Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccs1
Yield: 69.7 %

Procedure:
To a solution of 10.0 g (41.5 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 27.7 ml (200 mmol) of triethylamine in 100 ml of methylene chloride, 5.35 ml (50.0 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:20) to obtain powder. The powder was recrystallized from methanol/ethyl acetate (=1:20) to obtain 8.05 g of the desired compound (yield: 70.5%, yellow prisms).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]2[O:57][C:56]([F:59])([F:58])[C:55](=[O:60])[NH:54][C:53]=2[CH:61]=1>O1CCOCC1.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([NH:48][C:49]4[CH:50]=[CH:51][C:52]5[O:57][C:56]([F:59])([F:58])[C:55](=[O:60])[NH:54][C:53]=5[CH:61]=4)=[N:7][CH:6]=[CH:5][N:4]3[N:8]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(Nc2nc3c(Cl)nccn3n2)c1
Reactant: Nc1ccc2c(c1)NC(=O)C(F)(F)O2
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Nc2nc3c(Nc4ccc5c(c4)NC(=O)C(F)(F)O5)nccn3n2)c1

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl-(3,5-dimethyl-phenyl)-amine (0.075 g, 0.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.01 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.01 g, 0.02 mmol) and 6-amino-2,2-difluoro-2H-1,4-benzoxazin-3(4H)-one (0.049 g, 0.2 mmol) are taken in dry 1,4 dioxane (2 mL). Sodiumhexamethyldiisilylamide (1 M in tetrahydrofuran) (0.27 mL, 0.2 mmol) is added and the reaction irradiated in the microwave at 150° C. for 30 minutes. The reaction mixture is quenched with dry methanol (1 mL) and passed through a celite pad. The filtrate is concentrated and purified by flash column chromatography using Silica gel (230-400) mesh to get the titled product as an off white solid (10 mg, 10.4%). TLC: pet ether/ethylacetate (6/4) Rf-0.4. LCMS (method A): mass found (M+H+, 438), Rt (min): 5.11 area % 93.7 (max), 94.4 (254 nm); 1H NMR (400 MHz, DMSO-d6): δ [ppm] 11.99 (s, 1H), 9.63 (s, 1H), 9.39 (s, 1H), 8.27 (d, J=4.48 Hz, 1H), 7.93 (d, J=2.44 Hz, 1H), 7.63 (m, 1H), 7.57 (d, J=4.48 Hz, 1H), 7.35 (s, 2H), 7.27 (d, J=8.92 Hz, 1H), 6.55 (s, 1H), 2.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([O-:22])=O)[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.[Na+].[CH3:24][O:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([CH2:34][NH2:35])[N:27]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([NH:35][CH2:34][C:28]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[N:27]=3)=[O:22])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CN)nc1OC
Reactant: O=C([O-])c1cc(-c2cncc(Cl)c2)cnc1-c1ccccn1
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(Cl)c3)cnc2-c2ccccn2)nc1OC
Temperature: 60 °C

Procedure:
To a suspension of sodium 5″-chloro-2,2′:5′,3″-terpyridine-3′-carboxylate (12-4, 3.12 g, 9.35 mmol, 1.0 equiv) in dimethylformamide (47 mL) was added 1-(5,6-dimethoxy-pyridin-2-yl)methanamine (5-6, 1.65 g, 9.82 mmol, 1.05 equiv), EDC (3.58 g, 18.7 mmol, 2.0 equiv), HOAt (2.55 g, 18.7 mmol, 2.0 equiv), and diisopropylethylamine (4.83 g, 37.4 mmol, 4.0 equiv) and the system was heated to 60° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate (300 mL). The reaction mixture was washed with saturated sodium bicarbonate (2×100 mL), water (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (10 to 100% EtOAc in hexanes, then 0 to 23% methanol in EtOAc, silica) to afford the desired product (12-5) as a white solid after concentration. 1H NMR (500 MHz, CDCl3) δ 8.95 (d, J=2.5 Hz, 1H), 8.80 (s, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.38 (d, J=5.0 Hz, 1H), 8.26 (d, J=2.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.96 (bs, 1H), 7.78 (t, J=3.0 Hz, 1H), 7.47 (bs, 1H), 7.23 (dd, J=7.5, 5.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H). HRMS [M+H] C24H20ClN5O3 calc'd 462.1327. found 462.1332.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].F[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]#[N:27])=[CH:18][CH:17]=1>CS(C)=O>[C:26]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:17][CH:18]=1)#[N:27]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Temperature: 80 °C
Reaction time: 89 h
Yield: 76 %

