Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH:31]=O)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH2:31][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2]
Reactant: C1COCCN1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(C=O)nc2)cc(N(CC)C2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN3CCOCC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)benzamide (0.315 g, 0.59 mmol) in EDC (8 mL) at 0° C., was added morpholine (0.1 g, 1.18 mmol) and stirred at rt for 10 min. NaBH(OAc)3 (0.377 g, 1.78 mmol) was then added and stirred for 16 h. On completion, reaction was quenched with water. MeOH (8 mL) was added and layers were separated and extracted with 10% MeOH in DCM, and purified on column chromatography to afford the title compound (0.2 g, 56%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([CH2:17][OH:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[Br:19]N1C(=O)CCC1=O.O>CCOC(C)=O>[Br:19][C@@H:6]1[C@H:5]2[O:1][CH2:2][CH2:3][C@@:4]2([CH2:17][OH:18])[CH2:8][C@@H:7]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled solution of the product of Step F (343.60 g) in EtOAc (4 L) was added N-bromosuccinimide (237.60 g) followed by stirring at rt for 18 h. To the mixture was added water (5 mL) and the reaction heated to 60° C. for 30 min. The reaction was filtered, the filtrate was washed with aqueous sodium thiosulfate until the organic layer was negative for peroxides. The organic layer was washed with aqueous Na2CO3 (10%), dried (Na2SO4) and the reaction was concentrated under reduced pressure. Near the end of the concentration, heptane (1.2 L) was added, and the product was collected by filtration to provide the product of Step G. 1H NMR (400 MHz, CHLOROFORM-d) δ=4.78-4.91 (m, 1H), 4.41 (br. s., 1H), 4.31 (s, 2H), 3.88-3.98 (m, 1H), 3.61-3.77 (m, 3H), 2.08-2.24 (m, 1H), 1.82 (m, 2H), 1.60-1.70 (t, 1H), 1.45 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C@H:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:21][OH:22]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol) in EtOH (25 ml) at 0° C. was added triethylamine (1.6 ml, 11.6 mmol) and a solution of (2R)-2amino-2-(4-fluorophenyl)ethanol (prepared according to a procedure in J. Med. Chem. 1999, 42, 4981-5001, 1.2 g, 7.73 mmol). The reaction mixture was stirred at 0° C. for 3 hours. The solvent was removed and the residue was dissolved in EtOAc and was washed with water. The organic layer was concentrated. Flash chromatography on silica gel (20-50% EtOAc in hexanes) gave the title compound as a solid (703 mg, 29%). NMR (CDCl3) 4.00 (m, 2H), 5.50 (m, 1H), 7.07 (m, 2H), 7.38 (m, 2H), 9.04 (s, 1H), 9.10 (br s, 1H).
Reaction SMILES: Cl[C:2]1C(CN)=CC=C(Cl)N=1.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([N:18]([CH2:23][CH3:24])[C:19]([NH:21][CH3:22])=[S:20])=[CH:14][CH:13]=1.ClC1N=CC(N(C)C(NC)=S)=CC=1>>[CH3:2][S:20][C:19](=[N:21][CH3:22])[N:18]([C:15]1[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH2:23][CH3:24]
Reactant: CCN(C(=S)NC)c1ccc(Cl)nc1
Reactant: NCc1ccc(Cl)nc1Cl
Agent: CNC(=S)N(C)c1ccc(Cl)nc1
Product: CCN(C(=NC)SC)c1ccc(Cl)nc1

Procedure:
The reaction procedure of Example 59 (2) was reseated except that N-(6-chloro-3-pyridyl)-N-ethyl-N'-methylthiourea was used in lieu of N-(6-chloro-3-pyridyl)-N-methyl-N'-methylthiourea to give S-methyl-N-(6-chloro-3-pyridyl)-N-ethyl-N'-methylisothiourea as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.C(N(C(C)C)CC)(C)C>CO>[CH3:15][O:16][C:17](=[O:20])[CH2:18][N:12]1[CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11]1
Reactant: COc1cccc(C2CCNCC2)c1
Reactant: COC(=O)CBr
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCC(c2cccc(OC)c2)CC1
Yield: 90.4 %

Procedure:
A mixture of 4-(3-Methoxy-phenyl)-piperidine (0.8 g, 4.2 mmol), methylbromoacetate (1.28 g, 8.38 mmol), diisopropylethylamine (3.7 mL, 21 mmol) and MeOH (40 mL) was refluxed for 3 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The organic layer was washed with water, brine, dried and concentrated in vacuo to give the title compound as an oil (1.0 g, 91% yield). MS(ESI) 264.2 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 133.6 %

