Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].Cl.[CH3:9][O:10][C:11](=[O:17])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH2:13].C(N(CC)CC)C>C1COCC1>[CH3:9][O:10][C:11](=[O:17])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH:13][C:6]([NH:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:7]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C=NCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)NCCCCl)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloropropylisocyanate (0.31 mL, 3.0 mmol) was added to a slurry of L-valine methyl ester hydrochloride (0.5 g, 3.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred for 4 hours at room temperature and was then quenched with the addition of aqueous sodium bicarbonate. The quenched reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried and evaporated to give the desired product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[S:35]1[C:39]([CH2:40]O)=[CH:38][N:37]=[CH:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:40][C:39]3[S:35][CH:36]=[N:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: OCc1cncs1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2cncs2)cc1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), thiazol-5-ylmethanol (18.43 mg, 0.160 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(thiazol-5-ylmethoxy)phenyl)pyridin-3-yl)acetic acid (14.1 mg, 0.026 mmol, 49.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.03 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.17-7.09 (m, 2H), 7.09-7.03 (m, 1H), 5.83 (s, 1H), 5.54-5.40 (m, 2H), 3.28 (d, J=10.3 Hz, 1H), 2.78 (t, J=11.0 Hz, 1H), 2.43 (s, 3H), 2.17 (d, J=10.3 Hz, 1H), 2.06 (s, 3H), 1.97-1.82 (m, 1H), 1.49 (br. s., 1H), 1.28 (d, J=12.1 Hz, 1H), 1.17 (d, J=11.7 Hz, 1H), 1.13 (s, 9H), 1.01 (d, J=9.9 Hz, 1H), 0.85 (br. s., 3H), 0.58 (s, 3H). LCMS (M+H)=538.5.
Reaction SMILES: C1C(=O)[N:5](Br)[C:3](=O)C1.[Cl:9][C:10]1[C:11]([O:17][CH3:18])=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[C-]#N.[K+]>C(Cl)(Cl)(Cl)Cl.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:10]1[C:11]([O:17][CH3:18])=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][C:3]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1c(Cl)cccc1CC#N
Reaction time: 16 h
Yield: 81.1 %

