Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([OH:24])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1.[OH-].[K+]>C(O)C>[OH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1
Reactant: Oc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: CCCCCCC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
According to a known method, optically active 2-octyl bromide and 2,7-dihydroxyfluorene were reacted in ethanol in the presence of potassium hydroxide. The resultant reaction mixture was purified by a column chromatography and recrystallization to obtain optically active 2-hydroxy-7-(2-octyloxy)-fluorene.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[N:9][CH:10]=1.[C:23]1([C:29]2[C:33]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][NH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:23]1([C:29]2[C:33]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:31]([CH2:4][C:5]3[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)=[CH:7][CH:6]=3)[N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 2-(5-chloromethyl-2-pyridyloxymethyl)quinoline (498 mg), ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (428 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (651 mg, yield: 76%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(CN2CCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 13 h
Yield: 69.9 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (340 mg) was dissolved in tetrahydrofuran (8 ml) and methanol (8 ml), and then 10% palladium carbon (170 mg) was added, followed by stirring under a hydrogen atmosphere for 13 hrs. The catalyst was filtered off and washed with methanol. The filtrate and washings were concentrated under reduced pressure to give the titled compound (221 mg) as pale yellow solid.
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH:13]=3)[S:3]1.C([OH:33])C>Cl>[F:29][C:27]([F:28])([F:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:33])[NH:6][C:5]3=[O:7])[CH:10]=[N:11]2)=[CH:16][CH:15]=1
Reactant: N=C1NC(=O)C(Cc2cnc3cc(OCc4ccccc4C(F)(F)F)ccc3c2)S1
Reactant: CCO
Agent: Cl
Product: O=C1NC(=O)C(Cc2cnc3cc(OCc4ccccc4C(F)(F)F)ccc3c2)S1
Yield: 44 %

Procedure:
In a mixture of 2N hydrochloric acid (5 mL) and ethanol (3 mL) was dissolved 2-imino-5-[[7-(2-trifluoromethylbenzyloxy)-3-quinolyl]methyl]thiazolidin-4-one (200 mg, 0.47 mmol.). The resulting solution was heated under reflux for 12 hours. After the completion of reaction was confirmed, ethanol was distilled off. To the residue were added ethyl acetate and aqueous sodium hydrogen carbonate so that the aqueous phase was made to pH 7. The organic portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/8), to give 89 mg of the desired compound as pale brown crystalline powder (yield 44%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.[CH3:35][C:36]([C:39](O)=[O:40])([CH3:38])[NH2:37]>>[Cl:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH:21][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:39](=[O:40])[C:36]([CH3:38])([CH3:35])[NH2:37])=[O:34]
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CN)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Reactant: CC(C)(N)C(=O)O
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CNC(=O)C(C)(C)N)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12

Procedure:
Following the procedure described above with N-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide and N-[(1,1-dimethylethyl)oxy]carbonyl)-2-methylalanine provided the title product as a white solid. ESMS [M+H]+: 563.2.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][Al](C)C.Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH3:20][C:18]1([OH:19])[C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][NH:10][C:9]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Reactant: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC1(O)c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Temperature: 90 °C

Procedure:
3-Phenylindeno[1,2-c]pyrazol-4-(1H)-one (2.4 g) was suspended in toluene (40 ml) under nitrogen and trimethyl aluminium (2.2 ml of a 2M solution in heptane) was added at 20° C. with stirring. The mixture was heated at 90° C. for 16 hours, then cooled to ambient temperature and poured on to crushed ice (approx. 600 ml) containing concentrated hydrochloric acid (30 ml). The precipitated solid was collected by filtration and recrystallized from ethyl acetate with hot filtering to give 4-methyl-3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-4-ol, m.p.154-155° C.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:16][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CN(C)CCO
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(=O)OCCN(C)C
Yield: 62.6 %

Procedure:
A solution of 91.35 g (0.40 mol) of myristic acid, 35.7 g (0.40 mol) of 2-dimethylaminoethanol, 0.5 g of p-toluenesulfonic acid and a suitable volume of toluene was heated at reflux for approximately 48 hours in a 1-neck 3 liter flask equipped with Dean-Stark trap and condenser. At the end of this time, 7.0 ml of water had collected in the trap. The solution was cooled, stirred with K2CO3, filtered and concentrated. The residue was distilled to give 75.0 g of product; bp=145°-50° C./0.50 mm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][NH2:13]>CN(C)C=O.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1
Reactant: CN
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nc(Cl)ccc1C(N)=O
Temperature: 60 °C

