Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:41])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([C:10]4[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=4)[O:7][CH2:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[O:41])[N:23]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (4.30 g, 7.79 mmole) in TFA (20 mL) and CH2Cl2 (20 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and to the crude residue was added ca. 50 mL Et2O. The resulting bright yellow suspension was stirred for 15 minutes and filtered and dried giving 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide trifluroacetate salt. (4.1 g, mmol, %).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl-].[Li+].[F:28][C:29]([F:39])([F:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=O>C(#N)C.C(OC)(C)(C)C>[CH2:12]([O:14][C:15](=[O:25])/[CH:16]=[CH:36]/[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([F:28])([F:38])[F:39])[CH3:13]
Reactant: O=CCCCCCCC(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CCOC(=O)/C=C/CCCCCCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (436 μL, 2.92 mmol) was added to a solution of (diethoxy-phosphoryl)-acetic acid ethyl ester (633 μL, 2.43 mmol) and lithium chloride (144 mg, 3.41 mmol) in acetonitrile (20.0 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. A solution of 8,8,8-trifluoro-octanal (2.43 mmol) in acetonitrile (4.3 mL) was added dropwise to the reaction solution at 0° C., and the mixture was stirred for 10 minutes. Thereafter, the reaction mixture was stirred at room temperature for one hour and diluted with methyl tert-butyl ether (200 mL). The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution (30 mL), H2O (30 mL) and saturated brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (E)-10,10,10-trifluoro-dec-2-enoic acid ethyl ester as a colorless oily substance (426.6 mg, 70%).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13](=[N:18]O)[CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O.[Pd]>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCCCC(=NO)c1ccc(OC)c(OC)c1
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(N)c1ccc(OC)c(OC)c1
Yield: 87.4 %

Procedure:
To an N2 flushed solution of 3′,4′-dimethoxyvalerophenone oxime (0.5 grams, 2.1 mmol) in glacial acetic acid (10 milliliters) was added 0.1 grams of 5% Pd/C. The mixture was treated with 60 psi of H2 in a Parr Type Shaker for 24 hours. The catalyst was filtered off through celite and the filtrate was concentrated in vacuo to afford a yellow oil. The oil was taken up in water, the pH was adjusted to 12 using a saturated solution of sodium carbonate, and extracted with methylene chloride. The organic extract was dried over magnesium sulfate and concentrated to afford 0.41 grams (87%) of product as a yellow oil: 1H NMR (CDCl3) δ6.91-6.76(m, 3H), 3.98-3.78(m, 1H), 3.89(s, 3H), 3.87(s, 3H), 1.94-0.78(m, 11H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.N12CCCN=C1CCCCC2>CC#N>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O

Procedure:
A solution of ethyl acetoacetate and 4-methoxybenzyl chloride is stirred under an argon atmosphere with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature in CH3CN. The mixture is partitioned between 3 N HCl and EtOAc. The organic extract is washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:15]I.O>O1CCCC1.C(Cl)Cl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH3:15])[C:10](=[O:12])[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(=O)NCc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)Cc1ccc(F)cc1
Yield: 62.2 %

