Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.Cl[S:5]([N:8]=C=O)(=[O:7])=[O:6].[NH2:11][C:12]1[N:13]=[C:14]([Cl:37])[C:15]2[C:20]([C:21]#[C:22][CH2:23][CH2:24][OH:25])=[CH:19][N:18]([CH2:26][C:27]3[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=3)[C:16]=2[N:17]=1>CN(C)C(=O)C.C(Cl)Cl>[S:5](=[O:6])(=[O:7])([O:25][CH2:24][CH2:23][C:22]#[C:21][C:20]1[C:15]2[C:14]([Cl:37])=[N:13][C:12]([NH2:11])=[N:17][C:16]=2[N:18]([CH2:26][C:27]2[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=2)[CH:19]=1)[NH2:8]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O=CO
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCCOS(N)(=O)=O)c3c(Cl)nc(N)nc32)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of formic acid (0.463 g) and N,N-dimethylacetamide (1 drop) was added to a solution of chlorosulfonyl isocyanate (1.31 g) in DCM (9 mL), and heated to reflux for 3 h. The resulting solution was added to a solution of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (200 mg) in DMA (10 mL) and stirred at rt for 30 min. Work-up and reverse-phase preparative HPLC gave the title compound, as a solid. HPLC Rt=4.96 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.C(Cl)Cl.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>O>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)COCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)COCCOS(=O)(=O)c1ccc(C)cc1
Yield: 55 %

Procedure:
A mixture of ethyl (2-hydroxyethoxy)acetate (0.50 g, 3.37 mmol), triethylamine (1.4 ml)-and methylene chloride (B ml) was stirred under ice-cooling. Then, p-toluenesulfonyl chloride (0.96 g, 5.06 mmol) was added in small portions and the resulting mixture was stirred under ice-cooling for another 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate: n-hexane=1:5) to obtain 0.56 g of ethyl [2-(toluene-4-sulfonyloxy)ethoxy]acetate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(O)C.S(Cl)(Cl)=O>[Br:1][C:2]1[S:6][C:5]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(Br)s1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(Br)s1)C(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution containing 5.73 g 5-bromothiophene-2-carboxaldehyde and 5.0 g 2,4-pentanedione in 25 ml of 2-propanol, 2.9 ml thionylchloride was gradually added. The mixture was stirred for 2 h at 20° C. 120 ml of conc. Na2SO4 -solution was then added and the mixture was extracted with ether. The solvent was evaporated in vacuo and the crystalline residue was washed with cold ether. Yield 3.9 g, mp 70°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[N:14].[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH2:22]>C(#N)C>[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH:22][C:6]1[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]([C:13]#[N:14])=[C:2]([Cl:1])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(C#N)c1Cl
Reactant: NC1CCCCC1N
Solvent: CC#N
Product: N#Cc1c(Cl)c(Cl)c(NC2CCCCC2N)c(C#N)c1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
To the slurry of 2,4,5,6-tetrachloro-1,3-dicyanobenzene (2.0 g, 7.5 mmol) in acetonitrile (40 ml) triethylamine (5.0 ml) is added, then 1,2-diaminocyclohexane (0.86 g, 7.5 mmol) and the reaction mixture is heated under reflux for 1 h. It is cooled to ambient temperature, then deposited on ice for few hours, and the crystalline product is collected on filter. 2.32 g (89%) of the title product as pale-yellow powder are obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:15][C@@H:16]([OH:38])[C@@H:17]([NH:26][C:27](=[O:37])[O:28][C@@H:29]3[C@H:36]4[C@H:32]([O:33][CH2:34][CH2:35]4)[O:31][CH2:30]3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:43]([C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48]Cl)#[N:44].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:43]([C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:17]([NH:26][C:27](=[O:37])[O:28][C@@H:29]2[C@H:36]3[C@H:32]([O:33][CH2:34][CH2:35]3)[O:31][CH2:30]2)[C@H:16]([OH:38])[CH2:15][N:14]([S:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)(=[O:12])=[O:13])[CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:24][CH:23]=1)#[N:44]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Reactant: N#Cc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2cccc(C#N)c2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Yield: 34.3 %

