Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4](Cl)=[O:5])#[N:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]3[CH:17]([C:18](=[O:21])[NH:19][N:20]=2)[CH2:16]3)=[CH:10][CH:9]=1>O1CCCC1>[OH2:5].[C:1]([CH2:3][C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]3[CH:17]([C:18](=[O:21])[NH:19][N:20]=2)[CH2:16]3)=[CH:12][CH:13]=1)=[O:5])#[N:2].[C:1]([CH2:3][C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]3[CH:17]([C:18](=[O:21])[NH:19][N:20]=2)[CH2:16]3)=[CH:12][CH:13]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: C1CCOC1
Product: N#CCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Product: O
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
5.6 g (54.1 millimoles) of cyanoacetyl chloride were added dropwise to 6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one in 150 ml of absolute tetrahydrofuran at room temperature, while stirring. After the addition was complete, stirring was continued for a further 10 minutes at 50° C. The product was filtered off under suction at 10° C., washed first with tetrahydrofuran and then with water and recrystallized from dimethylformamide/water. 3.6 g (44%) of 2-[p-(cyanoacetylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one hemihydrate were obtained as pale beige crystals. Mp.: 284° C. (decomposition).
Reaction SMILES: CC(C)([O-:4])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][C@H:15]2[N+]([O-])=O)[CH:11]=[CH:12][CH:13]=1>ClCCl.CO>[Br:7][C:8]1[CH:9]=[C:10]([CH:14]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][C:15]2=[O:4])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cccc(Br)c2)N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CCC(=O)C(c2cccc(Br)c2)N1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Potassium t-butoxide (38.7 g) was added to a stirred solution of the trans-6-(3-bromo-phenyl)-5nitro-piperidin-2-one (96.3 g) in dichloromethane (500 ml) and methanol (500 ml). The mixture was cooled to -70° and ozone was vigorously bubbled through the stirred solution for 7 h. The mixture was purged with nitrogen and pH6.5 phosphate buffer (500 ml) added. Sodium thiosulphate (120 g) and water (500 ml) were added and the mixture stirred as it warmed to room temperature overnight. The mixture was tested for peroxides then extracted with dichloromethane (600 ml×3). The combined organic extracts were washed with water (500 ml) then saturated brine (500 ml), dried (MgSO4) and evaporated in vacuo. Trituration with ether and hexane gave the title compound as a white solid (70.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>C1(C)C=CC=CC=1.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>[OH:29][C:23]1([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:30]=[CH2:31])[CH:3]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)c1
Yield: 89.2 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (see Example 135, step 2) (141 mg, 0.300 mmol), tributyl(vinyl)tin (114 mg, 0.360 mmol, 1.2 equivalent), and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol, 5 mol %) in toluene (3 mL) was heated at reflux under nitrogen until all starting material was consumed and precipitation of black palladium occurred (1-2 h). Filtration through Celite® and purification via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 10% ethyl acetate/hexane) yielded 111 mg (90%) tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(3-vinylphenyl)ethyl]piperazine-1-carboxylate as a viscous colorless oil. MS (ES) m/z 415.4 ([M+H]+); HRMS: calcd for C25H38N2O3, 414.2882; found (ESI), 415.2966.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16]>O>[Cl:16][C:15]([Cl:18])([Cl:17])[CH:14]([C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1
Reactant: Oc1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ccc(C(c2ccc(O)cc2)C(Cl)(Cl)Cl)cc1
Yield: 98.2 %

Procedure:
A 4-necked 3-L flask, equipped with a mechanical stirrer, a nitrogen inlet, and thermometer, is charged with 83% sulfuric acid (640 g). To this sulfuric acid, phenol (354 g) is added at 20° C. Chloral (200 g) in an additional funnel is added dropwise to the phenolic stirring mixture. The reaction temperature is maintained below 30° C. After the addition, the mixture is allowed to stir at room temperature for 18 hours, before water (640 g) is added. The resulting mixture is filtered and washed with more water to afford 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (423 g) as white solids.