Procedure:
To a suspension of D-allo-threonine (2.09 g, 17.53 mmol) and K2CO3 (4.04 g, 29.21 mmol) in DMSO (40 mL) was added 4-fluoro-1-naphthonitrile (CAS 13916-99-9, 2.50 g, 14.61 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 89 h. The reaction mixture was allowed to cool to room temperature, quenched with H2O (150 mL) and extracted with EtOAc (3×100 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a light brown solid (3.0 g, 76%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 8.46 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.29-4.20 (m, 1H), 4.08-3.99 (m, 1H), 1.28 (d, J=6.1 Hz, 3H).
Reaction SMILES: [I:1]I.[CH2:3]([N:10]([CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>COC(C)(C)C.C([O-])(O)=O.[Na+]>[CH2:3]([N:10]1[CH2:11][C:12]([CH3:13])([CH3:15])[O:14][C:17]([CH2:19][I:1])([CH3:18])[CH2:16]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(C)CN(Cc1ccccc1)CC(C)(C)O
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC1(C)CN(Cc2ccccc2)CC(C)(CI)O1
Reaction time: 18 h
Yield: 93 %

Procedure:
Add solid I2 (21.1 g, 83.1 mmol) to a biphasic mixture of 1-[benzyl-(2-methyl-allyl)-amino]-2-methyl-propan-2-ol (17.6 g, 75.4 mmol) in tert-butyl methyl ether (250 mL) and 1 M NaHCO3 (100 mL). Stir for 18 h and then add 1 M Na2S2O3 (100 mL). Dilute the mixture with additional tert-butyl methyl ether (200 mL) and separate the organic solution. Wash the organic solution with a mixture of 1 M Na2S2O3 (100 mL) and 1M NaHCO3 (100 mL). Dry, filter, and concentrate the organic solution. Dry the residue at 60° C. under vacuum to give the title compound (25.2 g, 93%) as a golden oil. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 3.49 (1H, d), 3.47 (2H, s), 3.41 (1H, s), 2.49 (1H, d), 2.23 (1H, s), 2.20 (1H, s), 2.10 (1H, d), 1.24 (3H, s), 1.22 (3H, s), 1.15 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][OH:17].[H-].[Na+].[CH3:20]I>C1COCC1.CCOCC>[Br:1][C:2]1[C:3]([CH2:16][O:17][CH3:20])=[CH:4][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: CI
Reactant: COCOc1cc(CO)c(Br)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1cc(COC)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of (2-bromo-3,5-bis-methoxymethoxy-phenyl)-methanol (7.68 g, 24.94 mmol) in THF (50 mL) was added NaH at 0° C. The mixture was stirred at room temperature for 20 minutes then MeI (7.84 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with ether (50 mL), filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-bromo-1,5-bis-methoxymethoxy-3-methoxymethyl-benzene (5.66 g, 70%). 1H NMR (400 MHz, CDCl3δ 6.90 (s, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 5.25 (s, 2H), 5.20 (s, 2H), 4.50 (s, 23.77 (s, 3H), 3.40 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].CS(C)=O.[CH3:20][O-:21].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:21][CH3:20])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: O=C1NC(=O)C(c2c(F)cccc2Cl)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cccc(Cl)c1C1OC(=O)NC1=O
Temperature: 106 °C
Reaction time: 16 h

