Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][O:25][CH2:26][C:27]([NH:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)=[O:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][O:25][CH2:26][C:27]([NH:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: COCC(=O)Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 1 and 39 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-methoxymethylcarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[C:10]=12)=[O:5].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:2][O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]2[CH2:14][CH2:13][N:12]([C:30](=[O:31])[CH2:29][CH:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH2:33][C:34]3[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=3[F:42])[C@H:11]([CH3:15])[C:10]=12)=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1C(C)NCC2
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(C(F)(F)F)n2c1[C@@H](C)N(C(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 77.2 %

Procedure:
8-Methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 39c crude product (0.289 g, 0.96 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (0.353 g, 1.06 mmol) were dissolved in 10 mL of dichloromethane, followed by addition of triethylamine (0.4 mL, 2.9 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.368 g, 1.45 mmol) under stirring. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 39d (0.43 g, yield 77.2%) as a yellow oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH2:14][CH3:15]>C(OCC)C>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:13]([CH2:14][CH3:15])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][C:3]=2[O:2]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)CC
Solvent: CCOCC
Product: CCOC(=O)C=C(CC)NCCc1ccc2c(c1)OCO2
Reaction time: 12 h

Procedure:
In a manner similar to that described in Example IV, 5.0 grams (30 millimoles) of 4-(3,4-methylenedioxyphenethylamine is added dropwise with stirring at ambient temperature to 4.5 grams (31 millimoles) of ethyl propionylacetate and the stirring continued for about 12 hours at ambient temperature. Thereafter, the mixture is diluted with 250 milliliters of diethyl ether and the resulting ether solution washed with 50 milliliters of brine and then dried over sodium sulfate. The ether is vaporized off of the dried and filtered solution to obtain ethyl 3-[2-(3,4-methylenedioxyphenyl)ethyl]amino-2-pentenoate.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1>C1COCC1>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Reactant: Fc1ccc(C[Zn+])cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2nnc(Cl)c3c2CCCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 1,4-dichloro-5,6,7,8-tetrahydro-phthalazine (0.50 g, 2.46 mmol) in THF (5 mL) are added 4-fluoro-benzyl zinc chloride (0.5M in THF) (6.40 mL, 3.20 mmol) and palladium tetrakis triphenylphosphine (0.36 g, 0.31 mmol). The mixture is degassed and stirred at 50° C. overnight. Then the reaction mixture is cooled down to room temperature, sat. NaHCO3 and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/Hexane: 10%˜40%) to give 1-chloro-4-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-phthalazine (compound 10f) (0.51 g, 30%). m/z=277.11 [M+1]
Reaction SMILES: [F:1][C:2]([F:37])([C:33]([F:36])([F:35])[F:34])[C:3]([F:32])([F:31])[C:4]([F:30])([F:29])[O:5][C:6]([F:28])([F:27])[C:7]([F:26])([F:25])[O:8][C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[CH2:38]([C:46]1[CH:47]=[N:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=2)=[N:50][CH:51]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:38]([C:46]1[CH:51]=[N:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([F:20])([F:19])[C:10]([F:22])([F:21])[C:9]([O:8][C:7]([F:26])([F:25])[C:6]([F:28])([F:27])[O:5][C:4]([F:30])([F:29])[C:3]([F:32])([F:31])[C:2]([F:37])([F:1])[C:33]([F:36])([F:35])[F:34])([F:24])[F:23])=[CH:54][CH:53]=2)=[N:48][CH:47]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(4-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutoxy)butyl bromide (25.6 g, 38.5 mmol; prepared by combining 1,4-dibromobutane and 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10 g, 35 mmol). The resulting product was further purified by recrystallization from heptane, followed by Kugelrohr distillation (b.p. 200-210° C. at 0.4 torr; yield of 20.4 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1.[C:32](O)(=[O:35])[C:33]#[CH:34]>CN(C=O)C>[Br:31][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:32](=[O:35])[C:33]#[CH:34])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg, 1.04 mmol) was added to a solution of 6-amino-4-[(3-bromophenyl)-amino]quinazoline (158 mg, 0.5 mmol) and propiolic acid (0.08 mL, 1.1 mmol) in DMF (1.5 mL) stirred under N2 at 0° C. The resulting solution was stirred at 0° C. for 30 minutes and quenched with water. The formed fine solid was collected by Buchner filtration then dissolved in methanol and purified by preparative tlc on silica, eluting with 10% MeOH/CHCl3. The title compound was isolated as a yellow solid (21 mg, 12%), mp>310° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[C:17]([Cu])#[N:18]>CN1CCCC1=O.CCOC(C)=O>[C:17]([C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8])#[N:18]
Reactant: CCOC(=O)CCCc1ccc(O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc(O)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-(3-bromo-4-hydroxyphenyl)butanoate (19.8 g, 69 mmol) in 172 mL of N-methyl-2-pyrrolidinone was added CuCN (6.49 g, 72.4 mmol). The solution was heated to reflux for 4 hours then cooled to room temperature. The reaction was diluted with EtOAc and washed twice with 5% HCl and once with brine, then dried over sodium sulfate and concentrated. Purified on silica gel using 60:40 hexanes:EtOAc as the elutant. The yield of ethyl 4-(3-cyano-4-hydroxyphenyl)butanoate was 9.84 g (61%): 1H-NMR (CDCl3) 7.67 (1H, s), 7.24-7.29 (2H), 7.94 (1H, d), 4.14 (2H, q), 2.59 (2H, dd), 2.34 (2H, dd), 1.91 (2H, m), 1.28 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:13])([CH3:12])[C:5](=[O:11])[NH:6]2.C(O)(=O)C.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:18][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[C:4]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2cccc(F)c21
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccc(Br)c(F)c21
Reaction time: 24 h
Yield: 64.6 %

