Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:6](=[O:19])[C:5]2=O.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29].[C:30]([O-:33])(O)=O.[Na+]>FC(F)(F)S(O)(=O)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:6](=[O:19])[C:5]2([C:2]1[CH:3]=[C:4]([CH3:5])[C:30]([OH:33])=[C:9]([CH3:8])[CH:10]=1)[C:26]1[CH:25]=[C:24]([CH3:28])[C:23]([OH:29])=[C:22]([CH3:21])[CH:27]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccc(Br)cc21
Reactant: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(Cc3ccccc3Cl)c3ccc(Br)cc32)cc(C)c1O
Temperature: 0 °C

Procedure:
Combine crude 5-bromo-1-(2-chloro-benzyl)-1H-indole-2,3-dione (72 mg, 0.21 mmol) with 2,6-dimethylphenol (200 mg, 1.64 mmol) in trifluoromethanesulfonic acid (1 mL) and stir for 1 h. Dilute with CH2Cl2 and stir with ice water for 20 min. Pipette off ice water and stir with saturated NaHCO3 solution for 20 min. Remove aqueous by pipette and pass organic layer through a 5 mL Varian Chem Elut column. Concentrate in vacuo to give 131 mg solid. Triturate in MeOH to give 50 mg (41%) of a white solid. MS (ES): m/z=576, 578 (M+1), 574, 576 (M−1); 1H NMR(DMSO-d6): δ8.31 (s, 2H), 7.53 (d, J=7.9 Hz, 1H), 7.45 (m, 2H), 7.34 (t, J=7.6 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 6.95 (m, 2H), 6.71 (s, 4H), 5.06 (s, 2H), 2.09 (s, 12H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][CH:39]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@@H:28]([NH:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C=O.[C:42]([BH3-])#N.[Na+]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][CH:39]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@@H:28]([N:30]([CH3:42])[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](NCCC(F)(F)F)CC5)c3)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(CCC(F)(F)F)[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Yield: 83.7 %

Procedure:
Stir a solution of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N—[(S)-6-(3,3,3-trifluoro-propylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide (0.063 g, 0.11 mmol) and formaldehyde solution (0.08 mL, 1.14 mmol, 37 wt % in H2O) and sodium cyanoborohydride (0.014 g, 0.23 mmol) in 1 mL 20% MeOH/CH2Cl2 overnight at room temperature in a capped flask. Concentrate the mixture, add aq. H2O and extract the product 4×EtOAc, washed 3×H2O. Dry the mixture with a drying agent and concentrate. Purify the product on a prep plate eluting with 5% MeOH/CH2Cl2 which affords 0.052 g, 80% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N-{(S)-6-[methyl-(3,3,3-trifluoro-propyl)-amino]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-benzamide as a clear resin. MS, electrospray 565.71 (M+H), room temperature 1.60 min. The following compound is prepared analogously (Example 11)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:8]([CH2:10][OH:11])[CH3:9].[C:12]([C:16]([C:19](F)=[O:20])([F:18])[F:17])([F:15])([F:14])[F:13].[C:22]([O-:25])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:12]([C:16]([C:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:8]([CH2:10][O:11][C:19]([C:16]([C:12]([F:13])([F:14])[F:15])([F:17])[F:18])=[O:20])[CH3:9])=[O:25])([F:18])[F:17])([F:15])([F:14])[F:13]
Reactant: CC(CO)OCCOCCO
Reactant: O=C([O-])O
Reactant: O=C(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(COC(=O)C(F)(F)C(F)(F)F)OCCOCCOC(=O)C(F)(F)C(F)(F)F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
HO(CH2)2O(CH2)2OCH(CH3)CH2OH (5.1 g) obtained in Example 5-2 and chloroform (10 g) were charged into a flask and stirred while maintaining the internal temperature at 30° C. Together with nitrogen, CF3CF2COF (191 g) was supplied while maintaining the internal temperature at 30° C. After completion of the reaction, while supplying nitrogen gas, stirring was continued at an internal temperature of 30° C. for 2 hours, and then, a 5% NaHCO3 aqueous solution (30 ml) was added at an internal temperature of at most 15° C.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[CH3:11][O:12][CH2:13][CH2:14][CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][CH2:13][CH2:14][CH:15]([CH2:18][CH:19]=[CH2:20])[CH:16]=[O:17]
Reactant: C=CCC(CO)CCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(C=O)CCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Dry dimethylsulfoxide (18.4 mL, 260 mmol) in dry CH2Cl2 (30 mL) was added dropwise to a stirred solution of 2M (COCl)2 (65 mL, 130 mmol) at −78° C. during 15 min under nitrogen. The alcohol 4 (15 g, 104 mmol), prepared according to Example 3, in dry dichloromethane (50 mL) was then added during 10 min. resulting in a slightly cloudy solution, which was stirred for 30 min at −78° C. A solution of triethyl amine (75 mL, 520 mmol) in dichloromethane (50 mL) was then added dropwise during 15 min. The mixture was then stirred for 1h at room temperature, and the reaction was quenched by adding water (25 mL), with rapid stirring. The resulting slurry was immediately poured into ether (300 mL) and washed with 20% KHSO4 (2×200 mL). The layers were separated, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were washed with brine solution (2×100 mL), dried over MgSO4, filtered, and concentrated to afford the crude aldehyde 5 (12.4 g, 84%) as an oil, which was used in the following condensation with ethylene glycol, IR (KBr) υmax 2951, 2921, 2863, 1720, 1638, 1456, 1379, 1255, 1121, 1033, 997, 909 cm−1; 1HNMR (CDCl3) δ1.73-1.77 (m, 1 H), 1.92-1.96 (m, 1 H), 2.23-2.27 (m, 1 H), 2.42-2.46 (m, 1 H), 2.50-2.52 (m, 1 H), 3.29 (s, 3 H), 3.39-3.43 (m, 2 H), 5.05-5.10 (m, 2 H), 5.72-5.77 (m, 1 H), 9.64 (s, 1 H); 13CNMR (CDCl3) δ28.65, 33.04, 48.57, 58.57, 70.00, 117.40, 134.85; mass spectrum (EI), m/z (rel intensity) 167 (23), 157 (17), 149 (100), 143 (16), 142 (4, M+), 141 (12), 129 (28), 127 (64), 112 (22), 111 (26), 109 (14), 100 (16), 97 (23), 95 (31), 93 (22), 87 (24), 85 (36), 84 (53), 83 (45), 82 (21), 81 (49), 79 (27), 71 (70), 70 (26), 69 (51), 67 (55), 59 (49), 57 (80), 55 (87), 53 (31).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccncc1
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccncc3)c12

