Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C(O)C=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[C:24]([O:28][C:29]([NH:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O>[C:24]([O:28][C:29]([NH:31][C:32]1[CH:33]=[C:34]([O:38][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:35]=[CH:36][CH:37]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-aminophenol (2.18 g, 20 mmol) in tetrahydrofuran (10 ml) is added di-tert-butyl dicarbonate (4.578 g, 21 mmol) and the mixture is stirred for 15 hr at room temperature. To the residue obtained by concentrating the reaction mixture is purified by chromatography on silica gel (hexane/ethyl acetate (5:1)). To a solution of the resultant oily residue of 3-(N-tert-butyloxycarbonylamino)phenol in dimethylformamide are added ethyl 2-bromoacetate (2.44 ml, 22 mmol), potassium iodide (183 mg, 1.1 mmol) and potassium carbonate (3.04 g, 22 mmol) and the mixture is stirred for 15 hr at room temperature. The reaction mixture is concentrated under reduced pressure and the concentrate is partitioned between a mixture of ethyl acetate and water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resultant crude product is purified by chromatography on silica gel (toluene/ethyl acetate (9:1)) to give the titled compound as colorless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>C(O)C>[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3-c3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydroxide (1M, 2.5 ml, 2.5 mmol) was added to a solution of ethyl 2-ethoxy-3-{4-[2-(9H-fluoren-9-yl)-ethoxy]-phenyl}-propionate (0.19 g, 0.44 mmol) in ethanol (5 ml) and the mixture stirred at room temperature for 20 h. The resulting mixture was partitioned between water (20 ml) and dichloromethane (20 ml), acidified to pH 1 by adding 1N hydrochloric acid, and the organic phase collected. The aqueous phase was further extracted with dichloromethane (3×20 ml) and the combined organics were washed with brine, dried (Na2SO4) and evaporated to give the title compound as a waxy solid; 0.17 g (95%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1CNCCN1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of 0.75 g (2.68 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.07 g (10.4 mmol) of 2-methylpiperazine and 30 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with water/ethanol and acetonitrile, and dried in vacuo to give 0.42 g of the title compound, mp 189°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:45]1[CH2:49][CH2:48][N:47]=[C:46]1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH:58][CH3:59])=[CH:52][CH:51]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:58]([CH2:57][CH2:56][C:53]3[CH:52]=[CH:51][C:50]([C:46]4[NH:47][CH2:48][CH2:49][N:45]=4)=[CH:55][CH:54]=3)[CH3:59])=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cc(Br)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (54 mg, 0.12 mmol), EDCI (29 mg, 0.15 mmol) and HOBt (20 mg, 0.15 mmol) in DMF (3 mL) was added a solution of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (29 mg, 0.11 mmol) and DIPEA (0.084 mL, 0.48 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 18 h, then diluted with EtOAc. The solution was washed with water, saturated aqueous NaHCO3 and 1:1 saturated brine:water. The organic extracts were dried over MgSO4, and solvent was removed in vacuo. A portion of the crude product was purified using prep method C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C.[C:34]([C:42]1[CH:43]=[N:44][C:45]2[C:50]([C:51]=1[C:52]1[CH:53]=[C:54]([NH:58]CC3C=CC(CC([O-])=O)=CC=3)[CH:55]=[CH:56][CH:57]=1)=[CH:49][CH:48]=[CH:47][C:46]=2[C:70]([F:73])([F:72])[F:71])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Cu+2].C1(C)C=CC=CC=1>[NH:58]([C:54]1[CH:53]=[C:52]([C:51]2[C:50]3[C:45](=[C:46]([C:70]([F:73])([F:71])[F:72])[CH:47]=[CH:48][CH:49]=3)[N:44]=[CH:43][C:42]=2[C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:41])[CH:57]=[CH:56][CH:55]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(Nc2ccccc2)c1
Reaction time: 24 h
Yield: 118.6 %