Procedure:
4-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1 g, 22.9 mmol) was dissolved in dichloromethane (DCM) (50 mL) and acetic acid (2 mL) at room temperature. Bromine (0.386 mL, 7.5 mmol) was added and the solution allowed to stir 24 hours. The reaction mixture was poured into sodium thiosulfate solution, extracted with diethyl ether, the combined organic layers were dried over magnesium sulfate and evaporated. Trituration of the crude product with hexane gave 5-bromo-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.25 g, 87%): HRMS [M−H]− 255.9781
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH2:11])=[S:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([S:14][C:15](=O)[CH2:16]Br)[CH3:13]>C(O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(N)=S
Reactant: CCSC(=O)CBr
Solvent: CCO
Product: CCSc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
N-tert-butoxycarbonyl-thiourea (0.600 g, 3.40 mmole) was suspended in ethanol (5 mL) and the mixture was cooled in an ice-water bath. To this mixture was added a solution of bromo-thioacetic acid S-ethyl ester (0.880 g [75% pure]; 3.61 mmole) in ethanol (5 mL). Following completion of the addition, the mixture was warmed to room temperature and stirred overnight. After 20 hours, the reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was washed with water and brine. The aqueous phases were then backwashed with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes, to give (4-ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.514 g, 58%).
Reaction SMILES: [CH2:1]([O:4][N:5](C(OC(C)(C)C)=O)[C@H:6]1[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C:19](=[O:21])[NH2:20])[CH:8]=[C:7]1[CH2:22][O:23][CH3:24])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:19]([NH2:20])=[O:21])[CH:8]=[C:7]1[CH2:22][O:23][CH3:24])[CH:2]=[CH2:3]
Reactant: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1COC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1COC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
(2S,5R)-tert-butyl 5-(allyloxy(tert-butoxycarbonyl)amino)-2-carbamoyl-4-(methoxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 73, 3.07 g, 6.95 mmol) was dissolved in 20 mL DCM. Then 5.36 mL TFA was added dropwise at 0° C. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo and co-evaporated twice with 5 mL MeOH. The residue was dissolved in MeOH (10 mL) and ammonium hydroxide (30% in water) was added until it was basic. The mixture was rotovapored at rt and the residue was freeze-dried over night to give a solid. It was dissolved in DCM and purified on silica gel eluting with 0-100% MeOH/DCM to give a off-white solid (1.12 g, 66.8%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CCCCO
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Sodium borohydride (2.28 g, 60.4 mmol) was added to a solution of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (prepared as described in Parts A-C of Example 6, 17.0 g, 60.4 mmol) in ethanol (200 mL). The reaction mixture was stirred for 2 hours, then saturated aqueous sodium bicarbonate was added. The ethanol was removed under reduced pressure and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 15.7 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:20])[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:20][Br:21])[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2oc3ccc(C)cc3c(=O)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2oc3ccc(CBr)cc3c(=O)c12
Temperature: 25 °C
Yield: 44.8 %

Procedure:
Brominating agents include N-bromosuccinimide, bromine, complexed bromine such as pyridinium bromide, and the like can be used to convert 7-methyl-9-oxoxanthene-1-carboxylic acid methyl ester 40 to 7-bromomethyl-9-oxoxanthene-1-carboxylic acid methyl ester 41. Solvents include chlorinated hydrocarbons, dipolar aprotic solvents, and various ethers. Temperature can range from 0-100 C. For example, a suspension of 7-methyl-9-oxoxanthene-1-carboxylic acid methyl ester (0.1 mol), N-bromosuccinimide (0.12 Mol) and benzoylperoxide (10 mg) in dry carbon tetrachloride (300 mL) is stirred at 60 C for 6 hours. The mixture is filtered, and the solid is washed successively with small amounts of chloroform, water and ether, and then dried to leave a desired product as white solid. For example, to a solution of compound 40 (1.97 g, 7.4 mmol) in carbon tetrachloride (400 mL) was added N-bromosuccinimide (1.44 g, 8.1 mmol) and a catalytic amount of benzoyl peroxide (45 mg, 3%). The reaction mixture was heated to reflux for 6 h and cooled to room temperature. The white precipitate was filtered out. The solvents were removed and the residue was recrystallized from EtOAc and hexanes. The crude product (2.05 g) was obtained and further recrystallization gave a pure white solid product 41 (1.15 g, 45%). 1H NMR (400 MHz, CDCl3) of 2: 8.27 (d, J=2.5 Hz, 1H), 7.80-7.72 (m, 2H), 7.57 (dd, J=8.5 and 1.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.33 (dd, J=7.0 and 1.1 Hz, 1H), 4.57 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:11][C:4]1[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[C:6]([CH3:10])[N:5]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(C)c(C)nc1N
Product: COc1nc(C)c(C)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5,6-dimethyl-2-pyrazinamine (0.07 g) and 2,3-dichlorobenzenesulphonyl chloride (0.12 g). Yield 0.04 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([NH:15][CH:16]=O)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].[C:24](=O)([O-])[O-:25].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([NH:15][CH2:16][CH:24]=[O:25])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(NC=O)c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(NCC=O)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
The whole (0.0018 mole) of the ethyl 6,7-difluoro-1-(formylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVI) [prepared as described in Step (D2) above] was dissolved in 8 ml of dimethylformamide. 0.51 g (0.0037 mole) of potassium carbonate and 0.78 g (0.0052 mole) of methyl iodide were then added to the solution, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the solvent was distilled from the mixture under reduced pressure. The residue was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure to give 0.5 g of ethyl 6,7-difluoro-1-(N-formylmethylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVII, R10 =methyl) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(N)c1
Yield: 94.4 %

