Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([Li])CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32](=[O:37])N(OC)C)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:37])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Brc1ccc2ccccc2n1
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccc2ccccc2n1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
30% Potassium hydride dispersed in mineral oil (0.8 g, 6 mmol) was added to a stirred solution of 2-bromoquinoline (1.12 g, 5.29 mmol) (O. Sugimoto, Tet. Lett. 4, (1999), 7477-8) in anhydrous THF (20 ml) at −70° C. under argon. To this was added 2N n-butyllithium in hexanes (2.7 ml, 6.75 mmol) dropwise over 5 min. The resultant mixture was stirred for 10 min at −70° C. then a solution of (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (1.57 g, 5.77 mmol) in anhydrous THF (10 ml) was added over 2 min. The cooling bath was removed and the reaction mixture allowed to warm to −20° C. and held at −20° C. for 10 min. The mixture was poured into saturated ammonium chloride (300 ml) and extracted with ethyl actetate (2×100 ml). The combined organics were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate in pentane to yield the title compound as a pale yellow solid (1.2 g, 66%).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[O:13][CH3:14].CO>CCOCC>[Br:12][C:8]1[C:7]([O:13][CH3:14])=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: COc1c(Br)cccc1CO
Reaction time: 0.08 h

Procedure:
LiBH4 (5.00 g, 0.23 mmol) was added to a solution of 3-bromo-2-methoxy-benzoic acid methyl ester (10.50 g, 42.80 mmol) in Et2O at 0° C. The reaction mixture was stirred for 5 minutes, MeOH (8.70 mL, 0.22 mmol) was added in a dropwise fashion. The reaction mixture was then stirred for 30 minutes, and was quenched into 1N NaOH. The resulting solution was extracted with Et2O (3×200 mL) and the combined organic phases were washed with brine (1×150 mL), dried over MgSO4 and concentrated to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 1.68 (t, J=5.86 Hz, 1H), 3.90 (s, 3H), 4.61 (d, J=5.86 Hz, 2H), 6.89 (d, J=8.50 Hz, 1H), 7.25-7.30 (m, J=2.00 Hz, 1H), 7.57 (d, J=2.05 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[S:31][CH:32]=4)=[N:24][CH:25]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[S:31][CH:32]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[2-(2-phenyl-4-thiazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionate (603 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (500 mg, yield: 88%). This was recrystallized from acetone-hexane. Melting point: 107–108° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]([O:12][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A 50 mL three-necked flask was charged with 3-phenyllactic acid (1.0 g, 6.0 mmol) and dry CH2Cl2 (12 mL). To this white slurry was added benzoyl chloride (1.04 mL, 9.0 mmol) and the mixture was cooled to 0° C. Triethylamine (0.8 mL, 6.0 mmol) was added and a light yellow solution resulted. 4-Dimethylaminopyridine (367 mg, 3.0 mmol) was added and the reaction mixture was warmed to 25° C. and stirred for 3 hours. The reaction mixture was concentrated on a rotary evaporator and ether, ethyl acetate, and water were added. The mixture was extracted with ether (3×) and ethyl acetate, dried over MgSO4, filtered and evaporated. Purification by silica gel chromatography (4:1 hexanes/ethyl acetate increased to 1:1 hexanes/ethyl acetate) yielded 392 mg (24%) of 11 as a white solid. Rf 0.15 (1:1 hexanes/ethyl acetate); mp 113° C.; IR (CDCl3) 3564-2560 (broad acid), 3028, 2924, 1720 (broad), 1452, 1268, 716 cm−1; 1H NMR (300 MHz, CDCl3) δ11.25 (s, 1H), 8.08 (d, J=7.2 Hz, 2H) 7.45 (m, 8H), 5.56 (m, 1H), 3.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ175.5, 165.9, 149.9, 135.6, 133.4, 130.1, 129.7, 129.3, 128.9, 128.5, 128.4, 127.1, 72.9, 37.2; HRMS (FAB): Calcd for (M+Li) C16H14O4Li, 277.1052; Found, 277.1065; EA Calcd for C16H14O4: C, 71.10; H, 5.22; Found: C, 71.04; H, 5.24.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:28][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tert-butyloxycarbonyl-3-piperidinyloxy)benzoate from Step 2 above (1.50 g, 4.27 mmol) in DMF (40 mL) under N2 was added NaH (246 mg, 6.41 mmol). The reaction mixture was cooled, then CH3I (0.53 mL, 8.54 mmol) was added via syringe. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography, eluting with 20% ethyl acetate in hexanes. Methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-piperidinyloxy)benzoate was obtained as a colorless oil which crystallized on standing overnight.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:38].[NH4+]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:38])[NH2:3]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea (0.03 g, 0.077 mmol) in anhydrous ethanol (10 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to a solid and dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.023 g, 0.23 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then was concentrated in vacuo. N-(3-Amidinophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The major fraction eluting at 15 minutes was concentrated to give N-(3-amidinophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea as an amorphous solid; LRMS (M+H)+ m/z 406, (M+2H)+2 m/z 203.8; 1H NMR (DMSO-d6): 9.52(broad s, 1H), 9.27(s, 2H), 9.02(s, 2H), 7.5(m, 9H), 4.3(m,m, 2H), 3.95(m, 1H), 3.67(m, 2H), 3.42(m, 2H), 3.2(m,2H), 3.1(m, 2H), 2.05-1.6(m, 8H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8](O)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH:27](Cl)(Cl)[Cl:28]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:27][Cl:28])[CH2:3][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: Oc1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: FC(F)Oc1ccc(CCl)cc1OCC1CC1

