Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([CH2:6][CH:5]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:4][CH2:3][OH:2])[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: COC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(CCO)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
A solution of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyric acid methyl ester (300 mg, 0.795 mmol) in THF (5 mL) was added dropwise to a solution of LiAlH4 (93 mg, 2.37 mmol) in THF (10 mL). The reaction mixture was stirred at RT for 30 min. After consumption of starting material, the reaction mixture was cooled to −78° C. 0.2 mL of water and 0.2 mL of 15% NaOH solution was added and the reaction mixture was allowed to come to RT and diluted with THF and filtered. The filtrate was concentrated and the crude product was purified by passing through a column of silica gel (100-200 mesh) by using eluent 2% MeOH in DCM to obtain 69 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butan-1-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.48 (d, 2H), 7.18 (s, 1H), 7.1 (d, 1H), 7.01 (d, 2H), 6.97 (d, 1H), 4.2 (dd, 1H), 4.15 (dd, 1H), 3.64 (d, 1H), 3.56 (m, 2H), 3.4 (m, 2H), 2.7 (m, 3H), 2.4 (m, 1H), 2.5 (s, 3H), 2.43 (s, 3H), 1.94 (m, 2H). Separation by chiral HPLC provided enantiomers II-224a-b.
Reaction SMILES: [Li]CCCC.CC(OC(C)=O)=O.[CH2:13]([N:15]1[C:19]([C:20](=[O:22])[CH3:21])=[CH:18][N:17]=[C:16]1[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH3:14].C(N1C=CN=C1OC1C=CC(C)=CC=1)C.[BH4-].[Na+]>C1COCC1.C(=O)(O)[O-].[Na+].CO>[CH2:13]([N:15]1[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][N:17]=[C:16]1[O:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH3:14]
Reactant: CCn1c(C(C)=O)cnc1Oc1ccc(C)cc1
Agent: CCn1ccnc1Oc1ccc(C)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(C(C)O)cnc1Oc1ccc(C)cc1
Temperature: -100 °C
Reaction time: 3.5 h

Procedure:
To a solution of the compound obtained in Example 1-(2) (2.493 g) in THF (123 ml), n-BuLi (4.8 ml, 2.59 N in hexane) was added dropwise at −78° C. under an argon atmosphere and stirred at the same temperature for 3.5 hours. The reaction mixture was cooled to −100° C., mixed with Ac2O (2.3 ml), warmed to −65° C. over 50 minutes, diluted with saturated aqueous sodium bicarbonate, and extracted with AcOEt. After washing with brine, the organic layer was dried over MgSO4, filtered and then evaporated to remove the solvent. The resulting crude product was purified by column chromatography (NH-type silica gel, AcOEt/hexane=10% to 30%) to give a mixture of 1-(3-ethyl-2(4-methylphenoxy)-3H-imidazol-4-yl)-ethanone and 1-ethyl-2(4-methylphenoxy)-1H-imidazole (1.509 g, colorless oil). To a solution of the resulting compounds (1.508 g) in MeOH (13 ml), NaBH4 (243 mg) was added at 0° C. and stirred at the same temperature for 15 minutes and then at room temperature for 15 minutes. The reaction mixture was concentrated, diluted with water, and extracted with AcOEt. After washing with brine, the organic layer was dried over MgSO4, filtered and then evaporated to remove the solvent. The resulting crude product was purified by column chromatography (NH-type silica gel, AcOEt/hexane=20% to 99%) to give the titled compound (1.131 g, colorless oil).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH2:15][C:16]#[N:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([N+:18]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[NH2:17][C:16]1[CH2:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N:18]=1
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1[N+](=O)[O-])CC#N
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Temperature: 90 °C
Yield: 58 %

Procedure:
To a solution of (E)-ethyl 3-(4-bromo-2-nitrophenyl)-2-(cyanomethyl)acrylate (1.00 g, 2.9 mmol) in acetic acid (25 mL) was added iron powder (1.10 g, 19.0 mmol). The mixture was heated to 90° C. for 5 hours. Upon cooling the acetic acid was removed under vacuum and the resulting semisolid was dissolved in 50% K2CO3 (100 mL) and EtOAc (100 mL). The mixture was filtered to remove insoluble material and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The combined organics were dried and concentrated. The concentrate was purified via flash chromatography (Biotage 40 m, 5% MeOH/CH2Cl2) to yield (1E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate (0.52 g, 57%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([CH3:14])[CH:7]=1.CN(C)C=O>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[C:8]([CH3:14])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ccc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 0 °C
Yield: 100 %

Procedure:
Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0° C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH:5]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][O:11][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH:5]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc(CO)cc(-c2cccc(C#N)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccccc2)cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
30 mg of the 3-(3-cyanophenyl)-5-(hydroxymethyl)benzoic acid methyl ester produced in the production example 4 was dissolved in dry THF in the atmosphere of nitrogen, mixed with 10.5 mg of phenol, 35.4 mg of triphenylphosphine and 21 μl of azodicarboxylic acid diethyl ester at room temperature, and then stirred at room temperature overnight. The solvent was distilled away, and the residue was purified by silica gel chromatography to obtain 31 mg (77%) of the title compound (colorless, crystal).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCC(C)C.C(N([CH2:26][CH3:27])CC)C>>[CH2:1]([O:20][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:26][CH3:27])[CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCN(CC)CC
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCOC(C)CCCCCC
Temperature: 130 °C
Yield: 5000 %