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (6.23 g, 32.6 mmol) and methylamine (98 mL of 2M in THF, 196 mmol) in anhydrous dimethylformamide (60 mL) was heated to 60° C. for 4 h. The reaction was then cooled to room temperature and diluted with water (800 mL) and extracted with ethyl acetate (4×600 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give a light orange oil (7.10 g). The oil was diluted with CH2Cl2 (300 mL) followed by the addition of silica gel (50 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (200 g, 230-400 mesh) and eluted with gradient 30-50% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (4.73 g, 78% isolated yield). TLC eluted with 50% EtOAc/hexanes and rendered with UV lamp gave Rf=0.5; 1H NMR 400 MHz (CDCl3) δ 7.47 (d, J=8.5 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 1.48 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([O:31][CH3:32])[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH:30]=NC=N4)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.N1(CCCN)C[CH2:37][O:36][CH2:35][CH2:34]1>>[O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([O:31][CH3:32])[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:37][O:36][CH2:35][CH2:34]4)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COc1c(C(=O)NCCCn2cncn2)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Reactant: NCCCN1CCOCC1
Product: COc1c(C(=O)NCCCN2CCOCC2)cn2ncnc(C3C(=O)Nc4ccccc43)c12

Procedure:
Compound A of Example 128 was converted to the title compound by the procedure same as that for Example 126 except N-[3-(4-morpholinyl)propylamine was used. MS: (M+H)+=451.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:21]
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3cccnc3)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Temperature: 25 °C

Procedure:
Heat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[cis-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 27) (0.346 g, 0.705 mmol), pyridine-3-boronic acid (0.173 g, 1.41 mmol), Pd(PPh3)4 (81 mg), 7 mL of 0.1 M Na2CO3 aq solution in 7 mL of dimethoxy ethane at 80° C. for 24 h. Cool the mixture to room temp and quench with 20 mL of 1N HCl. Dilute the mixture with 20 mL of EtOAc. Wash the organic layer with water, brine and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 421 (M+1).
Reaction SMILES: [CH2:1]([N:8]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C@@H:9]([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C>[CH2:1]([N:8]([C@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[C@@H:9]([CH3:18])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
tert-Butyl (3S)-3-[benzyl-[(1S)-1-phenylethyl]amino]butanoate (24 g, 67.9 mmol) is dissolved in anhydrous THF (237 mL) and cooled to 0° C. under an argon atmosphere. 1 M Lithium aluminum hydride in THF (237 mL, 237 mmol) is added dropwise over 10 min. The reaction mixture is stirred at 0° C. for 1 h and then at 60° C. for 1 h. The mixture is cooled to room temperature (RT) and diluted with diethyl ether (500 mL). The reaction is quenched with a mixture of CELITE® and Na2SO4.10 H2O (1:1) is added portionwise over 15 min. The mixture is filtered and concentrated under a vacuum to afford the title compound as a colorless oil (17.54 g, 90%). LC-ES/MS m/z 284 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13]>C(#N)C>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.4 %

Procedure:
41.3 g of 4-nitrophenylhydrazine and 33 g of phthalide were dissolved in 300 ml of acetonitrile. The solution was heated under reflux with stirring over 4 hours. The reaction solution was allowed to stand for cooling to room temperature. The resulting solid was then filtered off, and recrystallized from acetonitrile to obtain 15.1 g of 1-(2'-hydroxymethylbenzoyl)-2-(4-nitrophenyl)hydrazine (yield of 21.0%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.S(=O)(=O)(O)O.[CH2:34](O)CC>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH2:25][CH3:34])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.04 g), n-propanol and a trace of concentrated sulfuric acid was heated under reflux for 4 hours. The mixture was concentrated and then partitioned between dichloromethane and water. The dichloromethane layer was washed with water, dried over MgSO4 and evaporated to give n-propyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.72 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([O:27]C)=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:19][CH2:20][CH2:21][S:22]2)[CH2:17]1)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)[C@H](C)NC(=O)OCc1ccccc1)SCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 25 °C