Procedure:
To a suspension of 2-amino-5-methoxybenzamide (2.42 g, 14.6 mmol) and pyridine (6 mL) in CHCl3 (120 mL) was added 3-nitrobenzoyl chloride (3.0 g, 16.1 mmol). The resulting mixture was stirred at RT for 6 h. The volatiles were removed in vacuo and the resultant solid was washed with Et2O to give the 5-Methoxy-2-(3-nitrobenzoyl)aminobenzamide (6.15 g) which was taken directly on to the next step. HPLC retention time 6.58 mins.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19]O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[CH:18]=2)=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=Cc2cc(Sc3ccccc3)ccc2OCC1
Reactant: OO
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ccc2c(c1)C=CCCO2
Reaction time: 2 h

Procedure:
6.00 g (23.6 mmol) of 2,3-dihydro-7-phenylthio-1-benzoxepin are introduced at 15°-20° C. into 59 ml of glacial acetic acid and, at this temperature, 5 ml of aqueous hydrogen peroxide solution (30% strength) are added dropwise. The mixture is stirred at this temperature for about 2 hours until all the precursor has reacted (TLC check). The mixture is then stirred into sodium bicarbonate/ice-water and extracted several times with diethyl ether. The combined ether phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvent is evaporated off in vacuo. 6.2 g of oil remain and are reacted without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](Br)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].O1CCN([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)CC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:24]2[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:16])[CH3:2]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CCOC(=O)C(Br)=NNc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCCC2
Yield: 54.9 %

Procedure:
A solution of bromo-(4-chlorophenyl)hydrazonoacetic acid ethyl ester (18.24 g, 60 mmol) in toluene (390 ml) and 10.02 g (60 mmol) of morpholinocyclohexene (10.02 g, 60 mmol) was cooled to 0° C. and triethylamine (12.6 ml, 90 mmol) was added. The solution was reacted for 1.5 hours at 0° C. and at ambient temperature for 48 hours. Triethylamine hydrochloride was filtered, the filtrate was washed with 10% hydrochloric acid, dried and evaporated. The crude product was crystallized from methanol to yield pure title compound (10.04 g), m.p. 139°-140° C. (lit 139°-141° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:17])[CH2:15]Cl)([CH3:3])[CH3:2].[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>O.CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:17])[CH2:15][S:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CS
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CSCC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A mixture of 18.8 g of N-(2,6-diisopropylphenyl)-2-chloroacetamide, 8.9 g of ethyl 2-mercaptoacetate, 20.4 g of potassium carbonate, and 100 ml of dimethyl sulfoxide was stirred at room temperature for 1 hour, and a mixture of 25 ml of concentrated hydrochloric acid and 100 ml of water was added thereto. The reaction mixture was extracted with 300 ml of ethyl acetate, and the extract was washed successively with a 1N hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to yield 22.6 g of N-(2,6-diisopropylphenyl)-2-(ethoxycarbonylmethylthio)acetamide as white needle crystals (m.p.=124.0°-125.0° C.).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].Br[CH2:9][C:10]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[N:7]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Reactant: CC(C)NC(N)=S
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Isopropyl-thiourea (2.47 mmol) and 3-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The volume was reduced to 5 mL and the mixture was then cooled to −20° C. and filtered. The solid was washed with a small amount of diethylether and dried. m/z=263.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].O>CN(C)C=O>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=1
Reactant: ClCCCCBr
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCCl
Yield: 796.2 %