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+].Cl>CCOCC.O>[OH:3][C:1]([CH3:2])([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[C:17]#[N:18]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(O)(C#N)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A mixture of 2-acetylfluorene (5.32g.) in ether (20ml.) and water (40ml.) is cooled to 5° and agitated vigorously. Sodium cyanide (2.45g.) is added portionwise and the solution is then treated with conc. HCl (4.8ml.) while maintaining the temperature between 5°-10°. The mixture is then stirred for 2 hr. at room temperature, diluted with water and extracted with ether. The ether extracts are dried (MgS04) and evaporated to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:30][N:31]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:30]#[N:31])=[CH:10][CH:9]=2)=[O:4]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C#N)ccc2c(=O)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), zinc cyanide (50 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg) and 1-methyl-2-pyrrolidone (6 ml) was stirred at 100° C. under an argon atmosphere for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with aqueous ammonia, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: CO[C:3]1[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:17].[NH4+:18]>C(O)C>[ClH:17].[NH:18]=[C:3]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NCCCN(C(=O)OC(C)(C)C)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C=CC=NC(=N)C1
Product: Cl

Procedure:
To a stirred solution of imino methyl ether from Step A (1.75 g, 7.66 mmol) in ethanol was added ammonium chloride (0.4 g, 7.68 mmol). The resultant mixture was refluxed for 4 h. Concentration gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[I:11](O)(=O)(=O)=O.II>C(O)(=O)C.O.S(=O)(=O)(O)O>[I:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a solution of 3-nitropyridin-2-amine (1.2 g, 8.63 mmol) in acetic acid (5 ml), water (1 ml) and sulfuric acid (0.2 ml) was added periodic acid (0.4 g, 1.72 mmol, 0.2 eq.) and the mixture was stirred at 90° C. for 15 min. Iodine (0.87 g, 3.45 mmol, 0.4 eq.) was added portionwise and the mixture was heated at 90° C. for 1 h. The mixture was quenched by the addition of water and extracted with ethylacetate (3×150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off to give the product in 57% yield (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.58 (d, 1H), 8.54 (d, 1H) 8.04 (br s, 2H); LC-MS (ESI); Calculated mass: 265.01: Observed mass: 265.9 [M+H]+ (rt: 1.36 min).
Reaction SMILES: C(OC([N:8]([C:26]1[CH:30]=[C:29]([CH3:31])[N:28](C(OC(C)(C)C)=O)[N:27]=1)[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[C:12](=[O:22])[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:23]([N:11]1[C:12](=[O:22])[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[C:9]([NH:8][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:10]1)([CH3:25])[CH3:24]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)n[nH]1
Reaction time: 48 h

Procedure:
1-[tert-Butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (13.0 mg, 0.02 mmol) was dissolved in a 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to give the title compound (Example M-1) as a white solid. 1H-NMR: (400 MHz, D6- DMSO), 9.34(1H, s), 8.73 (1H, s), 8.47 (1H, d), 8.26 (1H, d), 6.28 (1H, s), 5.20-5.17 (1H, m), 2.19 (3H, s), 1.26 (6H, d) MS (ESI+)=(M+H)+ 328.31.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:39])[C:10]=1[C:11]([NH:13][CH2:14][CH2:15][C@H:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[CH3:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[CH3:17])=[O:12])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C[C:54]2N(O)N=[N:57][C:55]=2[CH:56]=1.C(N)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:55]([NH:57][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:39])[C:10]([C:11]([NH:13][CH2:14][CH2:15][C@H:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][C:37]=3[CH3:38])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH3:17])=[O:12])=[C:2]([CH3:1])[CH:3]=1)([CH3:56])[CH3:54]
Reactant: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C(=O)O)cc2C)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C(=O)NC(C)C)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
