Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][S:12][C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=2)[C:7]([C:20]([F:23])([F:22])[F:21])=[N:6]1)(C)(C)C.Br.C(O)(=O)C>O>[Cl:10][C:9]1[NH:5][N:6]=[C:7]([C:20]([F:21])([F:23])[F:22])[C:8]=1[CH2:11][S:12][C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(C(C)(C)C)c2Cl)=NO1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(SCc2c(C(F)(F)F)n[nH]c2Cl)=NO1
Temperature: 45 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
19.8 g (53.4 mmoles) of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline was added to 170 ml of a 25% hydrogen bromide-acetic acid solution. The mixture was stirred at 40 to 50° C. for 2 hours to give rise to a reaction. After the completion of the reaction was confirmed, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 12.0 g (yield: 60.6%) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light yellow crystals (melting point: 120.0 to 122.0° C.)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9](Br)[CH:10]=[CH:11][C:12]=3[F:16])[NH:7][C:6]=2[CH2:5][CH2:4]1.CO.[OH-].[K+]>[Pd].O>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:16])[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2[nH]c3c(Br)ccc(F)c3c2C1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C1CCc2[nH]c3cccc(F)c3c2C1

Procedure:
Following a procedure similar to that described in Example 234 but using 2 g. of 3-(dimethylamino)-8-bromo-5-fluoro-1,2,3,4-tetrahydrocarbazole (Example 219), in 100 ml. of methyl alcohol, 1 g. of 10% palladium on charcoal and 1 g. of potassium hydroxide in 2 ml. of water there was obtained, after recrystallization from benzene, 1.3 g. of 3-(dimethylamino)-5-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 166°-168°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:33][C:30]3[S:31][CH:32]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[N:29]=3)=[O:18])=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid (10) (104 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-methoxyphenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 29 mg (25%). 1H-NMR: 10.08 (s, 1H), 8.63-8.60 (m, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.04-7.87 (m, 3H), 7.82 (d, J=8.5 Hz, 2H), 7.34 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.01-6.90 (m, 3H), 6.82 (d, J=9.0 Hz, 2H), 3.66 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2cccc(C(=O)N3CCCCC3)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (21 mg, 0.0496 mmol) and piperidine (8.4 mg, 0.0988 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (29 mg, 0.1512 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (8.2 mg, 0.0167 mmol, 34%).
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.N1C=CC=CC=1.[Br:18][CH2:19][C:20](Br)=[O:21]>CCOCC>[Br:18][CH2:19][C:20]([NH:11][CH2:10][C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)=[O:21]
Reactant: O=C(Br)CBr
Reactant: CC1(C)C2CCC1(CN)CC2
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1(C)C2CCC1(CNC(=O)CBr)CC2
Temperature: 25 °C

Procedure:
10-Bornanamine (0.5 g) in dry ether (30 ml) containing pyridine (C.45 ml) was treated at -80° with a solution of bromoacetyl bromide (0.3 ml) in ether (5 ml) over one minute with stirring. The mixture was allowed to warm to room temperature and after a further 30 min. it was partitioned between ether and water. The organic layer was washed with 2N-hydrochloric acid solution and then water. It was dried (MgSO4) and evaporated. The residue (0.73 g.) was purified by preparative layer chromatography and by crystallisation from petroleum ether (bp. 60°-80°) to give the title compound (0.48 g) mp. 89°, (Found: C, 52.4; H, 7.3; Br, 28.9; N, 5.0; C12H20BrNO requires C, 52.55; H, 7.35; Br, 29.1; N,5.1%).
Reaction SMILES: [Br:1]Br.CO[C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9](OC)[C:10]=1OC.O>C(O)C>[Br:1][CH2:16][C:15]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1)=[O:17]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Solvent: CCO
Solvent: O
Product: O=C(CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an 1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL) and the solution was stirred at 0° C. for 1 h and then poured into water to form a precipitate. This was recrystallized from ethanol to give bromoacetophenone (70%) and used directly for next step. A mixture of bromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol) in ethanol was refluxed for 1 h. The reaction mixture was concentrated in vacuo and purified with flash column to give 2i (167 mg, 51.1%). 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Br:22].C([O-])([O-])=O.[K+].[K+].CO>O>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Br:22]
Reactant: COc1nc2c(c(Br)c1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2c(c(Br)c1Br)C(C)CNCC2
Temperature: 57.5 °C
Yield: 92.1 %

