Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:26](OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([O:14][CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxypiperidine (1.0 g) in N,N-dimethyl formamide (10 ml) was added sodium hydride (0.14 g) under ice cooling. Then the reaction mixture was stirred for 30 minutes at room temperature and for 2 hours at 60° C. To the reaction mixture was added iodomethane (4.0 ml) at 60° C. After stirring for 6 hours at 60° C., the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 1-tert-butoxycarbonyl-4-(4-chlorophenyl)-4-methoxypiperidine (0.75 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>CO>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2nccs2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1c(-c2nccs2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 80 °C
Yield: 25.9 %

Procedure:
A mixture of methyl 6-benzenesulphonylmethyl-2-methoxy-3-(thiazol-2-yl)benzoate (Intermediate 34, 0.1 g) and lithium hydroxide (1M aqueous solution, 1.25 ml) in methanol (2 ml) was stirred and heated at 80° C. for 2 hours. The solution was evaporated to dryness and the residue was purified by HPLC (C18) eluting with a mixture of methanol and water containing 0.1% formic acid, with a gradient of 4-98%. The resultant gum was triturated with ether and the solid was collected by filtration to give 6-(benzenesulphonylmethyl)-2-methoxy-3-(thiazol-2-yl)benzoic acid (0.025 g) as a pale pink solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([PH:11](=[O:13])[OH:12])[CH:8]([CH3:10])[CH3:9]>>[CH2:7]([P:11]([CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:12])[OH:13])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C[PH](=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)CP(=O)(O)CC(C)C

Procedure:
The concentration of acid was determined by 31P NMR. 10% Na2CO3 solution was prepared in an amount sufficient to neutralize monoisobutylphosphinic acid. The oily fraction in the wash tank was washed with Na2CO3 solution in several portions each time separating the bottom aqueous layer from the wash tank. When removal of sodium monoisobutylphosphinate was completed, as monitored by 13P NMR, the additional water wash was performed on the remaining diisobutylphosphinic acid. The remaining water and toluene were removed under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6][OH:7].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>O>[Cl:19][CH2:18][CH:17]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])[CH2:5][CH2:6][O:7]1
Reactant: COc1ccc(OC)c(CCO)c1
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: O
Product: COc1ccc(OC)c2c1CCOC2CCl
Reaction time: 1 h
Yield: 105.1 %

Procedure:
To a mixture of 10 g of 2,5-dimethoxyphenethyl alcohol and 10 g of chloroacetaldehyde diethyl acetal was added 14 ml of 10% hydrochloric acid and, after stirring at 80°-90° C for 1 hour, the reaction mixture was diluted with 100 ml of water and extracted with benzene. The extract was rinsed with water, dried and concentrated under reduced pressure. The residue was recrystallized from a solvent mixture of ether and petroleum ether. By the above procedure was obtained 14 g of 1-chloromethyl-5,8-dimethoxyisochroman as colorless needles, melting point: 101°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:33](=[O:35])[CH3:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-(benzylamino-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic methyl ester and acetyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[O:5][CH:6]=1.[CH2:29]([O:31][C:32]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[CH3:30].C(OC1C(C(F)(F)F)=CC(B(O)O)=CN=1)C.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:4]2[O:5][CH:6]=[C:2]([C:35]3[CH:34]=[N:33][C:32]([O:31][CH2:29][CH3:30])=[C:37]([C:38]([F:41])([F:40])[F:39])[CH:36]=3)[CH:3]=2)=[CH:8][C:9]([C:25]([F:28])([F:27])[F:26])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: N#Cc1c(C(F)(F)F)cc(-c2cc(Br)co2)n(Cc2ccc(F)cc2F)c1=O
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOc1ncc(B(O)O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOc1ncc(-c2coc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)c2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 23.2 %

Procedure:
6-(4-Bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (98 mg, 0.22 mmol), 2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridine (125 mg, 0.54 mmol) (or corresponding 2-ethoxy-3-trifluoromethylpyridine-5-boronic acid), potassium carbonate (149 mg, 1.08 mmol), and tetrakis(triphenylphosphine)palladium (0) (25 mg, 0.1 mmol) were mixed with 2.5 ml 9:1 DME/H2O (v/v), then heated at 80° C. overnight. All solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (10→30% EtOAC/Hexane, 0.25% Et3N in hexane) to give 1-(2,4-difluoro-benzyl)-6-[4-(6-ethoxy-5-trifluoromethyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile as a yellow solid (29 mg, 37% yield). 1H-NMR (400 MHz, CDCl3): δ 1.45 (t, 3H, J=7.07), 4.53 (q, 2H, J=7.07), 5.58 (s, 2H), 6.83 (s, 1H), 6.84 (m, 1H), 6.87 (m, 1H), 7.04 (d, 1H, J=0.76), 7.13 (m, 1H), 7.87 (d, 1H, J=2.27), 7.90 (d, 1H, J=0.76), 8.38 (d, 1H, J=2.27).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 537.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:10]1[S:11][C:12]([C:15](OCC)=[O:16])=[CH:13][N:14]=1)[CH2:8][CH3:9].C(OCC)(=O)C.O>CCOCC>[CH2:7]([C:10]1[S:11][C:12]([CH2:15][OH:16])=[CH:13][N:14]=1)[CH2:8][CH3:9]
Reactant: CCCc1ncc(C(=O)OCC)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1ncc(CO)s1
Reaction time: 2 h
Yield: 52 %

