Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].C(I)C.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1([CH2:19][CH3:20])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Solvent: O
Product: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 1-tert-butoxycarbonylisonipecotic acid ethyl ester (576 mg) in THF (15 ml) was added a solution of lithium diisopropyl-amide (290 mg) in THF (10 ml) in a stream of argon gas at −78° C., and the reaction mixture was stirred at the same temperature for 1 hour. Ethyl iodide (0.36 ml) was added to the above solution at −78° C., and the mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (585 mg, yield 92%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:21][N:22]=[C:23]=[O:24]>ClCCl>[CH3:1][N:2]([C:23]([NH:22][CH3:21])=[O:24])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CNC(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N(C)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 62.1 %

Procedure:
Into 70 ml of dichloromethane, was dissolved 4.3 g of 1-(methylcarbamoyl)-4-(m-trifluoromethylphenyl)piperazine and 0.9 g of methyl isocyanate. To the solution, while being stirred and cooled in ice, was added dropwise 3.9 g of anhydrous stannic chloride. After 15 hours of reaction at room temperature, the precipitated matter was collected by filtration and stirred in a mixture of dichloromethane and water. The organic layer was separated and dried over anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was recrystallized from a mixture of ethanol and petroleum ether to obtain 3.2 g (62% yield) of 1-(2,4-dimethylallophanoyl)-4-(m-trifluoromethylphenyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1.[N:33]1([C:38](N2C=CN=C2)=[S:39])[CH:37]=[CH:36][N:35]=[CH:34]1>C(Cl)Cl>[N:33]1([C:38]([N:20]2[CH2:19][CH2:18][C:17]([CH2:16][CH2:15][N:14]3[C@H:12]4[CH2:11][CH2:10][C@@H:9]3[CH2:8][CH:7]([N:6]3[C:5]5[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=5[N:3]=[C:2]3[CH3:1])[CH2:13]4)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]2)=[S:39])[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=S)n2ccnc2)CC1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1H-benzimidazole (214 mg, 0.5 mmol) in methylene chloride was added 1-(1H-imidazol-1-ylcarbonothioyl)-1H-imidazole (89 mg, 0.5 mmol). The resulting mixture was stirred overnight. After evaporation of the solvents, the crude product was purified by flash chromatography, eluting with a gradient of 0-5% methanol in ethyl acetate, to afford 1-((1R,5S)-8-{2-[1-(1H-imidazol-1-ylcarbonothioyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (200 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.42-7.39 (m, 2H), 7.31-7.28 (m, 4H), 7.19-7.10 (m, 3H), 7.07 (s, 1H), 4.62-4.56 (m, 1H), 3.53 (br, 1H), 3.24-3.22 (m, 2H), 2.56 (s, 3H), 2.40-2.32 (m, 4H), 1.99-1.81 (m, 10, H), 1.62 (d, J=7.9 Hz, 2H). HRMS m/z (M+H)+ calcd: 539.2957, obsd: 539.2958.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]Br.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+]>O>[Cl:1][CH2:2][CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10]
Reactant: ClCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCCl
Reaction time: 2 h

Procedure:
1-Chloro-3-bromopropane (104.0 g) ethanol (250 ml), and water (90 ml) were stirred under reflux, and a solution of sodium sulphite (25.0 g) in distilled water (90 ml) was added to the stirred refluxing reaction mixture over a period of two hours. After the addition, refluxing was continued for a further 2 hours after which the excess alcohol and 1-chloro-3-bromopropane were removed by distillation. The remaining aqueous solution was evaporated to dryness on a steam bath and the product was recrystallised from alcohol to yield sodium 3-chloro-propane-sulphonate as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][CH:26]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-hydroxyphenylboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.CN1CCOCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[C:37]([F:38])=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[C:24]([F:39])[CH:23]=1>O1CCCC1>[C:33]([C:29]1[CH:28]=[C:27]([O:26][C:25]2[C:24]([F:39])=[CH:23][C:22]([NH:21][C:7]([C:1]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]3)=[O:9])=[C:37]([F:38])[CH:36]=2)[CH:32]=[CH:31][N:30]=1)(=[O:34])[NH2:35]
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 1,1-cyclopropanedicarboxylic acid (492 mg) in tetrahydrofuran (15 ml) was added dropwise 4-methylmorpholine (0.416 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 15 min. To the reaction mixture, was then added thionyl chloride (0.276 ml), followed by stirring at the same temperature for 30 min. To the reaction mixture were added 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and 4-methylmorpholine (0.416 ml) in this order while cooling in an ice water bath under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned after addition of a 1N aqueous solution of sodium hydroxide (15 ml) and tert-butyl methyl ether (30 ml). The separated aqueous layer was treated with 1N hydrochloric acid (15 ml) to precipitate a solid. The solid was collected by suction filtration and washed with water (10 ml, three times). Hot air drying at 60° C. provided 1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (674 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:5]=1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([N:15]([CH2:31][CH:30]=[CH2:29])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(-c2ncco2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Benzyloxycarbonylamino-5-oxazol-2-yl-benzoic acid methyl ester (330 mg, 0.927 mmol, I eq) is dissolved in THF (10 ml). NaH (48 mg, 60%,1.21 mmol, 1.3 eq) is added in portions, and the reaction mixture is stirred for 30 min at rt. TBAI (35 mg, 92.7 μmol, 0.1 eq) and allyl bromide (119 μl, 1.39 mmol, 1.5 eq) are added, and the reaction mixture is stirred for 20 h and then quenched with HCl (1N in H2O). The aqueous phase is extracted with EtOAc. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated to give the product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(CCOc2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 10.2 %

