Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.CCOC(C)=O>[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: NCCCCN1CCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCCC1)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-chloro-pyridine-2-carbonyl chloride (8.88 g, 49 mmol) in THF (100 mL) was added at 0° C. 4-pyrrolidin-1-yl-butylamine (7.0 g, 49 mmol). The reaction was stirred for 18 h at RT. The mixture was diluted with EtOAc, washed several time with aqueous 6 N NaOH and then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using a gradient CH2Cl2/MeOH/NH4OH (100%, 0%, 0% to 90%, 10%, 1%). The pure fractions were combined and the solvents removed under vacuum. The title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[C:3]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>CC(N(C)C)=O.O>[S:17]([NH:1][C:2]1[S:6][C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[C:3]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:20])(=[O:19])[NH2:18]
Reactant: N#Cc1c(N)sc2c1CCc1ccccc1-2
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1c(NS(N)(=O)=O)sc2c1CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4,5-dihydronaphtho[1,2-b]thiophene-3-carbonitrile (Example 93b) (250 mg, 1.11 mmol) in dimethylacetamide (5 mL) was added sulfamoyl chloride (385 mg, 3.33 mmol). The reaction mixture was stirred at room temperature under nitrogen for about 1 hr, then it was diluted with water and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product which was carried on for next step.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:6]([OH:16])[N:5]=[C:4](SC)[N:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1.Cl>O>[OH:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:6]([OH:16])[N:5]=[C:4]([NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CSc1nc(O)c(NC(=O)c2ccco2)c(O)n1
Agent: Cl
Solvent: O
Product: COc1ccc(CCNc2nc(O)c(NC(=O)c3ccco3)c(O)n2)cc1
Temperature: 90 °C
Yield: 16.6 %

Procedure:
A mixture of 4,6-dihydroxy-5-(2-furanylcarbonyl)amino-2-methylthiopyrimidine (2 g, 7.5 mM), p-methoxyphenethylamine (3.4 g, 22.5 mH), and water (25 ml) was heated at 90° C. for 15 hours. The mixture was then poured into water (100 ml) and acidified with concentrated hydrochloric acid until PH<3. The resultant precipitate was removed by filtration and recrystallised from methanol/water (3:1) to afford 4,6-dihydroxy-5-(2-furanylcarbonyl)amino-2-[(4-methoxy-phenyl)ethyl]aminopyrimidine as a white solid (0.46 g, 16.6% yield) m.p >250° C.; NMR: DMSO-d6 : 2.75(t,2H,ArCH2), 3.47(brq,2H,CH2NH), 3.73 (s,3H, OMe), 6.50(brs, 1H, NH), 6.61(m, 1H,furyl-H), 6.87(d,2H,ArH), 7.16(d,2H,ArH), 7.17(s,1H furyl-H), 7.82(d,1H,furyl-H), 8.64(brs,1H,NHCO), 10.58(brs,2H,OH ×2); m/e [M+H]+ , 371:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH:13]1([N:7]2[CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:6]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2
Yield: 61.6 %

Procedure:
A mixture of 0.053 g (0.0002 mole) of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10), 0.04 g (0.00024 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.049 g of 4-(9-cyclopentyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17]CC1C=CC=C(OC3C=CC=CC=3)C=1)=[O:16])[CH2:6]2.[OH-].[K+].C(O)C>O>[F:13][C:8]1[C:9]([Cl:12])=[C:10]([Cl:11])[C:2]([F:1])=[C:3]2[C:7]=1[CH2:6][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([OH:17])=[O:16])[CH2:4]2
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(F)c(Cl)c(Cl)c(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(Cl)c(Cl)c(F)c2C1

Procedure:
A mixture of m-phenoxybenzyl 2-(4,7-difluoro-5,6-dichloro-2-isoindolinyl)-3-methylbutanoate (0.38 g), KOH (0.134 g), ethanol (8 ml) and water (2 ml) is heated to reflux for 14 hours. After cooling, the reaction is concentrated under vacuum and about 50 ml of water added. The mixture is washed with ether. The aqueous phase is adjusted to pH 7 and then the water is removed by evaporation to yield 2-(4,7-difluoro-5,6-dichloro-2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: [C:1]1([C:7]2O[C:10]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=CC=1.[CH3:25]C(C)=O.[C:29](=[O:31])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:24][CH2:22][CH2:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([C:10]2[O:31][CH:29]=[CH:25][C:9]=2[C:8]2[CH:4]=[CH:5][CH:6]=[CH:1][CH:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1
Reactant: O=C=O
Reactant: CC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(CCO)c1)c1occc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The carboxylic acid (10) (50 mg, 0.15 mmol) was dissolved in anhydrous THF (0.1 ml) and placed under an atmosphere of N2. The solution was cooled to −78° C. using acetone/dry ice and stirred for 10 min. LiAlH4 (1M in THF) was added dropwise (0.31 ml, 0.31 mmol) and the resulting solution was stirred for 10 min at −78° C., then allowed to warm to room temperature and stirred for a further 2 h. After cooling to 5° C. using ice/water, the reaction mixture was quenched by dropwise addition of water (1 ml) then neutralised to pH 7 with 1M NaOH and extracted with EtOAc (2×1 ml). The combined organic layers were dried (Na2SO4), filtered and the solvent removed in vacuo. The crude residue was purified by column chromatography, eluting in 60% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1]C#CC1C=CC=CC=1.[OH-].[Na+].[CH3:12][C:13]([CH3:15])=O.[C:16]1([CH3:22])[CH:21]=[CH:20]C=C[CH:17]=1>>[NH2:1][C:12]1[CH:17]=[C:16]([C:21]#[CH:20])[CH:22]=[CH:15][CH:13]=1
Reactant: CC(C)=O
Reactant: Cc1ccccc1
Reactant: NC#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1cccc(N)c1

