Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][C@H:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:35][C@H:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
5.32 Grams of Z-Asn-OH was dissolved in 60 ml of tetrahydrofuran, 10 ml of dimethylformamide and 2.04 ml of N-methylmorpholine, to this mixture was added 40 ml of a dimethylformamide solution containing 2.64 ml of isobutyl chloroformate, 3.91 g of H-Leu-OEt.HCl and 2.80 ml of triethylamine and the reaction was carried out by a procedure similar to that described in Reference example 2. After removal of the solvent by distillation, to the residue obtained was added 1M-citric acid, the precipitate formed was collected by filtration, washed with water, dried under a reduced pressure, then was recrystallized from ethyl acetate to obtain 6.1 g of Z-Asn-Leu-OEt.
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]([CH3:28])=O>>[CH2:28]([O:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:26]=[CH2:25]
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Dissolve 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 g, 3.9 mmol) in acetone (5 mL) and add powdered potassium carbonate (2.8 g, 20 mmol). Add dropwise a solution of alkyl bromide (1.04 mL, 12 mmol) in acetone (3 mL) over 10 min and stir at ambient temperature overnight. Filter solids, wash with acetone and concentrate in vacuo to give the desired intermediate as an off-white solid (1.15 g, 98%). GC-MS m/z: 299 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:11](=[O:12])[CH:2]=[CH:3][CH2:4][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]4[CH2:26][OH:25])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: OCC1CCCCN1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCCCC1CO
Yield: 83.6 %

Procedure:
By using the method of Example 89, 1.05 g (3.06 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.1 g (18.4 mmol) of 2-hydroxymethyl-piperidine were converted to 0.67 g the title compound. The free base was obtained as an off-white powder: mass spectrum (electrospray, m/e): M+H 524.3, (M+2H)+2267.7.
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[C:14]([C:25]([O:27][CH3:28])=[O:26])=[C:13]([CH3:29])[N:12]=1)(=O)=O)C1C=CC=CC=1.[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>O1CCOCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1[C:14]([C:25]([O:27][CH3:28])=[O:26])=[C:13]([CH3:29])[N:12]=[C:11]([N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)[N:16]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1c(C)nc(S(=O)(=O)Cc2ccccc2)nc1-c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc(N2CCSCC2)nc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a stirred solution of methyl 2-(benzylsulfonyl)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate (17 mg, 0.037 mmol) in dioxane (2 mL) was added thiomorpholine (4.5 mL, 0.045 mmol). After at 40° C. for 1 hr, the reaction was concentrated under reduced pressure and diluted with EtOAc (10 mL). The organic layer was extracted with saturated NaHCO3 solution (2×6 mL), brine (5 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give methyl 4-(2,4-dichlorophenyl)-6-methyl-2-thiomorpholinopyrimidine-5-carboxylate (15 mg, 100%). The crude reaction product (>98% purity) was moved onto next step without further purification.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](/[C:18]2[NH:27][C:21]3=[N:22][CH:23]=[C:24]([F:26])[CH:25]=[C:20]3[CH:19]=2)\[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:27][C:21]3=[N:22][CH:23]=[C:24]([F:26])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 116, 147 mg, 0.38 mmol) and 10% palladium on activated carbon (0.2 g) in methanol (50 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine as a white solid (60 mg, 41%): LC/MS m/e calcd for C21H23FN2O2S [M+H]+ 387.49, observed 387.2; 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (t, J=2.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.58-7.66 (m, 3H), 6.40 (s, 1H), 4.31 (t, J=8.0 Hz, 1H), 3.09 (s, 3H), 2.24-2.32 (m, 1H), 2.08-2.16 (m, 1H), 1.60-1.87 (m, 5H), 1.45-1.56 (m, 2H), 1.18-1.30 (m, 2H).
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[N+:30]([C:33]1[CH:34]=[CH:35][CH:36]2[CH:41]([CH:42]=1)[C:40](OS(C(F)(F)F)(=O)=O)=[CH:39][CH2:38][CH2:37]2)([O-:32])=[O:31]>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[N+:30]([C:33]1[CH:34]=[CH:35][CH:36]2[CH:41]([CH:42]=1)[C:40]([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=1)=[CH:39][CH2:38][CH2:37]2)([O-:32])=[O:31]
Reactant: O=[N+]([O-])C1=CC2C(OS(=O)(=O)C(F)(F)F)=CCCC2C=C1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])C1=CC2C(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)=CCCC2C=C1
Reaction time: 1 h

