Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].C=[O:13].Cl[CH2:15][Cl:16]>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:13][CH2:15][Cl:16])=[O:9]
Reactant: C=O
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: ClCCl
Product: COC(=O)CCCCC(=O)OCCl

Procedure:
A mixture of 6-methoxy-6-oxohexanoyl chloride (0.040 mole) and paraformaldehyde (0.040 mole) are heated in a sealed vessel at 90 degrees for 3 hours. The reaction is cooled, and the solids are dissolved in dichloromethane. The solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which is purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 6-methoxy-6-oxohexanoate. See Bodor et al., J. Med. Chem., (1980) 23: 469; Ulich et al., J. Am. Chem. Soc., (1921) 43: 660.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].C(OCC)C>C(O)C.C(Cl)(Cl)Cl>[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:24][C:21]=1[CH:22]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8])([O-:19])=[O:18]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: O=Cc1cc(OCCCCS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1NC(=O)C(=Cc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2[N+](=O)[O-])N1
Reaction time: 1 h
Yield: 8.6 %

Procedure:
Sodium (0.386 g, 0.017 g, atom) was dissolved in ethanol (70 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (3.96 g, 17 mmol) added. After 1 hour, a solution of 2-nitro-5-[4-(phenylsulfonyl)butoxy]benzaldehyde (4.70 g, 13 mmol) (prepared by alkylating 5-hydroxy-2-nitrobenzaldehyde with 4-phenylsulfonylbutyl bromide) in ethanol and chloroform was added. After 20 minutes, the solvent was evaporated and the residue extracted with chloroform to give a foamy solid which was dissolved in acetontirile. Diethyl ether was added to the point of precipitate nd the mixture allowed to stand overnight. A solid (0.86 g) was collected and further purified gy crystallication from acetonitrile-diethyl ether to give 5-[[2-nitro-5-[4-(phenylsulfonyl)butoxy]phenyl]methylene]-2,4-imidazolidinedione (0.5 g). Concentration of the combined mother liquors afforded 4.1 g of material that was used without further purification. Yield (4.6 g, 61%). Crystallized material had m.p. 150°-152° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[C:14]([CH2:16][C:17]([NH2:19])=[S:18])#[N:15].C(N(C(O)C)CC)C>C(O)C>[C:14]([C:16](=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])[C:17]([NH2:19])=[S:18])#[N:15]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: N#CCC(N)=S
Agent: CCN(CC)C(C)O
Solvent: CCO
Product: N#CC(=Cc1c(O)ccc2ccccc12)C(N)=S
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 2-hydroxy-1-naphthaldehyde (172 mg, 1 mmol), 2-cyanothioacetamide (110 mg, 1.1 mmol), N,N-diethylaminoethanol (23 mg, 0.2 mmol) and 15 ml ethanol is stirred for 30 min at reflux under nitrogen. Then the mixture is chilled, the precipitate filtered, washed with ice-cooled ethanol and dried in a vacuum-oven. Thus an almost pure title compound is obtained in 85% yield (1080 mg). Recrystallization from ethanol furnishes very pure samples.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[Cl:8][C:9]1[C:10](=[N:15][NH2:16])[NH:11][CH:12]=[CH:13][CH:14]=1>>[F:1][C:2]([F:7])([F:6])[C:3](=[N:16][N:15]=[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][NH:11]1)[CH3:5]
Reactant: NN=c1[nH]cccc1Cl
Reactant: CC(=O)C(F)(F)F
Agent: NNc1ncccc1Cl
Product: CC(=NN=c1[nH]cccc1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to 3-chloro-2(1H)-pyridinone hydrazone (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20–25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure and the mixture partitioned between ethyl acetate (100 mL) and saturated aqueous sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64–64.5° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:27]3[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccnn3C)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (81 mg, 0.576 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-pyrazol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.32 (s, 1H), 7.18 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 6.01 (s, 1H), 3.6 (s, 2H), 3.2 (s, 3H), 3.0 (m, 4H), 2.7 (m, 4H), 2.52 (s, 3H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:11]([OH:14])(=[O:13])[CH3:12]>[Co+2]>[C:11]([O:14][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:13])[CH3:12].[C:11]([O:14][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([O:14][C:11](=[O:13])[CH3:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: C1C2CC3CC1CC(C2)C3
Agent: [Co+2]
Product: CC(=O)OC12CC3CC(C1)CC(OC(C)=O)(C3)C2
Product: CC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A mixture of 10 mmole of adamantane, 1 mmole of NHPI, 0.05 mmole of cobalt(II) acetylacetonato (Co(AA)2) and 25 mL of acetic acid was stirred for 6 hours at 75° C. under an oxygen atmosphere to give 1-acetyloxyadamantane and 1,3-diacetyloxyadamantane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=O>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:21](=[O:23])[C:20]2[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[C:18]([C:17]([F:16])([F:32])[F:31])[CH:19]=2)=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnc(Cl)cc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-phenyl-pyridazin-3-yl)-methyl-amine (example 5, intermediate a) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the compound as a colorless solid (5%). MS (ESI+): m/z=460.064 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18](O)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[CH3:31])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:65][CH2:66][CH2:67][CH:68]([O:72][CH2:73][CH3:74])[O:69][CH2:70][CH3:71]>CN(C=O)C.O>[CH2:70]([O:69][CH:68]([O:72][CH2:73][CH3:74])[CH2:67][CH2:66][NH:65][C:18]([C:15]1[CH:14]=[C:13]([C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[C:3]([NH:23][C:24]([C:26]4[O:27][CH:28]=[CH:29][C:30]=4[CH3:31])=[O:25])[CH:4]=3)[CH:12]=[CH:11][N:10]=2)[NH:17][CH:16]=1)=[O:19])[CH3:71]
Reactant: CCOC(CCN)OCC
Reactant: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(F)c(NC(=O)c4occc4C)c3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (300 mg, 0.71 mmol) in 10 ml of anhydrous DMF were added HATU (324 mg, 0.85 mmol) and N,N-diisopropylethylamine (200 mg, 1.55 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (157 mg, 1.06 mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide as white solid. Yield: 380 mg, 97%.