Procedure:
Sabourin, Prepr. Div. Pet. Chem., Am. Chem. Soc., vol. 24, pp. 233-239 discloses the preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol (an aminophenylacetylene) and 3-aminophenylacetylene in two and three steps, respectively, from 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol. In the first step, 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol were reacted in the presence of a catalyst system of bis(triphenylphosphine)palladium dichloride, additional triphenylphosphine, and cuprous iodide in triethylamine solvent at the reflux temperature to obtain 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol. In the second step, this nitrophenylacetylene was hydrogenated in isopropanol in the presence of a Ru/Al2 03 catalyst to obtain 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol. This reference states that is essential to stop the hydrogenation reaction at the stoichiometric point because reduction of the triple bond ensues. In the third step, this aminophenylacetylene was heated in toluene in the presence of sodium hydroxide pellets, with removal of the acetone co-product by distillation, to obtain 3-aminophenylacetylene.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.[CH3:17][O:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH:23]([C:25]1[N:30]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([O:37][CH3:38])=[CH:27][CH:26]=1)[OH:24]>ClCCl.CCCCCC>[CH3:17][O:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[N:30]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([O:37][CH3:38])=[CH:27][CH:26]=1)=[O:24]
Reactant: COC(=O)CCCC(O)c1ccc(OC)c(CCC(=O)OC)n1
Agent: O=[Cr](=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: COC(=O)CCCC(=O)c1ccc(OC)c(CCC(=O)OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
2.9 g of Collins reagent is added to a solution of 470 mg of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-(5RS)-5-hydroxypentanoic acid methyl ester in 50 ml of dichloromethane under argon atmosphere at 0° C., and the mixture is stirred for 2 hours at room temperature. Then, it is diluted with hexane, mixed with diatomaceous earth until paste formation, filtered on diatomaceous earth and rewashed with ethyl acetate. The filtrate is concentrated by evaporation, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 337 mg of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-5-oxopentanoic acid methyl ester of melting point 64°-66° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].CS(OC[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([N:26]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([CH:44]5[CH2:46][CH2:45]5)=[CH:40][CH:39]=4)=[C:32]([O:47][CH3:48])[CH:31]=3)[CH2:27]2)=[O:25])[CH:19]=1)(=O)=O.O.[CH3:50]N(C=O)C>>[CH:44]1([C:41]2[CH:40]=[CH:39][C:38]([CH2:37][O:36][C:33]3[CH:34]=[CH:35][C:30]([CH:28]4[CH2:29][N:26]([C:24]([C:20]5[CH:19]=[C:18]([C@H:7]([CH:5]6[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]6)[O:8][CH3:50])[CH:23]=[CH:22][N:21]=5)=[O:25])[CH2:27]4)=[CH:31][C:32]=3[O:47][CH3:48])=[CH:43][CH:42]=2)[CH2:46][CH2:45]1
Reactant: CN(C)C=O
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COc1cc(C2CN(C(=O)c3cc(COS(C)(=O)=O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C2CN(C(=O)c3cc([C@@H](OC)C4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-methanol (0.42 mL) in DMF (10 mL) was added NaH (0.14 g). The mixture was stirred at RT for 1 hr. To the mixture was added 2-{3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-ylmethyl methanesulfonate (0.80 g) prepared in (7). The reaction mixture was stirred for at RT for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, reduced pressure to give the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][CH:21]=1.B(F)(F)F.O(CC)CC>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:18][CH3:19])([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:21]=3)[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC=C(CC)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Yield: 87.3 %

