Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[C:1]([O:5][C:6]([C:7]1[C:8]([C:17]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=2[F:15])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Compound A (22.8 g, 88.6 mmol) and 2-fluoro-4-methylphenylboronic acid (15.0 g, 97.4 mmol) were suspended in isopropyl alcohol (75 mL, 980 mmol). A solution of sodium carbonate (16 g, 150 mmol) in water (75 mL, 4.2 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (1.0 g, 880 μmol) was then added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, EtOAc (200 mL) and water (200 mL) were added, and the mixture was filtered. The liquor was extracted with EtOAc (2×100 mL), washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography (0-15% EtOAc in hexanes) to yield compound B as a colorless oil (14.9 g, 96% purity).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OC2CCCC2)nc1
Temperature: 80 °C

Procedure:
A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 ml) was heated at 80° C. for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy-5-nitropyridine) was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N20); MS (ESI): 179 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Reactant: c1ccc2c(c1)CCN2
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cccc(Cl)c1)N1CCc2ccccc21
Temperature: 5 °C
Reaction time: 48 h
Yield: 86.1 %

Procedure:
Triethylamine (9.2 ml) was added at room temperature to a solution of indoline (20 g) in DCM (200 ml) and the mixture was cooled till 5° C. A solution of m-chloro-cinnamoyl chloride (40 g) in DCM (100 ml) was added dropwise and the mixture was stirred at room temperature for 48 hours. Water was added, the organic layer was decanted, washed with water, dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate 90/10), yielding 41 g (73%) of 1-[3-(3-chlorophenyl)-1-oxo-2-propenyl]-2,3-dihydro-1H-indole (interm. 37).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCCc2ccccc21

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: CO.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][C:6](=[N:21]O)[C:5]1=[O:23]>C(O)C.[Ni]>[NH2:21][CH:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5]1=[O:23]
Reactant: Cn1c(=O)c(=NO)nc(-c2ccccc2)c2ccccc21
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reaction time: 30 h
Yield: 95 %

Procedure:
A solution of 150 ml of methanol containing 5 g (17.9 mmole) of 1,3-dihydro-1-methyl-3-oximino-5-phenyl-1,4-benzodiazepin-2-one was treated with a slurry of active Raney-nickel catalyst1 in ethanol (10 g wet weight). The resulting suspension was hydrogenated on a Parr apparatus at 60 psi and 23° C. for 30 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford the title compound in 95% yield.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:22]2[CH2:27][CH2:26][C:25]([CH2:34][C:35]([CH3:37])=[CH2:36])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:38])([CH3:21])[CH3:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:22]2[CH2:27][CH2:26][C:25]([CH2:34][C:35]3([CH3:37])[CH2:36][O:9]3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:24][C:23]2=[O:38])([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(Br)cc2)C(=O)O1
Solvent: ClCCl
Product: CC1(CC2(c3ccccc3)CCN(C(C)(C)c3ccc(Br)cc3)C(=O)O2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of m-CPBA (49.2 mg, 285 μmol) in CH2Cl2 (10 mL) was added 3-(2-(4-bromophenyl)propan-2-yl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (61 mg, 142.5 μmol). The reaction mixture was stirred at rt for 1 h. The solution was washed with 30 wt % aqueous sodium thiosulfate (50 mL×3), saturated aqueous sodium bicarbonate and brine successively. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-(2-(4-bromophenyl)propan-2-yl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (57 mg, 90%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7].S(Cl)([Cl:19])=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][Cl:19])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccco1)N1CCN(CCO)CC1
Product: O=C(c1ccco1)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
Dissolved in 20 ml of thionyl chloride was 1.76 g of 1-(2-furanylcarbonyl)-4-(2-hydroxyethyl)piperazine. The resulting mixture was stirred at room temperature for 7.5 hours. The thionyl chloride was distilled off under reduced pressure and the residue was poured into cold water. After alkalinization of the resulting aqueous solution with sodium carbonate, the solution was extracted with benzene and the benzene layer was washed with water. The benzene layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure to give 1.2 g of an oily substance. The reaction product was provided for the next step in its unpurified form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.Cl.[C:15](OCC)(=O)C.Cl.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]3[CH2:8][CH2:9][NH:10][CH2:15][C:6]=3[NH:5]2)=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: NCCc1c[nH]c2cc(F)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c3c([nH]c2c1)CNCC3
Temperature: 25 °C
Yield: 68 %