Procedure:
Phenylboronic acid (0.12 g, 1.0 mmol), Cu(OAc)2 (0.036 g, 0.2 mmol), and myristic acid (0.046 g, 0.2 mmol) were combined in a 100-mL round-bottom flask with a large stir bar. A rubber septum was attached, and dry toluene (2 mL), 2,6-lutidine (0.116 mL, 1.0 mmol), and {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate (0.045 g, 0.09 mmol) were successively added. The resulting mixture was stirred at a high rate for 24 h, diluted with ethyl acetate (10 mL), filtered through a plug of silica gel, and then purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a yellow solid (0.05 g, 94%). MS (ESI) m/z 469; MS (ESI) m/z 467; HRMS: calcd for C29H19F3N2O, 468.1449; found (ESI, [M−H]−), 467.1362; Anal. Calcd for C29H19F3N2O: C, 74.35; H, 4.09; N, 5.98. Found: C, 74.27; H, 3.72; N, 5.82.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10]Cl>O1CCOCC1.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:1][CH:10]=[CH:9]2
Reactant: Nc1c(Cl)cccc1C(=O)CCl
Solvent: C1COCCO1
Solvent: O
Product: Clc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve 1-(2-amino-3-chlorophenyl)-2-chloroethanone (7.0 g, 34.30 mmol) in 10% aqueous 1,4-dioxane (75 mL). Carefully add NaBH (2.6 g, 68.6 mmol, 2 eq.) as a solid. Heat to reflux. After 4 hours, cool to room temperature, dilute with water (300 mL), and extract with dichloromethane (2×200 mL). Combine the organic layers, dry over MgSO4, filter, and remove the solvent in vacuo leaving a light brown oil in the flask. Purify the oil by HPLC (silica gel mobile phase: 100% hexane to 50% EtOAc in hexanes over 50 minutes), to give the title compound as a brown oil: 1H NMR (300 MHz, d6-DMSO-d6): 5.16 (m, 1H), 5.39 (d, 1H), 5.70 (bs, 1H), 6.59 (t, 1H), 7.09 (m, 2H); MS (ES+): m/z 154, 152 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:13][O:14][C:15]1[C:16](=[O:27])[NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](=[O:22])[CH:21]=1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[CH2:6]([O:5][C:3]([CH2:2][N:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](=[O:22])[CH:21]=[C:15]([O:14][CH3:13])[C:16]1=[O:27])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(=O)c2ccccc2n(CC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C

Procedure:
Benzyl bromoacetate (9.16 g, 0.04 mole) was added dropwise to a mixture of 3-methoxy-2,5-dihydro-1H-[1]benzazepine-2,5-dione [8.13 g, 0.04 mole, prepared as described in the Canadian J. Chem., 52, 610 (1974)] powdered potassium hydroxide (2.24 g, 0.04 mole) and tetrabutylammonium bromide (1.29 g, 0.004 mol) in 1 L of acetonitrile with stirring at room temperature. Upon complete addition, the suspension was stirred at room temperature for 64 hours, filtered, and the filtrate concentrated under reduced pressure to give a partially crystalline oil. This oil was triturated with ether to give a solid which was suspended and stirred in ethyl acetate (100 ml) for 1.5 hours. The insoluble material was filtered off and the filtrate concentrated to give the crude 1-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro-1H-[1]benzazepin-2,5-dione which was used directly in the next step.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12](C(C(O)=O)=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:1]([C:2]([Cl:4])=[O:3])=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(C(=O)O)cc(-c3ccccc3)nc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Cl)cc(-c3ccccc3)nc2c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
2.8 ml (32.3 mmol) of oxalyl chloride were dissolved in 60 ml of CH2Cl2. The solution was cooled at −10° C. and 6 g (19.0 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 7 g of the title compound, used without further purification.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 41.6 %

Procedure:
To a solution of 45 g of butane-1,4-diol in 0.25 1 of pyridine, cooled to 0° C., were added 139.4 g of triphenylchloromethane and the mixture was stirred at room temperature for 26 h. The precipitate formed was removed by filtration and the filtrate was evaporated in vacuo. The residue was taken up in 0.5 l of ethyl acetate and the solution was washed successively with 200 ml portions of water, 1N hydrochloric acid, water, 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from ethyl acetate/hexane afforded 69.0 g of 4-trityloxy-1-butanol as white crystals of m.p. 73°-74° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>CCOCC>[OH:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)C1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40 mmol) in ether (20 ml) was added dropwise phenylmagnesium bromide (10.3 mL, 3.0 M in ether, 6.21 mmol) at rt under nitrogen. The reaction was heated to reflux for 15 min, then cooled to rt, poured into sat. NH4Cl, extracted with ether (3x). The combined organic layers were dried over Na2SO4, concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (700 mg, 49.24%). LCMS (M+H) 264.160.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C.P(Br)(Br)(Br)=O>O.CCCCCCC>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: C=CC(=O)O
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: O=P(Br)(Br)Br
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 72.06 g (1.0 mole) of acrylic acid, 400 g of n-heptane and 212.5 g (2.10 moles) of triethylamine. After replacing the air in the container with nitrogen, 200.7 g (0.70 mole) of phosphorus oxybromide was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 80° C. for 1 hour. Thereafter, 500 g of water was added, and after cooling to room temperature, the deposited product was filtered off. The product obtained was washed with water until the washing became neutral to obtain 379.6 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate as a white crystal. Melting point, 132°-134° C. Yield, 96%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[C:5]([CH3:27])=[CH:4][N:3]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[CH3:27][C:5]1[C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:17])=[O:18])[CH2:14][CH2:15]2)=[N:7][CH:2]=[N:3][CH:4]=1
Reactant: [H][H]
Reactant: Cc1cnc(Cl)nc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cncnc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 92 was prepared from (2-chloro-5-methyl-pyrimidin-4-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=375.5.
Reaction SMILES: [C:1]([C:3]1[C:8](OC)=[CH:7][C:6]([CH2:11][C:12]([OH:14])=[O:13])=[C:5](F)[CH:4]=1)#[N:2].C(OC(C)(C)C)(=O)CC(OC(C)(C)C)=O.[Br:31]C1C=C(C=CC=1F)C#N>>[Br:31][C:8]1[CH:7]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Agent: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Product: N#Cc1ccc(CC(=O)O)cc1Br

