Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[CH2:10][CH2:11][NH:12][C:13]([CH:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][O:18][C:17]([CH3:24])([CH3:23])[O:16]1)=[O:14].[C:26](O)(=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:26]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[CH2:10][CH2:11][NH:12][C:13]([CH:15]1[C:20]([CH3:21])([CH3:22])[CH2:19][O:18][C:17]([CH3:24])([CH3:23])[O:16]1)=[O:14])(=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccccc2O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Oc1ccccc1NC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 67 %

Procedure:
N-(2-Hydroxyphenyl)-3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propanamide (350 mg) and 282 mg of oleic acid were reacted in the same manner as in Example 15 to obtain 411 mg of the title compound (yield: 67%).
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4](OCOC)[C:3]=1[C:21](=[O:23])C.[CH2:24]([OH:26])C>>[CH3:24][O:26][C:7]1[CH:2]=[C:3]([CH:4]=[CH:5][C:6]=1[O:13][CH2:14][O:15][CH3:16])[CH:21]=[O:23]
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Reactant: CCO
Product: COCOc1ccc(C=O)cc1OC

Procedure:
In 95.0 ml of ethanol were dissolved 14.8 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 1 and 9.0 g of the 3-methoxy-4-methoxymethoxybenzaldehyde obtained in Production Example 17, the solution was cooled to 0° C., and 138.0 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. The temperature was elevated to room temperature and the reaction liquid was stirred for 15 hours. The reaction liquid was made acidic by an addition of hydrochloric acid and extracted with diethyl ether. The ether layer was concentrated under a reduced pressure. The reaction mixture was subjected to the column chromatography [230-400 mesh Kieselgel 60; eluting solvent=hexane/ethyl acetate (3/1)] to obtain 13.1 g (yield=57.0%) of 2'-hydroxy-3-methoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:36].[NH4+].OO.O>CO>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]([NH2:32])=[O:36])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile (45 mg, 0.097 mmol) was dissolved in hot methanol (2 mL). Subsequently, the solution was cooled down to room temperature and 30% ammonium hydroxide (2 mL) was added. The reaction mixture was then cooled to 0° C., and 30% hydrogen peroxide was added. After stirring at room temperature for 8 hours, water was added and the resulting mixture extracted with ethyl acetate. The organics were dried over magnesium sulfate. Filtration and concentration, followed by purification with flash chromatography (95:5 dichloromethane:methanol), gave 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzamide (18 mg, 39% yield) as a yellow solid. 1H NMR (CDCl3): δ 8.12 (s, 1H), 7.99 (d, 1H), 7.92 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.32 (t, 1H), 6.28 (d, 1H), 6.18 (broad, 1H), 6.05 (d, 1H), 6.02 (d, 1H), 5.82 (broad, 1H), 5.25 (d, 1H), 4.30 (m, 1H), 4.00 (m, 1H), 2.15 (m, 2H), 2.03 (m, 2H), 1.81–1.50 (m, 12H). MS m/z 482 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)Cc1ccc(N)cc1
Yield: 879.1 %

Procedure:
To a solution of 4-nitrophenylacetamide 55 (3.2 g, 1.78 mmol) in methanol (50 mL) was added 10% Pd—C (0.32 g) and the resulted mixture was stirred at room temperature for 24 h under 1 atm hydrogen atmosphere. Pd—C was removed by filtration on Celite. The filtered solution was evaporated to provide 55a (2.35 g, 90% yield). 1HNMR (300 MHz, CDCl3-CD3OD): δ 7.06 (d, J=8 Hz, 2H), 6.72 (d, J=8 Hz, 2H), 3.41 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2].[CH2:27]([O:29]C(C1C=C(C2C=CC(F)=CC=2)N(C2C=CC(OC)=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([O:29][CH3:27])=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(OC)cc2)c1C
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Product: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(OC)cc2)c1CBr

Procedure:
Prepared in analogy to that of 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 5-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 430 (M−HBr+H+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[OH:20])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].O>C1COCC1>[CH3:30][C:26]1([CH3:29])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:20][C:33](=[O:34])[N:17]([CH2:16][CH2:15][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:18]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Reaction time: 21.5 h
Yield: 72.7 %