Procedure:
A solution of crude 3-cyclopropylmethoxy-4-difluoromethoxyphenyl alcohol (24.4 g) and pyridine (9.8 mL, 120 mmol) in chloroform (150 mL) under an argon atmosphere was treated with thionyl chloride (8.0 mL, 110 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil (26 g).
Reaction SMILES: [C:1]1([PH:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([OH:23])(=[O:22])[C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH2:17].C(O)(=O)CC>>[C:1]1([P:7]([CH2:17][CH:16]([CH2:18][C:19]([OH:21])=[O:20])[C:15]([OH:23])=[O:22])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: O=[PH](c1ccccc1)c1ccccc1
Solvent: CCC(=O)O
Product: O=C(O)CC(CP(=O)(c1ccccc1)c1ccccc1)C(=O)O
Yield: 6 %

Procedure:
303 g (1.5 mol) of diphenylphosphine oxide, 214.5 g (1.65 mol) of itaconic acid and 470 g of propionic acid are refluxed under a nitrogen atmosphere for 8.5 hours with lively stirring. The mixture is then cooled. After crystallization, an additional 500 g of propionic acid are added, the product is filtered off with suction, washed and dried. This gives 390 g of product having a melting point of from 169° to 172° C. and a purity of 98.8% (determined by means of the 31P-NMR spectrum). A further 30 g of desired product are isolated from the filtrate. The total yield is 84% of theory, based on diphenylphosphine oxide used.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]([CH2:18][C:19]1[CH:27]=[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]3[N:20]=[C:19]([CH2:18][O:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:27]=[C:22]3[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(OCc2cc3n(n2)CCNC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
4-Fluorobenzoyl chloride (0.14 mL, 1.2 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.3 g, 1.0 mmol) and pyridine (0.16 mL, 2.0 mmol) in DCM (13 mL) under N2 at 0° C. The reaction was stirred at room temperature for 1 hour, diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with DIPE to yield 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.21 g, 59% yield) as a white solid. C20H18FN3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.07 (br. s., 2H), 4.27 (br. s., 2H), 4.81 (br. s., 2H), 5.05 (s, 2H), 6.16 (br. s., 1H), 6.96 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.1, 7.8 Hz, 2H), 7.49 (dd, J=8.5, 5.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH3:19])=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:15]([C:27](=[N:29][OH:30])[NH2:28])=[N:14]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH:18][CH3:19])=[C:16]([S:20]([C:23]([F:25])([F:26])[F:24])(=[O:21])=[O:22])[C:15]([C:27]2[N:28]=[CH:32][O:30][N:29]=2)=[N:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNc1c(S(=O)(=O)C(F)(F)F)c(C(N)=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: COC(OC)OC
Product: CNc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 2396.7 %