Procedure:
6-Fluorotryptamine (0.71 g) was dissolved in tetrahydrofuran (30 ml), a 4N hydrochloric acid-ethyl acetate solution (1.2 ml) was added dropwise, and the mixture was stirred at room temperature. The solvent was evaporated under reduced pressure. Glyoxylic acid monohydrate (Aldrich Co., 403 mg), a 1N potassium hydroxide solution (3.98 ml) and water (80 ml) were added to the obtained residue, and the mixture was stirred with heating at 80° C. for 1.5 hr. After ice-cooling, the precipitate was collected by filtration and washed with water to give a pale-brown solid. Water (80 ml) and concentrated hydrochloric acid (2 ml) were added to the obtained solid, and the mixture was stirred with heating at 80° C. for 1 hr. Concentrated hydrochloric acid (2 ml) was further added, and the mixture was heated under reflux for 1 hr. The insoluble material was hot filtrated, and the filtrate was adjusted to pH 12 or above with a 6N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water, and dried to give 7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline (516 mg, yield 68%).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1)([O-:15])=[O:14].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:27]([C:25]3[O:26][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N+:13]([O-:15])=[O:14])=[CH:23][CH:24]=3)=[O:28])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-nitrophenyl)-2-furoic acid (Aldrich) according to methods A and C; yield 86 mg, 0.21 mmol (59%): 1H NMR (300 MHz, methanol-d4) δ 2.01 (d, J=13 Hz, 2H), 2.19-2.37 (m, 3H), 2.43 (s, 2H), 3.58 (s, 2H), 3.67 (s, 4H), 4.42 (s, 1H), 6.97 (d, J=4 Hz, 1H), 7.28 (d, J=3 Hz, 1H), 7.62 (dt, J=8, 1 Hz, 1H), 7.73 (dt, J=8, 1 Hz, 1H), 7.82 (dd, J=8, 1 Hz, 1H), 7.93 (dd, J=8, 1 Hz, 1H); MS (DCI/NH3) m/z 368 (M+H)+; Anal. C20H21N3O4.HCl.0.2H2O: C, H, N.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])=[CH:18][CH:19]=1)(=[O:37])=[O:36]
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (19%); 1H NMR (d6-DMSO) δ 12.56 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.69-7.53 (m, 3H), 7.39-7.08 (m, 13H), 6.85 (d, J=8.1 Hz, 2H), 6.47 (d, J=15.8 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 528 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([OH:30])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@H:41]([N:45]2[CH:49]=[CH:48][N:47]=[N:46]2)[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO.O>[C:53]([O:52][C:51]([NH:50][C@H:40]1[C@@H:41]([N:45]2[CH:49]=[CH:48][N:47]=[N:46]2)[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1)=[O:57])([CH3:54])([CH3:55])[CH3:56]
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (9.6 mg, 0.024 mmol), tert-butyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-3-yl]carbamate (8.0 mg, 0.021 mmol), and HATU (26 mg, 0.07 mmol) in DMF (0.23 mL), DIPEA (0.014 mL, 0.083 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with MeOH and H2O, then filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a bright yellow powder (5.4 mg, 33%). LCMS calc. for C40H47N10O6 (M+H)+: m/z=763.4. Found: 763.3.
Reaction SMILES: [CH:1]1([C:4]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-])=O)=[CH:21][CH:20]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.[H][H]>[Ni].CO.C1COCC1>[CH:1]1([C:4]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])=[CH:23][CH:24]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4[N+](=O)[O-])cc3)c2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4N)cc3)c2n1
Yield: 168.7 %

Procedure:
A solution/suspension of 1.59 g methyl 2-cyclopropyl-7-methyl-3-[(2'-nitrobiphen-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxylate and/0.5 g Raney Nickel in 30 mL methanol and 150 mL THF was stirred under 1 atm hydrogen for 2.5 hours. The mixture was filtered through Celite, stripped of solvent in vacuo, then was chromatographed on silica gel under medium pressure using 10% ethyl acetate in hexanes to give 2.50 g (17% yield) of the title compound as a light yellow crystalline solid. Rf 0.24 in 20% EtOAc/hexanes, visualized by UV, iodine, and ammonium molybdate/ceric sulfate stain.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([NH:18][NH2:19])=O>CO>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[NH:19][N:18]=1
Reactant: N#Cc1ccncc1
Reactant: NNC(=O)c1cnccn1
Agent: [Na]
Solvent: CO
Product: c1cc(-c2nc(-c3cnccn3)n[nH]2)ccn1
Temperature: 260 °C
Reaction time: 0.5 h

