Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16]S[CH2:14][CH2:13]1.[O:18]1CCCC1>[Ni].O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:18][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Reactant: C1CCOC1
Agent: [Ni]
Solvent: O
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1
Reaction time: 24 h

Procedure:
A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) was added to a Parr bottle containing a mixture of Raney nickel (1 g) in water (15 mL) under N2, and the reaction mixture was shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 24 hrs. The catalyst was removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate was diluted with water (50 mL) and EtOAc (50 mL), and the layers were separated. The organic phase was washed with saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil was chromatographed on a Flash 40M 90 g silica gel cartridge eluting with EtOAc/heptane (15/85). Pooling and concentration of those fractions with an Rt=0.19 by TLC (EtOAc/hexanes, 25/75) gave the title compound, mp 85-86° C.; MS (ESI+) for C10H12N2F2S m/z 231 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][CH:11]([CH3:24])[CH:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[CH3:10][CH:11]([CH3:24])[CH:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][C:16]([N+:6]([O-:9])=[O:7])=[CH:15][CH:14]=1
Reactant: CC(C)C(c1ccccc1)n1ccnc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CC(C)C(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Temperature: 0 °C
Yield: 97.8 %

Procedure:
To a stirred and cooled (0° C.) amount of 55.2 parts of sulfuric acid were added portionwise 13 parts of 1-(2-methyl-1-phenylpropyl)-1H-imidazole mononitrate. After stirring for 1/2 hour at 0° C., the reaction mixture was poured into ice-water. The whole was basified with ammonia and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 12 parts (97.8%) of 1-[2-methyl-1-(4-nitrophenyl)-propyl]-1H-imidazole (interm. 40).
Reaction SMILES: CC1C=CC(C)=CC=1[CH:9]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17]CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[CH3:13][C:12]1[CH:11]=[CH:10][C:15]([CH3:14])=[CH:22][C:21]=1[O:20][P:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:23])[OH:17]
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1cc(C)ccc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(OP(=O)(O)Cc2ccccc2)c1
Temperature: 110 °C

Procedure:
O,O-Diethyl 2,5-dimethylphenyl(phenyl)methylphosphonate (15.0 g, 45.1 mmol) was dissolved in ethanol (172 mL) and concentrated hydrochloric acid (290 mL). The resulting solution was heated at 110° C. for 52 hours. The mixture was cooled and the solid which formed was collected by filtration, washed with H2O(2×50 mL), CH2Cl2 (3×30 mL), and dried to afford 11.0 g (88.6 %) of analytically pure product as a white solid, mp 204°-207° C. 300 MHz 1H NMR (DMSO-D): δ,4.44 (d,1H, J=24.8 Hz, PCH), 2.25 (s, 3H, PhCH3), 2.20 (s, 3H, PhCH3). MS: 277 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[CH:18]12[O:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]2.B(F)(F)F.CCOCC>CCOCC.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[OH:24])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C1CCC2OC2C1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1CCCCC1c1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 8.00 g (32.9 mmol) 3-fluoro-5-trifluoromethyl-bromo-benzene in 40 ml Et2O under nitrogen was cooled to −78° C. and drop-wise 20.56 ml (32.9 mmol) of a 1.6 M butyl lithium solution in hexane were added. The reaction was strongly exothermic and the temperature was kept below −70° C. Then after 30 min. at −78° C. 2.66 ml (2.58 g, 26.3 mmol) cyclohexene oxide were added followed by 3.75 ml (4.2 g, 29.6 mmol) boron trifluoride diethyl etherate. The latter has to be added drop-wise to keep the temperature below −70° C. The reaction mixture was stirred for 2 h at −78° C. and then quenched with 40 ml saturated aqueous KHSO4 solution, warmed up to ambient temperature and extracted with tert.-butyl methyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product, 7.53 g light yellow crystals, was purified by re-crystallisation from n-heptane: 4.90 g rac-2-(3-fluoro-5-trifluoromethyl-phenyl)-cyclohexanol as colorless crystalls: m.p. 76.5–77.4° C., MS (EI): 262.1 M+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3C=N[CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1([S:37](Cl)(=O)=O)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:37][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13b, and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.60 (m, 1H), 8.49 (m, 1H), 7.87 (m, 4H), 7.61-7.51 (m, 3H), 7.26-7.08 (m, 3H), 6.75 (m, 1H), 6.63 (m, 1H), 6.58 (m, 1H), 4.38 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 1.47 (s, 9H); MS 546 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH2:21][C:22](OC)([O:24]C)[CH3:23])[C:13]=1[F:28]>CC(N(C)C)=O.Cl>[C:22]([CH2:21][C:14]1[C:13]([F:28])=[C:12]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])(=[O:24])[CH3:23]
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(F)c1F)OC
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60% sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for 1 hour at ambient temperature. A solution of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was evaporated and the residue was dissolved in TBF (2 ml) and 6N hydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hour at ambient temperature and the solvents were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56%).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C@H:10]2[CH2:12][O:11]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[NH:13]1[CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[N:13]1([CH2:12][C@@H:10]([OH:11])[CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1nccn1C[C@H]1CO1
Reactant: C1CN1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1nccn1C[C@H](O)CN1CC1

