Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:11]1([CH2:17][C:18]([O:20]CCCC)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]>FC(F)(F)C(O)=O>[C:9]([C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]
Reactant: CCCCOC(=O)CC1(C#N)CCCCC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
To a solution of 2.4 mL (2.4 g, 22 mmol) of anisole in 50 mL of trifluoroacetic acid is added 5.00 g (22.4 mmol) of (1-cyanocyclohexyl)acetic acid, 1-butyl ester. The reaction is monitored (TLC) for the loss of starting material and when the reaction is complete it is concentrated under reduced pressure. Water (˜10 mL) is added to the residue and the mixture is adjusted to pH=10-12 with base (NaOH). The basic aqueous layer is extracted with a suitable organic solvent (EtOAc) to remove impurities. The aqueous layer is acidified with acid (HCl) to pH=0-4 and extracted with a suitable solvent (EtOAc). The combined organic extracts of the acidified aqueous layer are dried and concentrated under reduced pressure to afford the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](Cl)=[O:13])=[CH:10][N:11]=2)[CH:2]=1.C(N(CC)CC)C.Cl.[CH3:23][O:24][NH:25][CH3:26]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH3:23][O:24][N:25]([CH3:26])[C:12]([C:9]1[S:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][CH:10]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(Cl)c1cnc(-c2cccnc2)s1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A suspension of 2-(3-pyridyl)thiazole-5-carbonyl chloride (4.6 g, 19.5 mmol) prepared according to WO 2009/149858) in methylene chloride (100 ml) was cooled to 0° C. and treated with triethyl amine (6.03 g, 58.4 mmol), dimethylamino pyridine (12 mg, 0.097 mmol) and then N-methoxymethanamine hydrochloride (2.9 g, 29.2 mmol). The mixture was allowed to warm up to ambient temperature and monitored by TLC and LC/MS. After completion, the reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate, and the solvent removed by concentration in vacuo, to give 3.99 g (82%) of N-methoxy-N-methyl-2-(3-pyridyl)thiazole-5-carboxamide as a pale solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Mg+2].[Cl-].[Cl-].C([O-])(=O)CC([O-])=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-chlorophenyl)-2-methylpropionic acid (1.99 g, 10.0 mmol, 1.0 eq.) in IPAc (10 mL) was treated with DMF (0.02 mL) and oxalyl chloride (0.92 mL, 10.5 mmol). The resulting solution was stirred at room temperature for 2 hours. In a separate vessel, was charged diethyl malonate (1.91 mL, 12.5 mmol), IPAc (14 mL), and MgCl2 (11.9 g, 12.5 mmol). The resulting malonate slurry was stirred at room temperature for 30 minutes and subsequently treated with TEA (4.7 mL, 33.5 mmol). The resulting suspension was aged at room temperature for 2 hours, cooled to 5° C. and treated with the above acyl chloride solution. The resulting mixture was warmed to ambient temperature and aged for 1 hour. The slurry was quenched with a 5N HCl solution (10 mL) and the phases were split. The organic phase was washed with saturated NaHCO3 solution (2×10 mL) and water (1×10 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to afford an orange oil. MS m/e=341.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[N:3]1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1ncc([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C