Procedure:
49 mg of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxy benzyl)propylcarbamate, 20 mg of m-cyanobenzylchloride, 20 mg of cesium carbonate and 0.5 ml of dimethyl formamide were stirred at rt for 5 h. The mixture was diluted with ethyl acetate and extracted with water. Chromatography on silica gel (1:1 ethylacetate/hexane) gave the title compound as a white solid (20 mg). 1H NMR: 0.87 (6H, dd), 1.58 (2H, m), 1.8 (1H, m), 2.75 (2H, m), 2.9 (4H, m), 3.1 (1H, m), 3.62 (3H, m), 3.8 (3H, m), 3.95 (1H, m), 4.25 (4H, m), 4.95 (2H, m), 5.0 (2H, s), 5.62 (1H, d), 6.82 (2H, d), 6.92 (1H, d), 7.1 (2H, d), 7.2 (2H, m), 7.45 (1H, t), 7.6 (2H, m), 7.75 (1H, s). MS:722(M+H)
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Bi](Br)(Br)Br.O[CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10]>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])[CH3:2]
Reactant: CCO
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(C)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To the solution of ethanol (77 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth(III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, the methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-ethoxy ethyl)benzoate (191 mg, 55%) as oil.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([C:25]([O:27]CC)=[O:26])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)C.Cl>C(O)C.O>[C:25]([C:22]([CH3:24])([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:30])=[O:5])=[CH:16][CH:17]=1)([OH:27])=[O:26]
Reactant: CCOC(=O)c1ccccc1COc1ccc(CC(C)(C)C(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(Cc1ccc(OCc2ccccc2C(=O)O)cc1)C(=O)O
Yield: 91.7 %

Procedure:
A solution containing 30.2 g of potassium hydroxide in 150 ml 95% ethanol was added to 2-[4-(2-ethoxycarbonyl-2-methylpropyl)phenoxymethyl]benzoic acid ethyl ester (20.3 g) and warmed to reflux for 8 hours. The solution was cooled, diluted with water and adjusted to pH 5 with 6N HCl. Cooling overnight gave a precipitate which was collected and air dried to give 15.9 g of 2-[4-(2-carboxy-2-methylpropyl)phenoxymethyl]benzoic acid as a powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH3:22])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.35 g, 1.04 mmol) in THF (6 ml) was added 1-bromomethyl-4-trifluoromethyl-benzene (0.27 g, 1.15 mmol) and Et3N (0.148 ml, 1.45 mmol). The reaction mixture was stirred overnight at RT and concentrated under vacuo. The product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 130 mg (29%) of the title compound as a colorless oil. ES-MS m/e: 492.9 (M+H+).
Reaction SMILES: C(O)C.C(Cl)(Cl)Cl.[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:26])[C:10]=1[C:27](=O)[CH2:28][CH3:29].[Cl:31][CH:32]=[CH:33][CH2:34][O:35][NH2:36].Cl>C(O)C>[Cl:31][CH:32]=[CH:33][CH2:34][O:35][N:36]=[C:27]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=2)[CH2:14][C:9]=1[OH:8])[CH2:28][CH3:29]
Reactant: NOCC=CCl
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCC(=NOCC=CCl)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into 40 ml of mixture solvent of ethanol-chloroform (1:1) was dissolved 2 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 10 ml of ethanol containing 10% of 3-chloroallyloxyamine at room temperature. The mixture was kept for 3 hours and it was poured into ice water. The mixture was acidified with hydrochloric acid and the oil separated was extracted with chloroform. The chloroform solution was dried with anhydrous magnesium sulfate and the chloroform was removed from it under reduced pressure and 1.5 g of the desired crude compound was obtained. It was purified by column chromatography and trans-cis mixture which was pale pink crystal having a melting point of 125°-127° C. was obtained.
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:15][C:16]1[C:24]2[N:23]=[C:22](Cl)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Br:15][C:16]1[C:24]2[NH:23][C:22]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:6][CH2:5]3)=[N:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: OCc1cccnc1N1CCNCC1
Product: OCc1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(Br)c3[nH]2)CC1