Procedure:
To a solution of CuBr2 (0.64 g, 2.88 mmol) and nBuNO2 (0.42 ml, 3.6 mmol) in MeCN (14 ml) was added a solution of 4-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (0.92 g, 2.41 mmol) in MeCN (10 ml) at room temperature. The reaction mixture was then stirred at 50° C. for 4 h. After removal of MeCN under reduced pressure, the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 813 mg (76%) of 3,4-dibromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 4.31 (0.5H), 4.01 (0.5H), 3.91 (3H), 3.85 (1H), 3.69 (1H), 3.39 (1H), 3.23 (1H), 3.12 (1H), 3.06 (1H), 1.17 (3H) ppm. A mixture of 3,4-dibromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (803 mg, 1.80 mmol), K2CO3 (746 mg, 5.40 mmol), MeOH (32 ml) and H2O (6 ml) was heated at 55-60° C. for 30 minutes. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 580 mg (92%) of 3,4-dibromo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.89 (s, 3H), 3.63 (m, 1H), 3.21 (m, 2H), 3.09 (dd, 1H), 2.94 (m, 2H), 2.72 (dd, 1H), 1.25 (d, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([C:27]([N:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)=[O:28])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN(C)C(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-N,N'-dimethylethylenediamine (1.0 g) and triethylamine (537 mg) in methylene chloride (20 ml) which was cooled to 0° C., was added morpholinocarbonyl chloride (794 mg). The mixture was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 5% hydrochloric acid, 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N'-(morpholinocarbonyl)-N,N'-dimethylethylenediamine (1.11 g) as an oil.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([Si:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([Si:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:9]=2)(=O)C.[OH-].[Na+].Cl>O1CCCC1>[C:30]1([Si:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]2[CH:14]=[CH:15][C:16]3[NH:4][C:5]4[C:10]([C:11]=3[CH:12]=2)=[CH:9][C:8]([Si:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:7][CH:6]=4)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)n1c2ccc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c2cc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc3[nH]c4ccc([Si](c5ccccc5)(c5ccccc5)c5ccccc5)cc4c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
The obtained 9-acetyl-3,6-bis(triphenylsilyl)carbazole (1.97 g) was dissolved in tetrahydrofuran (50 mL). A 50% by mass aqueous sodium hydroxide solution (1.1 g) was added to the solution. The resultant mixture was stirred at 50° C. for 3 hours and cooled to room temperature. Diluted hydrochloric acid was added thereto until the pH reached 5, followed by stirring for 30 min. The mixture was extracted with methylene chloride. The separated organic layer was washed with water and dried, and the methylene chloride was evaporated. The residue was purified with a recycle HPLC (name of apparatus: Recycling Preparative HPLC LC-9201, product of Japan Analytical Industry Co., Ltd., developing solvent: THF, flow rate: 3.5 mL/min), to thereby obtain 1.28 g of 3,6-bis(triphenylsilyl)carbazole as colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[C:13]1[C:14]2[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:5]4[C:6]5[O:10][CH2:9][O:8][C:7]=5[CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A69) and commercially available (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=[O:5].[CH3:13][Al](C)C.Cl>>[OH:5][CH:4]([C:3]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[CH3:13]
Reactant: O=Cc1c(O)cccc1[N+](=O)[O-]
Reactant: C[Al](C)C
Agent: Cl
Product: CC(O)c1c(O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 2-hydroxy-6-nitrobenzaldehyde (4.5 g, 26.926 mmol) was added dropwise trimethylaluminum (2M in toluene, 27 mL) under an argon atmosphere. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into a cold (0° C.) aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 2-(1-hydroxyethyl)-3-nitrophenol as an orange oil (4.660 g, yield; 95%).
Reaction SMILES: C([NH:6][NH:7][CH2:8][CH2:9][CH2:10][CH:11]1[NH:15]C(=O)N[C:12]1=[O:17])(OCC)=O.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:15][CH:11]([CH2:10][CH2:9][CH2:8][NH:7][NH2:6])[C:12]([OH:17])=[O:18]
Reactant: CCOC(=O)NNCCCC1NC(=O)NC1=O
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: NNCCCC(N)C(=O)O