Procedure:
A quantity comprising 69.0 gm (0.547 mol) of 1-methyl-1H-pyrazole-5-carboxylic acid of m.p.: 227°-228° C. (R. Huttel and M. E. Schon, Liebigs Ann. Chem 625, 55 [1959]) was added in small portions to a mixture of 200 ml of concentrated sulfuric acid and 60 ml of 90% fuming nitric acid under stirring. The temperature of the mixture rose from 75° C. at the beginning to a maximum temperature of 95° C. After the exothermal reaction was finished, heating was continued for 30 minutes up to 95° C. The cold mixture was stirred into 300 gm of cracked ice, and the resulting ice-cold suspension was filtered off by suction filtration. The filtration residue was washed with water, and after recrystallization from ethyl acetate, 44.0 gm (47% of theory) of pale yellow crystals were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:26])=[C:8]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[S:4][CH:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:26])=[C:8]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])[C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[S:4][CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a solution of methyl 2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.087 g; 0.237 mmol) in methanol (5 mL) and ethanol (2.6 mL) was added a 5% sodium hydroxide solution (6.8 mL; 8.500 mmol). The reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.052 g (62%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([NH:33][C:34](=[O:39])C(Cl)(Cl)Cl)[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:34]([NH:33][CH2:30][CH2:31][CH3:32])=[O:39])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Reactant: CCCNC(=O)C(Cl)(Cl)Cl
Product: CCCNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-propylaminocarbonyl-aminosulfonyl)-7-methoxychroman ##STR33## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-propylaminocarbonylaminosulfonyl)-7methoxychroman is prepared analogously to Example 1 from 4-(5Chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-(n-propyl)trichloroacetamide. Melting point: 159°-160° C.
Reaction SMILES: [NH2:1][C@:2]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=2)[CH2:3]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C@:2]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: COCCCCCC#Cc1ccc([C@H]2CC[C@](N)(C(=O)OC)C2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COCCCCCCCc1ccc([C@H]2CC[C@](N)(C(=O)OC)C2)cc1
Reaction time: 15 h

Procedure:
(1R,3S)-methyl 1-amino-3-(4-(7-methoxyhept-1-ynyl)phenyl)cyclopentanecarboxylate was taken up in ethanol (14.94 ml). To this was added Pearlman's Catalyst (0.052 g, 0.075 mmol) and the mixture was stirred at ambient temperature under the atmosphere of hydrogen. After about 15 hours, the reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to yield (1R,3S)-methyl 1-amino-3-(4-(7-methoxyheptyl)phenyl)cyclopentanecarboxylate (0.48 g, 1.38 mmol) as dark green oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:47][C:48]1[CH:49]=[CH:50][C:51]([CH3:79])=[C:52]([N:54]2[CH2:77][CH2:76][C:57]3[N:58]=[C:59]([NH:62][C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]5)=[CH:65][CH:64]=4)[N:60]=[CH:61][C:56]=3[C:55]2=[O:78])[CH:53]=1.Br[C:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[CH:84]=[CH:83][N:82]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:81]1([NH:47][C:48]2[CH:49]=[CH:50][C:51]([CH3:79])=[C:52]([N:54]3[CH2:77][CH2:76][C:57]4[N:58]=[C:59]([NH:62][C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:70][CH2:71][N:72]([CH3:75])[CH2:73][CH2:74]6)=[CH:65][CH:64]=5)[N:60]=[CH:61][C:56]=4[C:55]3=[O:78])[CH:53]=2)[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[CH:84]=[CH:83][N:82]=1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Reactant: Brc1nccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2nccc3ccccc23)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O

Procedure:
A mixture of 2,2′-Bis(diphenylphosphino)1,1′-binaphthyl [BINAP] (28.00 mg, 0.0451 mmol) and Palladium(II)acetate [Pd(OAc)2] (5.00 mg, 0.022 mmol) in dry toluene (3 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. To this, 6-(5-amino-2-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one [45] (200 mg, 0.451 mmol), 1-bromoisoquinoline (112.60 mg, 0.541 mmol) and dry cesium carbonate (443.0 mg, 1.352 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to 15 reflux overnight. The mixture was cooled, diluted with ethyl acetate, water was added and the layers separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodiumsulfate), filtered and concentrated. Further purification by silica gel chromatography using 5-10% ethyl acetate/hexane as eluent provided 6-(5-(isoquinolin-1-ylamino)-2-methylphenyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one [60] as a yellow solid [Yield: −223 mg, 87.0%].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[C:12]([NH:16][C:17]([C:19]1[O:20][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:21]3[O:20][C:19]([C:17]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)NC(=O)c1ccc(CN2CCNCC2)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)o1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of 4-amino-3-fluorobenzoic acid (0.883 g, 5.69 mmol), N-tert-butyl-5-(piperazin-1-ylmethyl)furan-2-carboxamide (1.51 g, 5.69 mmol) and triethyl-amine (0.576 g, 5.69 mmol, 0.791 mL) in dichloromethane was added 1-propanephosphonic acid cyclic anhydride (3.62 g, 5.69 mmol, 3.39 mL, 50% solution in ethyl acetate). The reaction was stirred for 2 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with sodium bicarbonate, water and brine. The organic phase was concentrated under reduced pressure to give the title compound (0.93 g). MS (ESI) m/z 403.6 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:19]N1C(C)(C)C(=O)N(Cl)C1=O.S(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[C:5]([Cl:19])=[CH:6][CH:7]=1
Reactant: Nc1cccn2nc(SCc3ccccc3)nc12
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Reaction time: 2 h

