Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].CCO[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.6 %

Procedure:
To a solution of 3,4-dimethoxyaniline (100 g, 0.65 mol) in 130 ml of N,N-dimethylformamide was added diethyl ethoxymethylene malonate (141.2 g, 0.65 mol). The mixture was stirred at room temperature for 21 hours. The solvent was evaporated in vacuo and the residual dark brown oil was recrystallized from 1.6 l cyclohexane and 50 g of activated carbon to give 150.5 g of desired product. Extraction of the carbon with hot cyclohexane gave another 27.1 g of product. Total yield 177.6 g, melting point 57°-59° C.
Reaction SMILES: [OH:1][C:2]1[CH:37]=[CH:36][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:39]>O>[OH:1][C:2]1[CH:37]=[CH:36][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:39])[C:7]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCN1CCCCC1
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(2-piperidinoethylthio)nonyl]-2,3-dihydro-4H-benzopyran (126 mg, 0.24 mmol) was dissolved in methanol (5 ml)and water (1.2 ml), and NaIO4 (62 mg, 0.29 mmol) was added thereto. The reaction was stirred for 4 hours at room temperature and then filtered. The filtrate was concentrated and the residue was purified with flash column chromatography (dichloromethane:ethanol=13:1→10:1) to obtain 96 mg (yield: 74%) of the title compound as a white foamy solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:52])[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43][C:42]([N:39]1[CH2:40][CH2:41][N:36]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][CH2:38]1)=[O:52])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(CCc1ccccc1O)N1CCN(Cc2ccccc2)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Triethylamine (0.84 ml) and octadecyl isocyanate (1.88 ml) were added to a solution containing 1-(4-benzylpiperazino)-3-(2-hydroxyphenyl)-1-propanone (1.76 g) in methylene chloride (18 ml) and stirred for 17 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 75 g, chloroform:methanol=60:1), thereby yielding the entitled compound (2.32 g) as white solid.
Reaction SMILES: Cl[Sn]Cl.O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add SnCl2.H2O (11.8 mmol, 2.7 g) over a solution of 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.4 mmol, 0.8 g) in 20 mL of ethyl acetate. Stir the solution at room temperature overnight. Add aqueous NaHCO3 solution until the solution pH is basic and extract with ethyl acetate. Filter the suspension through a pad of Celite®. Combine the organic layers and wash with saturated aq. sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound. MS(ES): m/z=293 [M+H].
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].Cl>>[Cl:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Br
Agent: Cl
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1NCc1ccccc1Cl
Yield: 53.1 %

Procedure:
2-Bromo-5-chloro-3-nitrobenzoic acid (2.30 g, 10 mmol) was refluxed with 2-chlorobenzyl amine (20 mmol, 2.82 g) overnight. The reaction mixture was then poured into 10% aqueous hydrochloric acid solution and the resulting solid was collected. Crystallization from aqueous methanol gave 1.81 g (53%) of 5-chloro[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid; mp 159.5°-161° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCOCCO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OCCOCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 50 g (475.56 mmol) of 2-(2-aminoethoxy)ethanol and 144.6 g (1.046 mol) of potassium carbonate in 600 ml of EtOH/60 ml of water is heated to 60° C. To this mixture is added dropwise within one hour 178.95 g (1.046 mol) of benzyl bromide and then the mixture is refluxed for 2 hours, evaporated under vacuum, the residue taken up with 1 liter of methylene chloride, and filtered off from the salts. The filtrate is concentrated under vacuum and purified by flash chromatography (silica gel/mobile phase: methylene chloride/hexane/acetone: 10/5/1).
Reaction SMILES: [C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[NH:14]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[NH2:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCC[C@H]1Nc1ccccc1
Reaction time: 8 h