Procedure:
Mix 5-[3-(carbethoxyhydrazino)-propyl]-hydantoin (2.44 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration and extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-5-hydrazino-pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].C([O-])(=O)C.[Na+].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde 39 prepared following Example 20 (65 mg, 1.0 eq) was dissolved in 1,2-dichloroethane (9.7 ml) and treated with hydrochloride salt of 1-methanesulfonylpiperazine (69 mg, 1.4 eq), sodium acetate (28 mg, 1.4 eq) and trimethyl orthoformate (0.27 ml, 10 eq). Reaction mixture was stirred at r.t. for 12 h. Sodium triacetoxyborohydride (62 mg, 1.2 eq) was added and reaction mixture was stirred at r.t. for 8 h. Reaction mixture was quenched with saturated aq. NaHCO3 and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (70 mg, 68%): MS (Q1) 416 (M)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][SH:16]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[NH:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][S:16]2)[CH:2]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1cnc2ccccc2c1
Solvent: CCO
Product: O=C(O)C1CSC(c2cnc3ccccc3c2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Quinoline-3-carbaldehyde (1.57 g ) and 1.21 g of L-cysteine were dissolved in 50 ml of 50% ethanol, and the solution was stirred at room temperature for 1 hour. The resultant crystalline precipitate was collected by suction filtration, washed with 50% ethanol and dried to give 1.95 g of 2-(3-quinolyl)thiazolidine-4-carboxylic acid. Melting point 173°-175° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14](O)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:32]=1>O1CCCC1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([NH:44][C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH:37][C:34]2[CH:33]=[CH:32][CH:31]=[CH:36][CH:35]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1ccccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66 %

Procedure:
To a solution of 545 mg (2.0 mmol) 3,5-bis(trifluoromethyl)phenylacetic acid in 2 ml tetrahydrofuran at 0° C. were added 325 mg (2.0 mmol) 1,1′-carbonyldiimidazole. After stirring for 2.5 h at room temperature, 305 mg (1.66 mmol) 2-aminodiphenylamine were added and stirring was continued for 8 h at 60° C. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 480 mg (66%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Product: COc1cc(C(=O)CC(Cc2ccc(NC(=O)OCc3ccccc3)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Yield: 69.5 %

Procedure:
Following the procedure described in Example 154, treatment of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (80 mg, 0.18 mmol) with benzyl chloroformate (0.039 mL, 0.27 mmol) provided 72 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-carbobenzyloxy)aminophenyl)ethylamide as a foam.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([O:14]C)[CH:4]=1>O>[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([OH:14])[CH:4]=1
Reactant: COc1cc(Cl)ccc1OCC(=O)O
Agent: [Br-]
Solvent: O
Product: O=C(O)COc1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
To a solution of 48% aqueous hyrdrogen bromide (20 mL) was added (4-chloro-2-methoxy-phenoxy)-acetic acid (2.1 g, 9.7 mmol). The resulting mixture was heated to reflux overnight. The mixture was cooled to ambient temperature, diluted with water and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give (4-chloro-2-hydroxy-phenoxy)-acetic acid. The crude product was added to a solution of pyridinium p-toluene sulfonate (0.10 g, 0.40 mmol) in toluene (100 mL). The resulting mixture was heated to reflux for five hours. The reaction was allowed to cool to ambient temperature and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.97 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:11][CH2:12][CH:13]([Br:17])[CH2:14][CH2:15][CH3:16])[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([NH:4][CH:5]([CH2:11][CH2:12][CH:13]([Br:17])[CH2:14][CH2:15][CH3:16])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCC(Br)CC[C@H](NC(C)=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(Br)CCC(NC(C)=O)C(=O)O
Reaction time: 8 h
Yield: 110 %

Procedure:
Ethyl(S)-2-(N-acetylamino)-5-bromooctanate (3.9 g) was dissolved in EtOH and 12.7 ml (1 eq) of 1N NaOH was added every 1 hour in the total amount of 50.8 ml (4 eq), followed by stirring overnight. After concentration, the aqueous layer was washed by liquid separation using diethylether. The pH of the aqueous layer was adjusted to about 1 to 2 using 1N HCl, followed by extraction with diethylether. The diethylether layer was washed with brine and dehydrated over sodium sulfate. After concentration, 3.9 g (86.3%) of 2-(N-acetylamino)-5-bromooctanoic acid was obtained as a white solid.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([CH3:45])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([NH2:33])[N:27]=[C:26]2[C:34]([N:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])=[O:12])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:9][C@@H:10]([CH3:45])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([NH2:33])[N:27]=[C:26]2[C:34]([N:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
911 μl of 4N HCl in dioxane are added to 220 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl (S)-2-tert-butoxycarbonylaminopropionate in 4 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off with suction and washed with 4 ml of dichloromethane. The residue is recrystallised from ethanol.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12]1)[CH2:10][C:9]2=[O:27].Cl>CC(O)=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:13]2[CH2:12][C:11]3([CH2:10][C:9](=[O:27])[C:8]4[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=4)[O:23]3)[CH2:14]2)=[CH:21][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2
Yield: 86.9 %

Procedure:
(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (360 mg, 0.94 mmol) was hydrolyzed with AcOH (6 ml) and aqueous 20% HCl (6 ml) following the procedure described in Example 31, Step B, giving (E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (300 mg, hydrochloride salt) as a pale yellow solid.