Procedure:
Sodium (0.4 grams) is added to pyridine-4-carbonitrile (8.3 grams, 0.08 mole) in methanol, and the solution is allowed to stand 30 minutes at room temperature. A suspension of pyrazine carboxylic acid hydrazide (9.6 grams, 0.07 mole) in methanol (160 ml.) is added, and the resulting solution is heated at reflux for 30 minutes. After cooling, the intermediate acylamidrazone is collected by filtration. The acyclic intermediate is then heated at 260° C. for 15 minutes, after which the reaction is cooled to room temperature. Upon recrystallization from acetonitrile-water, 3-pyrazinyl-5-(4-pyridyl)-1,2,4-triazole is obtained, m.p. 251°-252.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:12]([CH2:13][C:14]([OH:16])=O)=[C:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]=[C:7]3[N:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:25][NH2:26]>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:12]([CH2:13][C:14]([NH:26][CH3:25])=[O:16])=[C:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]=[C:7]3[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cn1c2cc(Cl)ccc2n2c(CC(=O)O)c(-c3ccccc3)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nc2n(C)c3cc(Cl)ccc3n12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A suspension of 1.7 g (0.005 mol) of 7-chloro-9-methyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.3 g (0.008 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred at 40° C. for 2 h. The solution obtained is treated with an excess of dry gaseous methylamine and stirred for 72 h. The solvent is evaporated under reduced pressure. The residue is treated with 50 ml of water. The insoluble matter is separated by filtration, washed with water and then dried. 1.66 g of solid are obtained which are purified by silica gel chromatography, eluting with a dichloromethane/methanol 95/5 mixture. The product is recrystallized from an N,N-dimethylformamide/water 75/25 mixture and then dried. 1.27 g of solid are obtained. Melting point: 274°-275° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([NH2:18])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].CO[CH:21](OC)[CH2:22]Br>COCCOCCOC>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([C:16]2[O:17][CH:21]=[CH:22][N:18]=2)=[CH:10]1)[CH3:15]
Reactant: COC(CBr)OC
Reactant: CCn1cc(C(N)=O)c2ccc(C(=O)OC)cc21
Solvent: COCCOCCOC
Product: CCn1cc(-c2ncco2)c2ccc(C(=O)OC)cc21
Temperature: 125 °C
Yield: 45.5 %

Procedure:
A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) is heated at 125° C. for 2 h. The reaction mixture is cooled and partitioned in H2O and EtOAc. The organic phase is dried and concentrated and the product is purified by silica gel chromatography (EtOAc/CH2Cl2 5-10%). The product containing fractions are combined and concentrated and the solid is triturated with hexanes to yield methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][NH2:12].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C(O)(=O)C>[CH3:17][C:15]1[CH2:14][C:13](=[O:18])[N:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[N:12]=1
Reactant: NNc1ccc2c(c1)CCCC2
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Temperature: 100 °C
Yield: 56.3 %

Procedure:
(5,6,7,8-Tetrahydro-naphthalen-2-yl)-hydrazine 7b (2.0 g, 12.3 mmol) was dissolved in 50 mL of acetic acid followed by addition of ethyl acetoacetate (1.57 mL, 12.3 mmol). The reaction mixture was heated to 100° C. overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 7c (1.58 g, yield 56.2%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH:18]([C:23](OC)=[O:24])[C:19](OC)=[O:20].[BH4-].[Na+].[Cl-].[Li+]>C(O)C.C1COCC1>[OH:24][CH2:23][CH:18]([C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:2]=1[F:1])[CH2:19][OH:20]
Reactant: COC(=O)C(C(=O)OC)c1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1ccc(C(CO)CO)c(F)c1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-(phenoxycarbonylamino)phenyl)malonate (3.0 g, 8.31 mmol, 1.0 eq) in ethanol (15 mL) and THF (15 mL) was added NaBH4 (621 mg, 16.62 mmol, 2.0 eq) followed by lithium chloride (705 g, 16.62 mmol, 2.0 eq) at 0° C. and the mixture was stirred at 0° C. for 5 h. The solvent was evaporated and the residue diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by CC using MeOH/DCM (1:19) as eluent to get phenyl 4-(1,3-dihydroxypropan-2-yl)-3-fluorophenylcarbamate (482 mg, 19%, white solid; TLC system: MeOH/DCM (1:9), Rf: 0.6)
Reaction SMILES: Br[CH:2]([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:26][NH:27][CH3:28].C1COCC1>C(OCC)C>[CH3:26][N:27]([CH3:28])[CH:2]([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCC(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1)N(C)C

Procedure:
A solution of 7.9 g (0.0195 mol) of 2-bromo-1-{4-[4-(2-hydroxy-2-methyl-propionyl)-phenoxy]-phenyl}-butan-1-one in diethyl ether was added drop wise to a solution of 58.5 ml of dimethylamine 2M in THF (0.117 mol), maintaining the temperature between 0° C. and 5° C. After one night the reaction was diluted with ether, washed three times with water, dried with sodium sulphate and evaporated obtaining 7.47 g of an oil used without purification in the following step.