Procedure:
5-(2-Chloro-6-fluorophenyl)oxazolidine-2,4-dione (22 g., 0.096 mole) was taken into a mixture of dimethylsulfoxide (100 ml.) and methanol (31.5 ml.). Sodium methoxide (10.8 g., 0.2 mole) was added over about 4 minutes, during which time the temperature of the reaction mixture rose to 57° C. As a matter of convenience the reaction mixture was allowed to stand for 16 hours at room temperature before heating at 106° C. for 5 hours. After cooling to 65° C., the reaction mixture was quenched by pouring into 450 ml. of ice and water, treated with activated carbon, filtered, and made strongly acidic with conc. hydrochloric acid. The precipitated product was recovered by filtration and the wet cake slurried in 100 ml. of toluene. Water was removed by azotropic distillation in vacuo. The residual slurry was taken into solution by the addition of 100 ml. acetone and warming. After clarification, the acetone was removed by evaporation in vacuo (final volume 70 ml.). Filtration gave purified 5-(2-chloro-6-methoxyoxazolidine-2,4-dione (20.3 g., m.p. 199°-202° C.). A lower melting second crop (0.9 g.) was obtained from mother liquor.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[NH:19]1[CH2:22][CH:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20]1>C(O)C>[CH3:31][N:23]([CH:21]1[CH2:20][N:19]([C:2]2[C:3]3[N:4]([N:8]=[N:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:22]1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Reactant: Clc1nccn2nnnc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CN(c2nccn3nnnc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A 2 L round bottom flask was charged with 8-chlorotetrazolo[1,5-a]pyrazine (100 g, 0.64 mol), triethylamine (195 g, 1.93 mol) and ethanol (1 L). To the above was added tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride (146 g, 0.66 mol) at 25° C. The resulting mixture was stirred at 25° C. for 1 h. Work-up: the resulting crystalline solid was collected by filtration, washed with ethanol (200 mL), and dried to afford 176 g (91%) of the product as a white solid. MS m/z: 306 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][C:6]4[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-methoxy-phenoxy)-1H-indazole (0.25 grams, 1.0 mmol), 4-fluorobromobenzene (0.23 mL, 0.36 grams, 2.08 mmol), cuprous oxide (0.15 grams, 1.0 mmol), potassium carbonate (0.29 grams, 2.08 mmol) and N,N-dimethylacetamide (0.25 mL) was stirred at 160° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0-100%), affording 1-(4-Fluoro-phenyl)-5-(4-methoxy-phenoxy)-1H-indazole as a colorless solid. MS: 335.3 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[CH2:7]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=NCc1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(NCc1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 88.7 %

Procedure:
According to the general procedure, a solution of 1-phenyl-N-(1-phenylethylidene)methanamine (50 mg, 0.24 mmol) and rac-32 (7.5 mg, 0.0048 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 72 h. Filtration of the reaction mixture and evaporation of the solvent gave 43 as a clear oil (45 mg, 88%). 1H NMR29 (300 MHz, CDCl3): δ 7.35-7.27 (m, 10H), 3.85 (q, 1H, J=6.6 Hz), 3.66 (ABq, 2H, J=13.2 Hz), 1.59 (bs, 1H), 1.39 (d, 3H, J=6.6 Hz); 13C NMR (75.5 MHz, CDCl3): δ 145.7, 140.8, 128.6, 128.5, 128.3, 127.0, 126.95, 126.8, 57.6, 51.8, 24.7.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][Si:9]([CH3:32])([C:28]([CH3:31])([CH3:30])[CH3:29])[O:10][CH2:11][C@@H:12]1[C@@H:19]2[C@@H:15]([O:16][C:17](=[O:20])[CH2:18]2)[CH2:14][C@H:13]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O.CO>[CH3:8][Si:9]([CH3:32])([C:28]([CH3:30])([CH3:29])[CH3:31])[O:10][CH2:11][C@@H:12]1[C@@H:19]2[C@@H:15]([O:16][CH:17]([OH:20])[CH2:18]2)[CH2:14][C@H:13]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
An anhydrous toluene (315 mL) solution of the compound 1 (68.4 g) was cooled to around −60° C. in a dry ice-methanol bath, and then a diisobutyl aluminum hydride/toluene solution (0.99M, 209 mL) was added dropwise over 33 minutes. The mixture was stirred for 2 hours, and then to the reaction mixture was added dropwise methanol (3.2 mL) at −65° C. over 3 minutes to stop the reaction. The reaction liquid was raised to around 0° C., and water was then added dropwise in two parts (18.5 mL+18 mL) while the mixture was stirred. Thereto was added anhydrous sodium sulfate (7.4 g), and the mixture was stirred at room temperature for 1 hour, and filtered with Celite (trade name). The solid that was filtered off was washed with tetrahydrofuran (160 mL), and concentrated to obtain a titled compound (70.7 g) having the following physical property values.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Rh].C(O)C>[O:12]1[C:8]2=[CH:7][CH:6]=[CH:5][C:4]([NH2:1])=[C:9]2[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2occc12
Agent: [Rh]
Solvent: CCO
Product: Nc1cccc2c1CCO2