Procedure:
Reaction of (S)-(-)-2-nitro-1-(2-oxiranylmethyl)-1H-imidazole with 1H--aziridine as described in Example 1(e) gives the product, mp 119.5°-121° C. [α]D24 =-28.7° [c1.15, chloroform].
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][CH2:23][C:24]([CH3:26])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:29][O:28][C:21](=[O:27])[CH2:22][C:23]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:24]=1[CH3:26]
Reactant: CCc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCCC4)cc1
Yield: 73.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-ethylphenyl)methanone (0.471 g; 1.65 mmol), methyl levulinate (0.233 mL; 1.81 mmol), chlorotrimethylsilane (0.845 mL; 6.6 mmol) in DMF (6.6 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.463 g (74%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].[OH-].[K+].Cl>C(Cl)Cl.C(O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a suspension of compound (ix) (320 mg, 0.83 mmol) in DCM (20 mL) was added DIPEA (0.43 mL, 2.49 mmol) followed by methanesulfonyl chloride (0.32 mL, 4.15 mmol) and the reaction mixture was stirred at RT for 3 h (monitored by LCMS). The mixture was diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), brine (20 mL) and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid. This material was taken up in ethanol (20 mL) and treated with powdered potassium hydroxide (210 mg, 3.80 mmol) and stirred for 5 min. The mixture was neutralized by addition of 1M aqueous hydrochloric acid and the resulting suspension was concentrated in vacuo to give an orange residue. The residue was taken up in DCM (20 mL), washed with water (20 mL), dried over MgSO4 and the solvent was removed in vacuo to give 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (1) (300 mg, 86%) as yellow solid. ESI-MS m/z calculated for [M+H]+: 463.04/465.04; found: 463.05/465.05. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=0.4 Hz, 1H), 7.68 (d, J=0.5 Hz, 1H), 7.65 (brd, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.09 (s, 1H), 5.80 (brd, J=4.1 Hz, 1H), 3.13 (s, 3H), 3.00 (d, J=4.9 Hz, 3H), 1.80 (dddd, J=13.6, 8.1, 5.4, 1.3 Hz, 1H), 1.16-0.99 (m, 2H), 0.79-0.67 (m, 2H).
Reaction SMILES: C(C1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]C=3)C[C@@H:13]2O)=[N:5]C(CC)=CN=1)C.Br[C:23]1[C:28]([CH2:29][CH3:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])=[C:25]([CH2:39][CH3:40])[N:24]=1.C(C1C(N)=NC(C)=CC=1)C>>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:26]1[N:27]=[C:28]([CH2:29][CH3:30])[C:23]([NH:5][C:4]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:20]=[C:12]([CH3:13])[N:11]=2)=[N:24][C:25]=1[CH2:39][CH3:40]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Agent: CCc1ccc(C)nc1N
Product: CCc1ccc(C)nc1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and 3-ethyl-6-methylpyridin-2-amine, and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ 0.95, 1.15, 2.33, 2.31, 2.51, 2.70, 6.95, 7.51, 7.75, 8.57; HRMS (ESI+) calcd for C22H24Cl2N4 (M+H)+ 415.1456, found 415.1442.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:17]([C:25]1([OH:42])[CH:33]=[C:32]2[CH2:34][NH:35][CH2:36][CH2:37][N:30]3[C:31]2=[C:27]([CH:28]=[CH:29]3)[CH:26]1[C:38]([F:41])([F:40])[F:39])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[OH:42][C:25]1([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:33]=[C:32]2[CH2:34][NH:35][CH:36]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH2:37][N:30]3[C:31]2=[C:27]([CH:28]=[CH:29]3)[CH:26]1[C:38]([F:41])([F:40])[F:39]
Reactant: O=C=Nc1ccccc1
Reactant: OC1(CCc2ccccc2)C=C2CNCCn3ccc(c32)C1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)C1Cn2ccc3c2C(=CC(O)(CCc2ccccc2)C3C(F)(F)F)CN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phenyl isocyanate (3.8 mg, 0.05 mmol) was added to a solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indol-6-ol trifluoroacetate (14 mg, 0.039 mmol) in THF (3 mL) containing triethylamine (11 mg, 0.11 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure, the residue dissolved in ethyl acetate and the resulting solution was washed sequentially with water, NaHCO3 (sat'd. aq) and brine. The organic phase was dried (Na2SO4) and concentrated to yield 6-hydroxy-6-phenethyl-N-phenyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (MH+=482).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)([OH:16])[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].C(Cl)(Cl)Cl.CO>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[C:11]1([OH:16])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: OC1(c2ccc3ccccc3c2)CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC1(c2ccc3ccccc3c2)CC2CCC(C1)N2
Temperature: 50 °C
Reaction time: 21 h
Yield: 72 %