Procedure:
(2-Piperazin-1-ylpyridin-3-yl)methanol (0.48 g, 2.5 mmol, Example 46a) reacted with 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.60 g, 2 mmol, Example 6b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 456 (M+1).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=C(C)C=2N=1.Cl.[CH3:33][N:34]([CH3:64])[C:35]1[N:40]=[CH:39][C:38]([C:41]2[N:42]=[C:43]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)[C:44]3[S:49][C:48]([CH2:50][N:51]4[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]4)=[C:47]([CH3:57])[C:45]=3[N:46]=2)=[CH:37][N:36]=1.[C:65](O)(=[O:69])[C@H:66]([CH3:68])[OH:67]>>[CH3:64][N:34]([CH3:33])[C:35]1[N:40]=[CH:39][C:38]([C:41]2[N:42]=[C:43]([N:58]3[CH2:59][CH2:60][O:61][CH2:62][CH2:63]3)[C:44]3[S:49][C:48]([CH2:50][N:51]4[CH2:56][CH2:55][N:54]([C:65](=[O:69])[C@@H:66]([OH:67])[CH3:68])[CH2:53][CH2:52]4)=[C:47]([CH3:57])[C:45]=3[N:46]=2)=[CH:37][N:36]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N(C)C)nc3)nc12
Agent: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N(C)C)nc3)nc12

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (100 mg) was reacted with 70 mg 2-(dimethylamino)pyrimidin-5-yl-5-boronic pinacol ester via General Procedure A. This crude intermediate was subjected to General Procedure D in which 100 mg of the crude HCl salt of N,N-dimethyl-5-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with 60 mg L-lactic Acid via General Procedure B to give 25.5 mg of 407 after reverse phase HPLC purification. MS (Q1) 527.3 (M)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[N+]([CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([O-])=O>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]2[C:12]3[CH2:13][NH:8][CH2:9][CH2:10][C:11]=3[N:19]([CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[F:15])[CH:27]=2)=[CH:30][CH:31]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1F
Product: Fc1ccccc1Cn1cc(-c2ccc(Cl)cc2)c2c1CCNC2

Procedure:
The title compound (129.2 mg) was prepared from 0.49 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 286 μL of 2-fluorobenzylamine, and 0.46 g of (2-nitro-vinyl)-4-chlorobenzene, replacing SiO2 with crushed 4 Å molecular sieves. MS (ESI): exact mass calculated for C20H18ClFN2, 340.11; found, m/z 341.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.30 (m, 5H), 7.18-7.12 (m, 3H), 7.10-7.06 (m, 1H), 5.20 (s, 2H), 4.35-4.34 (m, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.94 (t, J=6.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][C:25](=[O:27])[CH3:26]>C1COCC1>[O:27]=[C:25]([CH3:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cccc2cccnc12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)COc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
8-Hydroxyquinoline (0.73 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) were stirred at room temperature for 30 min. To this solution was added chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) in one portion. The resulting mixture was stirred at room temperature for 24 h. (monitored by TLC) and then poured into ice water (100 ml). The pale yellow solid thus obtained was collected and crystallized from dichloromethane and ether to afford 8-(2-oxopropoxy)quinoline (7a) (0.68 g, 67%) as a pale yellow needle crystal. mp: 58°-59° C.; 1H-NMR (CDCl3): δ2.32 (s, 3H, CH3), 4.88 (s, 2H, OCH2), 6.88-8.97 (m, 6H, Ar--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C([Li])CCC.[C:21]1(=[O:26])[O:25][CH2:24][CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][OH:26])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=C1CCCO1
Reactant: COc1cc2c(cc1OC)CCNCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CCN(C(=O)CCCO)CC2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 6.0 g (29 mmol) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 mL of THF, at 0° C., there are added, dropwise, over 15 minutes, 11.6 mL (29 mmol/1 eq.) of 2.6M n-butyl lithium solution in hexane. The mixture is then cooled to about −78° C. and poured dropwise, over 10 minutes, into a solution of 2.7 mL (34.8 mmol/1.2 eq.) of gamma-butyrolactone in 15 mL of THF. Stirring is carried out at −78° C. for 30 minutes and the temperature is then brought to −30° C. and held there for 1 hour; the temperature is then allowed to return to ambient temperature, where stirring is carried out for 48 hours. The mixture is poured into 75 mL of saturated aqueous ammonium chloride solution and is then extracted twice with 120 mL of ethyl acetate. The combined organic phases are washed with 150 mL of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is taken up in 300 mL of ethyl acetate and washed twice with 75 mL 1M aqueous hydrochloric acid solution. The combined aqueous acid phases are re-extracted twice with 100 mL of dichloromethane. The organic phases are combined, dried over magnesium sulphate and concentrated to yield the desired product.
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4]C.[CH3:20]C(C)CCS>>[CH3:20][CH:3]([CH3:4])[CH2:2][CH2:1][S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Reactant: CC(C)CCS
Product: CC(C)CCSc1c[nH]nc1C1CN2CCC1CC2
Yield: 20 %

