Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=[S:23])[CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(C#N)c3)cc21

Procedure:
Prepared by heating under reflux overnight a stirred mixture of 3-(4,4-dimethyl-2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl)benzonitrile and an equal weight of phosphorus pentasulfide in pyridine and workup as in the previous example gave a yellow solid: mp 220-223° C. dec. 1H-NMR (DMSO-d6) δ 12.35 (s, 1H), 8.21 (s, 1H), 8.10 (d, 1H, J=6.0 Hz), 7.80 (d, 1H, J=7.9 Hz), 7.72 (s, 1H), 7.65 (m, 2H), 7.21 (d, 1H, J=8.4 Hz), 2.85 (s, 2H), 1.27 (s, 6H); MS (APCI (−)) m/z 291 [M−H]− Anal. Calc. For C18H16N2S 3H2O: C, 62.40, H, 6.40, N, 8.09. Found: C, 62.12, H, 4.88, N 7.77.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[NH:33][CH3:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:34])[CH:35]=[CH:36][C:37]=1[Cl:38]
Reactant: CNc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(Cl)c(Cl)c1
Yield: 63 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3,4-dichloro-N-methylaniline, the title compound was isolated as a yellow solid in 63% yield (91% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Nc1ccc(Cl)cc1
Product: Clc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
6-Bromo-N-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and 4-chloroaniline (97 mg, 0.76 mmol) in a similar manner as described in Example 13 to give 29 mg (20%) of an off-white solid. 1H-NMR (DMSO-d6): δ 11.07 (s, 1H), 7.56 (s, 1H), 7.23 (d, 1H), 7.13-7.08 (m, 3H), 6.71 (d, 2H), 6.20 (d, 1H), 4.76-4.72 (m, 1H), 2.68-2.54 (m, 2H), 1.99-1.85 (m, 2H), 1.80-1.74 (m, 2H); MS m/z (M−1) 373, 375.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>C(#N)C>[CH2:27]([N:29]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[CH2:30][CH3:31])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-ethylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 87 (6), 86 (bp), 84 (2), 58 (5).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.C[O-].[Na+:41].CO>CO.C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:31][CH:32]=2)=[O:11])=[CH:5][CH:6]=1.[Na+:41]
Reactant: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Yield: 102 %

Procedure:
7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (42 mg, 0.07955 mmol) was dissolved in MeOH-THF (1 ml-1-ml). A 0.5 M solution of NaOMe in MeOH (159.1 μl, 0.0795 mmol) was added and the mixture was stirred for few minutes. The crude mixture was concentrated and chased with EtOAc and dichloromethane to provide 44.6 mg of the title compound as a white solid (102%). MS (apci) m/z=528.1 (M+2H-Na).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:41])([CH3:40])[C@@H:14]([O:32]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:31])[CH2:22][O:23]CC1C=CC=CC=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].CO>[Pd].C(OCC)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:41])([CH3:40])[C@@H:14]([OH:32])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:31])[CH2:22][OH:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)CO
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of [2-(phenylmethoxy)acetyloxy]ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (45a) (0.10 g, 0.17 mmol) and 0.1 g of 10 wt.-% of palladium on activated carbon in 6 mL of a mixture of methanol (MeOH) and ethyl acetate (EtOAc) was stirred overnight under a hydrogen atmosphere. After work-up and further purification by mass-guided preparative HPLC, 51 mg (73% yield) of the title compound (45) was obtained as a colorless, viscous oil after lyophilization of the solvents. 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.02-1.05 (2s, 3H), 1.10-1.13 (2s, 3H), 1.60 (t, J=5.2 Hz, 3H), 2.01 (s, 3H), 2.05-2.12 (m, 2H), 2.84-3.03 (br. m, 1H), 3.14-3.26 (m, 2H), 3.34-3.46 (m, 2H), 3.97-4.16 (m, 3H), 4.22 (s, 2H), 5.56-5.96 (br. m, 1H), 7.00-7.08 (m, 1H) ppm. MS (ESI) m/z: 414.02 (M+H)+, 435.96 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 10.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 10.0 g of 1-methylpiperazine and 10.4 g of potassium carbonate in 93 ml of DMSO is stirred at ambient temperature overnight. The mixture is diluted with 160 ml of water and extracted three times with 150 ml of ethyl acetate. The organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 200 g of silica, elution being carried out with dichloromethane/methanol (98/2 then 95/5), so as to obtain 13.6 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+]>CO>[F:23][C:19]1[CH:18]=[C:17]([C:16]2[N:8]([C:5]3[N:6]=[N:7][C:2]([O:28][CH3:27])=[CH:3][CH:4]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([N:24]([CH3:26])[CH3:25])[N:12]=[CH:11][N:10]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: C[O-]
Reactant: CN(C)c1ncnc2c1nc(-c1cccc(F)c1)n2-c1ccc(Cl)nn1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2c(-c3cccc(F)c3)nc3c(N(C)C)ncnc32)nn1
Yield: 53.2 %