Procedure:
The cis-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer from above (0.095 g, 0.33 mmol) was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (2 mL) and the mixture stirred overnight. The reaction was worked up to afford the title compound (0.069 g) as a pale yellow solid. 1H NMR (CDCl3) 1.28-1.37 (m, 5H), 1.50-1.63 (m, 6H), 3.18 (br s, 1H), 3.42-3.45 (m, 1H), 6.63-6.70 (m, 3H), 7.16 (br t, 2H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([OH:15])[CH:3]=1.[OH-].[Na+].Cl>O>[NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:15])[CH:3]=1
Reactant: CCOC(=O)c1cc(C#N)c(N)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(C(=O)O)c(O)cc1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Ethyl 4-amino-5-cyano-2-hydroxybenzoate (3 g, 14.55 mmol) is treated with 60 ml of a 10% strength sodium hydroxide solution and the mixture is stirred at 50° C. for one hour. After cooling, the reaction solution is acidified with concentrated hydrochloric acid, diluted with water and the precipitate is filtered off with suction. The desired product is obtained after recrystallization from ethanol in 62% yield (1.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
tert-Butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 1.24 mmol) was dissolved in CH2Cl2 (15 mL) followed by the addition of TFA (8 mL). The reaction was stirred for 1.5 h, and the solvents were evaporated to an oily liquid which was diluted with CH2Cl2 and neutralized with a 1 M aqueous NaOH solution. The organic layer was separated, and the aqueous layer was washed two times with CH2Cl2. After drying the combined organic phases over MgSO4, they were filtered, and concentrated to afford 2-(4-((R)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol as a solid (0.354 g, 85%). LC/MS: m/z 335.7 (M+H)+ at 1.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:35]([O:38][P:39]([CH2:45]Br)(=[O:44])[O:40][CH:41]([CH3:43])[CH3:42])([CH3:37])[CH3:36]>CC#N>[CH:41]([O:40][P:39]([CH2:45][NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:3]=1[C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:44])[O:38][CH:35]([CH3:37])[CH3:36])([CH3:43])[CH3:42]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1NC(=O)c1c(NCP(=O)(OC(C)C)OC(C)C)cccc1Sc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 41 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in MeCN (40 mL) and treated with anhydrous potassium carbonate (2.0 equiv.) at room temperature. To this mixture diisopropyl(bromomethyl)phosphonate (1.2 equiv.) was added via a micro syringe. After being stirred for 4 Hours at 60° C., the reaction mixture was concentrated under reduced pressure. The crude residue was diluted by ethyl acetate (50 mL), and washed with water (2×10 mL). Then it was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:4 v/v ethyl acetate/petroleum ether) to provide a yellow solid (235.2 mg, 41% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:19]1[CH2:20][C:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[N:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[NH:18]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C#N)nc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyano-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M184) (295 mg, 0.562 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (125 mg, 55%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH3:13])=[CH:11][N:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:9]=1)=[O:6]
Reactant: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added at a temperature in the region of 20° C. under an argon atmosphere to 1 g (3.97 mmol) of 3-carboxy-4-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 20 mL of chloroform. After stirring at the reflux point of the solvent for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and then brought back to dryness to give 1.07 g (3.97 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole in the form of a beige-coloured solid which is used directly in the following step.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][CH:6]([CH3:14])[C:7](=O)[CH2:8][C:9](OC)=[O:10].C([O-])([O-])=O.[K+].[K+].Cl>O.CO>[CH:6]([C:7]1[N:4]=[C:2]([SH:3])[N:1]=[C:9]([OH:10])[CH:8]=1)([CH3:14])[CH3:5]
Reactant: NC(N)=S
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1cc(O)nc(S)n1
Temperature: 105 °C
Yield: 67.8 %

Procedure:
Thiourea (1.0 g, 13 mmol) was dissolved in 1.6 mL of water at 70° C. Methyl 4-methyl-3-oxopentanoate (2.8 g, 20 mmol) was added and followed by K2CO3 (2.7 g, 19 mmol). The reaction was heated at 105° C. open to air for 1 hour to boil off any remaining methanol. After being cooled to room temperature, water (6.6 mL) was added and followed by 6 mL of concentrated HCl. The white precipitate was collected by filtration and washed with water and 1 N HCl to afford 6-isopropyl-2-mercaptopyrimidin-4-ol as a white solid (1.5 g, yield: 46%). 1H NMR (400 MHz, DMSO-d6): δ 12.34 (s, 1H), 12.19 (s, 1H), 5.67 (s, 1H), 2.66 (m, 1H), 1.13 (d, J=6.8 Hz, 6H). LCMS (ESI) m/z: 171.0 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:35].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:34](=[O:35])[CH2:33][N:3]2[C:4](=[O:31])[C:5]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=3[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[C:2]2=[O:1])=[CH:37][CH:38]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-fluorophenyl)ethanone (0.89 g) and N,N-dimethylformamide (50 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran to give the title compound as colorless crystals (1.08 g, 55%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-butyl-cyclopentane carboxylate (6.42 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 3-methyl-benzoyl chloride (6.00 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, and then using 10% aqueous solution of sodium carbonate for three times, then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 11.99 g of brown liquid. MS: m/e 332(M+′), 287, 213, 196, 167, 119(base), 99.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[C:5](=[O:13])[C:4]([C:14]([O:16]CC)=[O:15])=[CH:3]1.[OH-].[Na+]>O>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[C:5](=[O:13])[C:4]([C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: CCOC(=O)c1cn(N)c2nc(C)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(=O)c(C(=O)O)cn(N)c2n1
Yield: 88 %