Procedure:
To a solution of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.020 g, 0.053 mmol) in DMSO (1 ml) were added N-methylpiperazine (11 μl, 0.106 mmol) and triethylamine (12 μl, 0.106 mmol). The reaction was heated to 150° C. via microwave irradiation and held at that temperature for 25 minutes. Purification was performed by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide (0.0024 g, 0.0054 mmol, 10%) as an off white powder. 1H NMR (CD3OD) δ 2.57 (3H, s), 2.76-2.96 (10H, m), 4.24 (2H, t), 7.06 (2H, m), 7.22 (2H, m), 7.64 (1H, m), 8.26 (2H, m). LCMS (2) 2.25 min; m/z (ES+) 443.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(Cl)Cl>[CH2:16]([N:18]([CH2:19][CH3:20])[C:7]([C:6]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:8])[CH3:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of 17.4 g. (0.075 mol.) of 3,4 dinitrobenzoylchloride in 250 ml. of methylene chloride is treated at 0°-20° C with a solution of 11 g. (0.15 mol.) of diethylamine in 100 ml. of methylene chloride. The solution is kept at 20°-25° C for 2 hrs., the solvent is evaporated and the residue triturated with water. Recrystallization from methanol affords 4-(N,N-diethylcarbamoyl)-1,2-dinitrobenzene.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:29])=[CH:9][C:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:11][C:12]=3[C:13]32[CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)=[CH:4][CH:3]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>>[F:29][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:36]4[C:31]([F:30])=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:3][CH:4]=3)[C:13]3([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)[C:12]=2[CH:11]=[C:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:9]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 25 °C

Procedure:
A vial was charged with (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine (158 mg, 0.341 mmol), 2-fluoropyridin-3-ylboronic acid (96 mg, 0.682 mmol), potassium phosphate (217 mg, 1.023 mmol), and AmPhos (12.07 mg, 0.017 mmol) were added. The vial was flushed with Ar (g), then 1,4-dioxane (1279 μL) and water (426 μL) were added in sequence. The vial was heated to 90° for 45 min. The mixture was cooled to RT and extracted with EtOAc (3×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (E)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.24 (td, J=1.5, 4.8 Hz, 1 H), 8.10 (ddd, J=1.9, 7.5, 10.4 Hz, 1 H), 7.64-7.53 (m, 2 H), 7.49 (ddd, J=1.9, 5.0, 7.3 Hz, 1 H), 7.34 (d, J=8.3 Hz, 1 H), 6.95 (dd, J=2.7, 12.4 Hz, 1 H), 6.81 (dd, J=1.4, 2.7 Hz, 1 H), 6.11 (br. s., 2 H), 3.84-3.69 (m, J=4.2 Hz, 2 H), 3.67-3.54 (m, 4 H), 2.98-2.75 (m, 2 H), 1.06-0.95 (m, 9 H). MS m/z=480.2. Calc'd for C27H28F2N3O3: 480.2. The purified racemates (58 mg) were separated using a chiral SFC column, eluting with 55% MeOH with diethylamine, to afford (S)-enantiomer (peak 1) and (R)-enantiomer (peak 2) as white solids.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C:16]1=[O:21])([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C([O-])(O)=O.[Na+].[CH2:28]([OH:30])[CH3:29]>OS(O)(=O)=O>[CH2:28]([O:30][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH2:4][C@@H:3]1[OH:1])[CH3:29]
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O