Procedure:
N-[9-(6-Chloro-3-pyridazinyl)-8-(3-fluorophenyl)-9H-6-purinyl ]-N,N-dimethylamine (50 mg, 0.18 mmol) in Example 54 was dissolved in 5 ml anhydrous methanol, and sodium methoxide (15 mg, 0.28 mmol) was added thereto and heated under reflux for 2 hours. The reaction solution was cooled, evaporated and suspended in water, and the precipitated solid were separated by filtration, to give the title compound (35 mg, 52%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14](=[O:19])[CH:15](Br)[CH2:16]Br)=[O:12])=[CH:6][CH:5]=1)[CH3:2]>C(O)(C)(C)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[CH2:16])[C:14](=[O:19])[NH:13][C:11]2=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(NC(=O)NC(=O)C(Br)CBr)cc1
Solvent: CC(C)(C)O
Product: C=C1C(=O)NC(=O)N1c1ccc(OCC)cc1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
70 g (0.178 mole) of N-(4-ethoxyphenyl)-N'-(2,3-dibromopropionyl)-urea and 72 g of potassium tert. -butylate (90% strength, about 0.58 mole) in 400 ml of tert.-butanol were heated under reflux for 30 minutes, the solvent was distilled off and the residue was warmed to 120° C. in vacuo for 20 minutes. The batch was then taken up in 500 ml of hot water, the mixture was filtered and the filtrate was acidified with dilute hydrochloric acid. The product which had precipitated was filtered off and dried. 30 g of 1-(4-ethoxyphenyl)-5-methylene-2,4-dioxo-imidazolidine were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:17].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.CC(NC(C)C)C>CO>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]5=[N:6][C:5]=4[CH3:17])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: COC1CCc2nc(C)c(CCCl)c(=O)n2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CO
Product: COC1CCc2nc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c(=O)n2C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4.8 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride, 6.1 parts of N-(1-methylethyl)--2-propanamine and 16 parts of methanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.5 parts (100%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one as an oily residue. (intermediate 5)
Reaction SMILES: [NH3:1].[OH:2][C:3]([CH3:19])([CH3:18])[C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1)=[O:5]>O1CCOCC1>[OH:2][C:3]([CH3:19])([CH3:18])[C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([NH2:1])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: N
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)O)cc1
Solvent: C1COCCO1
Product: CC(C)(O)C(=O)c1ccc(OCC(N)=O)cc1
Reaction time: 2 h