Procedure:
A solution of 8-amino-2-benzylthio[1,2,4]triazolo[1,5-a]pyridine (14.0 g, 0.0546 mol) and 1,3-dichloro-5,5-dimethylhydantoin (5.4 g, 0.0273 mol) were combined in 500 mL of dichloromethane and the mixture was heated at reflux with stirring for two hours. Additional 1,3-dichloro-5,5-dimethylhydantoin (5.0 g, 0.025 mol) was added and the reaction was ]heated with stirring for an additional hour. The reaction mixture was cooled and dilute aqueous sodium bisulfite was added with stirring and allowed to react for an hour. The mixture was then washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with dichloromethane to obtain 6.0 g (38 percent of theory) of the title compound as a light tan powder melting at 113°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.ClCCl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(OC)(C)(C)C.CCCCCC.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([CH3:12])[C:3]=1[C:4]([C:21]1[C:22]([O:26][CH3:27])=[C:23]([O:24][CH3:25])[C:18]([O:17][CH3:16])=[CH:19][C:20]=1[CH3:28])=[O:6]
Reactant: Cc1c(Cl)ccc(Cl)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)ccc(Cl)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
14 g (68.29 mmol) of 2,5-dichloro-6-methylbenzoic acid were introduced into 1000 ml of dichloromethane. 11.2 g (61.6 mmol) of 3,4,5-trimethoxytoluene and 28 g of finely ground phosphorus pentoxide were added. After 2 hours of stirring at room temperature, the reaction solution, which by now was orangey red, was poured into water and extracted three times with dichloromethane. The combined organic phases were washed twice with water, dried with sodium sulfate and concentrated, and the reaction product was then isolated by column chromatography using a methyl tert-butyl ether/hexane gradient. This gave 20.1 g of the title compound (yield 80%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]([O:15]CC)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[C:19]=[O:20]>CN(C)C1C=CN=CC=1.ClC(Cl)Cl>[CH2:21]([N:18]1[C:13](=[O:15])[CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=2)[C:19]1=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)CNc1ccc(NC(C)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCN1C(=O)CN(c2ccc(NC(C)=O)cc2)C1=O
Yield: 83 %

Procedure:
A mixture of 25 parts of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate, 20 parts of 1-isocyanatobutane, 2 parts of N,N-dimethyl-4-pyridinamine and 300 parts of trichloromethane was stirred and refluxed for 48 hours. The reaction mixture was evaporated and the residue was stirred and refluxed for 8 hours in 180 parts of dimethylbenzene. After cooling, the precipitated product was filtered off, washed with 2-propanol and dried, yielding 25.5 parts (83%) of N-[4-(3-butyl-2,4-dioxo-1-imidazolidinyl)phenyl]acetamide; mp. 192.8° C. (13).
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br.C(N(CC)CC)C>ClCCl.BrN1C(=O)CCC1=O>[C:1]([N:9]1[CH2:15][CH2:14][CH:13]([Br:21])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=C1CCCN(C(=O)c2ccccc2)c2ccccc21
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2N(C(=O)c2ccccc2)CCC1Br
Temperature: 25 °C

