Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][CH:8]=[CH:7]2.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([C:12]#[N:13])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:14])[C:2]=2[Cl:1]
Reactant: N#Cc1cccc2ccc(O)c(Cl)c12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a mixture of 8-chloro-7-hydroxy-1-naphthonitrile (0.127 g, 0.63 mmol) and glacial acetic acid (1 mL) in a pressure tube was added a solution of bromine (0.24 g, 1.5 mmol) in glacial acetic acid (2 mL). The tube was sealed and the mixture was stirred at 100° C. overnight. The reaction was cooled, poured into water (50 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, stripped of solvent, and purified on a silica column (20% ethyl acetate-hexanes) to yield 0.10 g (56%) of the title compound as a yellow solid. An. analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 148–150° C.; 1H NMR (DMSO-d6): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1)#[N:21]
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(C#N)cc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)-c1nc(C(=O)O)sc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 9-cyano-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (80 mg) in THF (6 mL) and ethanol (3 mL) was added sodium hydroxide solution (18 mg in 3 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2M hydrochloric acid and the resulting solid was filtered and air-dried to give 9-cyano-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.17 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 429 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: N[C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N(OC(C)(C)C)=O.[NH4+].[Cl-:20]>C(#N)C.Cl[Cu]>[Cl:20][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: [Cl-]
Reactant: COC(=O)c1nc(N)sc1I
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Agent: [NH4+]
Solvent: CC#N
Product: COC(=O)c1nc(Cl)sc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of methyl 2-amino-5-iodothiazole-4-carboxylate (8A) (9 g, 31.7 mmol) in acetonitrile (60 mL) was added CuCl (4.75 g, 48 mmol) followed by t-butyl nitrite (6.19 g, 60 mmol). The mixture was stirred at rt for 2 hours. NH4Cl was then added slowly to the stirring mixture to quench the reaction. The mixture was extracted with EtOAc and the combined extracts were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 7.5 g (78%) of the desired product methyl 2-chloro-5-iodothiazole-4-carboxylate (88): LC/MS (APCI): m/z 304.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[Na+].Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].O>CN(C=O)C>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[CH:6]=1)=[O:9]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
3-(trifluoromethyl)pyrazole-4-carbaldehyde (200 mg, 1.22 mmol) was dissolved in DMF (10 mL). NaH (60% [w/w] suspension in oil, 50 mg, 1.25 mmol) was added portionwise and the reaction mixture stirred at RT for 30 min. 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (386 mg, 1.22 mmol) was added and the reaction mixture heated at 65° C. for 2 h, then allowed to cool to RT. Water (10 mL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×10 mL), brine (10 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the desired product (470 mg, 1.17 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[C:6]([Cl:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[Cl:10][C:6]1[C:7]([OH:8])=[C:2]([Cl:1])[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: COc1c(Cl)nc(-c2ccccc2)nc1Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Oc1c(Cl)nc(-c2ccccc2)nc1Cl
Temperature: 0 °C

Procedure:
15.3 g of 4,6-dichloro-5-methoxy-2-phenylpyrimidine and 30 ml of 25% boron trichloride solution in methylene chloride are heated at 40° C. in a bomb tube for 15 hours. The reaction mixture is subsequently added dropwise to a mixture of methanol and methylene chloride (1:1), and then diluted with ice-water. The organic phase is separated, and the aqueous phase is extracted with methylene chloride. The combined organic phases are concentrated by evaporation and chromatographed on silica gel to thus obtain 8.7 g of 4,6-dichloro-5-hydroxy-2-phenylpyrimidine, m.p. 138°-140° C. (compound No. 34).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]([CH:16]=O)=[C:10]([CH:15]=1)[C:11](OC)=[O:12].[NH2:27][C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[CH:15]=[C:10]2[C:9]([CH2:16][N:27]([C@@H:28]3[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]3)[C:11]2=[O:12])=[C:8]([CH3:18])[C:7]=1[CH3:19]
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(C=O)c(C)c2C)cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.2 %