Procedure:
A solution of N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (3.29 g, 1.5 mmol) in dimethylformamide (33 ml) and potassium carbonate (4.14 g, 30 mmol) was reacted with 1-bromo 4-chorobutane (3.86 g, 2.5 mmol) at 60° C. for 2 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic phase was dried (magnesium sulphate), concentrated and the residue was purified by chromatography on silica gel. Elution with dichloromethane:ethyl acetate (8:2) then increased polarity to (6:4) yielded N′-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamide as a white solid (3.7 g, 80% yield):
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=2)=[C:23]([CH3:36])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[NH2:38][OH:39].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[OH:39][NH:38][C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[C:8]([CH3:20])[CH:7]=3)[CH2:1][CH3:2])=[CH:22][C:23]=2[CH3:36])=[CH:32][CH:31]=1)=[O:35]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: NO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)NO)cc2)c(C)c1
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
4′-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-carboxylic acid (Example 170-(3); 25.7 mg, 0.053 mmol), hydroxylamine hydrochloride (7.4 mg, 0.106 mmol) and dichloromethane (0.5 mL) were placed in a reaction vessel. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.2 mg, 0.069 mmol) was added at 0° C., and then the mixture was stirred for 30 minutes. Subsequently, diisopropylethylamine (0.0184 mL, 0.106 mmol) and 4-dimethylaminopyridine (1.94 mg, 0.016 mmol) were added and the mixture was stirred at room temperature overnight. 1 N hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=10:1) to give the title compound (1.2 mg, 5%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>ClCCl>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: BrBr
Reactant: O=C1CCCC(=O)C1
Solvent: ClCCl
Product: O=C1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
To a stirred solution of 1,3 Cyclohexandione (10 g, 89 mmol) in dichloromethane (22 mL) at 0° C. was added a solution of bromine (3.8 mL, 89 mmol) in dichloromethane (3 mL) over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered and the residue washed with hexane (200 mL). The residue was taken into water (75 mL) and heated at 80° C. for 30 minutes. It was cooled to room temperature, filtered and dried under reduced pressure to give the desired product (14 g, 82%) as a solid. ESMS [M+H]: 191.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 1-phenylpiperazine (9.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C21H21N3O2: 347.1634, found 347.1628.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Under argon, 15 g (60.84 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate are initially charged in 750 ml of ethyl acetate and 750 ml of ethanol. 15.82 g (15.82 mmol) of ammonium formate and 1.50 g of palladium on activated carbon (10%) are added. The mixture is stirred at 90° C. for 30 minutes and then cooled and filtered off through Celite, which is washed with ethyl acetate. The solvent is removed under reduced pressure and the residue is dissolved in chloroform and washed twice with water. The organic phase is dried with sodium sulphate, filtered and concentrated under reduced pressure using a rotary evaporator.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH:16]([CH3:22])[C:17](OCC)=[O:18]>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([CH3:22])=[C:17]([OH:18])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CCOC(=O)C(C)C(=O)c1ccccc1F
Reactant: Nc1ccccc1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1O

Procedure:
Prepared according to procedure R using aniline (0.91 mL, 10 mmol) and ethyl 3-(2-fluorophenyl)-2-methyl-3-oxopropanoate (4 g, 20 mmol) in PPA (4 g, 40 mmol). The resulting precipitate was collected by filtration, washed with water, and dried to give 2-(2-fluorophenyl)-3-methylquinolin-4-ol. Mass Spectrum (ESI) m/e=254 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14].CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(C)c(S)c1
Reactant: CC(C)(CCl)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C)c(SCC(C)(C)C(=O)O)c1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A 100-ml round-bottomed flask was charged with 1.38 g (10.00 mmol) of 2,5-dimethylthiophenol, 1.40 g (10.26 mmol) of 3-chloropivalic acid and 15 ml of acetone. Then, 2.07 g (15.0 mmol) of potassium carbonate was added, and the mixture was refluxed under heat for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then about 100 ml of water was added. An aqueous layer was washed with n-hexane once, and neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution. A precipitated solid was extracted with ethyl acetate, and an organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.90 g (yield 80%) of 3-(2,5-dimethylphenylthio)pivalic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1Cl
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (1.81 g, 0.0077 mol), 4chlorophenyl isothiocyanate (1.59 g, 0.0094 mol) and toluene (10 ml) was refluxed for 2.5 hours, cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.54 g (90%), m.p. 177° 179 ° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>CN1C(=O)CCC1.CO>[OH:21][CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:2]2[C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[N:5]=[CH:6][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:16][CH2:17]1
Reactant: NC(=O)c1cnn2cccc2c1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnn2cccc2c1NC1CCC(O)CC1
Temperature: 80 °C
Yield: 85 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide, Preparation 3 (15 mg, 0.077 mmol) and (trans)-4-aminocyclohexanol (22.08 mg, 0.192 mmol) in NMP (0.3 ml) was heated at 80° C. for 1.5 h. The product mixture was diluted with methanol and purified by preparative HPLC (condition A) to afford the title compound as a white solid (17.8 mg, 85% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.44-1.56 (m, 4 H) 1.97-2.08 (m, 2 H) 2.17-2.28 (m, 2 H) 3.62-3.76 (m, 1 H) 4.03-4.19 (m, 1 H) 6.69 (dd, J=4.52, 2.76 Hz, 1 H) 6.91 (dd, J=4.77, 1.51 Hz, 1 H) 7.56 (dd, J=2.64, 1.63 Hz, 1 H) 8.10 (s, 1 H). HPLC (method F): ret. Time 2.105 min.; LC/MS [m/z, (M+H)] 275.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][N:19]([CH3:27])[C:15]=3[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3ncn(C)c3c2)c(SC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (as prepared in Example 38, step e) (100 mg, 0.22 mmol) in dimethylformamide (2 mL) was added MeI (13.9 μL, 0.22 mmol) and K2CO3 (61.8 mg, 0.45 mmol), then stirred overnight at room temperature. The solvents were removed in vacuo and the residue was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (15 mL) and brine (25 mL), and dried over MgSO4. The solvent was removed in vacuo to afford 20 mg (19%) of 4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(7-bromo-1-methyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a mixture. This mixture was used directly in the following step.