Procedure:
1-Benzoyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.6 (54.2 g, 205 mmol), N-bromosuccinimide (3.6 g, 20.4 mmol) and bromine (11.1 ml, 214.7 mmol) were dissolved in dichloromethane (1.0 liter). Triethylamine (30 ml, 215 mmol) was added dropwise over 30 minutes then the reaction mixture was heated at reflux for 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added and the reaction mixture was heated at reflux for a further 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added again and the reaction mixture was heated at reflux for a further 4 h. On cooling to room temperature, the reaction solution was washed with 5% aqueous sodium metabisulfate solution (150 ml) and the aqueous phase was diluted with water (600 ml). The organic phase was separated, washed with saturated Na—HCO3 (aq), dried over sodium sulphate and filtered. The filtrate was diluted with EtOAc (100 ml), filtered through a silica pad (eluant; CH2Cl2) and reduced in vacuo to yield the title compound (73.6 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([C:24]([O:26]C)=[O:25])=[O:23])=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].O.[OH-].[Li+]>>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([C:24]([OH:26])=[O:25])=[O:23])=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C(=O)C(=O)OC)cc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 80.8 %

Procedure:
252 mg of ethyl 2-ethoxy-1-[(2'-methoxalylbiphenyl4-yl)methyl]benzimidazole-7-carboxylate [prepared as described in step (a) above] were subjected to hydrolysis using 136 mg of lithium hydroxide monohydrate in the same manner as described in Example 17(b), to give 186 mg of the title compound as a powder, melting at 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccc(Cl)cc2)cs1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 35 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (65 mg, yield 35%). 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=1.8 Hz, 1H), 9.24 (d, J=1.8 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H), 7.82-7.80 (m, 3H), 7.41 (s, 1H), 7.38-7.36 (m, 2H), 4.05-4.01 (q, J=5.8 Hz, 2H), 3.43-3.40 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated for C20H13ClF3N5O2S: 479.04. found: 480.0 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30](O)=[O:31])=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:20][CH:19]=1>>[S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:30]([C:25]2[C:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:28][N:27]([CH3:29])[N:26]=2)=[O:31])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: c1ccc2sc(CC3CCCCN3)cc2c1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2cc3ccccc3s2)n1
Yield: 2.4 %

Procedure:
The title compound (6 mg) was prepared from 2-benzo[b]thiophen-2-ylmethyl-piperidine D83 (133 mg) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (140 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[O:13]1[CH:14]=[C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[N:11]=[CH:12]1
Reactant: COC(=O)c1csc(-c2cocn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1csc(-c2cocn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
5-Oxazol-4-yl-thiophene-3-carboxylic acid methyl ester (0.338 g, 1.62 mmol) was dissolved in methanol (3 mL) and sodium hydroxide (1 N, 2.1 mL) was added. The mixture was stirred at room temperature for 2 hours then a further amount of sodium hydroxide (1 N, 1 mL) was added and stirring continued overnight. The mixture was concentrated and the residue treated with HCl (1 N, 3.5 mL). The resultant precipitate was collected by filtration to give the title compound as a tan/off-white solid (0.158 g). The filtrate was passed through an SCX-2 cartridge (20 g) and concentrated to give a further amount of the title compound as a tan solid (0.078 g). LCMS m/z 196.13 [M+H]+ R. T.=3.22 min (Analytical Method 9).
Reaction SMILES: [F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].C(P(CCCC)CCCC)CCC.O[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[N:44][CH:45]=1.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1COCC1>[F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6])[C:14]1[CH:15]=[C:16]2[C:20]([CH2:19][CH2:18][CH2:17]2)=[CH:21][C:22]=1[O:23][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[N:44][CH:45]=1
Reactant: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Reactant: CCOC(=O)c1ccc(CO)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(COc2cc3c(cc2N(C[C@H](C)F)S(=O)(=O)c2nc(C)cs2)CCC3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
133 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide, 94.4 mg of tributylphosphine, and 71.5 mg of ethyl 5-(hydroxymethyl)pyridine-2-carboxylate were dissolved in 1.33 mL of THF, and 118 mg of 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine was added thereto, followed by stirring overnight at room temperature. After the insoluble materials were removed by filtration, the solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to obtain 116 mg of ethyl 5-{[(6-{[(2S)-2-fluoropropyl][(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyridine-2-carboxylate.