Procedure:
39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide are added to 31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CCl4. It is refluxed over 16 hours, allowed to cool and filtered. Solvent is removed from the filtrate, and the filtrate is dissolved in 214 ml of N,N-dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of potassium cyanide is added at 0° C. and stirred over 16 hours. The reaction mixture is diluted with water and extracted several times with tert-butyl-methyl ether. The organic phase is washed several times with saturated sodium chloride solution and dried on sodium sulfate. The solvent is removed in a vacuum and after chromatographic purification on silica gel (hexane/ethyl acetate 20%), 29.7 g of product is obtained.
Reaction SMILES: [CH:1]1[CH:14]=[C:13]([NH2:15])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([S:9]([OH:12])(=[O:11])=[O:10])[C:3]=2[CH:2]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:23]([NH:15][C:13]1[CH:14]=[CH:1][CH:2]=[C:3]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:9]([OH:12])(=[O:10])=[O:11])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc2c(S(=O)(=O)O)cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2c(S(=O)(=O)O)cccc12)c1ccccc1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 1-naphthylamine-5-sulfonic acid (2 g, 8.9 mmol) in dichloromethane (5 mL), was added triethylamine (1.87 mL, 13.4 mmol). Benzoyl chloride (1.14 ml, 9.85 mmol) was added and the resultant solution was stirred at room temperature overnight. The reaction mixture was quenched by pouring into ice water, and the product was extracted into ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide crude intermediate 43 as a white solid that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: COC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.3 g, 1.234 mmol) in DCM (5 ml) EDCI (0.284 g, 1.48 mmol) and HOBt (0.2 g, 1.48 mmol) were added at about 0° C., after 10 minutes methyl 3-aminopropanoate hydrochloride (0.254 g, 2.47 mmol) and Et3N (0.9 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as solid. Wt: 0.336 g; Yield: 88.9%; 1H NMR (300 MHz, CDCl3): δ 5.89 (brs, 1H), 4.79 (d, 1H, J=8.1 Hz), 3.88-3.73 (m, 1H), 3.70 (s, 3H), 3.59-3.42 (m, 2H), 2.54-2.51 (m, 2H), 2.39-2.20 (m, 2H), 2.11-1.99 (m, 1H), 1.43 (s, 9H), 1.26 (s, 3H), 0.87 (s, 3H); Mass: [M+Na]+ 351 (100%); IR (KBr, cm−1): 3359, 3319, 2973, 1737, 1696, 1667, 1539, 1454, 1366, 1271, 1254, 1176, 1051, 1024, 782, 683; M.R: 98.6° C.-100.2° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)[CH:10]=[CH:9]1.C(N(CC)CC)C.[C:37](Cl)(=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:38][C:37]([N:27]1[CH2:26][CH2:25][N:24]([C:16]2[N:15]=[C:14]([O:13][C@@H:11]3[CH2:12][C@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:9]=[CH:10]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:29][CH2:28]1)=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C1=C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)C[C@@H]1OC1CCCCO1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](OC4CCCCO4)C3)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]-2-(1-piperazinyl)quinazoline (11.07 g) in dry methylene chloride (110 ml) is added triethylamine (7.75 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (4.40 ml) in dry methylene chloride (20 ml). The mixture is stirred under ice-cooling for one hour. The reaction mixture is washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]quinazoline (12.57 g) as oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18]CC)=[O:17])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+].Cl>O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the product of Step A was added ethanol (25 mL) followed by a solution of NaOH (1.93 g, 48.3 mmol) in water (25 mL). The reaction was stirred at ambient temperature for 1.5 hours. To the mixture was added dropwise 1 N HCl (95 mL), and the mixture was stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×20 mL), and dried in a vacuum oven at 45° C. overnights to give 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.71 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.8, 1.9, 1.1 Hz, 1H), 8.15 (dt, J=7.8, 1.4 Hz, 1H), 8.34 (t, J=1.7 Hz, 1H), 10.98 (s, 1H), 13.54 (s, 1H); MS (ESI) m/z 344 (M−H)−.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)#[N:2].[O:8]([CH2:15][CH2:16][CH2:17]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: BrCCCOc1ccccc1
Reactant: N#CC1CCCN1
Product: N#CC1CCCN1CCCOc1ccccc1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 2-cyanopyrrolidine [Helv. Chim. Acta 50(8), 2520-2531 (1967)] and 3-phenoxypropyl bromide.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1([F:20])[CH2:16][CH:15]1[C:17](O)=[O:18].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17]([CH:15]3[CH2:16][C:14]3([F:20])[F:13])=[O:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)C1CC1(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol; Example 1, Step H), 2,2-difluorocyclopropanecarboxylic acid (212 mg, 1.74 mmol), and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (5 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol). The mixture was stirred at room temperature for 18 hours. 2M LiOH.H2O (3 mL) was then added to the mixture and stirred for 30 minutes. Water (10 mL) was added, and the formed solid was filtered, washed with additional water (3×5 mL), and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide (158 mg, 54% yield) as a solid. LCMS (APCI+) m/z 334, 336 (M+H)+.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][CH:11]([CH2:24][CH2:25][NH:26]CC2C=CC(OC)=CC=2)[CH2:12][CH2:13][NH:14]CC2C=CC(OC)=CC=2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][CH2:10][CH:11]([CH2:24][CH2:25][NH2:26])[CH2:12][CH2:13][NH2:14]
Reactant: COc1ccc(CNCCC(CCNCc2ccc(OC)cc2)CCNCc2ccc(OC)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCCC(CCN)CCN
Reaction time: 5 h
Yield: 49.7 %

Procedure:
1,1,1-tris[2(p-methoxybenzylamino)ethyl]methane (20.0 gram, 0.036 mol) was dissolved in methanol (100 ml) and Pd(OH)2 (5.0 gram) was added. The mixture was hydrogenated (3 bar, 100° C., in an autoclave) and stirred for 5 hours. Pd(OH)2 was added in two more portions (2×5 gram) after 10 and 15 hours respectively. The reaction mixture was filtered and the filtrate was washed with methanol. The combined organic phase was evaporated and the residue was distilled under vacuum (1×10−2, 110° C.) to give 2.60 gram (50%) of 1,1,1-tris(2-aminoethyl)methane identical with the previously described Example 1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: C=Cc1ccc(-c2ccc(-c3ccc(OCCC)c(F)c3F)cc2)[se]1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc(-c3ccc(CC)[se]3)cc2)c(F)c1F

Procedure:
3.0 g (5.0 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)-5-vinylselenophene are hydrogenated in 90 ml of ethyl acetate/toluene (2:1), in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=2:1). The further purification is carried out by recrystallisation from n-heptane. 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)-5-ethylselenophene is obtained as a solid having an m.p. of 126° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:43]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[N:20]([CH3:43])[C:19](=[O:31])[C:18]=1[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3n(C)c2=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (100 mg in 3.5 mL N,N-dimethylformamide) at 0° C. was added 7.6 mg sodium hydride and the mixture stirred for 1 hour at low temperature. At this time, 0.012 mL iodomethane were added continued stirring. After 30 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was washed with water and brine then dried over magnesium sulfate to give the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([NH:12]C(=O)OC)=[N:5][C:4]=2[CH:3]=1.CC(O)=O>[OH-].[Na+]>[NH2:12][C:6]1[NH:7][C:8](=[O:11])[C:9]2[NH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N:5]=1
Reactant: COC(=O)Nc1nc2cc(C)[nH]c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc2nc(N)[nH]c(=O)c2[nH]1
Temperature: 55 °C
Yield: 90.7 %