Procedure:
Dissolve 1.05 g of 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester in 100 ml of methanol. Add 10 ml of 2.5N sodium hydroxide and stir the mixture at room temperature for sixteen hours. Concentrate the mixture under nitrogen, dissolve the oil in 0.1N sodium hydroxide and dilute with ice water. Extract the aqueous solution with ethyl acetate. Acidify the aqueous solution with concentrated hydrochloric acid and then extract with ethyl acetate. Dry the organic phase over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (100 g, 60-200 mesh) and elute with chloroform:glacial acetic acid 19:1 to obtain 7-[N-benzyloxycarbonyl-(S) -alanyl]-1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid, [α]D26 -15.8° (ethanol).
Reaction SMILES: N1C=CC=CC=1.[CH:7]([N:10]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)(=[O:13])=[O:12])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:7]([N:10]([CH2:22][CH2:23][CH2:24][CH:25]=[O:26])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)(=[O:12])=[O:13])([CH3:9])[CH3:8]
Reactant: CC(C)N(CCCCO)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N(CCCC=O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Pyridine-chromic acid complex was prepared by adding chromium trioxide (26.4 g, 94 m. moles) to pyridine (41.76 g) in methylene chloride (660 ml). The reaction mixture was stirred at room temperature for 3/4 hours. Then N-isopropyl-N-(4-hydroxybutyl)-3,4-dichlorobenzenesulfonamide prepared in the preceding paragraph (15.01 g) in methylene chloride (150 ml) was added all at once. After 1/2 hour the liquid was decanted and washed with 5% aqueous NaOH, 5% aqueous HCl, 5% aqueous NaHCO3 and finally brine. After removal of solvent there was obtained N-isopropyl-N-(4-oxobutyl)-3,4-dichlorobenzenesulfonamide as a dark oil (9.01 g) which started to nicely crystallize but was used below without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:12]1([S:18][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCc2cc(Sc3ccccc3)ccc21

Procedure:
5-Fluoro-1-indanone from Aldrich Sigma Chemical Co. (Cat No. 18,566-3) was treated with benzenethiol in the presence of potassium carbonate using the procedure of step 4 of Example 1 to afford 5-phenylsulfanyl-indan-1-one. MS: 241 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]=4[CH:24]=[CH:25][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=1>CS(C)=O.C(OCC)(=O)C>[O:23]=[C:21]1[NH:22][C:18]2=[C:17]3[C:16](=[CH:25][CH:24]=[C:19]2[NH:20]1)[O:15][CH2:14][CH:13]([CH2:12][NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=1)[O:26]3
Reactant: CC(=O)Nc1cccc(OCCCN)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)Nc1cccc(OCCCNCC2COc3ccc4[nH]c(=O)[nH]c4c3O2)c1
Temperature: 95 °C

Procedure:
A mixture of 0.60 g (1.6 mmole) of (8R)-1,3,7,8-tetrahydro-8-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2H-[1,4]dioxino[2,3-e]benzimidazol-2-one and 1.6 g (8.0 mmole) of N-[3-(3-amino-propoxy)phenyl]-acetamide in 30 mL of DMSO was heated at 90-100° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give the free base of the title compound. This was recrystallized from ethanol with the addition of fumaric acid to give 0.19 g of the (S)-enantiomer of the title compound as a white solid fumarate, three-quarter hydrate, m.p. 125° C. (d).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:26][C:27]#[N:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.[Sn]([N:44]=[N+:45]=[N-:46])(CCCC)(CCCC)CCCC.Cl>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][C:27]2[NH:46][N:45]=[N:44][N:28]=2)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC#N)Cc2ccc(Cl)cc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(Cc2ccc(Cl)cc2)Cc2nnn[nH]2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-cyanomethyl-amide, Compound 68 (1 eq.) in toluene was added Bu3SnN3 (10 eq.). The reaction was refluxed for 6 h and cooled to 20° C. then HCl 2N in Et2O was added. After 15 h of stirring, the solid was filtered, dissolved in DCM and precipitated with iPr2O. The solid was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 95/5) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(1H-tetrazol-5-ylmethyl)-amide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:20][CH:11]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH-].[K+]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(C2OC2C(=O)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 5.63 g of 3-(4-carboxyphenyl)-1-phenyl-2,3-epoxy-1-propanone in 100 ml of ethanol at 85°-90° C. was added a solution of 6 g of potassium hydroxide in 100 ml of ethanol with stirring over 5 min. The reaction mixture was heated at 85°-90° C. for 5 min. and then allowed to cool to room temperature. The solution was evaporated to dryness and the residue was dissolved in 300 ml of ice-water and acidified with 125 ml of hydrochloric acid. After stirring for 30 min., the precipitate was collected and washed with water. The precipitate was dissolved in 600 ml of ethyl acetate and the solution was dried and filtered. The filtrate was evaporated to give 5.63 g (100%) of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:24][N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])[C:13]1=[O:23]
Reactant: OB(O)c1cccnc1
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(-c4cccnc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 39 mg, 0.100 mmol) and 3-pyridineboronic acid (Aldrich, Buchs, Switzerland, 15 mg, 0.122 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.08 min (Method A); M+H=385 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.70-8.64 (m, 1H), 8.60-8.55 (m, 1H), 8.16-8.10 (m, 1H), 7.99-7.92 (m, 1H), 7.90-7.84 (m, 1H), 7.54-7.47 (m, 2H), 3.82 (s, 3H), 3.60 (s, 3H), 2.09 (s, 3H), 1.92 (s, 3H))