Procedure:
To 32 g (0.1 mole) of isostearic acid there is added 0.3 ml (0.002 mole) of triethylamine. The resulting mixture is heated to 130° C. under a nitrogen atmosphere and there are slowly added thereto 40 g (0.1 mole) of 2-octyl dodecyl ether of glycidyl obtained according to the above method. After heating for 3 hours and 15 minutes at 130° C., the amount of the reaction determined by acid index is 93%.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>C1COCC1>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCn1ccnc1)O2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.3 %

Procedure:
A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 mL THF was treated with 358 mg CDI and stirred for 1.25 h at room temperature. To this clear yellow solution was added a solution of 278 mg 1-(3-aminopropyl)imidazole in 10 mL THF over 1 h. The solution was stirred overnight at room temperature, concentrated to a pale brown oil, dissolved into 70 mL CH2Cl2, washed 1×50 mL saturated NaCl, and dried over Na2SO4. The organic layers were concentrated and flashed chromatographed to yield 524 mg of N-(3-(1H-imidazol-1-yl)propyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[N:9]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])[C:10]([OH:12])=[N:11][C:6]2=[N:5][CH:4]=1)=[CH2:2]>[Pd].CO>[C:15]1([C@@H:13]([N:9]2[C:7]3=[N:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=[C:6]3[N:11]=[C:10]2[OH:12])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Agent: [Pd]
Solvent: CO
Product: CCc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Yield: 86 %

Procedure:
A scintillation vial equipped with a stirbar was charged with (S)-6-vinyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), methanol (280 volume equivalents), and catalytic Pd/C. The resulting mixture was purged with hydrogen for 45 minutes; the reaction was complete as judged my LCMS. The mixture was then filtered through a pad of diatomaceous earth and the pad of diatomaceous earth was washed twice with MeOH. The solution was concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (86%) as a foam. LCMS m/z (APCI)=269.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1)[CH3:2].Br[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1>>[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH:4]=1)[CH3:2]
Reactant: BrCC1CCCO1
Reactant: CCc1cnc(N)s1
Product: CCc1cn(CC2CCCO2)c(=N)s1

Procedure:
A mixture of 5-ethylthiazol-2-amine and 2-(bromomethyl)tetrahydrofuran were processed using the method described in Example 2A to afford the title compound. MS (ESI) m/z 213 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:23]=[C:11]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:23]=[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)C3)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-n2cc3c(n2)CCNC3)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(6-methylpyridazin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.38 g, 7.55 mmol) in dioxane (20 ml) is added 4N HCl in dioxane (20 mL, 80 mmol) and the mixture is stirred at rt overnight. The solvent is removed and the residue is washed with ether to give the title compound as a white solid. MS (M+1): 216.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=2)[C:7]=1[F:39].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[C:7]=1[F:39]
Reactant: COC(=O)COc1ccc(F)c(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(-c4cccnc4)cc23)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To [2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-acetic acid methyl ester (550, 40.0 mg, 0.071 mmol, prepared as described in Example 65, Scheme 46) in tetrahydrofuran (5.0 mL) was added tetra-n-butylammonium fluoride (22.2 mg, 0.085 mmol). The reaction was stirred at room temperature for 10 minutes. The crude compound was concentrated with silica gel and purified by silica gel column chromatography eluting with 3% methanol in methylene chloride to give the compound as white solid (P-1465, 20 mg, 69%). MS (ESI) [M+H+]+=410.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-aminoethanol using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.42 (1H, b), 8.53 (1H, s), 8.25 (1H, s), 7.21-7.26 (2H, m), 6.97 (2H, t, J=8 Hz), 4.38 (2H, t, J=7 Hz), 4.15 (2H, s), 3.86 (2H, t, J=5 Hz), 3.49-3.66 (4H, m), 3.35 (2H, b), 2.85 (1H, t, J=5 Hz), 2.35 (2H, b), 1.72-1.76 (4H, m); ES+ MS: 483 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[CH2:6][CH2:7][CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O>CCO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: COCCN(C)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: COCCN(C)CCCN
Temperature: 5 °C
Yield: 95.2 %

