Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]([F:53])([F:52])[C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][NH2:47]>C1COCC1>[F:42][C:43]([F:52])([F:53])[C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46][NH:47][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1C(F)(F)F)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 2-trifluoromethyl-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 600.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.Cl.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@@H](O)C3)ccc12
Temperature: 120 °C
Yield: 58.7 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (1 g), (3R)-3-piperidinol hydrochloride (0.424 g) and triethylamine (1.2 mL) were placed into a 10 mL microwave vial followed by the addition of acetonitrile (3 mL). The vial was sealed and heated at 120° C. in a single mode microwave for 45 minutes. On cooling a solid crystallised from the reaction mixture which was filtered and washed with acetonitrile (10 mL) to afford the sub-title compound (0.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:12]>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([Br:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cccc(F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc(F)c1
Yield: 78.6 %

Procedure:
Dissolve (±)-1-(3-fluorophenyl)ethanol (250 mg, 1.786 mmol) in carbon tetrachloride (10 mL). Add phosphorus tribromide (0.1 mL, 1.786 mmol) at 0° C. and stir the solution at room temperature overnight. Dilute the reaction mixture with dichloromethane and wash with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain the title compound (285 mg) that was used without any further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: C[O-]
Reactant: Cc1c(N)nnc(Cl)c1C
Agent: [Na+]
Solvent: CO
Product: COc1nnc(N)c(C)c1C
Yield: 49 %

Procedure:
6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 500 mg, 3.17 mmol, 1.0 eq) in 14.51 mL of a 25% solution (w/w) of sodium methylate in MeOH was heated for 1 h at 130° C. in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried (Na2SO4 anh.). Volatile components were removed by the use of a rotary evaporator and the crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP NH2 cartridge: hexane→hexane/EtOAc 1/1) to give 250 mg (49% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Si:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cc(Cl)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1N

Procedure:
A solution of 2-amino-4-chlorophenol (14.3 g, 100 mmol), tert-butyldimethylsilyl chloride (18 g, 120 mmol) and imidazole (14 g, 200 mmol) in DMF (250 mL) was stirred at room temperature for 24 hours, concentrated, and partitioned between brine (300 mL) and ethyl acetate (300 mL). The aqueous phase was extracted with ethyl acetate. The combined phases were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 18.5 g (71.7% )of the desired product. MS (DCI/NH3) m/z 258 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 6.70 (d, J=2.71 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.57 (dd, J=2.7 and 8.5 Hz, 1H), 3.75 (br s, 2H), 1.01 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(NC(=O)CCC)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(NC(=O)CCC)cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-butanoylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]([F:24])([F:23])[C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([CH2:14][C:15](OCC)=[O:16])=O>>[OH:16][C:15]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:12]([C:11]2[CH:10]=[C:9]([C:8]([F:7])([F:23])[F:24])[CH:22]=[CH:21][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc[nH]n1
Product: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12