Procedure:
The title compound, white solid (24 mg, 33%), MS (ISP) m/z=296.3 [(M+H)+], mp 309° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[C:34](O)(=[O:37])[CH2:35][OH:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:35](=[O:36])[CH2:34][OH:37])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: O=C(O)CO
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.9 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (105 mg), glycolic acid (44 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (167 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→methanol:ethyl acetate=1:9) to give the title compound (108 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23](CCl)=[CH:22][CH:21]=1.[CH3:28]CN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:28][C:27]1[CH:26]=[CH:23][CH:22]=[CH:21][C:20]=1[O:19][CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: COc1ccc(CCl)cc1
Solvent: CC#N
Product: COc1ccccc1CNC1=NC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 4-methoxybenzylchloride (56.24 mg, 0.40 mmol) and Hunig's base (77.40 mg, 0.60 mmol) in acetonitrile (6 mL) was heated to reflux under argon for 13 hrs. Cool to r.t., the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give an oil which was purified by preparative TLC, eluted with 50% nHex/EtOAc to give 2-(2-methoxyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (60.0 mg, 42.5%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I.Cl>C1COCC1>[Cl:13][C:14]1[N:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([I:24])=[CH:18][CH:19]=1
Reactant: II
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1nc(Cl)ccc1I
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7.1 ml of n-BuLi (1.6M in hexane, 11.3 mmol) in 7 ml THF under argon at −73° C. were added 1.6 ml of diisopropylamine (11.3 mmol) in 3 ml THF within 8 min. After 10 min stirring at the same temperature a solution of 1 g of 2-chloro-6-(trifluoromethyl)-pyridine (5.51 mmol) in 5 ml THF was added within 15 min (temperature between −76 and −75° C.). The dark brown solution was stirred at −75° C. for 1 h 15 min. Finally a solution of 1.4 g of iodine (5.51 mmol) in 10 ml THF was added at −75° C. over 25 min. After additional 45 min stirring at the same temperature 12 ml 2M aqueous HCl were added within 2 min (temperature raised from −78 to −50° C. The cooling device was then removed, the reaction mixture diluted with diethylether. After separation of the organic phase, the aqueous phase was reextracted with diethylether. The combined organic phases were successively washed with 10 ml 1M sodium thiosulfate, saturated NaHCO3 and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo to yield 1.54 (69%) of 6-chloro-3-iodo-2-trifluoromethyl-pyridine as a brown semisolid residue. MS: 307.0
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9](N)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].N([O-])=O.[Na+].[ClH:26]>O>[Cl:26][C:9]1[N:8]2[N:19]=[CH:20][N:21]=[C:7]2[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Reaction time: 0.5 h