Procedure:
10 g of 4-methoxy-2-nitrophenol was dissolved in 120 ml of methanol and 80 ml of ethyl acetate. Thereafter, 800 mg of 10% palladium carbon was added to the reaction solution, followed by reduction under hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the residue was then concentration under a reduced pressure. The generated solid was suspended in hexane-t-butylmethyl ether, and the suspension was then filtered, so as to obtain 7.77 g of the subject compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9]([CH:10]=O)=[C:8]([O:19][CH3:20])[CH:7]=1.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9](/[CH:10]=[CH:24]/[C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:25])=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
The title compound was prepared by condensing 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50C) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 199–201° C., 60% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.23 (d, 2H, J=8.7 Hz), 8.06–8.11 (m, 3H), 7.93 (d, 1H, J=15.0 Hz), 7.71 (d, 1H, J=3.3 Hz), 7.54 (d, 1H, J=5.1 Hz), 7.13–7.16 (m, 1H), 6.87 (s, 1H), 4.62 (brs, 2H), 4.27 (d, 2H, J=5.1 Hz), 4.00 (s, 3H), 3.62 (brs, 4H), 2.11–2.15 (m, 1H). MS (ESI) m/z=469 ([M+H]+, 100%). Anal. Calcd. for C25H24O7S.¼H2O: C, 63.48; H, 5.22; S, 6.78. Found: C, 63.45; H, 5.29; S, 6.61.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[OH:9].C(N(CC)CC)C.[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:17]1([C:23]([O:25][CH3:26])=[O:24])[O:9][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2=[N:2]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: N=C1CCCCN1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(C(=O)OC)N=C2CCCCN2O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-iminopiperidin-1-ol hydrochloride in chloroform was added triethylamine. The mixture was stirred for 5 min. at room temperature, then cooled to 0° C. and 1.2 eq. of dimethyl acetylenedicarboxylate were added dropwise under stirring. The cooling bath was removed and the mixture was stirred at room temperature for one hour. The solvent was removed under reduced pressure and the solution was partitioned between ethyl acetate and half saturated aq. ammonium chloride. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered through silica gel. The solvent was removed under vacuum to afford methyl 2-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2H-[1,2,4]oxadiazolo[2,3-a]pyridine-2-carboxylate as a light yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:25]([CH:22]([CH2:23][CH3:24])[CH2:21][N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]1=[O:27])[CH3:26]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(-c3cccnc3)c21
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (585 mg, 6.6 mmol) and NaOMe solution (10 mL, 4.9 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound as an off-white solid. MS: (+) m/z 515.36 (M+1).
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][NH:4][CH2:5][CH:6]=[CH2:7].C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][N:4]([CH2:3][CH:2]([F:8])[F:1])[CH2:5][CH:6]=[CH2:7])=[CH:23][CH:24]=1
Reactant: C=CCNCC(F)F
Reactant: ClCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(Cc1ccc(Cl)nc1)CC(F)F
Temperature: 70 °C
Yield: 100.7 %

Procedure:
An amount of 16.46 g (0.135 mol) of N-(2,2-difluoroethyl)prop-2-en-1-amine is placed in 31.9 g (0.244 mol) of N,N-diisopropylethylamine and 20 g (0.122 mol) of 2-chloro-5-(chloromethyl)pyridine are introduced at 70° C. The mixture is heated at 70° C. for 16 hours and the excess N,N-diisopropylethylamine is subsequently distilled off. The residue is treated with 100 ml of water and extracted twice with 50 ml of dichloromethane. After drying the combined organic phases over magnesium sulphate, they are filtered through a layer of silica gel and the solvent is removed under vacuum. An amount of 30.3 g (98% content) of N-[(6-chloropyridin-3-yl)methyl]-N-(2,2-difluoroethyl)prop-2-en-1-amine is obtained (corresponds to 97.9% yield).