Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][S:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:18][C:16]([F:17])([F:19])[C:15]([NH:14][CH2:13][CH:12]1[CH2:11][S:10][CH2:9][NH:8]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CSCC1CNC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CSCN1)C(F)(F)F
Reaction time: 20 h

Procedure:
To a cold (0° C.) solution of 4-[(2,2,2-trifluoro-acetylamino)-methyl]-thiazolidine-3-carboxylic acid tert-butyl ester (19 mmol) in dry DCM (10 mL) was added dropwise TFA (133 mmol, 7 eq). The reaction mixture was stirred for 20 h and concentrated in vacuo to give the title compound. LC-MS: tR=0.24 min; [m+H]+=214.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]1[C:21]2[C:12](=[CH:13][C:14]3[CH:15]4[CH2:25][CH2:24][CH2:23][CH:16]4[C:17](=O)[NH:18][C:19]=3[CH:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>COCCOC>[C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]1[C:21]2[C:12](=[CH:13][C:14]3[CH:15]4[CH2:25][CH2:24][CH2:23][CH:16]4[C:17](=[S:43])[NH:18][C:19]=3[CH:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)C1CCc2cc3c(cc21)NC(=O)C1CCCC31
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)C1CCc2cc3c(cc21)NC(=S)C1CCCC31

Procedure:
A solution of 100 mg (0.21 mmol) of 7-(N-tert-butoxycarbonyl-3-chlorobenzyl-amino)-1,2,3,3a,7,8,9,10b-octahydro-dicyclopenta[c,g]quinolin-4-one and 96 mg (0.23 mmol) of Lawesson's reagent in 10 ml of DME is stirred for 2 hours at room temperature. After concentration by evaporation, the residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 70 mg of product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[CH:2]([CH3:1])[CH2:6][CH2:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: CC1CCC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3)CC2)c(C)c1
Yield: 51.8 %

Procedure:
Using 4-(2-methyl-5-oxopyrrolidin-1-yl)benzoic acid (438 mg) described in Preparation Example 50 and 1-(3,5-dimethylpyridin-2-yl)piperazine (383 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 93, the title compound (406 mg) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)(=O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of methyl 5-formyl-2-hydroxybenzoate (21.76 g), triethylamine (13.46 g), ethyl acetate (300 mL) was added dropwise methanesulfonyl chloride (15.24 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-formyl-2-methanesulfonyloxybenzoate as a colorless oil (31.20 g, yield 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C.C1COCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Clc1ncccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncccn1)C2
Yield: 71.7 %

Procedure:
A solution of 3,8-diaza-bicyclo[3,2,1]octane-8-carboxyli acid tert-butyl ester (50 mg, 0.24 mmol), 2-chloropyrimidine (27 mg, 0.24 mmol), triethylamine (0.1 ml, 0.72 mmol) and THF (2.5 ml) was heated at 180° C. for 10 minutes. The solution was concentrated to afford a solid residue that was dissolved in dichloromethane, which was washed sequentially with sat. aq. sodium bicarbonate and brine, dried (Na2SO4), filtered, and concentrated to afford 50 mg (71%) of the product as a brown solid: 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J=12.0 Hz, 2H), 6.52 (t, J=12.0 Hz, 1H), 4.38-4.29 (m, 4H), 3.13 (sb, 2H), 2.42 (m, 2H), 1.69 (q, J=18.0 Hz, 2H), 1.49 (s, 9H); MS (M+1)=291.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-])=O.P(OCC)(OCC)(OCC)=O>O>[CH:21]1[C:22]2[C:23]3[NH:1][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[C:10]=3[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1-c1cc2ccccc2c2ccccc12
Solvent: O
Solvent: CCOP(=O)(OCC)OCC
Product: c1ccc2c(c1)[nH]c1c3ccccc3c3ccccc3c21
Temperature: 150 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Next, a mixed solution of 2.0 g of 9-(2-nitrophenyl)phenanthrene and 40 ml of triethyl phosphate was heated and stirred under a nitrogen gas stream at 150° C. for 8 hours. After cooling to room temperature, 50 ml of water was poured into the solution, followed by extraction with 50 ml of toluene. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The concentrate was purified by silica gel chromatography and then vacuum-dried to obtain 840 mg of 13H-13-azaindeno[1,2-l]phenanthrene.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][OH:37])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:37][CH2:36][CH2:35][CH2:34][N:31]1[CH:32]=[CH:33][C:29]([NH:28][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:30]1
Reactant: Nc1ccn(CCCO)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2ccn(CCCO)n2)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 43 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 5% methanol/ethyl acetate) to afford (R)—N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (63 mg, 50%) as an off white foam: [α]29589=−60.6° (c=0.16, methanol); ES-HRMS m/e calcd for C21H24N3O3F3 (M+H)+ 424.1843, observed 424.1842; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.74-2.29 (m, 10H, 5×CH2), 3.33 (m, 2H, OCH2), 3.94 (m, 1H, ArCHCO), 4.02 (t, J=6.8 Hz, 2H, NCH2), 4.55 (t, J=5.4 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4](=[O:18])[C:5]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[Si:14]([CH3:17])([CH3:16])[CH3:15])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4](=[O:18])[C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[Si:14]([CH3:16])([CH3:15])[CH3:17])[CH3:20]
Reactant: CCN(CC)C(=O)c1c(C=O)ccc(F)c1[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)C(=O)c1c(CO)ccc(F)c1[Si](C)(C)C
Yield: 82 %