Reaction SMILES: [Na+].CS([CH2-])=O.[H-].[Na+].[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.F[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.[C:25]([O-:30])(=[O:29])[C:26]([O-:28])=[O:27]>O.CS(C)=O>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[C:22]([C:19]1[CH:20]=[CH:21][C:16]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:17][CH:18]=1)(=[O:24])[CH3:23]
Reactant: OC1CCNCC1
Reactant: O=C([O-])C(=O)[O-]
Reactant: CC(=O)c1ccc(F)cc1
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(OC2CCNCC2)cc1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimsyl sodium, prepared from 43.2 g of NaH (0.90 mol; 50% in oil, washed 3 times with hexane) and 1200 ml of DMSO was added in aliquots, 100 g (0.989 mol) of 4-hydroxypiperidine such that the temperature remained below 23° (using an ice bath). To the mixture was then added dropwise 120 ml (0.99 mol) of p-fluoroacetophenone. The mixture was then stirred at room temperature overnight, poured into water, extracted twice with ether, washed with saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The oil was filtered through 500 g of alumina and eluted 2×500 ml of 5% methanol/ether and 2×500 ml of 10% methanol/ether. The material was contained in fractions 2-4. Evaporation of the solvent provided an oil. The yield of the oxalate was 51.2 g (0.165 mol, 18.4%). Recrystallization from methanol provided analytically pure material, m.p. 183- 187.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[CH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.I[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[C:29]2=[O:36]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30](=[O:35])[C:29]3=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#CCCN3CCC(Cc4ccccc4)CC3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of 4-benzyl-1-(3-butynyl)piperidine (904 mg, 4 mmol), Et3N (4 mL), CuI (76 mg, 0.4 mmol) and Pd(PPh3)2Cl2 (41 mg, 0.1 mmol) in DMF (10 mL) is stirred at room temperature under N2 for 30 min. 5-Iodoisatin (546 mg, 2 mmol) is added and stirring continued overnight. The mixture is evaporated and the residue purified by medium-pressure column chromatography on silica gel eluting with 50% EtOAc/hexanes (+1% Et3N) to give an orange solid (238 mg). The solid is recrystallized from hot 90:10 isopropanol:water to give the title compound as orange crystals (152 mg): mp 140-141° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(C)c1OCC(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.019 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (s, 9 H), 1.41 (t, J=11.77 Hz, 1 H), 1.58 (m, 1 H), 2.10 (s, 6 H), 2.77 (m, 4 H), 3.57 (s, 3 H), 3.65 (m, 1 H), 3.81 (d, J=9.56 Hz, 1 H), 4.07 (m, 4 H), 5.02 (d, J=5.52 Hz, 1 H), 6.92 (m, 4 H), 7.25 (m, 8 H), 7.56 (d, J=9.56 Hz, 1 H), 7.85 (m, 3 H), 7.96 (d, J=8.46 Hz, 2 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](N(CC)CC)[CH3:11].C(Br)C.O>C1C=CC=CC=1>[CH2:10]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[CH3:1])[CH3:11]
Reactant: Cc1c(N)cccc1Cl
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Solvent: CCBr
Product: CCNc1cccc(Cl)c1C
Temperature: 25 °C

Procedure:
In 100 ml of benzene is dissolved 14 g of 2-methyl-3-chloroaniline obtained in Reference Example 1 and, after adding 12 g of triethylamine, 13 g of ethyl bromide is added to the solution to conduct the reaction under reflux of benzene for 3 hours. After the completion of the reaction, the mixture is cooled to room temperature and shaken with 200 ml of water. The benzene layer is separated, dried over anhydrous magnesium sulfate, and concentrated. Distillation of the residue results in 12 g of N-ethyl-2-methyl-chloroaniline as the fraction of 125°-126° C./10 mmHg.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[N:23][C:22]([CH3:25])=[N:21]4)[O:16][C:15]3=[O:26])=[CH:9][C:8]=2[F:27])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:29].[Na+].CO>ClCCl>[O:29]=[S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([F:27])=[CH:9][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[N:23][C:22]([CH3:25])=[N:21]4)[O:16][C:15]3=[O:26])=[CH:11][C:12]=2[F:13])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)n1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCS(=O)CC4)c(F)c3)C(=O)O2)n1
Yield: 9.1 %

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(5-methyl-2H-tetrazol-2-yl)methyl]oxazolidin-2-one (Example 34) (0.53 g, 1.34 mmol) was oxidized with sodium periodate (0.314 g, 1.47 mmol) as described for Intermediates 42 and 43. Chromatography on silica gel with 0-5% methanol in dichloromethane gave a mixture together with the corresponding E-isomer, which was separated on a Chiracel OD chiral chromatography column using hexanes/isopropanol (1:1) as eluant to give the title compound (50 mg) as a colourless solid.