Procedure:
Step b) Add acetyl chloride (9.28 g, 118 mmol) to a mixture of triethylamine (16.0 g, 158 mmol) and 4-fluorobenzylamine (9.90 g, 78.8 mmol) in 200 mL of ethyl acetate at 0° C. and stir for 12 hours. Add 100 mL of water to the mixture. Extract aqueous layer with ethyl acetate (3×100 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4 Remove solvent under reduced pressure to give N-(4-fluorobenzyl)acetamide (13.5 gm) in 100% yield as a yellow oil. Add NaH (6.5 g, 162 mmol) to N-(4-fluorobenzyl)-acetamide (13.5 g, 80.8 mmol) in 200 mL of tetrahydrofuran at 0° C. and stir for 4 hours. Then add methyl iodide (22.9 g, 161.6 mmol) to the above mixture and stir for 12 hours. Pour mixture into 200 mL of water. Extract aqueous layer with methylene chloride (3×200 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, 5% acetone in hexanes, 50% acetone in hexanes) to give N-(4-fluorobenzyl)-N-methylacetamide (9.1 gm) in 64% yield as a yellow oil. Add Lawesson reagent (20.3 g, 50.3 mmol) to N-(4-fluorobenzyl)-N-methylacetamide (9.1 g, 50.3 mmol) in 200 mL of toluene and heat to 100° C. for three hours. Remove solvent under reduced pressure. Purify the residue with a column chromatography (silica gel, 2% methylene chloride in hexanes, 100% methylene chloride) to give N-(4-fluorobenzyl)-N-methylthioacetamide (5.6 g) 56.5% as a yellow solid: MS 198 (MH+).
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33](=O)[CH2:32][C@H:31]1[C:36]([OH:38])=[O:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33](=[CH2:1])[CH2:32][C@H:31]1[C:36]([OH:38])=[O:37])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of methylenetriphenyl phosphorane, previously prepared from 37 g (777 mmol, 50% NaH in mineral oil, 4 eq) and 277.6 g (777 mmol, 4 eq) methyltriphenyl-phosphonium bromide in 1.5 l THF by stirring at 50° C. for 4 h, were added 44.5 g (194 mmol, leq) (2S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 300 ml over a period of 30 min at RT. The suspension was stirred at 50° C. over night. After cooling to RT the suspension was added to a 5% NaHCO3 solution, washed with ether, the inorganic phase was acidified and extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated. 32.1 g (72%) (2S)-4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were isolated as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[S:25])[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2C(OCC)=O)=[C:4]([F:26])[CH:3]=1>[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[S:25])[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1C(=S)Nc1cc(OC(C)C)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Product: CC(C)Oc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of ethyl 2-(4-chloro-2-fluoro-5-(-methylethoxy)phenylaminothioxometyl)-3,4,5,6-tetrahydro1(2H)pyridazinecarboxylate (0.8 g) in a 5% ethanolic potassium hydroxide solution (10 ml) was heated under reflux for 3 hours. After being allowed to cool to room temperature, ethanol was removed under reduced pressure. The residue was dissolved in ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 0.3 g of 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)-3,4,5,6-tetrahydro-(1H,2H)-pyridazine. M.P., 113°-114.5° C. δ (ppm): 1.35 (6H, d), 1.7 (4H, m), 2.95 (2H, m), 3.45 (1H, t), 4.2 (2H, m), 4.4 (1H, m), 6.95 (1H, d), 8.25 (1H, d), 9.85 (1H, m).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C[C:11]([N:13](C)C)=O>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:11]#[N:13])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)cnc1Br
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1cc(Cl)cnc1C#N
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218 mmol), zinc cyanide (8.30 mL, 131 mmol), tris(dibenzylideneacetone)dipalladium (0) (4.99 g, 5.45 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in dimethylacetamide (40 mL) was heated to 110° C. for 4 hours. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate. The organic phase obtained was concentrated under reduced pressure and residue purified by chromatography on silica gel using ISCO eluting with 0-60% EtOAc/hex to afford the title compound 5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76% yield). LC/MS (ESI+) m/z=153.1 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O.CN(C)C=O>COC(C)(C)C>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Acetoxy-2-methylbenzoic acid was slurried in methyl-t-butyl ether (MTBE) and treated with 1.2 equivalents of thionyl chloride and catalytic dimethylformamide. After three hours at ambient temperatures, the reaction was complete, giving a brown soluton. Solvent (MTBE) was removed by vacuum distillation. Residual thionyl chloride was removed by addition of toluene followed by vacuum distillation. The resulting 3-acetoxy-2-methylbenzoyl chloride was isolated either directly as an oil or by crystallization from two volumes of heptane at <10° C. Product was obtained in >100% yield when isolated as an oil and 82-85% yield when crystallized from heptane.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:5]=1[NH:6][C:7]([CH3:18])([CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=1.CCN(CC)CC>CO.[Fe]>[Cl:3][C:4]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]([CH3:18])([CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=1
Reactant: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of water (20 mL) and iron powder (697 mg, 12.50 mmol) at 65° C. was added concentrated hydrochloric acid (0.2 mL) dropwise and the mixture was stirred for 15 min. The aqueous layer of the mixture was poured out and a solution of 2-chloro-N-(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)-4-nitroaniline (446 mg, 1.25 mmol) in MeOH (20 mL) was added to the above processed iron powder. The mixture was adjusted to pH 2-3 and stirred at 65° C. for 20 min. The mixture was then cooled to rt, adjusted to pH 11 with Et3N, and filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the solution was washed with water (30 mL×3) and brine (30 mL×2), dried over anhydrous Na2SO4 (10 g) and concentrated in vacuo to give the crude product, which was used for next step with out further purification. The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[F:32][C:33]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:35]3[CH2:36][CH2:37][C:33]([F:38])([F:32])[CH2:34]3)[CH:8]=2)[N:3]=1
Reactant: FC1(F)CCNC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCC(F)(F)C3)ccc2n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 104 mg of 3,3-difluoropyrrolidine hydrochloride are added, and the mixture is stirred at 40° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[O:5].[C:12](OC)(OC)(OC)[O:13][CH3:14]>CO>[CH3:12][O:13][C:14]1[N:6]([OH:7])[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1ccccc1C(=O)NO
Solvent: CO
Product: COc1nc2ccccc2c(=O)n1O
Temperature: 5 °C
Yield: 59 %