Procedure:
To a solution of methyl 5-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.09 g) in THF (2.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.03 g) and anhydrous magnesium sulfate (0.06 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, and the residue was diluted with methanol (2.00 mL)-THF (2.00 mL). Sodium triacetoxyborohydride (0.11 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (0.04 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[NH:52]([CH2:56][CH2:57][OH:58])[CH2:53][CH2:54][OH:55]>>[OH:55][CH2:54][CH2:53][N:52]([CH2:56][CH2:57][OH:58])[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:41])([CH3:42])[N:38]([O:43][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: OCCNCCO
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(N(CCO)CCO)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and diethanolamine according to the procedure of Example 1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6](=[O:23])/[C:7](/[CH2:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:8]\[C:9]([O-:11])=[O:10])[CH3:2].[S:28]([O-:31])([OH:30])=[O:29].[Na+:32].O.C(O)C>C(OCC)(=O)C>[CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6](=[O:23])[C:7]([CH2:12][C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])([S:28]([OH:31])(=[O:30])=[O:29])[CH2:8][C:9]([O-:11])=[O:10])[CH3:2].[Na+:32]
Reactant: CCCCC(CC)COC(=O)/C(=C\C(=O)[O-])CC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCCCC(CC)COC(=O)C(CC(=O)[O-])(CC(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)O
Yield: 31.7 %

Procedure:
80.3 g (0.196 mol) of mono(2-ethylhexyl)mono(2,2,3,3,4,4,4-heptafluorobutyl)maleate, 20.4 g (0.196 mol) of sodium hydrogen sulfite and 80 mL of water/ethanol (1/1 v/v) were mixed together and heated under reflux for 10 hr. Thereafter, 1000 mL of ethyl acetate was added, and the organic phase was washed with a saturated aqueous sodium chloride solution. The resultant organic layer was collected, and the organic solvent was distilled off in vacuum. Purification by silica gel column chromatography (chloroform/methanol: 9/1 v/v) was performed. The collected organic phase was washed with a saturated aqueous sodium chloride solution, and the organic solvent was distilled off in vacuum, thereby obtaining 32 g (yield: 32%) of desired compound as a colorless transparent solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>O1CCCC1>[OH:11][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)([CH3:10])[CH3:9]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a stirred solution of 2-(2-bromophenyl)propan-2-ol (step 1, 6.91 g, 32.1 mmol) in tetrahydrofuran (32 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (46.5 mL, 73.9 mmol) at −78° C. for 20 min and the mixture was stirred for 1 h at the same temperature. To the mixture was added dropwise a solution of 1-methylpiperidin-4-one (5.09 g, 45.0 mmol) in tetrahydrofuran (18 mL) at −78° C. for 10 min. This resulting mixture was slowly warmed up to room temperature and stirred for 18 h at the same temperature. The reaction mixture was quenched by the addition of water, and concentrated to give an orange residue. The crude material was partitioned between diethyl ether and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1), then dichloromethane/methanol/triethylamine (10/1/1) to afford 4.62 g (58%) of the title compound as a slight yellow syrup:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.CC(C[AlH]CC(C)C)C>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cc(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Product: OC/C=C/c1cc(Br)cc(Br)c1

Procedure:
(E)-Ethyl 3-(3,5-dibromophenyl)-acrylate (example109a) was reduced with DIBAL-H by a procedure analogous to that described in example 50b, to give the colourless solid (E)-3-(3,5-dibromophenyl)-prop-2-en-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].[Cl-]>CN(C)C(=O)C.C(#N)C.N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:6][CH:7]=2)(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=CNNc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: -5 °C
Yield: 77.8 %