Procedure:
A mixture of 3.0 g. of 4-nitrobenzofuran, 0.5 g of 5% Rhodium on carbon and 25 ml. of ethanol is hydrogenated in a Parr apparatus at a hydrogen pressure of 50 p.s.i. and temperature of 35°C. until the uptake of hydrogen ceases. The catalyst is removed by filtration and the filtrate evaporated in vacuo to obtain an oil of 2,3-dihydro-4-benzofuranamine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[C:7]([Cl:11])[C:6]=2[C:5]2[CH2:12][N:13]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:14](=[O:22])[C@H:15]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:16][C:4]=2[CH:3]=1.O.O.[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[C:7]([Cl:11])[C:6]=2[C:5]2[CH2:12][N:13]([CH2:23][C:24]([F:25])([F:26])[F:27])[C:14](=[O:22])[C@H:15]([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
(S)-Methyl 2-(4-bromo-1-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (210 mg, 0.448 mmol) was dissolved in a mixture of tetrahydrofuran (3.0 ml) and methanol (3.0 ml). Water (3.00 ml) was added to the mixture followed by lithium hydroxide hydrate (30 mg, 0.715 mmol). Reaction was warmed to 50° C. and held with stirring for 5 hours. Mixture was cooled to room temperature and allowed to stand for 64 hours. More lithium hydroxide hydrate (24.9 mg, 0.593 mmol) was added to the mixture. Reaction was warned to 50° C. and held for 3 hours. Mixture was cooled to room temperature. Organic solvents were removed from the mixture by roto-vap. Residue was diluted with water. Mixture was neutralized with 1.4 mL 1N hydrochloric acid. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as off-white solid in quantitative yield. LCMS (M−H)−=453.9.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:13]2=[O:28])=[N:9][C:8]=1[CH3:29])=O.O.[NH2:32]N>C(O)C>[CH3:29][C:8]1[N:9]=[C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[C:13]2=[O:28])[S:11][C:7]=1[C:5]1[CH:4]=[CH:3][NH:2][N:32]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1cc[nH]n1
Yield: 72 %

Procedure:
To a solution of (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one (0.44 g, 1.00 mmol) in ethanol (10 mL) was added hydrazine monohydrate (0.12 mL, 1.58 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a colorless solid in 72% yield (0.30 g): mp 212-213° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3& CD3OD) δ 7.54-7.20 (m, 5H), 6.24 (s, 1H), 4.39 (s, 2H), 3.98-3.89 (m, 2H), 3.35-3.30 (m, 2H), 2.27 (s, 3H): 13C NMR (75 MHz, CDCl3 & CD3OD) δ 156.9, 155.8, 139.8, 130.2, 129.8, 129.3, 128.2, 125.6, 125.5, 122.0, 103.8, 47.2, 41.9, 41.8, 15.7: MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CO>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([NH2:14])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Yield: 102.8 %