Procedure:
A mixture of 22.8 g (0.15 mol) of o-amino-benzhydroxamic acid, 50 ml of methanol and 27.2 g (0.2 mol) of tetramethyl orthocarbonate is boiled under reflux for 2 hours and then cooled to 5° C. The product which crystallizes out is filtered off under suction. In this manner, 17 g (60% of theory) of 2-methoxy-3-hydroxy-3,4-dihydro-4-oxo-quinazoline are obtained in the form of colorless crystals of melting point 220° C. ##STR18##
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:32][O:33][C:34](=[O:41])[CH2:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>C1COCC1>[CH3:32][O:33][C:34](=[O:41])[CH2:35][CH:36]1[CH2:40][CH2:39][N:38]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:37]1
Reactant: COC(=O)CC1CCNC1
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.1 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:18]=[C:19](C)[CH:20]=1)[O:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:3]=[CH:2][CH:20]=[CH:19][CH:18]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 89 %

Procedure:
A mixture of 6-(2-phenoxyacetylamino)-n-hexanoic acid (made in analogy to Intermediate 15, 3.15 g, 11.9 mmol, 1.1 eq), 2-(m-nitrobenzenesulfonyl)ethanol (2.5 g, 10.8 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in 100 mL of benzene was refluxed overnight with Dean-Stark trap. Thereafter water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure. The residual oil was purified by column chromatography (1% MeOH in CH2Cl2) to give 4.6 g (89%) of 6-(2-phenoxy-acetylamino)-n-hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:33])=[C:27]4[CH3:34])=[N:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[O:35][CH3:36])C1C=CC=CC=1.N>[Pd].CN(C=O)C.CO>[CH3:33][C:28]1[NH:29][C:30]2[C:26]([C:27]=1[CH3:34])=[CH:25][C:24]([NH:23][C:17]1[C:16]3[C:21](=[CH:22][C:13]([OH:12])=[C:14]([O:35][CH3:36])[CH:15]=3)[N:20]=[CH:19][N:18]=1)=[CH:32][CH:31]=2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: N
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Ammonium formate (20 g, 326 mmol) and 10% palladium on carbon (1 g) were added to a solution of 7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline (10 g, 22 mmol) in DMF (100 ml) and methanol (300 ml). After stirring for 3 hours at ambient temperature, aqueous ammonia (120 ml) was added. The precipitate was filtered, washed with water and dried under vacuum. The residue was triturated with ethyl acetate and ether and was filtered, dried under vacuum and purified by column chromatography eluting with methanol/methylene chloride (5/95 followed by 10/90) to give 4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (5.5 g, 75%).
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:21][CH2:20][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37].Cl>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:10][CH2:11][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[N:13]3[C:36]([C:32]3[NH:31][CH:35]=[CH:34][CH:33]=3)=[O:37])[CH2:20][CH2:21]2)=[CH:22][CH:23]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.5 %

Procedure:
In 6 ml of methylene chloride were dissolved 0.30 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 0.47 ml of triethylamine. After adding 0.18 g of 1H-2-pyrrolecarbonyl chloride at 0-5° C., the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After purifying the residue by column chromatography [eluent: chloroform:ethanol=200:1], isopropyl ether was added and the deposited crystal was collected by filtration. Thus, 0.14 g of (3R)-8-(4-isopropylphenoxy)-4-(1H-2-pyrrolylcarbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid was obtained as a yellow crystalline product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4].[O-:39]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:28])[CH3:29])=[CH:16][C:15]=2[CH3:38])[CH:9]=[CH:10][C:11]=1[C:12]([OH:39])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of 3-butoxy-4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-carbaldehyde (0.125 g, 0.227 mmol) in t-BuOH (2.0 mL) and 2-methyl-2-butene (1.0 mL) at 0° C. is treated with a solution of NaClO2 (205 mg, 2.27 mmol) and NaH2PO4—H2O (313 mg, 2.27 mmol) in water (2.0 mL). The mixture is stirred at 0° C. for 60 minutes. The organic layer is separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified using silica gel chromatography eluting with 50%-100% ethyl acetate in hexanes to give the title compound (0.120 g, 93%). ES/MS m/e 566.8; 568.7 (M+1).