Procedure:
To a 200 mL round bottomed flask was added 7 (1 g, 4.5 mmol) suspended in 1 N NaOH (35 mL). The reaction mixture was heated at 55° C. for 3 h. The resulting solution was cooled in an ice bath and neutralized with AcOH. The precipitated solid was collected by filtration, washed with brine, and dried in vacuo to afford 0.67 g (92%) of 8 as a white solid: mp 252-254° C.; TLC Rf0.15 (MeOH/CHCl3, 1:5); 1H NMR (DMSO-d6) δ 2.20 (s, 3 H), 5.65 (s, 1 H), 5.65 (s, 2 H), 10.21 (s, 1 H), 11.15 (s, 1 H). Anal. (C7H8N4O0.73H2O) C, H, N.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C:16]([CH:19]=O)([CH3:18])[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:50]([F:55])([F:54])C([O-])=O.[Na+]>COCCOCCOC>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C:16]([CH:19]=[C:50]([F:55])[F:54])([CH3:18])[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CC1(C=O)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: CC1(C=C(F)F)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 21.7 %

Procedure:
To 2.0 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-formyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (5 mmole), was added 4 g of triphenylphosphine (15 mmole), 3 g of sodium chlorodifluoroacetate (20 mmole) and 15 ml of diglyme. The mixture was heated slowly to reflux over 1 hour. Gas evolved. After refluxing for 20 minutes the mixture was colled, partitioned between ether and water, dried, rotovaped and chromatographed (ether/hexane) to yield 0.5 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-(2,2-difluorovinyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide mp 142°-8° C. NMR data was consistent with the structure.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:39])[C:23]([C:36]([OH:38])=[O:37])=[CH:24][N:25]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])=[CH:20][C:19]=3[F:40])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:41]>>[ClH:41].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:39])[C:23]([C:36]([OH:38])=[O:37])=[CH:24][N:25]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])=[CH:20][C:19]=3[F:40])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC1CCO2
Agent: Cl
Product: NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]-oct-7-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 235° C. (with decomposition).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 90.3 %

Procedure:
A solution of Example 39H (2.76 g, 5.80 mmol), mesyl chloride (1.79 mL, 23.2 mmol), and pyridine (3.75 mL, 46.4 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.71 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 m, 1 H) 0.74 m, 7 H) 1.34 (m, 1 H) 1.57 m, 3 H) 2.15 m, 2 H) 3.08 m, 3 H) 7.56 m, 3 H) 7.75 m, 3 H) 8.16 m, 1 H) 10.26 m, 1 H) 13.76 m, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.CCCCCC.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH2:35][CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Reactant: Fc1ccc(CCCBr)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(C(CCCc2ccc(F)cc2)n2ccnc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-(4-cyanobenzyl)-imidazole (1 g, 0.0054 mol) is dissolved into dry tetrahydrofuran (30 ml) and cooled to -70° C. n-BuLi in hexane (0.0054 mol) is added dropwise into the reaction mixture. After stirring for additional 30 min at -70° C. 3-(4-fluorophenyl)propyl bromide (1.5 g, 0,0069 mol) in THF (10 ml) is added to the mixture and stirring is continued for 2 hours. Then the mixture is allowed to warm to room temperature. Saturated aqueous ammonium chloride solution is added to the mixture, shaked and then the layers are separated. THF-phase is dried and evaporated to dryness. The residue is crystallized from isopropanol as hydrogen chloride salt. The filtrate is purified by flash chromatography.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH:17]2[CH2:20][C:21](OC)=[O:22])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>CCOCC>[C:7]([C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH:17]2[CH2:20][CH2:21][OH:22])=[CH:13][CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)CC1CCc2ccc(C(C)(C)C)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)C(CCO)CC2
Yield: 112.3 %

Procedure:
To a suspension of 1.72 g of LiAlH4 (45.03 mmole) in 100 ml of ether was added dropwise a solution of 10.7 g of methyl 6-tert-butyl-1-indanacetate (36.9 mmole) dissolved in 50 ml of ether. After refluxing the suspension during 2 h, 8.6 ml of 1 N NaOH were carefully added and, after 1 h, the suspension was filtered and concentrated to give 9.05 g of raw 2-(6tert-butyl-1-indanyl)-1-ethanol 78.1% pure. Bulb-to-bulb distillation (150°/20 Pa) provided 8.53 g of 2-(6-tert-butyl-1-indanyl)-1-ethanol with a GC purity of 82.3%. Yield of the last three steps: 71.0%.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].Br[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:18]([C:16]1[O:17][C:13]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([C:1]#[N:2])=[CH:4]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(-c2ccc(C=O)o2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A suspension of 3-cyanoindole (0.14 g), 5-bromo-2-furaldehyde (0.18 g), and cesium carbonate (0.39 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature or 3 hours. This reaction mixture was heated at 50° C., stirred for 2 hours. After cooling to ambient, water was added to this reaction mixture. This mixture was extracted with ethyl acetate, and this organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.086 g).