Procedure:
A solution containing 100.8 g of 8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (0.36 moles) dissolved in 600 ml of concentrated hydrochloric acid and 420 ml. of water is cooled to 3° C. with constant stirring. To the cooled solution is added (below the surface of the solution) a mixture containing 54 g. of sodium nitrite (0.72 moles) in 75 ml of water over a period of fifteen minutes. The reaction mixture is stopped and stirred in an ice-bath for 0.5 hour and then stirred at room temperature for one hour. To the reaction mixture is added 150 ml of water and the resulting mixture is allowed to remain overnight at room temperature. A precipitate formed and the mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is recrystallized from diethylether yielding 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine represented by the structural formula ##STR18## as a white solid having a melting point of 134°-135° C. and the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([N:19]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1>C1COCC1.Cl>[NH2:19][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Yield: 80.2 %

Procedure:
A solution of N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.520 g, 1.116 mmol) in THF (8 mL) and hydrochloric acid, 2N (J. T. Baker) (0.837 mL, 1.674 mmol) was stirred at rt in a sealed tube for 30 min. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g, 20% to 40% acetone in hexanes) to give the product as a yellow solid (0.270 g). m/z (ESI, +ve ion) 302.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J=8.77, 4.97 Hz, 2H); 7.61 (d, J=2.63 Hz, 1H); 7.34 (d, J=2.48 Hz, 1H); 7.16 (t, J=8.48 Hz, 2H); 6.82 (br. s., 1H); 3.84 (br. s., 2H).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[OH:30])=[O:22]>>[CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[OH:30])=[O:22])[CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Reactant: O=C(CCCCl)c1ccc(F)cc1O
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3)c1ccc(F)cc1O

Procedure:
The title compound was prepared by the method of Example 361 as a yellow oil (8 mg, 17%) from (±)-cis-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-[2,3,4-hi]pyrido[4,3-b]indole (30 mg, 0.12 mmol) and 4-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-butanone (52 mg, 0.24 mmol). 1H NMR (CDCl3, 300 MHz) δ1.85-2.13 (m, 5H), 2.25-2.47 (m, 3H), 2.63-2.95 (m, 3H), 2.99 (t, J=7.0 Hz, 2H), 3.17-3.35 (m, 3H), 4.43 (dd, J=6.9, 2.2 Hz, 2H), 6.59-6.75 (m, 5H), 7.81 (dd, J=8.7, 6.6 Hz, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:9]=2N2CCCCC2)=O)=[CH:4][CH:3]=1.CCN(CC)CC.Cl.[CH3:33][CH:34]([CH3:38])[C:35](=[NH:37])[NH2:36]>C(O)(CC)(C)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[C:8]3[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:9]=3[N:37]=[C:35]([CH:34]([CH3:38])[CH3:33])[N:36]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=N)N
Reactant: CC(=O)N1CCC(N2CCCCC2)=C(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Solvent: CCC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C(C)C)nc(-c3ccc(F)cc3)c2C1
Temperature: 25 °C

Procedure:
A solution of crude 1-[5′-(4-fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone in t-amyl alcohol (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and 2-methyl propanimidamide hydrochloride (82.6 g, 0.67 mol). The reaction mixture was heated at reflux for 16 h and then was cooled to rt. The mixture was concentrated, and the residue was diluted with water (2 L) and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated to afford the crude title compound, which was used in next reaction without further purification. HPLC: RT=8.11 min. MS (ESI): exact mass calcd. for C18H20FN3O, 313.16; m/z found, 314.0 [M+H]+. 1H NMR (CDCl3; mixture of rotamers): 7.60-7.50 (m, 2H), 7.24-7.12 (m, 2H), 4.71 (s, 1.4H), 4.56 (s, 0.6H), 3.93 (t, J=6.2, 0.6H), 3.80 (t, J=6.2, 1.4H), 3.18 (sept, J=6.8, 1H), 3.07 (t, J=6.2, 1.4H), 3.02 (t, J=6.2, 0.6H), 2.15 (s, 2.1H), 2.00 (s, 0.9H), 1.34 (d, J=6.8, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.C(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([Cl:21])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCCC2