Procedure:
The compound of Example 41 (1.2 g, 4.1 mmol) and sodium borohydride (200 mg, 5.3 mmol) in ethanol (20 mL) were stirred at ambient temperature for 2 h. The solution was concentrated and partitioned between ether and 10% citric acid. The ether layer was washed with water and then brine, dried (MgSO4), concentrated, and recrystallized from cold hexanes to afford 1.0 g of the title compound, an 82% yield. m.p. 107-108° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1([F:23])[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([CH:13]2[CH2:14][CH2:15][CH2:16][C:12]2([F:23])[F:11])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC1CCCC1(F)F
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
22.6 ml (22.6 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −20° C., and a solution of 2.90 g (15.09 mmol) of (+/−)-ethyl (2,2-difluorocyclopentyl)acetate in 20 ml of abs. toluene was added dropwise. The mixture was stirred at −20° C. for 10 min Cooling was removed, and a solution, prepared beforehand, of 3.75 g (19.61 mmol) of 4-bromo-chlorobenzene, 110 mg (0.49 mmol) of palladium(II) acetate and 374 mg (0.95 mmol) of 2′-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of abs. toluene was then added dropwise. The resulting reaction mixture was stirred initially at RT for 1 h, and then at 90° C. for 2 h. After cooling, the reaction mixture was added to water. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The residue gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1), 2.70 g of the title compound (59.1% of theory, diastereomer ratio about 1:4.3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(CCCC(=O)O)nc1
Solvent: c1ccncc1
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2cccc(Cl)c2)cn1
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A solution of 3-chlorobenzenesulphonyl chloride (1.17 g), dissolved in 5 ml pyridine, was added dropwise to a solution of 4-(5-aminopyrid-2-yl)butanoic acid (1 g) in pyridine (10 ml). The resulting solution was allowed to stand at room temperature overnight when the solvent was removed under reduced pressure. The residue was taken up in dilute sodium hydroxide solution (40 ml) and extracted with chloroform (4×50 ml) the chloroform extracts were discarded. The aqueous layer was adjusted to pH 4 with hydrochloric acid, extracted with chloroform (3×100 ml) and then ethyl acetate (2×100 ml). Chloroform and ethyl acetate extracts were dried over magnesium sulphate, solvents removed and residue recrystallised from acetonitrile/water to give the title compound (1.29 g) as a white solid. m.p. 141°-142° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH2:20][CH3:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH2:19][CH2:20][CH3:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CCCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 719 mg (12.16 mmol) of propylamine were stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 211 mg (yield: 77.7%) of the title compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:20])[CH2:18]C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:21]1[C:22]2[S:35][CH:34]=[CH:33][C:23]=2[N:24](C(OC(C)(C)C)=O)[N:25]=1)=O)(C)(C)C.C[Mg]Br.O1CC[CH2:41][CH2:40]1>>[NH:24]1[C:23]2[CH:33]=[CH:34][S:35][C:22]=2[C:21]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([C:17]([OH:20])([CH2:40][CH3:41])[CH3:18])=[CH:14][CH:15]=3)=[N:25]1
Reactant: C1CCOC1
Reactant: CCC(=O)c1ccc2c(c1)cc(-c1nn(C(=O)OC(C)(C)C)c3ccsc13)n2C(=O)OC(C)(C)C
Agent: C[Mg]Br
Product: CCC(C)(O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-propionyl-indole-1-carboxylic acid tert-butyl ester [450 mg, 0.908 mmol, Intermediate (15)] in anhydrous tetrahydrofuran (25 mL) that is cooled to −78° C. is added methylmagnesium bromide (1M in tetrahydrofuran, 3 mL) via syringe under nitrogen. After stirring for 30 minutes cooling bath is removed and brought the reaction to room temperature. The reaction is cooled to −78° C. then additional 5 mL of methyl magnesium bromide is added. After 30 minutes, the cooling bath is removed and reaction temperature is brought to room temperature. After 4 hours, it is quenched by the addition of saturated ammonium chloride (6 mL). After stirring for 10 minutes, water (20 mL) is added and extracted three times with ethyl acetate (40 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. Purification by chromatography (35 g silica gel cartridge, 1:1 ethyl acetate/heptane) afforded 2-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-butan-2-ol [148 mg, 52%, Example 32] as a white solid; 1H NMR [(CD3)2SO)]: δ 13.204 (1H, s), 11.402 (1H, s), 7.743 (1H, d), 7.595 (1H, s), 7.333-7.192 (3H, m), 6.598 (1H, s), 4.658 (1H, s, OH), 1.728 (2H, q), 1.461 (3H, s), 0.702 (3H, t); LC/MS: 312 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:14][CH2:13]3)[C:11](=[O:31])[N:10]([CH2:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36]([O:38]C)=[O:37])[CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:14][CH2:13]3)[C:11](=[O:31])[N:10]([CH2:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36]([OH:38])=[O:37])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.44 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.037 g, 0.88 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.05 g, 13%); 1H NMR (DMSO-d6): δ 1.62 (d, 2H, J=13.2 Hz), 1.81 (t, 2H, J=6.4 Hz), 2.27-2.37 (m, 4H), 2.50-2.69 (m, 4H), 3.83 (t, 2H, J=6.8 Hz), 4.56 (d, 4H, J=15.2 Hz), 6.88-6.91 (m, 2H), 6.95-6.98 (m, 3H), 7.08 (d, 2H, J=5.2 Hz), 7.13-7.16 (m, 1H), 7.47-7.52 (m, 2H), 7.85-7.87 (m, 2H), 10.81 (s, 1H), 13.10 (br, 1H); MS for C31H32FN5O4 m/z 558.02 (M+H)+.
Reaction SMILES: [N:1]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][C@H:11]([C:28]([O:30]CC1C=CC=CC=1)=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[Cl:23])=[O:18])=[O:9])[CH3:7])=[O:4].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[N:1]1([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][C@H:11]([C:28]([OH:30])=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[Cl:23])=[O:18])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
At 0° C. to the solution of 135 mg (0.2 mmol) of Boc-Pro-Ala-Lys(ClZ)-OBzl in 5 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Pro-Ala-Lys(ClZ)-OBzl. The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 100 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])C=C.[C:24]1(C)[CH:29]=C(C)C=C(C)[CH:25]=1>>[CH2:29]([C:13]1[CH:12]=[CH:11][C:10]2[N:9]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[CH:8]=[CH:7][C:6]=2[C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Product: C=CCc1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1O