Procedure:
The compound (29.3 g, 123 mmol) of step A was dissolved in methanol (500 ml), ferric chloride (FeCl3) (1.73 g, 10.7 mmol) and activated carbon (4.5 g) were added and the mixture was stirred at room temperature. Then, hydrazine monohydrate (20 ml, 412 mmol) was added, and the mixture was heated under reflux for 45 min. The reaction mixture was cooled, filtered through celite, and the solution was concentrated under reduced pressure. The obtained oil was diluted with an ethyl acetate-hexane=1:1 mixed solvent (300 ml), washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (26.2 g) as a pale-yellow oil.
Reaction SMILES: F[C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[N:26]=[C:7]3[C:6]=2[C:5](F)=[CH:4][CH:3]=1.Cl.Cl.[F:38][C:39]1[C:40]([NH:45][C@@H:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]2[NH2:52])=[N:41][CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:25]1[C:24](=[O:34])[C:8]2=[CH:9][N:52]([C@@H:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C@H:46]3[NH:45][C:40]3[C:39]([F:38])=[CH:44][CH:43]=[CH:42][N:41]=3)[C:5]3[CH:4]=[CH:3][CH:2]=[C:11]([NH:10][CH2:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH:23]=[CH:22][CH:21]=[N:20]5)=[CH:15][CH:14]=4)[C:6]=3[C:7]2=[N:26]1
Reactant: N[C@@H]1CCCC[C@H]1Nc1ncccc1F
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3c(F)ccc(F)c3c-2nn1-c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2cn([C@@H]3CCCC[C@H]3Nc3ncccc3F)c3cccc(NCc4ccc(-n5cccn5)cc4)c3c-2nn1-c1ccccc1F
Temperature: 95 °C
Reaction time: 1 h

Procedure:
6,9-Difluoro-2-(2-fluorophenyl)-5-{[4-(1H pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 28, 74 mg, 0.16 mmol), (±)-trans-N-(3-fluoropyridin-2-yl)cyclohexane-1,2-diamine bishydrochloride (43 mg, 0.19 mmol, 1.2 equiv) and potassium carbonate (0.22 g, 1.6 mmol, 10 equiv) were combined in degassed dimethylsulfoxide (5 mL) and placed into an oil bath preheated at 95° C. for 1 hour. Additional (±)-trans-N-(3-fluoropyridin-2-yl)cyclohexane-1,2-diamine bishydrochloride (0.10 g, 0.44 mmol, 2.3 equiv) and potassium carbonate (0.42 g, 3.0 mmol, 16 equiv) were added and the mixture was heated at 95° C. for an additional 2 hours. The mixture was cooled to ambient temperature, filtered and purified by preparative reverse phase HPLC (eluting 70:30 to 5:95; water containing 0.1% TFA: acetonitrile containing 0.1% TFA). The appropriate fractions were poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (1×50 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a light yellowish-green solid: 1H-NMR (400 MHz, CDCl3) δ 8.73 (1H, s), 8.32 (1H, br s), 7.85 (1H, d, J=2.8 Hz), 7.77 (1H, d, J=4.6 Hz), 7.69 (1H, d, J=1.8 Hz), 7.61-7.56 (3H, m), 7.44 (2H, d, J=8.6 Hz), 7.30-7.24 (1H, m), 7.21-7.15 (2H, m), 7.11 (1H, dd, J=13.6, 9.8 Hz), 6.90 (1H, ddd, J=11.2, 7.9, 1.3 Hz), 6.83 (1H, dd, J=9.4, 3.0 Hz), 6.44 (1H, dd, J=2.4, 1.9 Hz), 6.39 (1H, ddd, J=7.9, 5.0, 3.5 Hz), 4.77-4.67 (3H, m), 4.56 (1H, br t, J=10.2 Hz), 4.35 (1H, br m), 2.33 (1H, br d, J=10.9 Hz), 2.23 (1H, br d, J=12.8 Hz), 2.01-1.79 (3H, m), 1.67-1.51 (3H, m) ppm; high resolution mass spectrometry (ES+) m/z 661.2621 [(M+H)+; calculated for C37H32F3N8O: 661.2646].