Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:17]([O:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22][CH2:21]3)=[N:16][CH:15]=[N:14][C:13]=2[S:12][CH:11]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:17]([O:19][CH:20]3[CH2:21][CH2:22][CH:23]([NH:26][CH3:27])[CH2:24][CH2:25]3)=[N:16][CH:15]=[N:14][C:13]=2[S:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3scc(-c4cc5ccccc5o4)c23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3scc(-c4cc5ccccc5o4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A solution of tert-butyl N-(4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexyl)-N-methylcarbamate (60 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrochloric acid (1 mL, 12 M) at 0° C. and stirred for 1 h at room temperature. The pH value of the solution was adjusted to 9 with sodium carbonate (sat.) and extracted with 3×20 mL of dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 40 mg (84%) of 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N-methylcyclohexan-1-amine as colorless oil which was used directly for next step. To a solution of 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N-methylcyclohexan-1-amine (40 mg, 0.11 mmol, 1.00 equiv) in methanol (2 mL) was added HCHO (37%, 0.07 mL, 1.06 mmol) and stirred for 1 h at room temperature. Then NaBH3CN (20 mg, 0.32 mmol, 3.01 equiv) was added and stirred for additional 1 h at room temperature. The reaction was then quenched by the addition of 20 mL of NH4Cl (sat.) and extracted with 3×20 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (60 mg) was re-crystallized from ethyl acetate to give 15 mg (36%) of pure 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES, m/z): 394 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.66 (s, 1H), 8.08 (s, 1H), 7.68-7.65 (d, 1H), 7.56-7.54 (d, 1H), 7.38-7.25 (m, 3H), 5.45-5.42 (m, 1H), 3.33 (s, 1H), 2.90 (s, 6H), 2.53-2.50 (d, 2H), 2.23-2.20 (d, 2H), 1.82-1.66 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: NCc1ccc(Cl)c(N)c1F
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Yield: 36 %

Procedure:
The sub-title compound is prepared from crude 3-amino-4-chloro-2-fluoro-benzylamine, 2,2-dimethyl-propionic acid chloride and TEA in analogy to example Ae.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:32][C:31]3[CH2:30][CH2:29][NH:28][CH2:27][C:26]=3[CH:25]=1)=[O:23])=[O:13])=[CH:6]2.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.Cl.O.C(O)(=O)C.C(N(CC)CC)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:32][C:31]3[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][C:26]=3[CH:25]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)c1cc2c(s1)CCNC2)c1cc2cc(Cl)ccc2[nH]1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2sc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
(±)-cis-N1-[(5-Chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (171 mg) was suspended in dichloromethane (10 ml), and triethylamine (0.104 ml) was added to stir the mixture at room temperature for 10 minutes. After acetic acid (0.059 ml) was added to the reaction mixture, a 35% aqueous formaldehyde solution (0.070 ml) and sodium triacetoxyborohydride (118 mg) were added, and the mixture was stirred at room temperature for 30 minutes. After a 1N aqueous solution (3 ml) of sodium hydroxide was added to the reaction mixture, water was added to conduct liquid separation. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=50:3) to obtain a colorless foamy substance. This substance was suspended in 1N hydrochloric acid, and the suspension was concentrated under reduced pressure to obtain the title compound (85 mg) as a colorless foamy substance.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(O)C>O>[CH2:18]([S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(SCC(=O)c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.33 g. (6 m moles) of 3-mercapto-5-trifluoromethylbenzoic acid, 12 ml. of 1N sodium hydroxide solution and 930 mg. (6 m moles) of α-chloroacetophenone in 20 ml. of ethanol is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, extracted with ether and the resulting aqueous phase acidified with 12N hydrochloric acid. The light yellow oil which separates gradually crystallizes and is filtered, 1.8 g., m.p. 135°-150° C. A sample is sublimed at 165° C. and 0.05 mm pressure, m.p. 153°-155° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH2:11])=[O:10].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>CC(C)=O>[C:16]1([C:14]2[C:7]([CH2:8][C:9]([NH2:11])=[O:10])=[C:2]3[N:1]([CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)CCc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: NC(=O)Cc1c(-c2ccccc2)cn2ccccc12
Reaction time: 48 h

Procedure:
2-Pyridinepropaneamide (8.0 g, 53 mmol) was dissolved in warm acetone (500 mL). 2-Bromoacetophenone (12.0 g, 60 mmol) was added and the reaction mixture was heated under reflux overnight. After standing at room temperature for 2 days, the solvent was decanted from the tan precipitate, which was dissolved in ethanol and heated under reflux for 6 h. After standing overnight at ambient temperature, the ethanol was removed under reduced pressure to give a residue which was recrystallized from heptane (500 mL) to give 2-(2-phenyl-indolizin-1-yl)acetamide. 2-(2-Phenylindolizin-1-yl)acetamide (450 mg, 1.8 mmol) was suspended in ethyl ether. To the suspension was added lithium aluminum hydride (360 mg) and the reaction mixture was heated under reflux overnight under a nitrogen atmosphere. After cooling to room temperature, an aqueous solution of Rochelle salt was cautiously added with stirring until a solution was observed. The phases were separated and the aqueous phase was extracted 3 times with ether. The combined organic layers were extracted with 0.1 N HCl, and the aqueous layer was made basic with 2.5 N NaOH. The aqueous phase was extracted with methylene chloride three times and the organic phase was evaporated under reduced pressure to give crude product. The product was purified by chromatography on silica gel eluting with 5-11% methanol in methylene chloride containing 1% ammonium hydroxide. A 53% yield of the title compound was obtained, mp 212-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[C:7](=O)[C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[ClH:35].[NH2:36][OH:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CC(C)=O>[ClH:35].[N:36](=[C:7]1[C:6]2[CH:31]=[C:32]([O:33][CH3:34])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:8]1=[O:29])[OH:37]
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=NO)C2=O)cc1OC