Procedure:
Compound 49H was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using 3-methyl-1-butanethiol as reagent. Subsequent purification by flash chromatography (EtOH) afforded compound 49G.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:13]1[C:18]([CH3:19])=CC(C)=C(C)C=1O)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]1([CH3:60])[CH:59]=CC=[CH:56][CH:55]=1>C1COCC1>[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]2[C:13]3[C:18]([CH3:19])=[CH:56][C:55]([CH3:23])=[C:54]([CH3:60])[C:59]=3[O:1][CH2:2]2)=[CH:5][CH:6]=1)([CH3:11])[CH3:12]
Reactant: Cc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(C)c(C(CO)c2ccc(C(C)C)cc2)c(O)c1C
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5,6-trimethylphenol obtained in Reference Example 8 (7.85 g, 26.3 mmol) and triphenylphosphine (7.58 g, 28.9 mmol) in THF (60 mL) was added diethyl azodicarboxylate (a 40% toluene solution, 12.6 g, 28.9 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.70 g (yield 84%) of the title compound. Melting point: 48-49° C. (methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[C:17](O)(=O)[CH3:18].[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:22].[Na+].C(=O)([O-])O.[Na+]>CCOCCOC1C=CC(C2C=CC3N(C=O)CCC(C(NC4C=CC(CN(C)C5CCOCC5)=CC=4)=O)=CC=3C=2)=CC=1F.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH2:22][CH2:17][CH3:18])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: CC(=O)O
Agent: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,2-dichloroethane (20) were dissolved methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g), n-butylaldehyde (1.3 ml) and acetic acid (0.41 ml), and to the solution was added sodium triacetoxyborohydride (3.8 g). The mixture was stirred at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-butyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.9 g) as pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](N2CCOCC2=O)=[CH:7][CH:6]=[CH:5][C:4]=1[S:16]([NH:19][C@H:20]([C:31]([N:33]1[CH2:38][CH2:37][O:36][C@H:35](C)[CH2:34]1)=[O:32])[CH2:21][NH:22][C:23]([C:25]1[S:26][C:27]([Cl:30])=[CH:28][CH:29]=1)=[O:24])(=[O:18])=[O:17])[CH3:2].[CH3:40]CN(C(C)C)C(C)C.C(C1C([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=CC=CC=1S(Cl)(=O)=O)C>C(Cl)Cl>[ClH:30].[CH2:1]([C:3]1[C:8]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[S:16]([NH:19][C@H:20]([C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]1[CH3:40])=[O:32])[CH2:21][NH:22][C:23]([C:25]1[S:26][C:27]([Cl:30])=[CH:28][CH:29]=1)=[O:24])(=[O:17])=[O:18])[CH3:2]
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCO[C@H](C)C1
Reactant: CCc1c(-c2ccccn2)cccc1S(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1c(-c2ccccn2)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCOC[C@@H]1C
Product: Cl
Reaction time: 1.5 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-2-amino-3-((S)-3-methyl-morpholin-4-yl)-3-oxo-propyl]-amide (Intermediate 3) (95 mg, 0.287 mmol) was dissolved in 2 ml DCM and DIPEA (151 μl, 0.861 mmol). Intermediate 61 (81 mg, 0.287 mmol) in 2 ml DCM was slowly added and the reaction was stirred for 1.5 h. Then the solution was evaporated to dryness and purified by prep. HPLC. After lyophilization the title compound is obtained as colorless, amorphous solid. The material was dissolved in 20 ml water and 150 μl 4N HCl in dioxane were added. The solution was lyophilized again. Yield: 77 mg, 44%. MS (ES+): m/e=577.1/579.1, chloro pattern.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:31])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNC(=O)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (2.00 g) was dissolved in methylene chloride (80 ml) and a solution of 4-chlorophenyl isocyanate (1.13 g) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated under reduced pressure to give 4-tert-butoxycarbonylaminomethyl-1-(5-(3-(4-chlorophenyl)ureido)pentyl)piperidine.