Procedure:
A solution of 2α,3α-epoxy-5α-androstane-11,17-dione (5.0 g) in absolute ethanol (250 ml) was treated with eight drops of fuming H2SO4 at room temperature. After 45 minutes the reaction mixture was treated with aqueous NaHCO3 and evaporated to low volume. Water was added to the mixture which was then refrigerated overnight. The precipitate was collected by filtration, washed with water and dried. Recrystallisation from water-ethanol afforded the title compound (2.1 g), m.p. 164°-167°, [α]D +114°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].CN.ClC1C=[C:20]([NH:22]C)C([N+]([O-])=O)=C(NC)C=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:22][CH3:20])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: CNc1cc(Cl)cc(NC)c1[N+](=O)[O-]
Agent: CN
Solvent: CCO
Product: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h

Procedure:
0.150 mole (34 g) of 2,4,6-trichloronitrobenzene is added portionwise, at ambient temperature, to 300 ml of a 30% strength solution of methylamine in absolute ethanol. After stirring for 23 hours at ambient temperature, a precipitate, consisting essentially of 4-chloro-2-methylamino-6-methylaminonitrobenzene, is removed by filtration. The filtrate is evaported to dryness under reduced pressure. 800 ml of concentrated hydrochloric acid are added to the dry extract obtained in this manner. The insoluble fraction is removed by filtration. After dilution of the filtrate with 650 ml of water, the expected product precipitates. It is washed with water and is then dried under vacuum in the presence of phosphorus pentoxide. After recrystallization from isopropanol and then from absolute ethanol, it melts at 120° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH3:10][O:11]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:10]=[O:11])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(C=O)ccc1O

Procedure:
45.5 g of titanium tetrachloride was dropwise added, under stirring with ice, to a solution obtained by dissolving 14.64 g of 2-ethylphenol in 200 ml of dichloromethane. After the completion of the dropwise addition, 22.76 g of α,α-dichloromethyl methyl ether was dropwise added thereto. The ice bath was removed, and the reaction solution was stirred at room temperature for 2 hours. Then, the reaction solution was poured into a 10% hydrochloric acid aqueous solution, and the mixture was stirred for 2 hours. The reaction mixture was extracted with chloroform. The chloroform layer was washed with water, and then extracted with a 10% sodium hydoxide aqueous solution. The alkali extract layer was washed twice with chloroform, and then acidified to a pH of about 2 by gradually adding concentrated hydrochloric acid. Then, the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a dark reddish purple oily substance. This product was purified by silica gel column chromatography by using benzene-ethyl acetate (16 : 1, v/v) as the developer, whereby 6.90 g of the above identified compound was obtained as a pale red oily substance.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:17]([CH3:19])[CH3:18])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH:17]([CH3:19])[CH3:18])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)N(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 72.9 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-isopropyl-3-L-arabinopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.4 g of 1-(2-chloroethyl)-1-nitroso-3-isopropyl-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=O)[CH:19]=3)[CH2:14]2)=[O:11])=[CH:4][CH:3]=1.[CH:39](C1C=C2C(=CC=1)C[C@H](N)CC2)=C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)(=[O:27])=[O:28])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[CH2:39])[CH:19]=3)[CH2:14]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2
Reactant: C=Cc1ccc2c(c1)CC[C@@H](N)C2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2

Procedure:
A solution of 3-(R)-(4-fluoro-phenyl)-N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (391 mg, 1 mmol), crude (6-vinyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-amine (190 mg, 1.1 mmol), HOBt (135 mg, 1 mmol) and EDC (191 mg, 1 mmol) in 2 mL of DMF was stirred overnight at RT. After quenching with Sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, hexane/EtOAc=1:2) gave the desired compound as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=2)[C:23]([NH:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[O:24])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)[C:44]([CH3:59])=[CH:43][C:41]=1[NH2:42])[CH3:38].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:44]([CH3:59])[C:45]([N:47]4[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:35][CH3:36]
Reactant: COc1ccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 170 °C
Yield: 70.8 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)-2-(methyloxy)benzamide (Example 197, step A) (132 mg, 0.26 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (Example 215, step C) (80 mg, 0.24 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (120 μL, 0.47 mmol). The mixture was stirred and heated on a microwave at 170° C. for 45 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum, and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (139 mg, 0.17 mmol, 73%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 ppm 9.79 (s, 1H), 9.39-9.48 (m, 1H), 8.41 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.5, 1.7 Hz, 1H), 7.61 (dd, J=9.6, 2.5 Hz, 1H), 7.53 (s, 1H), 7.35-7.44 (m, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.17-7.23 (m, 2H), 6.99-7.04 (m, 1H), 6.76 (s, 1H), 6.59 (d, J=5.1 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.00 (s, 3H), 3.14-3.22 (m, 2H), 3.03-3.10 (m, 2H), 2.98 (s, 3H), 2.61 (t, J=10.9 Hz, 2H), 2.15 (s, 3H), 1.77-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.45-1.54 (m, 1H), 1.30-1.41 (m, 2H), 1.23-1.28 (m, 3H). MS (ESI): 813 [M+H]+.