Procedure:
At ambient temperature, 15.34 ml of 3M ethylmagnesium bromide are poured into 16.74 g of 4-iodo-1-trityl-1H-imidazole dissolved in 250 ml of tetrahydrofuran. After 1 hour, 76.6 ml of a 1N solution of zinc chloride in diethyl ether are poured in. After contact for 1 hour, 12.4 g of the product obtained in Step 1 dissolved in 100 ml of tetrahydrofuran and 2.22 g of tetrakis(triphenylphosphine)palladium(O) are added and the whole is heated at reflux. Following hydrolysis with a saturated solution of ammonium chloride and extraction with dichloromethane, the organic phase is washed with water. The solvent is then evaporated off and the residue is purified by chromatography on silica gel using as eluant an 80/20 cyclohexane/ethyl acetate mixture.
Reaction SMILES: S1C2C=CC=CC=2N=CN1.[Cl:11][C:12]1[C:13]([S:24][CH2:25][CH2:26][CH3:27])=[CH:14][C:15]2[S:20](=[O:22])(=[O:21])[NH:19]C=[N:17][C:16]=2[CH:23]=1>>[S:20]([C:15]1[CH:14]=[C:13]([S:24][CH2:25][CH2:26][CH3:27])[C:12]([Cl:11])=[CH:23][C:16]=1[NH2:17])(=[O:21])(=[O:22])[NH2:19]
Reactant: CCCSc1cc2c(cc1Cl)N=CNS2(=O)=O
Agent: C1=Nc2ccccc2SN1
Product: CCCSc1cc(S(N)(=O)=O)c(N)cc1Cl

Procedure:
By replacing the 1,2,4-benzothiadiazine derivative employed in Step A-1 by an equivalent quantity of 6-chloro-7-n-propylthio-1,2,4-benzothiadiazine-1,1-dioxide, prepared as described in Example 4, and following substantially the same procedure described in Step A-1 there is obtained 2-sulfamoyl-4-n-propylthio-5-chloroaniline, m.p. 109°-111° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1B(O)O.O1CCOCC1.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:12][C:10]1[CH:11]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[CH3:17])[CH:3]=[C:4]2[C:9]=1[N:8]1[C:13]([CH3:16])=[N:14][N:15]=[C:7]1[CH2:6][CH2:5]2
Reactant: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Reactant: Cc1ccncc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(F)c2c(c1)CCc1nnc(C)n1-2
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-bromo-9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (109-5; 1.8 g, 0.0063 mol) and (4-methylpyridin-3-yl)boronic acid (1.73 g, 0.0127 mol) in the mixture of 1,4-dioxan (10 mL) and water (10 mL) was added potassium acetate (1.88 g, 0.0191 mol). Reaction mass was purged with argon for 20 min. Then catalyst Pd(dppf)2Cl2 (0.260 g, 0.000319 mol) was added and allowed to stir at 100° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) 8.46-8.44 (d, J=8 Hz, 1H), 8.422 (s, 1H), 7.52-7.48 (d, J=16 Hz, 1H), 7.423 (s, 1H), 7.36-7.35 (d, J=4 Hz, 1H), 2.99 (m, 4H), 2.52 (s, 3H), 2.31 (s, 3H). HPLC purity 98.68%, MS (M+1): 294.7.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([CH2:13][CH:14]=[CH2:15])=[CH:8][C:7]=1[Cl:16])[CH:2]1[O:4][CH2:3]1.C(OO)(=[O:19])C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Na+]>[CH2:1]([O:5][C:6]1[C:7]([Cl:16])=[CH:8][C:9]([CH2:13][CH:14]2[O:19][CH2:15]2)=[CH:10][C:11]=1[Cl:12])[CH:2]1[O:4][CH2:3]1
Reactant: CC(=O)OO
Reactant: C=CCc1cc(Cl)c(OCC2CO2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc(CC2CO2)cc(Cl)c1OCC1CO1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A 100 ml sulfurating flask equipped with stirrer, cooler, thermometer and drip funnel is charged with 13.0 g (0.05 mole) of 4-allyl-2,6-dichlorophenyl glycidyl ether in 40 ml of toluene and 0.5 g of sodium acetate. Over 2 hours, 14.0 g (0.07 mole) of 10% peracetic acid are then added dropwise at 30°-50° C. After the dropwise addition, the reaction mixture is diluted with 300 ml of toluene, the resultant aqueous phase is separated and the organic phase is washed with two 150 ml portions of NaHCO3 (5%) and then washed with 150 ml of water. The organic phase is dried over sodium sulfate and made peroxide-free with sodium sulfite and filtered. The filtrate is concentrated, affording 12.7 g (92.3%) of a pale yellow resin with an epoxide content of 5.62 eq/kg (77.75%) and a viscosity of 280 mPas/25° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH2:12][SH:13])=[CH:5][CH:4]=1.[C:14](=O)(OC1C=CC=CC=1)[O:15]C1C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:11][CH2:12][S:13][C:14]2=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(CNCCS)cc1
Solvent: CCO
Product: COc1ccc(CN2CCSC2=O)cc1
Yield: 32.6 %