Procedure:
75.0 g of 25% strength ammonia are added dropwise with stirring to 25.2 g (0.1 mol) of methyl 4-(2-hydroxy-2-methylpropionyl)phenoxyacetate (obtained by esterifying compound IIg using methanol) in 50 ml of dioxane.After being stirred for 2 hours, the mixture is evaporated to solidification. The crude product is recrystallized from hot water, 22.1 gof compound IIt of melting point 139° C. being obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:10][C:11]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[N:10]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=2)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C2=CC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
0.10 g (0.35 mmole) of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one produced in Example 1, 0.02 g of sodium hydride (60%), and 0.06 g (0.42 mmole) of methyl iodide were dissolved in 4 ml of N,N-dimethylformamide and the solution was stirred at room temperature for one night. The reaction solution was quenched with water, then was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by flash chromatography (SiO2; eluted by 2% methanol/methylene chloride) to obtain the title compound 0.10 g (yield 93.4%) as a colorless solid.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O)=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:39])[CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][F:7])=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:39])[CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCF
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
DAST (0.16 gram, 1 mmol) was added slowly to a cooled solution (−78° C.) of Compound 29a (0.047 gram, 0.1 mmol) in dichloromethane (2 ml) and the resulting mixture was allowed to warm to room temperature and was thereafter stirred for 12 hours. The reaction mixture was then poured to a saturated solution of sodium bicarbonate), diluted with water, extracted thrice with dichloromethane, washed with brine, and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded Compound 35a (0.036 gram, 78% yield) having a purity of 94%, as determined by HPLC. The compound was used in the following procedures without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH2:18])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>C(#N)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH:18][CH2:26][C@@H:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=3)[OH:27])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:20]
Reactant: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)N)c[nH]c2c1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c2c1
Yield: 63.2 %

Procedure:
To a solution of (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid diethylamide (960 mg, 3.51 mmol) in acetonitrile (10 ml) is added (R)-(+)-3-chlorostyrene oxide (1.09 g, 7.02 mmol), and the mixture is refluxed for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform/methanol=20/1→(a saturated ammonia solution in chloroform)/methanol=20/1) to give 3-{(2R)-2-[2-(3-chloro-phenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-6-carboxylic acid diethylamide (950 mg, 2.22 mmol, 63%).
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].P(Cl)(Cl)(Cl)=O.[CH2:12]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[C:2]([C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)N(C)C
Reactant: c1ccc(Cc2cc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c(Cc2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of 29.5 g (39 mmol) of dimethylacetamide was added dropwise under ice-cooling 7.00 g (76.9 mmol) of phosphorus oxychloride. After stirring for 30 min at room temperature, to the mixture was added 8,00 g (38.6 mmol) of 2-benzylindole (prepared in accordance with the literature (Khim.Geterotsikl.Soedin.1994,p133)). After stirring for 2 hours at 100° C., the mixture was poured to ice-water, neutralized with 2N NaOH, extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The obtained crystal was washed with n-hexane to give 5.1 g of the titled compound. Yield: 52%.
Reaction SMILES: [N:1]([C:4]1[C:14]([F:15])=[C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:5]=1[F:30])=[N+]=[N-].[BH4-].[Na+].O>CO>[NH2:1][C:4]1[C:14]([F:15])=[C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:5]=1[F:30]
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(N=[N+]=[N-])c(F)c1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(N)c(F)c1OC1CCCCO1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93.7 %

Procedure:
4.64 g (10.9 mmol) of the above ethyl 4-azido-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 100 mL of methanol, 2.90 g (76.7 mmol) of sodium borohydride was added in several portions under ice-cooling, 10 mL of water was further added and the mixture was stirred at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure, water was added and the mixture was extracted once with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 4.09 g of ethyl 4-amino-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 21 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 520.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:27]=1[C:28](O)=[O:29]>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:29]
Reactant: CCCc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Product: CCCc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-chloro-6-propylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-chloro-6-propylbenzoic acid using the general procedures described in example 15 and was obtained as a white solid: mp 225-227° C. ES-HRMS m/e calcd for C26H28ClN3O5 (M+Na) 520.1611, found 520.1615.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[N:13]([CH3:22])[CH:12]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:21][O:20][C:15]1[N:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:3]3[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=3[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:12][N:13]([CH3:22])[C:14]=12
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3F)cn(C)c12
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Nc3ccccn3)cn(C)c12
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 77 %

Procedure:
A mixture of Example 23a (0.122 g, 0.405 mmol) and 2-aminopyridine (0.042 g, 0.445 mmol) in dimethyl sulfoxide (6 mL) was treated with potassium 2-methylpropan-2-olate (0.091 g, 0.81 mmol) and stirred at ambient temperature for 23.5 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-15% ethyl acetate in dichloromethane) to give 0.117 g (77%) of the title compound.