Procedure:
A mixture of 0.83 g. of 3-aminopyrazole and 2.61 g. of ethyl m-trifluoromethylbenzoylacetate is heated on a steam bath for 2 hours. After cooling the desired compound is collected by filtration, m.p. 305°-310° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:26][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([N+:27]([O-:29])=[O:28])[CH:3]=1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:36][O:35][C:33]([N:11]([C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:26][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:27]([O-:29])=[O:28])(=[O:10])=[O:9])=[O:34]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 112, 0.25 g) in THF (10 mL) was added dropwise with stirring to a cooled suspension of sodium hydride (0.1 g) in THF (5 mL) at 0° C. On completion of the addition, the mixture was stirred at room temperature for 30 minutes. Methyl chloroformate (0.3 g) was added dropwise and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether to give methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(4-fluoro-2-nitrobenzenesulfonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.2 g) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:36]([OH:38])=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>ClCCl>[CH:26]1[C:27]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:36]([O:38][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([CH3:7])[CH3:6])=[O:37])=[O:33])[C:29]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Reactant: C=CCOC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: ClCCl
Product: C=CCOC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Phenylpropan-2-yl 2,2,2-trichloroacetimidate separately synthesized by a conventional method (2.17 g, 7.74 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoic acid (Compound 106) (1.80 g, 4.55 mmol) in dichloromethane (40 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to afford 4-allyl 1-(2-phenylpropan-2-yl) (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)succinate (Compound 107) (2.17 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)OC(C)(C)C)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate H) (9.5 g, 29.3 mmol) and K2CO3 (2.5 eq, 10.31 g, 73.3 mmol) in a round bottom flask is treated with dry DMF. tert-Butyl bromoacetate (1.02 eq, 4.2 ml, 30 mmol) is added dropwise via syringe under argon. The reaction suspension is stirred at RT for 1 hour. The reaction mixture is diluted with distilled water and extracted with EtOAc (3×). The separated organic layer is dried over MgSO4, filtered and the solvent is concentrated in vacuo. The title compound is obtained as a brown viscous oil, crystallizing on standing.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:24]=1[CH:25]=O.C([O-])(=O)C.[NH4+]>CCO>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:30][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2CC[C@@H]1O2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4CC[C@H]3O4)c(Cl)cnc2[nH]1
Temperature: 70 °C

Procedure:
(1S,2R,3S,4R)-3-(2,3-diamino-5-chloropyridin-4-ylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide (17) (140 mg, 0.47 mmol), 2-methoxy-4-morpholinobenzaldehyde (93 mg, 0.42 mmol) were taken in EtOH (15 ml) to which ammonium acetate (40 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with hot ethanol to afford the desired product (120 mg, 51%) as an off white solid. NMR: δ (1H, 400M Hz, CDCl3): 1.50-1.80 (4H, m), 2.95 (1H, d, J=8.4 Hz), 3.27 (4H, bs), 3.76 (4H, bs), 3.96 (3H, s), 4.32 (1H, d, J=4.4 Hz), 4.57 (1H, s), 5.51 (1H, t, J=4.4 Hz), 6.63 (1H, s), 6.69 (1H, d, J=8.4 Hz), 6.90 (1H, d, J=8.4 Hz), 7.18 (1H, s), 7.60 (1H, s), 7.91 (1H, s), 8.05 (1H, d, J=8.8 Hz), 12.14 (1H, s). LCMS (254 nm): [M+H]+ 499.00 (100%). HPLC: (254 nm) 97.68%.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(F)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11FN4, 279. Found, 279.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CC(N(C)C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCNC1
Reactant: Clc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: c1ccc(N2CCCNCC2)nc1
Yield: 72.9 %

Procedure:
2-Chloropyridine (3.00 g, 26.4 mmol), DIPEA (9.20 mL, 52.8 mmol) and homopiperazine (7.90 g, 79.3 mmol) were dissolved in DMA (10 mL) and heated using a microwave (180-200° C., absorption high) for 40 min. The reaction mixture was diluted with DCM (150 mL), washed with sat aq Na2CO3 (100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (3.41 g, 72%) as a brown liquid. LCMS (ES+): 178.6 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:17][C:18]1[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([CH3:27])=[N:20][CH:19]=1>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]4[C:18]([F:17])=[CH:19][N:20]=[C:21]([CH3:27])[CH:22]=4)[CH:10]=3)[C:6]([CH3:16])([CH3:15])[C:7]2=[O:14])[CH2:12][CH2:13]1
Reactant: Cc1cc(C(=O)O)c(F)cn1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Product: Cc1cc(C(=O)Nc2ccc3c(c2)N(C2CC2)C(=O)C3(C)C)c(F)cn1