Procedure:
A solution of phthalimide 298 (50.0 g, 181 mmol) and N2H4—H2O (17.5 mL, 362 mmol) in EtOH (500 mL) was stirred at reflux temperature for 2 h. The solution was cooled to 5° C. for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5° C. for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated. The residue was dissolved in 1 M HCl (50 mL), washed with Et2O (2×50 mL) and the pH of the aqueous fraction adjusted to 10 with dilute aqueous NH3 solution. The mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 299 (Sandberg, R., et al., Acta Pharmaceutica Suecica 1979, 16, 386-395) as a pale yellow oil (25.2 g, 95%) which was used without further purification: 1H NMR [(CD3)2SO] δ 3.38 (t, J=6.0 Hz, 2H, CH2O), 3.21 (s, 3H, OCH3), 2.60 (t, J=6.8 Hz, 2H, CH2N), 2.46 (t, J=6.0 Hz, 2H, CH2N), 2.36 (t, J=7.0 Hz, 2H, CH2N), 2.14 (s, 3H, NCH3), 1.50 (p, J=7.0 Hz, 2H, CH2), NH2 not observed; HRMS (Cl+) calcd for C7H17N2O (M-H+) m/z 145.1341, found 145.1337.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:50])[C@@H:18]([NH:28][C:29]([C:31]2[CH:35]=[C:34]([O:36][CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[N:33]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:32]=2)=[O:30])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][C@H:18]([NH:28][C:29]([C:31]1[CH:35]=[C:34]([O:36][CH2:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[N:33]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:32]=1)=[O:30])[C:17](=[O:50])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)N1CCNCC1
Reaction time: 24 h
Yield: 115.7 %

Procedure:
To a solution of 4.4 g 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid benzyl ester in 40 ml ethanol were added 0.9 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 24 h. It was filtrated, washed with ethanol and the solvent evaporated to give the title compound as colorless oil (4.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]([C:24](=O)[CH3:25])[CH2:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].Cl.[NH2:28]O>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]3[O:23][N:28]=[C:24]([CH3:25])[C:21]=3[CH2:20][CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1-c1onc(C)c1CCC2
Temperature: 100 °C
Yield: 76 %

Procedure:
In a sealed tube were 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and hydroxylamine hydrochloride (2.2 mmol) and 10 mL EtOH. The mixture is heated at 100° C. for 16 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 3-methyl-4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester as a white solid (76%). 1H NMR (CDCl3+CD3OD) 1.3 (t, 3H), 1.90-1.98 (m, 2H), 2.10 (s, 3H), 2.35 (t, 2H), 2.75-2.82 (m, 2H), 4.21 (q, 2H), 7.15 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[NH:13][CH3:14].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[NH:13][CH3:14]
Reactant: ClCCCBr
Reactant: CNc1cc(C(C)=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 134.5 %

Procedure:
To a stirred suspension of sodium hydride (0.87 g, 18.2 mmol of a 50% oil dispersion) in dimethylformamide (25 ml) under nitrogen and cooled to 0° in an ice-salt bath was added, dropwise, a solution of 1-(4-hydroxy-3-methylamino-phenyl)ethanone (3.0 g, 18.2 mmol) dissolved in dimethylformamide (55 ml) so that the temperature did not rise above 3° C. After the addition was complete, the reaction was stirred for 80 minutes at ambient temperature. The reaction was cooled to 5° C. and a solution of 1-bromo-3-chloropropane (3.1 g, 0.0120 mol) in dimethylformamide (20 ml) was added dropwise. After this addition was complete, the ice bath was removed and the reaction was stirred at ambient temperature for 2.5 hours. Water (75 ml) was carefully added and after stirring vigorously for 5 minutes, the reaction was left to stand overnight. The aqueous mixture was extracted with ethyl acetate and the ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 3.9 g of a dark solid. The compound was purified by preparative HPLC to afford 2.4 g of a beige solid. This was combined with an additional sample (3.8 g total) and two consecutive recrystallizations from ethanol gave 2.1 g (31%) of 1-[4-(3-chloropropoxy)-3-methyl-aminophenyl]ethanone as a fluffy, beige solid, m.p.=115°-117° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)#[N:2]>N.CO.CO.[Ni]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:4][CH2:3][CH2:1][NH:2][C:6]2=[O:8])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CCC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 90A (560 mg, 1.700 mmol) as a solution in 7 M ammonia/methanol (20 mL) was added to solvent-washed Raney®-nickel (2800 mg, 47.7 mmol) in a 250 mL stainless steel pressure bottle and stirred at room temperature for 24 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane and was concentrated. The residue was dissolved in methanol/dichloromethane (1:1), filtered and concentrated to give a solid which was slurried in methanol, filtered and dried to give the title compound. MS (DCI) m/z 288 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CN(C)C=O.CS(O[CH:17]1[CH2:20][CH:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:22]([O:21][CH:19]1[CH2:18][CH:17]([N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Ic1cn[nH]c1
Reactant: CS(=O)(=O)OC1CC(OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(C2CC(OCc3ccccc3)C2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A 250-mL round-bottom flask was charged with 4-iodo-1H-pyrazole (1.97 g, 10.2 mmol), N,N-dimethylformamide (20 mL), 3-(benzyloxy)cyclobutyl methanesulfonate (2.60 g, 10.2 mmol) and cesium carbonate (9.75 g, 29.9 mmol), and the resulting mixture stirred overnight at 80° C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole (3.00 g, 83%) as yellow oil. MS (ESI, pos. ion) m/z 355 [M+H]+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[CH3:33][NH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][CH:35]([NH:34][CH3:33])[CH2:36]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)c(N)n4)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 101 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 82 mg of the title compound as a colorless powder.