Procedure:
Refluxing a solution of 4-(allyloxy)-1-[(4-methylphenyl)sulfonyl]-1H-indole in mesitylene followed by removal of the solvent and subsequent purification by flash column chromatography provides 5-allyl-1-[(4-methylphenyl)sulfonyl]-1H-indol-4-ol.
Reaction SMILES: [H-].[K+].[CH3:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[CH2:10](Br)[C:11]#[CH:12]>C1COCC1.C1(C)C=CC=CC=1>[CH3:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:12][C:11]#[CH:10])[C:5]1=[O:9]
Reactant: C#CCBr
Reactant: CN1CCNC1=O
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCN1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of potassium hydride (10.44 g of a 35% by wt suspension in mineral oil, washed with ether to remove oil, 0.09 mol) in dry THF (50 mL) was added dropwise, with cooling, to a stirred solution of 1-methyl-2-imidazolidinone (7.6 g, 0.076 mol) in dry THF (150 mL). After warming to room temperature and stirring for 20 min, the reaction was cooled again and propargyl bromide (13.54 g of an 80% solution in toluene, 0.09 mol) was added dropwise. The reaction was then allowed to slowly warm to room temperature and was stirred for 0.5 hr. The reaction was quenched with methanol and water and the solvents were removed under reduced pressure. The residual oil was partitioned between ethyl acetate and water; evaporation of the organic phase gave 10.65 g crude product. The compound was purified by chromatography on silica gel in chloroform to get 4.51 g of crystalline product.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:14])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:5]([CH2:4][CH:3]([OH:14])[CH2:2][Cl:1])[C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:12][CH:11]=1
Reactant: OC(CCl)CNCc1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(Cc1ccc(F)cc1)CC(O)CCl
Reaction time: 1 h
Yield: 126 %

Procedure:
To a solution of 3-chloro-1-(p-fluorobenzylamino)-2-propanol (20.78 g, 66.50 mmol) in methylene chloride (150 ml) were added in turn triethylamine (10.2 ml, 73.2 mmol), dimethylaminopyridine (812 mg, 6.65 mmol), ethyl chlorocarbonate (5.7 ml, 73 mmol) under ice-cooling and the mixture was stirred for one hour, allowed to rise to room temperature and then stirred for further 19 hours. The reaction mixture was diluted with chloroform (100 ml), washed successively with 10% aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give crude ethyl N-(p-fluorobenzyl)-N-(3-chloro-2-hydroxypropyl)carbamate (24.28 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH2:15][CH3:16]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:15][CH3:16]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CCCO
Agent: Cl
Product: CCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-propanol and the suspension is saturated with hydrogen chloride gas for 21/2 hours at 50°. After concentration, the residue is dissolved in 15 ml of n-propanol, 15 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:3 yields E-2-amino-5-phosphono-3-pentenoic acid propyl ester, m.p. 161°-162°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][N:16]([CH3:29])[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=O)=[CH:19][CH:18]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:15][N:16]([CH3:29])[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=3)[N:1]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc2nc(-c3ccc(N(C)C)c4ccccc34)[nH]c(=O)c2cc1OC
Yield: 56 %

Procedure:
2-(4-(Dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-Dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (159 mg, 56%) was isolated as a white solid. Selected data: MS (m/z): 376.13; MP 235.5-236.5° C.