Procedure:
A solution containing 4.53 g (0.025 mol) of N-(4-methoxyphenylmethyl)-cysteamine and 5.35 g (0.025 mol) of diphenyl carbonate in 25 ml of ethanol is refluxed under nitrogen for 24 hours, then evaporated. The residue is taken up in ethyl acetate, washed with 2N sodium hydroxide solution until it becomes free from phenol, then washed with water, dried and evaporated. The residue becomes solid under ether. Thus, 1.82 g (32.6%) of the title compound are obtained, m.p.: 84°-86° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CCCC)CCCC)CCC.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:15][O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(I)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: COC(=O)/C=C/c1ccc(OC)cc1
Yield: 70 %

Procedure:
Table 1, Entry 1. In the reaction tube were mixed 4-iodoanisole (0.234 g, 1.0 mmol), methyl acrylate (0.108 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), tri-n-butylamine (0.185 g, 1.0 mmol) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 3.50 min with an effect of 60 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane/diethyl ether (4/1) as the eluent. The yield was 70% (white solid).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:35])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[N:3]=1.CO.[ClH:46].O1CCOCC1>>[ClH:46].[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:35])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)c2C)c1
Yield: 63 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (20 mg, 0.034 mmol) was deprotected in methanol/1,4-dioxane HCl in (0.3/1 ml). This afforded 10 mg (63% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.74 (s, 1H), 8.65 (s, 1H), 7.86 (s, 1H), 7.71-7.69 (d, 2H), 7.32-7.29 (t, 1H), 7.20-7.15 (m, 4H), 7.09-7.07 (d, 1H), 5.51 (s, 2H), 3.53-3.50 (m, 4H), 3.41-3.38 (m, 4H), 2.36-2.34 (m, 9H). MS: m/z=477.2 (M+1) HPLC 98.14% (method B).
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=[CH:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([C:4]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC=Cc1c(C(C)C)nn2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C(C)C)nn2ccccc12
Yield: 79.2 %

Procedure:
A solution of 2.0 g of the compound obtained in Example 38 in 20 ml of ethanol was stirred in a hydrogen atmosphere at atmospheric pressure and room temperature in the presence of 100 mg of 10% palladium-on-charcoal for an hour. The solution was filtered and concentrated to dryness in vacuo. The residue was subjected to silica gel column chromatography, eluted with dichloromethane to give 1.6 g (62%) of the desired compound as colorless needles, mp 41°-42° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[OH-].[K+].I[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>[Cu].O>[CH2:2]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCOc1cccc(N)c1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1cccc(Nc2ccccc2C(=O)O)c1
Reaction time: 16 h

Procedure:
m-Phenetidine (5 ml, 38.7 mmol) is added to a solution of KOH (7.385 g, 131.6 mmol), water (77 ml) and 2-iodobenzoic acid (9.6 g, 38.7 mmol). Powdered copper (77 mg, 1.22 μmol) is added and the mixture is refluxed under stirring over night (16 h).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]2)[N:3]=1>CO.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]2)[N:3]=1
Reactant: CCC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(C)n2)C1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N1CCC(Oc2ccc(N)c(C)n2)C1