Procedure:
Cool a solution of 6-(1-ethyl-propenyl)naphthalene-2-carboxylic acid methyl ester (0.74 g, 2.75 mmol) and o-cresol (2.0 mL, 19.4 mmol) in CH2CL2 (20 mL) to −78° C.; dropwise add BF3-OEt2 (1.22 mL, 9.6 mmol). Remove the cooling bath and stir the reaction at RT for 16 h. Quench the reaction with ice water; then dilute with EtOAc (200 mL). Wash the resulting mixture twice with brine, dry over Na2SO4, filter, and concentrate the filtrate. Purify the product using medium pressure silica gel chromatography (100% hex to 25:75 EtOAc:hex) to give the title compound as a white solid (0.87 g, 87%). MS (ES) in/e 363 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22]([O:24]C2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22]([N:60]3[CH2:59][CH2:58][N:57]([CH:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)[CH2:62][CH2:61]3)=[O:24])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[O:49])[CH2:38][CH2:39]1)=[O:36]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 1-(N-methylpiperidin-4-yl)piperazine (68.7 mg), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1 then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (30.1 mg, 63.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33]C1C=C(CCC(O)=O)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1cccc(CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(3-methoxy-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Si:11]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([CH:36]([NH2:38])[CH3:37])=[CH:27][C:28]([Cl:35])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(O)C>[Si:11]([O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[C:26]([CH:36]([NH:38][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:37])=[CH:27][C:28]([Cl:35])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.262 g, 1.31 mmol), 1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethanamine (0.276 g, 0.657 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) in ethanol (2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude product was used directly in the next step (0.20 g, 57%). LCMS calculated for C27H37ClN7OSi (M+H)+: m/z=538.2; Found: 538.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][CH3:15])=[O:13])[CH:9]=1)([O-])=O.[S-2].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][CH3:15])=[O:13])[CH:9]=1
Reactant: CNC(=O)/C=C/c1cc([N+](=O)[O-])ccc1OC
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)/C=C/c1cc(N)ccc1OC
Temperature: 80 °C
Yield: 76.4 %

Procedure:
(E)-3-(5-Nitro-2-methoxy-phenyl)-N-methyl-acrylamide (0.75 g) and sodium sulphide (1.0 g) were combined in 1,4-dioxan/water (1:1, 20 ml) and warmed at 80° C. for 3 h. Solvent was removed at reduced pressure, the residue extracted with 10% methanol/dichloromethane and the extract filtered. The filtrate was evaporated to dryness and the residue column chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.50 g). 1 H NMR δ: 2.68 (3H, d, J=0.4.8Hz), 3.71 (3H, s), 6.44 (1H, d, J=15.9 Hz), 6.60 (1H, dd, J=2.8 9.2 Hz), 6.73 (1H, d, J=2.8 Hz), 6.78 (1H, d, J=9.2 Hz), 7.57 (1H, d, J=15.9 Hz), 8.00 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.S([N:34]=[C:35]=[O:36])(C1C=CC(C)=CC=1)(=O)=O.N[CH2:38]C>CN(C=O)C.C1COCC1>[CH3:38][NH:34][C:35]([NH:17][C:15]1[N:16]=[C:12]2[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=[C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:13]2[N:14]=1)=[O:36]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCN
Reactant: Cc1cccnc1-c1cc(-c2cccnc2)cc2nc(N)nn12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ncccc3C)n2n1

Procedure:
The product of Step 1 (240 mg, 0.79 mmol) was taken up in DMF (2 mL) to which was added TosNCO (0.31 g, 1.6 mmol) all at once. The mixture was stirred at room temperature for 1 h whereon a 2 M solution of H2NEt (3 mL, 6 mmol) in THF was added. The homogeneous solution was microwaved at 100° C. for 10 min. On cooling, SiO2 was added and the solvent was removed. Column chromatography afforded the title compound. MS m/z 374 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cn(CCC)cn4)cc2)CCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cn(CCC)cn4)cc2)CCN3CC(C)C)cc1
Yield: 71.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-4-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (140 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (78 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methanol-ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-4-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 394) as yellow amorphous.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][C@@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][C:16]=1[OH:17].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][C@@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@H](O)Cc1ccc(O)c(Br)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](O)Cc1ccc(OCOCC[Si](C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.7 mL (39.1 mmol) ethyldiisopropylamine were added to a solution of 10.2 g (34.6 mmol) methyl (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mL DCM and the reaction mixture was cooled in the ice bath. Then a solution of 7.9 mL (44.6 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane in 20 mL DCM was added. The reaction mixture was stirred for 3 h at RT and then combined with another 0.67 mL ethyldiisopropylamine and 0.8 mL (4.5 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane to complete the reaction and stirred for 1.5 h at RT. The reaction mixture was washed with 5% Na2CO3 solution and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, Cyc/EtOAc 75:25).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][C:46](=[O:49])[N:45]([CH2:50][CH2:51][CH2:52][CH2:53][O:54][Si:55]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])[C:44]=2[CH:65]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:41]=[CH:42][C:43]3[O:48][CH2:47][C:46](=[O:49])[N:45]([CH2:50][CH2:51][CH2:52][CH2:53][O:54][Si:55]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[CH:62]([CH3:63])[CH3:64])[C:44]=3[CH:65]=2)=[CH:9][CH:10]=1
Reactant: CC(C)[Si](OCCCCN1C(=O)COc2ccc(CCl)cc21)(C(C)C)C(C)C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCO[Si](C(C)C)(C(C)C)C(C)C)C(=O)CO3)cc1

Procedure:
Analogously to Method D, 1.30 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.30 g of 6-chloromethyl-4-(4-triisopropylsilanyloxybutyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=7.54.