Procedure:
A mixture of 3.6 gm of (6.8 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane, 0.57 gm of hydroxylamine hydrochloride and 0.87 gm of sodium carbonate was refluxed for 8 hours in 100 ml of ethanol. The solvent was then distilled off in vacuo; the residue was dissolved in water/methylene chloride, and the organic phase was separated, dried over magnesium sulfate and concentrated by evaporation. The residue was purified on silica gel, using methylene chloride and 5% ethanol as the eluant. The free base product thus obtained was dissolved in acetone, and the hydrochloride was precipitated by the addition of ethereal hydrochloric acid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:27]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>ClCCl>[NH2:47][C:7]1[C:6]2[N:27]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:5]=2[C:14]2[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 16 h

Procedure:
tert-Butyl 2-{[2-ethyl-5-oxido-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (wet from above) was slurried in dichloromethane (25 mL) and ammonium hydroxide (25 mL). p-Toluenesulfonyl chloride (0.810 g, 4.25 mmol) was added in one portion and the reaction was stirred for 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed with water, then saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated. The material was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform) to afford 1.8 g of tert-butyl 2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as a white foam. Recrystallization from acetonitrile of a small portion provided an analytical sample as a white solid, mp 200-201° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][N:33]1[CH:37]=[C:36](B(O)O)[C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:36]3[C:35]([C:41]([F:44])([F:43])[F:42])=[N:34][N:33]([CH3:32])[CH:37]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1cc(B(O)O)c(C(F)(F)F)n1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1cc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)cs2)c(C(F)(F)F)n1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid gave 252. 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 4.98-4.72 (m, 2H), 4.22-4.03 (m, 1H), 4.00 (s, 3H), 3.97-3.88 (m, 1H), 3.75 (s, 3H), 3.30-3.17 (m, 1H), 2.14-2.03 (m, 1H), 1.92-1.68 (m, 3H), 1.66-1.57 (m, 1H). LCMS (ES+) m/z 488 (M+1).
Reaction SMILES: [NH:1]([CH3:3])[CH3:2].C[Al](C)C.C1(C)C=CC=CC=1.FC(F)(F)C([NH:19][CH2:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](OCC)=[O:23])=O>C(Cl)Cl>[NH2:19][CH2:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([N:1]([CH3:3])[CH3:2])=[O:23]
Reactant: CNC
Reactant: CCOC(=O)C(CNC(=O)C(F)(F)F)c1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C(CN)c1ccccc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
To a stirred 4° C. CH2Cl2 solution (5 mL) containing HNMe2 (180 mg, 4 mmol) under N2, was added 2M AlMe3 in toluene (2 mL, 4 mmol). The reaction was warmed to 20° C. and stirred for five minutes before adding a CH2Cl2 solution (4 mL) containing α-[[(trifluoroacetyl)amino]methyl]benzeneacetic acid, ethyl ester (600 mg, 2.1 mmol). After two days, the reaction was quenched with 1 N aq. HCl, and extracted 3× with EtOAc. The EtOAc fractions were washed with brine, dried over Na2SO4, and concentrated. The crude product was chromatographed on silica gel using 4:1 hexane/EtOAc to elute 380 mg (63%) of the desired trifluoroacetamide which was heated to 60° C. for five hours in MeOH (2 mL) containing 1N aq. NaOH (3 mL). The reaction was diluted with brine, extracted 4× with EtOAc, dried over Na2SO4, and concentrated to yield the title compound as a clear oil (280 mg, 74%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH:27]=[CH2:28].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([N:29]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:31]=[N:30]1)[CH:27]=[CH2:28]
Reactant: COC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)OC)nc3)ccn2)cn1
Temperature: 90 °C
Yield: 15.3 %