Procedure:
1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfonyl-3-pyrazolecarboxamide oxime 500 mg (1.00 mmol) was dissolved in 5 ml of trimethyl orthoformate, and then 5 mg of p-toluenesulfonic acid monohydrate was added. After the mixture was was stirred at room temperature for 6hrs, trimethyl orthoformate was distilled off in vacuo, and then added 20 ml of ethyl acetate. The ethyl acetate solution was washed once with 30 ml of aqueous saturated sodium hydrogencarbonate solution, and then four times with 30 ml of aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The resulting concentrated residue was purified by silica gel column chromatography [eluent: chloroform] to obtain 320 mg (0.63 mmol) of the title compound as a colorless crystal. Yield 63%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42]O)[CH3:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[O:10])[CH2:12][CH2:13]4)=[O:15])=[CH:18][C:19]=3[F:37])=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])[CH3:39]
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Reactant: CCN(CC)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (186 mg, 0.36 mmol) in CH2Cl2 (10 mL) was added 2-(diethylamino)ethanol (63 mg, 0.54 mmol), and PPh3 (141 mg, 0.54 mmol). DIAD (109 mg, 0.54 mmol) was then added as a CH2Cl2 (1 mL) solution. The resulted solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. To the residue was added 1 N HCl (50 mL), and it was washed with EtOAc (50 mL×2). The aqueous phase was basified by adding 15% NaOH aqueous solution until pH=11-13, and then extracted with ether (50 mL×2). The combined organic layer was dried (MgSO4), and concentrated in vacuo. The residue was purified on preparative HPLC to give N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide (74 mg, 34%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1 H), 10.02 (br s, 1 H), 8.47 (d, J=5.2 Hz, 1 H), 7.91 (br d, J=13.9 Hz, 1 H), 7.54-7.52 (m, 2 H), 7.55-7.50 (m, 1 H), 7.52 (s, 1 H), 7.50-7.40 (m, 1 H), 7.41 (s, 1 H), 7.16 (br t, J=8.7 Hz, 2 H), 6.41 (br d, J=4.7 Hz, 1 H), 4.18 (t, J=6.0 Hz, 2 H), 3.94 (s, 3 H), 2.87 (br t, J=6.3 Hz, 2 H), 2.59 (q, J=7.1 Hz, 4 H), 1.47 (br s, 4 H), 1.00 (t, J=7.0 Hz, 6 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:20])(=[S:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:19][C:17](=[O:20])[CH3:18])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)=S
Reactant: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC(C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 11.9 g (47.0 mmol) crude methanesulfonic acid 2-tert-butoxycarbonylamino-1-methyl-ethyl ester in 100 ml DMF was added to a mixture of 5.0 g (1.4 equiv.) thioacetic acid and 15.3 g (1.0 equiv.) Cs2CO3 in 150 ml DMF. The reaction mixture was stirred for 4 h at 80° C. under argon and light protection. The mixture was poured into 300 ml water and extracted twice with 300 ml ethyl acetate each. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: CH2Cl2) gave pure thioacetic acid S-(2-tert-butoxycarbonylamino-1-methyl-ethyl) ester as brown oil.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCNCCCC
Solvent: ClCCCl
Solvent: O
Product: CCCCN(CCCC)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (10.0 g, 61.8 mmol) in anhydrous DCE (150 mL) was added dibutylamine (21.5 mL, 2 equiv, 0.123 mol) in one portion. A white solid formed immediately and the suspension was stirred vigorously for 3 h at room temperature. DCE (200 mL) and water (200 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (2×200 mL) and brine (200 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (15.7 g, quantitative). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.91-0.97 (dt, J=7.2, 7.4, 12H), 1.21-1.38 (m, 4H), 1.46 (s, 6H), 1.47-1.57 (m, 4H), 2.47 (s, 4H), 3.25-3.32 (m, 4H). LRMS (ESI+) for C13H26N4O (254.2); Found: 255 (MH+)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][C:12]3([C:17]([C:19]3([CH3:44])[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[CH:43]=[CH:42][C:27]4[N:28]([CH3:41])[C:29]([CH2:31][NH:32][C:33]5[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=5)=[N:30][C:26]=4[CH:25]=3)=[O:18])[CH3:16])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:45][NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][CH:48]=1.[ClH:55].C(=O)([O-])[O-].[NH4+:60].[NH4+:61]>C(O)C>[ClH:55].[CH3:41][N:28]1[C:27]2[CH:42]=[CH:43][C:24]([CH:20]3[CH2:21][CH2:22][CH2:23][C:19]3([C:17]([C:12]3([CH3:16])[CH2:13][CH2:14][CH2:15][CH:11]3[C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([CH2:45][NH:46][C:47]5[CH:52]=[CH:51][C:50]([C:53](=[NH:60])[NH2:54])=[CH:49][CH:48]=5)=[N:4][C:5]=4[CH:10]=3)=[O:18])[CH3:44])=[CH:25][C:26]=2[N:30]=[C:29]1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:61])[NH2:40])=[CH:37][CH:38]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C3CCCC3(C)C(=O)C3(C)CCCC3c3ccc4c(c3)nc(CNc3ccc(C#N)cc3)n4C)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C3CCCC3(C)C(=O)C3(C)CCCC3c3ccc4c(c3)nc(CNc3ccc(C(=N)N)cc3)n4C)ccc21

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-(1-methylcyclopent-1-yl)ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH2:21].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH:21][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: COC(=O)c1cccnc1N
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccnc1NC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of 2-pyridyl-acetic acid hydrochloride (310 mg) and 2-amino-nicotinic acid methyl ester (270 mg) (Example 1.1) in dichloromethane (5 ml) was added diisopropylethylamine (0.32 ml). The reaction mixture was stirred at ambient temperature for 20 minutes. To this solution was added 4-dimethylaminopyridine (43 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (“EDAC”) (410 mg). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between dichloromethane and water. The phases were separated and the organic layer concentrated. The residue was purified by column chromatography on silica gel (eluent: 15% acetone in dichloromethane) to give 2-(2-pyridin-2-yl-acetylamino)-nicotinic acid methyl ester as a yellow solid (86 mg). 1H-NMR (400 MHz, CDCl3): 11.14 (bs, 1H), 8.63-8.64 (m, 1H), 8.58-8.59 (dd, 1H), 8.25-8.27 (dd, 1H), 7.66-7.70 (m, 1H), 7.38 (d, 1H), 7.20-7.23 (m, 1H), 7.05-7.08 (dd, 1H), 4.11 (s, 2H), 3.92 (s, 3H) ppm.
Reaction SMILES: O.[NH3:2].[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:2])(=[O:14])=[O:13]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1OC(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction had subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yielded 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C.