Procedure:
(3-Bromo-4-cyanophenyl)acetic acid was prepared in a similar fashion to the previously described synthesis of (4-cyano-2-fluoro-5-methoxyphenyl)acetic acid starting from di-tert-butyl malonate and 3-bromo-4-fluorobenzonitrile. LC-MS (IE, m/z): 239, 241 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:7]1[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: ClCCCCBr
Reactant: Clc1ccc2nc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: ClCCCCn1cnc2ccc(Cl)cc21
Temperature: 60 °C
Yield: 62.1 %

Procedure:
6-chloro-1H-benzimidazole (15.2 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Post treatment was performed based on common method one for synthesis. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 15.1 g of 1-(4-chlorobutyl)-6-chloro-1H-benzimidazole, with a yield of 62.3%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:36][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylamine (20 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[H-].[Na+].Cl[CH2:35][S:36][CH2:37]Cl>CN(C)C=O>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[C:13]=2[C:14]([O:16][CH2:35][S:36][C:37]2[CH:19]=[CH:20][CH:12]=[CH:13][CH:14]=2)=[O:15])[N:27]=1
Reactant: ClCSCCl
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCSc2ccccc2)n1
Yield: 126.7 %

Procedure:
1.7 g (4.0 mmol) of 2,6-bis[(4,6-dimethoxypyrimidin-2-yl) oxy]benzoic acid, 0.2 g of 60% sodium hydride and 0.72 g (4.4 mmol) of chloromethylsulfide were reacted in N,N-dimethylformamide, treated and purified in the same manner as in Example 1 to obtain 1.4 g of a white crystal having a melting point of from 89° to 93° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](OCCOCC)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:27])[CH:3]=1.ClC1C(Cl)=CC(NC2C3C(=[CH:42][C:43]([O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59]CCO)=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[C:12]([O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:43][CH3:42])[N:11]=2)=[C:4]([F:27])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCO
Reactant: CCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1N
Product: CCOCCOCCOCCOc1nc(Nc2cc(Cl)c(Cl)cc2F)c2cc(N)ccc2n1

Procedure:
Compound 41b is prepared as described hereinabove for Compound 41a, using Compound 29b a starting material.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:17]=[N:18][N:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:14][N:13](C(OC(C)(C)C)=O)[C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:17]=[N:18][N:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: CC(c1ccccc1)n1cc(-c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cnn(C)c4)cc23)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(c1ccccc1)n1cc(-c2c[nH]c3ncc(-c4cnn(C)c4)cc23)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-(1-methyl-1H-pyrazol-4-yl)-3-[1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl]pyrrolo[2,3-b]pyridine-1-carboxylate (90 mg, 0.176 mmol) is dissolved in MeOH (5 ml), potassium carbonate (85 mg, 0.615 mmol) is added, and the mixture is stirred at RT for 1 h. Water is added, and the mixture is extracted three times with ethyl acetate. The organic phase is washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The residue is triturated with ether and filtered off with suction, washed with ether and dried in a high vacuum, giving 5-(1-methyl-1H-pyrazol-4-yl)-3-[1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridine as colourless solid; HPLC/MS: Rt=1.874 min, [M+H]+ 370;
Reaction SMILES: [CH3:1][C:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH:3]=1.[H][H]>[Ni].[Pd].C(O)(C)C>[CH3:1][CH:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[O:5][CH2:4][CH2:3]1
Reactant: CC1=CCOC2(CCCC2)C1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1CCOC2(CCCC2)C1
Yield: 90.8 %

Procedure:
A solution of 9-methyl-6-oxaspiro[4.5]dec-8-ene (1.52 kg, 10.0 mols), isopropyl alcohol (1000 ml) and Raney nickel (100 g), Pd/C (100 g) or other suitable sponge-metal catalyst was hydrogenated at 450 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 9-methyl-6-oxaspiro[4.5]decane (1.4 kg, yield: 95%, purity: 98%).
Reaction SMILES: Cl.[OH:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl.[CH3:13]O>>[OH:2][C:3]1([C:9]([O:11][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: O=C(O)C1(O)CCNCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-4-piperidinecarboxylic acid hydrochloride salt (1 g, 5.1 mmol) was added to a 2% hydrochloric acid solution in methanol (25 mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt (1 g, 92%) as a white solid. δH (400 MHz, DMSO-d6) 9.06 (broad, 2H), 5.89 (broad, 1H), 3.68 (m, 3H), 3.14 (m, 2H), 3.02 (m, 2H), 2.07 (m, 2H), 1.79 (m, 2H).