Procedure:
Prepared in analogy to example 26 from 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c) and 5-fluoro-2-methyl-isonicotinic acid (prepared according to U. Abel et al., WO200645514). The title compound was obtained as light yellow solid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29](=O)[C:28]5[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=5[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>CO>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]5=[N:42][NH:43][C:31](=[O:33])[C:27]6[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=65)[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c1)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: O=C(c1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
A mixture of methyl 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (64 mg, 0.12 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (8 mg, yield 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.73-0.81 (m, 4H), 1.18-1.19 (m, 1H), 3.20-3.71 (m, 8H), 4.23-4.25 (d, J=10.0 Hz, 1H), 4.59-4.61 (d, J=8.4 Hz, 1H), 7.08-7.26 (m, 10H), 7.45-7.54 (m, 2H); LC-MS (ESI) m/z: 520(M+1)+.
Reaction SMILES: [NH2:1][OH:2].Cl[C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12>CO.C(O)C>[OH:2][NH:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: NO
Solvent: CO
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(NO)ncnc21
Reaction time: 0.5 h

Procedure:
A solution containing 0.7 grams of anhydrous hydroxylamine in 50 milliliters of methanol was added to a solution containing 1.4 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine dissolved in 600 milliliters of ethanol, at a temperature of 30°C. and the mixture was allowed to stand for 30 minutes at room temperature. The mixture was gently heated at reflux for a further 15 minutes and cooled. The crystalline product was washed with ether and dried. Recrystallisation from dimethylformamide gave 4-hydroxyamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, having melting point 294°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13]([CH3:15])=O.N1CCCC1.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]([CH3:15])([CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1
Yield: 71 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)-ethanone (21.4 g, 0.1 mol), acetone (365 mL) and pyrrolidine (8.4 mL) in toluene (220 mL) was refluxed for 4 h. To the reaction mixture was added acetone (36.5 mL). The mixture was refluxed for 15 h. Then 1 N HCl (220 mL) was added, and the resulting mixture was extracted with ethyl acetate (200 mL, 3×). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2,2-dimethyl-chroman-4-one (18.0 g, 71%). 1H-NMR (CDCl3): 1.45 (s, 6H), 2.71 (s, 2H), 6.82 (d, 1H), 7.52 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O>>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(C)cc3)cnc21
Reactant: NO
Agent: Cl
Product: CCn1ncc2c3noc(-c4ccc(C)cc4)c3cnc21
Reaction time: 2 h
Yield: 60.7 %

Procedure:
4-Chloro-1-ethyl-5-(4-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.40 g) and hydroxylamine hydrochloride (14.0 g) were mixed dry and then suspended in a solution prepared from 200 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid. The reaction mixture was then brought to reflux with mechanical stirring. After two hours, the reaction was allowed to cool and then the acetic acid was evaporated. The residue was distributed between dichloromethane and an aqueous sodium bicarbonate solution and then the organic phase was dried and evaporated. The crude product was chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). The appropriate fractions were combined, evaporated, and then washed with pentane, giving 2.48 g of product, mp 221°-222° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>ClCCl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:6][CH:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)C(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 87.8 %

Procedure:
DL-Alanine methyl ester hydrochloride (13.96 g; 0.1 mol) is dissolved in 800 ml of dichloromethane and placed at 0° C. Triethylamine (2.3 eq.; 230 mmol; 32 ml) is added dropwise, along with portionwise addition of 2-nitrobenzenesulfonyl chloride (1 eq.; 100 mmol; 22.16 g), and the reaction medium is allowed to return to room temperature overnight. The reaction medium is washed with water and then dried over sodium sulfate, filtered through silica and evaporated to dryness to give 25.3 g of solid corresponding to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[CH3:16][N:17]([CH3:19])[CH:18]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ccc(F)cc1
Yield: 34.3 %

Procedure:
Combined ethyl 2-(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100° C. for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2% yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 3H) 2.64 (s, 6H) 3.98 (q, J=7.1 Hz, 2H) 7.06-7.15 (m, 4H) 7.49 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1)(=[O:26])=[O:25]
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of benzyl 3-hydroxycyclobutanecarboxylate (Intermediate 32; 0.90 g; 4.4 mmol), Et3N (1.20 mL; 8.6 mmol) in DCM (50 mL) was added MsCl (0.40 mL; 5.2 mmol) under nitrogen. The reaction mixture was stirred for 1 hour, quenched with water (20 mL), and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.24 g (100%) of the title compound as a yellow oil, which was used directly without further purification.