Procedure:
5.8 g of mixed lithium aluminum hydride were added with stirring under a nitrogen atmosphere to 150 ml of anhydrous ether and a solution of 15.1 g of ethyl 2-propyl-thiazole-5-carboxylate in 30 ml of anhydrous ether was added thereto dropwise. The mixture was stirred for 2 hours, cooled and then 20 ml of ethyl acetate followed by 20 ml of water were added. The organic phase was decanted after filtering off the precipitate formed and the ether phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was distilled to obtain 6.2 g of 2-propyl-thiazole-5-methanol with a boiling point of 86° C. at 0.01 mmHg. The product could be used to fill capsules with 500 mg of the said product and sufficient polyoxyethyleneglycol to fill the capsules.
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@@H:5]([OH:7])[C@H:4]([OH:8])[CH2:3]1.O.C([O-])([O-])=O.[Na+].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:32]2[CH2:35][CH:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([CH2:50][CH3:51])=[CH:46][CH:45]=4)=[C:38]([O:52][CH3:53])[CH:37]=3)[CH2:33]2)=[O:31])[CH:25]=1)(=O)=O>C(O)CC>[OH:8][C@H:4]1[C@H:5]([OH:7])[CH2:6][N:2]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:32]3[CH2:33][CH:34]([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[CH:45]=[CH:46][C:47]([CH2:50][CH3:51])=[CH:48][CH:49]=5)=[C:38]([O:52][CH3:53])[CH:37]=4)[CH2:35]3)=[O:31])[CH:25]=2)[CH2:3]1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5C[C@@H](O)[C@H](O)C5)ccn4)C3)cc2OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a mixed solution of (3R,4R)-pyrrolidine-3,4-diol monohydrochloride (2.1 g) in 1-propanol (60 mL)/water (2.0 mL) was added Na2CO3 (4.0 g). The mixture was stirred at 60° C. for 1 hr. To the mixture was added 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-yloxy)ethyl methanesulfonate (6.7 g) prepared in (1). The reaction mixture was stirred at 100° C. for 10 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=40/1 to 5/1) to give the title compound (4.7 g, 70%).
Reaction SMILES: C(C1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#N.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>O>[O:12]=[C:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH2:8][O:7][C:6]2[CH:17]=[CH:18][C:21]([C:20]([OH:23])=[O:22])=[CH:4][C:5]1=2
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Reflux 27.3 gm. of 2-cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin in a mixture of 300 cc. of 37% aqueous hydrochloric acid and 300 cc. of glacial acetic acid for 24 hours. Cool, dilute with water and separate the solids by filtration in order to obtain the title product (m.p. 250° C. dec.).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[F:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([NH:13][CH:14]([C:19](OC)=[O:20])[C:15](OC)=[O:16])=[O:12])=[CH:9][CH:8]=1.[Na]>C(O)C>[OH:20][C:19]1[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:23]=[CH:24][C:7]([F:6])=[CH:8][CH:9]=2)=[C:15]([OH:16])[N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: CC(=N)N
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc(O)c(NC(=O)c2ccc(F)cc2)c(O)n1
Yield: 78.8 %

Procedure:
Acetamidine hydrochloride (1.05 g, 11.1 mmol) and dimethyl 2-(4-fluorobenzamido)malonate (1.0 g, 3.71 mmol) were added to a solution of sodium (0.26 g, 11.1 mmol) in ethanol (37 ml). The reaction mixture was refluxed for 3 hours. Then, after cooling, the solid product was collected and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried to give the title compound as a white solid (0.77 g, 79%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=1.[CH3:45][O:46][C:47](=[O:50])[CH2:48]Br.C(N(C(C)C)CC)(C)C>CO>[CH3:45][O:46][C:47](=[O:50])[CH2:48][N:20]1[CH2:19][CH2:18][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:44])[F:43])[C:3]=3[Cl:2])[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:12]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 50 °C

Procedure:
To a solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine hydrochloride (114 mg, 0.187 mmol—Example 168) in methanol (15 mL) was treated with bromo-acetic acid methyl ester (57 mg, 0.375 mmol) and diisopropyl-ethyl-amine (48 mg, 0.375 mmol). The resulting solution was heated at 50° C. for 3 hours, cooled to room temperature, and concentrated. The crude material was dissolved in EtOAc and washed with water (1×). The organic layer was then washed with brine (1×), dried over sodium sulfate, and filtered. The EtOAc was concentrated and the sample was dried under vacuum to title compound as an oil (99 mg, 78%). MS(ES) m/e 622.2 ([M−COOCH3]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].OO.C(=O)(O)[O-].[Na+]>C(O)=O>[CH2:18]1[N:13]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=3[N:1]=[C:14]2[CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1ccc(N2CCCCC2)c(N)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCCC1
Yield: 74.3 %