Procedure:
2-Methyl-3-nitro-6-[(1-propionylpyrrolidin-3-yl)oxy]pyridine (940 mg) was dissolved in methanol (50 mL) and hydrogenated (H-cube from ThalesNano, 10% Pd/C, 60° C., 50 bar, 1 mL/min). The methanol was removed in vacuo. Yield: 800 mg (95%, colorless oil).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a 500 mL one-neck flask was added 4-fluorobenzophenone (35 g), piperazine (13 g), potassium carbonate (22 g) and dimethyl sulfoxide (100 mL). The reaction mixture was heated to 100° C. for 20 hours. The mixture was cooled to room temperature and poured into water (400 mL). The mixture was extracted with chloroform (200 mL) and the recovered bottom layer was dried over sodium sulfate. The solvent was removed and the product was dried in vacuum oven at 60° C. for 6 hours to afford 40 g of waxy 4-piperazinobenzophenone.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Br[CH2:14][C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:21][C:16]1[C:15]([CH2:14][N:9]2[C:8](=[O:10])[CH2:7][NH:6][C:5]3[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]2=3)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1ncccc1CBr
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1cccnc1Cl
Yield: 58 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.189 g) was reacted with 3-(bromomethyl)-2-chloropyridine as in General Procedure 1 to give the title compound as an orange solid (58% yield). m.p.=249° C., LCMS: m/z=401.18 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.29 (2H, s), 5.16 (2H, s), 7.04 (1H, s), 7.26 (1H, m), 7.36 (1H, d, J=7.6 Hz), 7.91 (1H, s), 8.34 (1H, d, J=4.3 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:17])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CSc1ccc(CO)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1ccc(CCl)cc1C(F)(F)F
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 4-(methylthio)-3-(trifluoromethyl)benzyl alcohol (3.00 g, 13.5 mmol) in toluene (15 mL) was added thionyl chloride (1.18 mL, 16.2 mmol) at room temperature, and the resulting mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1), and crystallized from hexane to give the title compound (2.54 g, yield 78%) as colorless crystals.
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]1([C:30]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][C:37]3[NH:36][N:35]=[C:34]([C:39](O)=[O:40])[C:33]=3[CH:32]=[CH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[NH4+]>C(Cl)(Cl)Cl>[C:24]1([C:30]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][C:37]3[NH:36][N:35]=[C:34]([C:39]([NH2:3])=[O:40])[C:33]=3[CH:32]=[CH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
0.718 g of 1-hydroxybenzotriazole hydrate and 1.27 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to 1.4 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in suspension in 200 cm3 of chloroform. After stirring for 30 minutes at a temperature in the region of 20° C., 1.5 cm3 of aqueous 28% ammonium hydroxide solution are added dropwise to the reaction mixture. After stirring at a temperature in the region of 20° C. for about 20 hours, the reaction mixture is diluted with 300 cm3 of chloroform and washed with three times 100 cm3 of water. The organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The solid is taken up in 10 cm3 of dichloromethane, cooled to a temperature in the region of 5° C., drained by suction, washed with three times 5 cm3 of diisopropyl ether and dried over potassium hydroxide under reduced pressure (13 kPa), at a temperature in the region of 20° C. 1.2 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxamide are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH:10]=2)O1.I[C:23]1[C:24]([CH:34]=[O:35])=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:18]1[CH2:17][CH2:16][N:15]([CH:12]2[CH2:13][CH2:14][C:9]([C:23]3[C:24]([CH:34]=[O:35])=[N:25][N:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[CH:27]=3)=[CH:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: O=Cc1nn(C2CCCCO2)cc1I
Reactant: CC1(C)OB(C2=CCC(N3CCOCC3)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: O=Cc1nn(C2CCCCO2)cc1C1=CCC(N2CCOCC2)CC1
Temperature: 85 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
A mixture of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)morpholine (293 mg, 1.00 mmol, 1.00 equiv), (R/S) 4-iodo-1-(oxan-2-yl)-1H-pyrazole-3-carbaldehyde (306 mg, 1.00 mmol, 1.00 equiv), K3PO4 (640 mg, 3.02 mmol, 3.02 equiv) and Pd(dppf)Cl2 (65.1 mg, 0.10 mmol, 0.10 equiv) in ethylene glycol dimethyl ether (5 mL) was stirred under nitrogen at 85° C. for 12 h. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified on a silica gel column eluted with 50-100% of ethyl acetate in petroleum ether to give 280 mg (81%) of (R/S) 4-(4-morpholinocyclohex-1-enyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde as a brown oil. LCMS (method C, ESI): RT=0.70 min, m/z=346.2 [M+H]+.