Procedure:
A solution of (1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (4.803 g) in THF (100 ml) under nitrogen was treated with 1,1′carbonyldimidazole (1.702 g) and the mixture was stirred at 20° for 21.5 h. Water (125 ml) was added, the mixture was stirred for 10 min and then extracted with Et2O. The extract was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in THF (60 ml) and was treated with a solution of tetrabutyl ammonium fluoride in THF (1.0 M, 15.95 ml). The mixture was stirred at 20° for 100 min, water (30 ml) was added and the mixture was extracted with Et2O. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by chromatography on a Biotage cartridge (90 g). Elution with EtOAc-petroleum ether (2:3) gave the title compound (2.82 g). LCMS RT=3.01 min ES+ve 370 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]1[S:20][C:21]([CH:24]=[O:25])=[CH:22][N:23]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]1[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CNC(=O)CNc1ncc(C=O)s1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)CNc1ncc(CO)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of material from Example 106 (10 mg, 0.026 mmol) in methanol (1.5 mL) is added sodium borohydride (3.5 mg, 0.093 mmol). The reaction is allowed to stir at room temp for 1 min, cooled to 0° C., quenched with trifluoroacetic acid (26.5 μL, 0.344 mmol) and the solvent removed in vacuo. The resulting residue is used immediately in the next reaction. LC/MS (Condition A): ret, T=2.54 min, (M+Na) 411.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:63]1([CH2:66][C:67](O)=[O:68])[CH2:65][CH2:64]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:63]1([CH2:66][C:67]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:68])[CH2:65][CH2:64]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(O)CC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)CC6CC6)CC5)c4)cnn23)c1

Procedure:
A mixture of N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0310 mmol) (prepared by the procedure for Example 30, step 5), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (15.1 mg, 0.0340 mmol), cyclopropylacetic acid (4.65 mg, 0.0464 mmol, Lancaster, Cat. No. L09616) and N,N-diisopropylethylamine (30.0 μL, 0.172 mmol) in DMSO (0.5 mL) was stirred at for 3 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=567.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:32][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: NCCc1ccccc1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and phenethylarnine in DME. ES-MS m/e (%): 326 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]([F:25])([F:24])[C:13]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]([F:25])([F:24])[C:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])([OH:15])[CH2:14][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2(C(F)(F)SCCOCc3ccccc3)CO2)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCOCc1ccccc1
Yield: 17.6 %

Procedure:
Using 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (3.0 g, 0.008 mol), DMSO (30 ml), 1,2,4-triazole (1.4 g, 0.02 mol) and potassium carbonate (2.8 g, 0.02 mol), 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.62 g, yield: 17.4%) was obtained as a colorless oil by similar procedures to Example 14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2>CCO.Cl.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2ccccc21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a suspended solution of 3-(2,6-dichloro-3-nitro-phenyl)-1-methyl-1H-quinolin-2-one (50 mg, 0.143 mmol) in EtOH (3.0 mL) is added a solution of Sn(II)Cl2 (122 mg, 0.644 mmol) in concentrated HCl (2.0 mL) at 75° C. After the mixture is stirred for 30 minutes at 75° C., the mixture is diluted with EtOAc and neutralized with K2CO3 until a pH of 8 is achieved. The organic layer is washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product (44.2 mg, 96.7%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29](O)=[O:30])=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]([NH2:35])=[O:30])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The reaction was carried out under argon. (7R)-7-(4-Cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic acid (62 mg, 145 μmol) and ammonium chloride (116.7 mg, 2.2 mmol, 15 eq.) were initially charged in dry DMF (3.5 ml) at 0° C., and HATU (415 mg, 1.8 mmol, 7.5 eq.) and triethylamine (147 mg, 1.45 mmol, 10 eq.) were added. The mixture was stirred for 12 h, during which time it gradually warmed to RT. The reaction mixture was then concentrated, and the residue was taken up in acetonitrile (with 0.1% TFA) and then purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless amorphous solid (36 mg, 58% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1NC(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (2.2 g), anhydrous acetonitrile (22 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 5; 2.4 g) and DBU (1.22 g) was refluxed for 5 hours. The reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (20 ml) and, after cooling, the resulting precipitate was collected by filtration to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (3.62 g) as yellow needle, mp 210°-213° C. (decompd.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)C=CC=CC=1>>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:24]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[CH2:16][CH2:15]1)=[O:23]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(Nc1nccs1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from 1-benzo[1,3]dioxol-5-ylmethyl-piperazine and thiazol-2-yl-carbamic acid phenyl ester in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 7.30 (d, J=4.0 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J=3.8 Hz, 1H), 6.77 (s, 2H), 5.97 (s, 1H), 5.96 (s, 2H), 3.62 (bs, 4H), 3.53 (s, 2H), 2.54 (bs, 4H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:5]=[CH:4][CH:3]=[N:2]1.CCCCCC>C1COCC1>[N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([CH2:11][OH:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(Cn2cccn2)c(OC)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cn1cccn1
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate (330 mg crude) in THF (6 ml) DIBAL-H 1M in Hexane (4.02 ml, 4.02 mmol) was added dropwise at −70° C. The reaction mixture was stirred at −70° C. for 3.5 h. The reaction mixture was quenched subsequently with ethyl acetate (2 ml) and saturated aqueous NH4Cl. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (4-((1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)methanol. MS [M+H]+=219.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CC1C=CC=CC=1C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Solvent: Cc1ccccc1C
Product: c1ccc(Cn2ccc3cc(N4CCNCC4)ccc32)cc1
Temperature: 110 °C
Yield: 89 %