Procedure:
Ethyl 3-amino-4-piperidin-1-ylbenzoate (5.38 g, 21.7 mmol) prepared in the Step 3-1-2 was dissolved in formic acid (90%, 40 ml). Hydrogen peroxide solution (20 ml) was added to the solution, and the mixture was heated under reflux for 40 minutes. After being allowed to cool, the mixture was neutralized with a saturated sodium bicarbonate solution and a 25% ammonia water and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (3.94 g, 74%) as a light-brown powder.
Reaction SMILES: N#N.[Br:3][C:4]1[N:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1.CCN(CC)CC.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:18]([O:10][CH2:9][C:6]1[S:7][CH:8]=[C:4]([Br:3])[N:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(Br)cs1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc(Br)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-bromo-thiazol-2-yl)-methanol (695 mg, 3.58 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.67 mL, 4.74 mmol) followed by DMAP (44 mg, 0.36 mmol) and Ms-Cl (0.36 mL, 4.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromothiazol-2-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (257 mg, 3.91 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-bromothiazole as a yellow oil. LC-MS-conditions 01: tR=0.83 min.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[N:28]=[C:27]4[CH3:39])=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[N:28]=[C:27]4[CH3:39])=[CH:22][CH:23]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1nc(C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
A 1 N solution of sodium hydroxide (384.4 μL, 384.4 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinazolinecarboxylate (110.8 mg, 192.2 μmol) in tetrahydrofuran and methanol (1:1, 1.9 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (384.4 μL), water added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 104.0 mg (99%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinazolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.47 (br s, 1H), 8.43 (d, J=2 Hz, 1H), 8.33 (dd, J=9, 2 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 7.65-7.62 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.90 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 3.03 (s, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[N:14]([CH2:17][CH3:18])=[C:15]=[O:16]>CN(C=O)C>[CH2:17]([NH:14][C:15](=[O:16])[NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: CCN=C=O
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCNC(=O)NNC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a mixture of 2-nitro-benzoic acid hydrazide (3 g) in DMF (20 mL) was added isocyanato-ethane (1.3 g). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo to provide 4 g of 4-ethyl-1-(2-nitrobenzoyl)-semicarbazide: 1H NMR (300 MHz, CDCl3) δ 8.2 (dd, 1H), 7.8 (s, 3H), 6.4 (bs, 1H), 3.3 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][CH2:16][NH2:17])[CH3:2].[C:19](Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][CH:16]=[CH:15][C:7]=12)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1c(CCN)[nH]c2ccccc12
Product: CCOC(=O)Cc1c2ccccc2n2c(-c3ccccc3)nccc12

Procedure:
12,2 g of 1-phenyl-pyrimido[1,6-a]indole-5-acetic acid ethyl ester (m.p. 59°-62°), obtained from 2-aminoethyl-indole-3-acetic acid ethyl ester and benzoylchloride and the resulting 1-phenyl-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl ester (m.p. 83°-84°), are stirred with 30 ml of ethanol and 40 ml of 2n sodium hydroxide in the course of 3 hours at room temperature. The mixture is acidified with concentrated hydrochloric acid to pH=3 and 30 ml of propyleneoxide, while stirring, are added. After short time 1-phenyl-pyrimido[1,6-a]indole-5-acetic acid crystallises out and is filtered off. The acid is recrystallised from ethanol, m.p. 198-204 (decomposition).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH:8][C@H:9]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])=[O:19])=[O:15])[CH2:10][C:11](=[O:13])[OH:12])=[O:7])[CH2:4][OH:5].[N+](C1C=CC(O[C:45](=[O:69])[C@H:46]([CH:58](CC2C=CC=CC=2)[C:59]([OH:61])=[O:60])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])=CC=1)([O-])=O>>[C:48]([NH:47][C@H:46]([C:45]([NH:2][C@H:3]([C:6]([NH:8][C@H:9]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])=[O:19])=[O:15])[CH2:10][C:11](=[O:12])[OH:13])=[O:7])[CH2:4][OH:5])=[O:69])[CH2:58][C:59](=[O:60])[O:61][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CO)C(=O)O
Agent: Cl
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A method which comprises reacting L-seryl-L-aspartyl-L-prolyl-L-arginine hydrochloride with N-carbobenzoxy-β-benzyl-L-aspartic acid p-nitrophenyl ester to give N-carbobenzoxy-O-benzyl-L-aspartyl-L-seryl-L-aspartyl-L-prolyl-L-arginine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: OCCCNc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cccc(NCCCOC2CCCCO2)n1
Reaction time: 15 h

Procedure:
A solution of 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol (4.2 g, 18 mmol), 3,4-dihydro-2H-pyran (1.6 mL, 18 mmol), TsOH (0.34 g, 1.8 mmol) and CH2Cl2 (100 mL) were stirred at RT. After 15 h, the reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a pale-yellow oil. MS m/z: 316.0 (M+H). Calc'd for C13H19BrN2O2 315.21.