Procedure:
One hundred parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one was heated under a nitrogen atmosphere (nitrogen was slowly passed through the system at atmospheric pressure) in a 3-neck, round-bottomed flask, fitted with a mechanical stirrer, dry ice condenser, an addition funnel with a gas-inlet and dry ice condenser above it. Phosgene was condensed into the addition funnel from a pressurized cylinder, and 44 parts of phosgene was added dropwise over 2 hours, maintaining a temperature of 178°-180° in the reaction mixture for the first 11/2 hours and allowing it to fall to 135° during the last 1/2 hour. The dry ice in the condenser was removed and the excess phosgene was passed through a 10% sodium hydroxide solution as it evaporated. The reaction mixture was poured out into a pan and allowed to cool. There was obtained 100.6 parts of 2-(4-chloro-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole, m.p. 81°-85° (80.4% pure as determined by gas chromatography).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8](CS(C1C=CC=CC=1)(=O)=O)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Si:31]([O:38][CH2:39][CH:40]([CH2:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)C=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[CH2:54](OCC)[CH3:55].CCCCCCC>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH:54]=[CH:55][CH:40]([CH2:39][O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:33])[CH3:32])[CH2:43][C:44]1[CH:45]=[CH:46][C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:53]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)CS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC(C=O)Cc1ccc2ccccc2c1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](C=CC(CO[Si](C)(C)C(C)(C)C)Cc1ccc2ccccc2c1)Cc1ccc2ccccc2c1

Procedure:
This compound was prepared as in example 9. ((1R)-1-benzenesulfonylmethyl-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (3.71 g; 8.74 mmol) and 2-(tert-butyldimethylsilanyloxymethyl)-3-(2-naphthyl)propionaldehyde (4.3 g; 13.11 mmol) were used as starting materials. Chromatography was carried out using diethylether/heptane 1:3 as eluent on silica (5×25 cm) to afford 2.20 g of ((1R)-4-(tert-butyldimethylsilanyloxymethyl)-1-((2-naphthyl)methyl)-5-(2-naphthyl)pent-2-enyl)carbamic acid tert-butyl ester as a mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].[N+:20]([O-])([OH:22])=[O:21]>O>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([N+:20]([O-:22])=[O:21])[C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5]
Reactant: COc1ccc(C(=O)c2c(Cl)cccc2Cl)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-4'-methoxy-2'-methyl-benzophenone (0.75 g; 2.5 mmol) is added to nitric acid (10 ml; 65%). The mixture is stirred at 80° C. for 1hour. After addition of water the reaction product crystallises and is chromatographically purified (flash column filled with 30 g of silicagel, elution with toluene). White crystals (0.35 g; 41% y); mp. 156°-160° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[C:3]2[N:4]([C:10](=[O:11])[NH:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]nc2c(Br)cccn12
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 1-4 (5.0 g, 26.6 mmol) in THF (50 mL) was added carbonyldiimidazole (5.61 g, 34.6 mmol), and the heterogeneous mixture was stirred for 2 h. The reaction was diluted with water (150 mL) and EtOAc (150 mL), causing a precipitate to form. The mixture was filtered through a sintered glass filter, yielding 2.0 g (35%) of 1-5 as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ12.73 (s, 1H), 7.88 (dd, J=7.2, 0.9 Hz, 1H), 7.58 (dd, J=7.2, 0.9 Hz, 1H), 6.51 (app t, J=7.2 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccc(F)cc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5′-Amino-5,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 ml), 48% aqueous hydrobromic acid (40 ml) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 ml) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 ml). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 ml), water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography [silica gel, 2-6% EtOAc/isohexane (containing 0.5% methanol)] gave the title compound as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 7.13 (1H, dd, J 9, 9 Hz), 7.19-7.23 (2H, m), 7.52-7.60 (2H, m), 7.81 (1H, dd, J 8, 5 Hz).