Procedure:
In 90 ml of N,N-dimethylacetamide, 76 ml of acetonitrile, and 17 ml cf pyridine were dissolved 35.4 g of 2-(4-aminophenyl)-1-formylhydrazine in a nitrogen gas atmosphere and after cooling the solution to -5° C., 59.9 g of 4-chloro-3-nitrobenzenesulfonyl chloride were gradually added to the solution while cooling with stirring so that the liquid temperature was not over -5° C. After further stirring the mixture for 1.5 hours at temperature below -5° C., the temperature was raised to room temperature and the reaciton mixture was poured into 1 liter cf a saturated aqueous solid chloride solution. Crystals formed were collected by filtration and washed with water to provide 67.5 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1.O>C(Cl)Cl.CN(C=O)C>[C:20]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cc(CC(OC)C(=O)O)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC(OC)C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid (1.02 g, 4.87 mmol) in CH2Cl2-DMF (20 mL=10:1) was added tert-butyl-dimethylsilyl chloride (1.75 g, 11.68 mmol) and imidazole (0.70 g, 10.24 mmol). The resulting solution was stirred at room temperature overnight. Water (15 mL) was added, and the aqueous phase was extracted with hexanes (30 mL). The hexanes layer was washed with water (10 mL), dried (MgSO4), filtered, and concentrated. The crude product was dissolved in ethyl acetate (10 mL), and a saturated solution of K2CO3 (5 mL) was added. The resulting mixture was stirred for 2 hours at room temperature. The aqueous layer was extracted with ethyl acetate (10 mL), acidified to pH 3, and extracted again with ethyl acetate (3×10 mL). The later organic layers were combined and washed with brine (20 mL), dried (MgSO4), and concentrated to a yellow oil (1.2 g, 77%). 1H-NMR (200.15 MHz, CDCl3): δ 6.78–6.67 (m, 3H), 3.96 (dd, 1H, J=7.8, 4.0), 3.78 (s, 3H), 3.35 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd, 1H, J=14.2, 7.8), 0.98 (s, 9H), 0.13 (6H, s).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][N:53]=[CH:52][C:51]=1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][N:50]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: NCc1cnccn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnccn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyrazin-2-ylmethanamine, the title compound was obtained as a colorless solid in 42% yield: mp 185-187° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.53-8.51 (m, 2H), 7.30-7.25 (m, 2H), 7.07-7.01 (m, 2H), 6.83 (br s, 1H), 4.76 (d, J=6.0 Hz, 2H), 4.46 (s, 2H), 4.09 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:23][CH3:24])[O:9][CH:10]=[C:11]([CH2:12][O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C@H:6]2[CH2:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:2]([C:3]1[C@H:7]2[C@H:8]([O:23][CH3:24])[O:9][CH:10]=[C:11]([CH2:12][O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C@H:6]2[CH2:5][CH:4]=1)=[O:1]
Reactant: COc1ccc(COCC2=CO[C@@H](OC)[C@@H]3C(CO)=CC[C@H]23)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(COCC2=CO[C@@H](OC)[C@@H]3C(C=O)=CC[C@H]23)cc1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
0.240 g (0.72 mmol) of (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran was dissolved in 5 ml of methylene chloride and 0.311 g (1.44 mmol) of pyridiniumchlorochromate was added thereto. The reaction solution was stirred for one hour, filtered through diatomaceous earth, and then concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexanelethylacetate=4/1, v/v) to obtain 0.167 g (Yield 70%) of (1R,4aS,7aS)-7-formyl-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:14][C:15]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(Cl)nc1NCc1ccncc1
Reactant: NCCN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(NCCN2CCOCC2)nc1NCc1ccncc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (18 mg, 0.044 mmol, made from 2,6-dichloronicotinic acid) and 2-morpholin-4-ylethylamine (300 μL) was stirred at 80° C. for 20 h. The reaction mixture was purified on silica gel chromatography to yield N-(3,4-dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+):501 (M+H)+; (ES−):499 (M−H)−. Calc'd for C24H26Cl2N6O2—500.15.
Reaction SMILES: [CH3:1][N:2]([S:30]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)(=[O:32])=[O:31])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:19]3)=[CH:15][N:16]=1)=[CH:8]2.O1CCCC1.[OH-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][N:2]([S:30]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)(=[O:32])=[O:31])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]3)=[CH:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(CN4CCN(CC(=O)O)CC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a solution of ethyl {4-[(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]piperazin-1-yl}acetate (0.490 g) in a mixed solvent of tetrahydrofuran (10 ml) and methanol (5 ml) was added 8N aqueous sodium hydroxide solution (1.5 ml), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with ethyl acetate and water, and dried to give the title compound (0.360 g, yield 57%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[C:38]([C:40]([O:42]C)=[O:41])[CH:37]=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[C:38]([C:40]([OH:42])=[O:41])[CH:37]=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)c2cnc(N3CCCN(C(=O)OC(C)(C)C)CC3)cn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(C(=O)Nc3cc(C(=O)O)ccc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-[5-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzamide (Example P10, 0.610 g, 1 mmol) in THF (6 mL) and water (2 mL) was added lithium hydroxide (0.240 g), and the solution was stirred overnight. THF was evaporated off under vacuum, and the remaining aqueous layer was acidified to pH 2 with 0.1 N HCl before it was extracted with ethyl acetate (3×20 mL), dried over magnesium sulfate and the solvent evaporated. This crude product was used as such for deprotection in the next step.