Reaction SMILES: N1CCCCC1.BrC1SC(C=O)=CC=1.[N:15]1([C:21]2[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[S:25][C:21]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(N2CCCCC2)s1
Agent: O=Cc1ccc(Br)s1
Solvent: C1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCCCC3)s2)cc1OC
Yield: 52.4 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from piperidine (1.02 g) was introduced into 5-bromothiophene-2-carboxaldehyde (764 mg), to thereby yield 5-piperidin-1-yl-thiophene-2-carbaldehyde (yield: 500 mg, 64%). The produced 5-piperidin-1-yl-thiophene-2-carbaldehyde (293 mg) was condensed with 3,4-dimethoxybenzyl cyanide (266 mg) through Method A (production step 2), to thereby yield the target product (yield: 279 mg, 53%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].O=[C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][CH2:4][CH:3]1[O:6][C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:1][CH2:2]1
Reactant: OCC(O)CS
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(CCC(=O)OCC)OC(CO)CS1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 3-mercapto-1,2-propanediol (10.8 g, 0.1 mol), diethyl 4-oxopimelate (23 g, 0.1 mol) and boron trifluoride etherate (2.5 ml) in methylene chloride (300 ml). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 14.5 g (45%) of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[Cl:19][C:20]1[C:21]2[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[N:27]=[CH:26][C:22]=2[N:23]=[CH:24][N:25]=1>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:20]3[C:21]4[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[N:27]=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: CN(C)c1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.52 (1H,s), 8.90(1H,s), 8.60(1H,s), 8.24(1H,s), 8.14(1H,s), 7.85(2H,m), 7.70(1H,d), 7.49(1H,s) 7.10(3H,m), 5.72(2H,s), 3.19(6H,s); m/z (M+1+) 414.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH:20]=1)=O)C.CO>ClCCl>[CH:14]([C:16]1[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:19][CH:20]=1)=[O:13]
Reactant: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
Diisobutylaluminum hydride (1.0N hexane solution, 66 ml) was added dropwise to a solution of 4-ethoxycarbonyl-2-(trans-styryl)oxazole (8.57 g) in dichloromethane (80 ml) at −78° C. After 15 minutes, methanol (11 ml) was added dropwise, and the mixture was warmed to room temperature over 1 hour. The reaction mixture was filtered through Celite, and the resultant pasty substance was dissolved in ethyl acetate (200 ml) and a saturated aqueous solution (200 ml) of ammonium chloride was added, and an organic layer was separated. The water layer was then extracted with dichloromethane (2×100 ml). The resultant organic layers were collected and washed with a saturated aqueous solution (100 ml) of sodium hydrogencarbonate and saturated saline (100 ml), combined with the filtrate obtained by the filtration through Celite and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=5:1→dichloromethane:methanol=10:1) to obtain the title compound (5.86 g) as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.Cl.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (0.90 g, 4.9 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (Example 204, step C) (1.20 g, 4.9 mmol) and K2CO3 (0.81 g, 5.8 mmol) in DMSO (15 mL) was heated at 100° C. for 48 h. The reaction was cooled to rt, poured into H2O and extracted exhaustively with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.09 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (s, 1H), 6.69 (s, 1H), 3.90 (s, 3H), 3.29-3.38 (m, 2H), 3.06-3.15 (m, 4H), 2.87 (s, 3H), 2.68-2.79 (m, 2H), 2.59-2.66 (m, 4H), 2.40-2.48 (m, 1H), 2.20 (s, 3H), 1.80-1.92 (m, 2H), 1.49-1.67 (m, 2H).