Procedure:
A flask was charged with 75 ml of o-xylene, 6.21 g of N-benzyl-5-bromoindole, 11.2 g of piperazine and 2.85 g of NaOBut. The flask was flushed with nitrogen for 10 minutes, and then, 6.0 mg of palladium acetate (the ratio of palladium atom/N-benzyl-5-bromoindole=0.10% by mole) and 0.07 ml of a solution in toluene of tri-tert.-butylphosphine having a concentration of 0.25 g/ml were added into the flask. Then the content was heated to 110° C. and maintained at that temperature for 3 hours. Extraction, drying and concentration were conducted, and finally recrystallization was conducted from toluene to give N-benzyl-5-(1-piperazinyl)indole. The yield was 89% by mole on the basis of N-benzyl-5-bromoindole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([Sn](CCCC)(CCCC)CCCC)=[N:28][CH:29]=1>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.C1(C)C=CC=CC=1>[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]([CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])=[N:28][CH:29]=1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(S(C)(=O)=O)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(S(C)(=O)=O)c2)nc1

Procedure:
A mixture of 3-bromo-N-((6-methylpyridin-3-yl)methyl)-5-(methylsulfonyl)benzamide (71 mg, 0.18 mmol), 5-methyl-2-(tributylstannyl)pyridine (91 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0093 mmol) and toluene (2.0 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to allow the product to precipitate. The solvent was discarded and the precipitated solids were rinsed with hexane and then purified by preparative HPLC (100×21.2 mm C18 column, 30-70% CH3CN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C@@H:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C@@H:25]([OH:26])[CH2:27][NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[CH:28][CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCc1ccc(O)cc1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Product: Oc1ccc(CCNC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared from tyramine and (S)-2-(4-benzyloxyphenoxymethyl)oxirane according to the method described in Procedure 13.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:11][CH2:10][CH3:9]
Reactant: O=C1CCNCC1
Reactant: CCCCOCCCCCl
Product: CCCCOCCCCN1CCC(=O)CC1

Procedure:
1-(4-Butoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-butoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([OH:8])[CH2:4][N+:5]([O-])=O.[H][H].[ClH:14]>C(O)C.CO.[Pd]>[ClH:14].[NH2:5][CH2:4][C:3]([CH3:9])([OH:8])[C:2]([F:11])([F:10])[F:1]
Reactant: [H][H]
Reactant: CC(O)(C[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(O)(CN)C(F)(F)F
Reaction time: 48 h

Procedure:
Pd/C was added (1 g) to a 200 ml glass vessel. Ethanol (50 ml, dry) was added cautiously under an atmosphere of CO2. 1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 g, 57.8 mmol) was dissolved in ethanol (50 ml, dry) and added to the glass vessel. The reaction mixture was put under a positive pressure of hydrogen (5 bar) at room temperature and hydrogenated for 2 days. The reaction mixture was filtered through Celite® (filter material) and washed with excess ethanol. The solvent was removed in vacuo to yield a colourless oil. The oil was dissolved in MeOH (50 ml) and treated dropwise with HCl (1M) in MeOH (30 ml). The solution was left to stir for 30 minutes and concentrated in vacuo azeotroping with MeCN to afford the title compound as a waxy white solid; 1H NMR (DMSO-d6, 400 MHz) δ 8.3 (3H, broad s), 6.9 (1H, broad), 3.0 (2H, q), 1.4 (3H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccccc12
Product: Clc1ccnc2ccccc12
Temperature: 90 °C
Yield: 89 %

Procedure:
POCl3 (50 ml) was added to quinolin-4-ol (5.0 g, 34.9 mmol) and the mixture was heated at 90° C. for 0.5 h. After cooling, the mixture was concentrated in vacuo. The residue was quenched with cold sat. NaHCO3 solution under cooling and the resulting aqueous phase was extracted with chloroform. The combined organic phases were washed with water, dried (Na2SO4) and concentrated in vacuo to give the title compound (5.0 g, 89%) which was used in the next step without further purification.