Procedure:
A mixture of Example C5 (0.12 g, 0.33 mmol), 1-allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.085 g, 0.36 mmol) and K2CO3 (0.14 g, 0.99 mmol) in dioxane (4 mL) and H2O (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.034 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via reverse phase silica gel chromatography (MeCN/H2O (0.1% TFA)) to obtain N-((5-((2-(1-allyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide (22 mg, 14.6%). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 10.21 (br s, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.33 (s, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 8.03 (br s, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 6.77 (d, J=5.7 Hz, 1H), 6.02 (m, 1H), 5.21 (m, 1H), 5.13 (m, 1H), 4.77 (d, J=5.8 Hz, 2H), 3.21 (s, 3H), 1.36 (s, 6H); MS (ESI) m/z: 437.2 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16].Cl.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH2:28][C@H:27]2[NH2:33])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:33][C@H:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([C:22]([O:21][CH3:20])=[O:23])[CH:25]=2)[CH2:29][CH2:28]1)(=[O:17])=[O:16]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Triethylamin (2.195 mmol, 2,5 eq.) and 2-chlorobenzene-1-sulfonyl chloride (0,878 mmol, 1 eq.) were added to an ice-cold solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-03 HCl) (0.878 mmol, 1 eq.) in methylene chloride under an inert atmosphere. The mixture was then stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic phase was washed with 10% NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml) and sat. NaCl solution (20 ml). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (cyclohexane/ethyl acetate, 2:1) to obtain the desired product. Yield: >99%
Reaction SMILES: [C:1](=[O:15])(OC1C=CC=CC=1)[O:2][CH2:3][C:4]([NH:6][CH3:7])=[O:5].[CH2:16]([NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[CH2:16]([NH:26][C:1](=[O:15])[O:2][CH2:3][C:4]([NH:6][CH3:7])=[O:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCN
Reactant: CNC(=O)COC(=O)Oc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OCC(=O)NC

Procedure:
A solution of 136 mg (0.65 mmol) of 2-(methylamino)-2-oxoethyl phenyl carbonate and of 133 mg (0.85 mmol) of decylamine in 2 ml of dichloromethane is stirred at ambient temperature for 18 h.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:8].[C:22]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])(=[O:33])=[O:32])[CH2:27][CH2:26]1)(=[O:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([NH:1][C:2]2[S:3][C:4]3[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=3[C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:8])=[O:38])(=[O:32])=[O:33])[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Reactant: COc1ccc(NC(=O)c2c(N)sc3c2CCCC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2c(NC(=O)c3cccc(S(=O)(=O)N4CCN(C(C)=O)CC4)c3)sc3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 10.6 mg of 2-amino-N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, 10.9 mg of 3-(4-acetyl-piperazine-1-sulfonyl)benzoic acid, 16.0 mg of HATU, 0.012 mL of N,N-diisopropylethylamine, and 1 mL of DMA was stirred at room temperature overnight. The reaction mixture was separated by the addition of chloroform and water, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to obtain 5.2 mg of 2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH3:7])[OH:6])[CH3:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[H-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH3:7])[O:6][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OCCCCBr

Procedure:
The lactic acid ethyl ester and 1,4-dibromo-butane were reacted in THF in the presence of NaH to obtain 7-bromo-2-methyl-3-oxaheptanoic acid ethyl ester and subsequently, the exchange of bromine and iodine was carried out, as described in 4(d).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([Cl:17])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([Cl:17])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a stirred solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorobenzaldehyde (WO 2003051797, 1.58 g, 5.83 mmol) in methanol (5 mL) was added sodium borohydride (264 mg, 7.00 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, and quenched by addition of aqueous ammonium chloride. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over sodium sulfate, and evapolated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (20/1 to 10/1) to afford 1.51 g (95%) of the title compound as a colorless oil:
Reaction SMILES: C(CCC(N)C(C(OCC)=O)(OC1CCOCC1)C(OCC)=O)(OC(C)(C)C)=O.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O.[CH2:44]([O:46][C:47]([C:49]([C:61]([O:63][CH2:64][CH3:65])=[O:62])([O:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)[CH2:50][CH2:51][CH2:52][NH3+:53])=[O:48])[CH3:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C.CCOC(C)=O>[NH2:53][CH2:52][CH2:51][CH2:50][C:49]([C:47]([O:46][CH2:44][CH3:45])=[O:48])([O:54][CH:55]1[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62]
Reactant: CCOC(=O)C(CCC[NH3+])(OC1CCOCC1)C(=O)OCC
Agent: CCOC(=O)C(OC1CCOCC1)(C(=O)OCC)C(N)CCC(=O)OC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(CCCN)(OC1CCOCC1)C(=O)OCC
Yield: 96.1 %

Procedure:
A solution of ethyl 5-BOC-amino-2-ethoxycarbonyl-2-[4-tetrahydropyranyloxy]-pentanoate in CH2Cl2 (20 ml), cooled at 0-5° C., is added with trifluoroacetic acid (5 ml). After a night at room temperature, the mixture is evaporated under vacuum to obtain, after trituration of the residue in ethyl ether, 3.86 g of 4,4-diethoxycarbonyl-4-(4-tetrahydropyranyloxy)-butylammonium trifluoroacetate. A suspension of the salt in AcOEt (25 ml) is neutralized, under stirring at 0-5° C., by careful addition of a 5% sodium bicarbonate aqueous solution. After separating the organic phase and re-extracting the aqueous phase with AcOEt (3×5 ml), the combined organic phases are dried over Na2SO4, and solvent is evaporated off to obtain 2.73 g of ethyl 5-amino-2-ethoxycarbonyl-2-[4-tetrahydropyranyloxy]-pentanoate.