Procedure:
A mixture of 10.0 g (0.0405 m) of ethyl 1-amino-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, 1.94 g (0.0486 m) of sodium hydroxide and 350 ml of water was heated on a steam bath for two hours. The resulting solution was filtered, cooled and neutralized with 3 ml of acetic acid while stirring. The solid product was collected by filtration, washed with water and recrystallized by dissolving it in 100 ml of boiling dimethylformamide and adding 100 ml of ether to the cooled solution. There was obtained 7.8 g of 1-amino-1,4-dihydro-7-methyl-4-oxo-1,8naphthyridine-3-carboxylic acid, colorless needles, m.p. 239°-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:11][Li].O>C1COCC1>[C:5]([C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)(=[O:7])[CH3:11]
Reactant: [Li]C
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccnc(Cl)c1
Temperature: -70 °C

Procedure:
In 440 ml of THF was suspended 22 g of 2-chloroisonicotinic acid, and under nitrogen flow, the mixture was cooled to −70° C. or lower, 245 ml of methyl lithium (1.14 M solution in diethyl ether) was added dropwise to the mixture. After stirring at the same temperature for an hour, a temperature of the mixture was raised to 0° C. over an hour, and stirred at the same temperature for further an hour. To the reaction mixture was added 500 ml of water, and the reaction mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Activated charcoal was added to the mixture, and after filtration, the filtrate was concentrated under reduced pressure to give 19.5 g of 4-acetyl-2-chloropyridine as colorless crystals. Melting point: 36° C.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][CH:18]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>C(O)C>[CH2:27]([O:29][N:30]=[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][CH:18]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2])[CH3:28]
Reactant: CCON
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1
Agent: Cl
Solvent: CCO
Product: CCON=C(C)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1

Procedure:
To a solution of 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole (7) (free base from above) in ethanol was added O-ethyl hydroxylamine hydrochloride. The mixture was heated to reflux for 1.5 hours whereafter the solvent was removed under reduced pressure. The residue was triturated with a mixture of diethyl ether and ethanol leaving 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole O-ethyl oxime (3f8) as hygroscopic crystals. Mp 138-143° C., m/e 374.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[O:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[C:10]4[N:9]5[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]5=[C:7]([CH3:16])[C:6]=4[CH:5]=[C:4]([F:17])[CH:3]=3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Cc1c2n(c3c(-c4ccc5c(c4)OCO5)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (73 mg, 86%), MS (ISP) m/z=339.5 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available benzo[d][1,3]dioxol-5-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]([OH:29])[CH:13]([CH2:16][CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[F:40][C:41]1[CH:54]=[CH:53][C:44]([C:45]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])=[CH:43][CH:42]=1>CN(C=O)C>[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:17][CH2:16][CH:13]3[CH:12]([OH:29])[C:11]4[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][O:9][C:10]=4[CH2:15][CH2:14]3)[CH2:49][CH2:48]2)=[O:46])=[CH:53][CH:54]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3onc(-c4ccccc4)c3C2O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCC2CCc3onc(-c4ccccc4)c3C2O)CC1
Temperature: 80 °C
Yield: 15 %

Procedure:
To a solution consisting of 3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (8.0 g) and DMF (100 ml) was added diisopropylethyl amine (6.7 ml) and 4-(4-fluorobenzoyl)piperidine hydrochloride (7.1 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 4.5 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 1.3 g of 5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-phenyl-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C@@H:19]1[CH2:23][C:22](=[O:24])[O:21][C:20]1=[O:25]>>[CH3:17][O:18][C@@H:19]([C:20](=[O:25])[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)[CH2:23][C:22]([OH:24])=[O:21]
Reactant: CO[C@@H]1CC(=O)OC1=O
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Product: CO[C@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 1a from 6-bromo-2-phenyl-benzoxazole and (R)-3-methoxy-dihydro-furan-2,5-dione.