peak 1, 256 mg (desired), peak 2, 186 mg (undesired).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([NH2:28])[CH3:27].[C:29]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:41]3[C:49]4[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=4[N:43]([CH3:50])[N+:42]=3[O-:51])[N:39]=2)[N:34]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:33]=1)(O)=[O:30]>ClCCl>[CH:26]([NH:28][C:29]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:41]3[C:49]4[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=4[N:43]([CH3:50])[N+:42]=3[O-:51])[N:39]=2)[N:34]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:33]=1)=[O:30])([CH3:27])[CH3:25]
Reactant: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c4c(n(C)[n+]3[O-])CCCC4)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (46.3 mg, 122 μmol.20) and propan-2-amine (24.0 mg, 406 μmol) then 3-(7-carboxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 101 μmol) dissolved in dichloromethane (2.50 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield 3-(7-(isopropylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 92.8 μmol, 91.5%) as a clear foam. MS (M+H)+=485.1 (100% purity); 1H NMR (CDCl3) δ: 7.91 (s, 1H), 6.41 (d, J=8.1 Hz, 1H), 6.11 (s, 1H), 4.54 (s, 2H), 3.22-3.37 (m, 1H), 2.36-2.46 (m, 2H), 2.31 (s, 3H), 1.22-1.44 (m, 2H), 1.00-1.14 (m, 2H), 0.82-1.00 (m, 4H), 0.16 (d, J=6.6 Hz, 7H), −0.30-−0.12 (m, 2H), −1.19 (s, 9H).
Reaction SMILES: O.NN.[CH2:4]([N:11]1[CH2:16][C@@H:15]2[CH2:17][C@H:12]1[CH2:13][N:14]2[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[F:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C>C(O)C.[Ni]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:13][C@@H:12]3[CH2:17][C@H:15]2[CH2:16][N:11]3[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[C:19]([F:27])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)c(F)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2C[C@@H]3C[C@H]2CN3Cc2ccccc2)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Hydrazine hydrate (0.57 ml) was added to a suspension of 4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2,2,1}heptan-5-yl]-3-fluoro-1-nitrobenzene (1.63 g, 5 mmol) in ethanol (35 ml) with stirring, followed by Raney nickel (˜1 g). The mixture was heated at 60° C. for 1.5 hours. More hydrazine hydrate (0.2 ml) and Raney nickel (˜0.5 g) were added and heating continued for a further 3 hours. The mixture was cooled and stirred with charcoal (0.5 g) for 1 hour and filtered. The filtrate was evaporated to give 1-amino-4-[(1S)(4S)-2-benzyl-2,5-diazabicyclo{2.2.1}heptan-5-yl]-3-fluorobenzene (1.28 g, 86%) as an oil. MS: 287 (MH+); NMR(CDCl3); 1.8-1.95 (2H, dd); 2.73-2.9 (2H, dd); 3.17-3.5 (5H, m); 3.71 (2H, s); 4.12 (1H, s); 6.32-6.52 (3H, m); 7.18-7.35 (5H+CHCl3).