Procedure:
To 3.80 g (11.1 mmol) 8-benzyl-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol was added 1.20 g (19.0 mmol) of ammonium formate, 100 mL MeOH, and 2.46 g Pd/C (10 wt. %). The reaction mixture was heated to 50° C., and was monitored by TLC on a SiO2 plate with CHCl3:MeOH (10:1). After 21 h, the mixture was cooled to room temperature, filtered through a pad of celite and evaporated to afford 2.0 g (7.9 mmol, a 72% yield) of the title compound as an off-white solid. MS (ES) m/z: 344 (MH)+.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:47]=[C:46]2[C:42]([CH2:43][C:44](=[O:49])[N:45]2[CH3:48])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:39]2[CH:47]=[C:46]3[C:42]([CH2:43][C:44](=[O:49])[N:45]3[CH3:48])=[CH:41][CH:40]=2)=[CH:7][CH:6]=1
Reactant: CN1C(=O)Cc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1C(=O)Cc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Yield: 21.8 %

Procedure:
A solution of (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 200 mg) and 6-bromo-1-methylindolin-2-one (87 mg) in acetonitrile (5 mL) was treated with potassium carbonate (107 mg) and purged with nitrogen. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (15 mg) was added and the reaction stirred is under reflux under nitrogen for 4 h and then evaporated in vacuo. The residue was partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous was further extracted with ethyl acetate (40 mL) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (45 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(Cl)(Cl)Cl>C1COCC1>[F:18][C:14]1([F:17])[CH2:15][CH2:16][C:11]([OH:37])([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)C1CCC(F)(F)CC1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)C1(O)CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of benzyl-4,4-difluorocyclohexanecarboxylate (6.5 g, 25.56 mmol) in 128 ml of THF was cooled to −78° C. under nitrogen. Potassium bis(trimethylsilyl)amide (76.7 mL of 0.5 M solution in toluene) was added, and the mixture was stirred at −78° C. for one hour. A THF solution (35 mL) of 3-phenyl-2-(phenylsulfonyl)oxaziridine (9.35 g, 35.79 mmol) was added, and the reaction was stirred for 40 minutes. After quenching with a saturated aqueous ammonium chloride solution and warming to room temperature, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine prior to drying over sodium sulfate. Filtration and removal of solvent provided crude product which was stirred with 100 mL of chloroform, and then filtered to remove the insoluble material. The filtrate was concentrated under vacuum and the residue was subjected to silica gel chromatography eluting with 5 to 20% EtOAc in hexane to afford benzyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([O:33][CH3:34])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:34][O:33][C:24]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27]/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:32]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and methyl anthranilate in DMF and subsequent brief treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:32])[N:11]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[CH3:8]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:7]([O:9][C:10](=[O:32])[N:11]([C:21]1[CH:26]=[C:25]([C:4]2[O:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[CH3:8]
Reactant: Cc1cocn1
Reactant: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(-c2nc(C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methyl-oxazole (40 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano-benzyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (30 mg), giving the product (65 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:38]2)=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[S:38])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: S=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Yield: 16.7 %

Procedure:
A mixture of the resulting quinoline-6-carboxylic acid 4-benzyloxy-benzylamide (310 mg, 0.84 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (1.4 g, 3.4 mmol) and tetrahydrofuran (10 mL) was refluxed for 1 hour. After cooling, the solvent was evaporated in vacuo, dichloromethane was added to the residue, which was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (55 mg, 0.14 mmol, 17%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccnc4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4cccnc4)cc2-3)cc1
Temperature: 100 °C
Yield: 99 %

Procedure:
6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.49 g, 0.98 mmol) was dissolved in MeOH and treated with concentrated HCl (0.3 mL, 9.4 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.35 g, 0.97 mmol) as brown solid in 99% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14]Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[C:30]([F:32])[CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>CN(C)C=O>[CH3:9][O:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:20]2[CH:29]=[C:30]([F:32])[CH:31]=[C:18]([F:17])[CH:19]=2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: COC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1

Procedure:
21.3 g of potassium carbonate powder, 1.5 g of finely powdered potassium iodide and 16 g of 2-chloroethylcarbamic acid methyl ester are added to a solution of 17.1 g of 4-(3,5-difluorophenoxy)-phenol in 100 ml of dimethylformamide, and the reaction mixture is heated at +95° C. for 15 hours. The reaction mixture is then cooled, poured onto ice-water and extracted repeatedly with ether. The combined ether phases are washed with water and dried over sodium sulfate. The solvent is distilled off completely. The crude product is purified further by chromatography over silica gel (eluant: petroleum ether (40° C.-65° C.)/diethyl ether, 5:1), yielding 2-[4-(3,5-difluorophenoxy)-phenoxy]-ethylcarbamic acid methyl ester, n21D : 1.5394.