3,5-Dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-terephthalamic acid (50.0 mg, 0.09 mmol), EDCI (19.9 mg, 0.10 mmol) and HOBT (14.1 mg, 0.10 mmol) were combined in DMF (4 mL) to give a pale yellow solution. To this solution was added isopropylamine (8.9 μL, 0.10 mmol) followed by DIPEA (19.7 μL, 0.11 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded N′-isopropyl-2,6-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-terephthalamide as a white foam (10.1 mg, 19%). 1H NMR (CDCl3) δ 1.02 (br s, 3H), 1.22 (d, 6H, J=7 Hz), 1.83 (m, 3H), 2.22 (m, 1H), 2.29 (s, 3H), 2.34 (s, 6H), 2.55 (m, 1H), 2.80 (m, 4H), 3.38 (m, 1H), 3.62 (m, 1H), 3.76 (m, 1H), 4.10 (s, 2H), 4.23 (sext, 1H, J=6 Hz), 6.04 (d, 1H, J=7 Hz), 6.59 (d, 2H, J=8 Hz), 6.72 (t, 1H, J=7 Hz), 7.05 (d, 1H, J=5 Hz), 7.16 (t, 2H, J=8 Hz), 7.34 (br s, 1H), 7.39 (s, 2H), 8.27 (s, 1H), 8.33 (d, 1H, J=5 Hz). ES-MS m/z 570 (M+H), 593 (M+Na). Anal. Calcd. For C35H47N5O2: C, 73.78; H, 8.31; N, 12.29.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[C:21](N(OC)C)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-:35].[NH4+]>O1CCCC1>[ClH:35].[ClH:35].[C:21]([CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [Cl-]
Reactant: Br[Mg]c1ccccc1
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
1,4-Bis(phenylmethyl)-N-methoxy-N-methyl-2-piperazine carboxamide (2.9 g, 8.1 mmol) was dissolved in tetrahydrofuran (30 mL) under argon atmosphere. A 1.0 M solution of phenylmagnesium bromide in tetrahydrofuran (24 mL, 24 mmol) was added dropwise thereto over 30 minutes with ice cooling. After the mixture was stirred at room temperature for 14 hours, an aqueous saturated ammonium chloride solution (200 mL) was added dropwise thereto with ice cooling, and the resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane to hexane:ethyl acetate=2:1). The fractions were collected and concentrated. The residue was dissolved in ethyl acetate, a 4 N hydrogen chloride/ethyl acetate solution (4 mL) was added thereto, and the resulting mixture was stirred at room temperature for 5 minutes. The resulting crystals were collected by filtration and washed with ethyl acetate to obtain the title compound (1.5 g, yield 51%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=C(CBr)C(CBr)=[CH:5][C:4]=1[CH2:13]Br.[OH-:15].C([N+](CCCC)(CCCC)CCCC)CCC.O1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[C:34]12[CH2:35][O:36][CH2:37][C:38]1=[CH:5][C:4]1[CH2:13][O:15][CH2:2][C:3]=1[CH:8]=2
Reactant: [OH-]
Reactant: BrCc1cc(CBr)c(CBr)cc1CBr
Reactant: C1COCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: c1c2c(cc3c1COC3)COC2
Temperature: 90 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
To a mixture of 1,2,4,5-tetrakis-(bromomethyl)-benzene (150 g, 0.33 mmol) and 1,4-dioxane (2 L) was added a 55% aqueous solution of tetrabutylammonium hydroxide (640 mL) at room temperature, followed by stirring at 90° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate after addition of a 2 N aqueous solution of hydrochloric acid (2 L). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to give the title compound (35 g, 63% yield).
Reaction SMILES: C[C@H]1C[O:29][C@@:5]2([O:9][C@H:8]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)[CH2:4][CH2:3]1.[O:31]=[C:32]=NC1CC(C)(C)CC(C)(CN=C=O)C1.C[C:48](=[O:51])[CH2:49][CH3:50]>>[C:5]([OH:29])(=[O:9])[CH2:4][CH2:3][CH2:50][CH2:49][C:48]([OH:51])=[O:31].[OH:51][CH2:48][C:49]([CH3:32])([CH2:8][OH:9])[CH3:50]
Reactant: CCC(C)=O
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Product: CC(C)(CO)CO
Product: O=C(O)CCCCC(=O)O

Procedure:
A 4-neck flask was fitted with a variable speed stirrer, thermocouples in combination with a controller, a condenser, a nitrogen in- and outlet, an addition funnel, and a heating mantle. In the flask were placed 77.03 g isophorone diisocyanate and 70 g dry 2-butanone. A mixture of 36.8 g Tegomer D3403 (available from Tego Chemie Service), 80.22 g dry 2-butanone, 23.82 g of Rucoflex S-107-210 (a polyesterdiol resulting from the reaction of adipic acid and neopentyl glycol, available from Ruco Polymers), 59.9 g of acetal-functional intermediate E, described above, 0.22 g tin(II)octanoate, and 21.14 g of acetal functional intermediate D, described above, was added during 1 hour. The mixture was further heated to 85° C. and kept at this temperature for 19 hours. After this time, the isocyanate content of the mixture was below 0.1%. The mixture was cooled to 45° C. and transferred to a 2 I round-bottom flask with baffles and the above-mentioned equipment. The stirring speed was set to 350 RPM and 435 g water were added at a rate of 2.7 ml/min. When the addition of water was complete, the emulsion was transferred to a 2 I flask fifted with the above-mentioned equipment and a distillation head. The temperature was maintained at 45° C. A vacuum pump was connected to the flask and the pressure was gradually lowered until substantially all 2-butanone was distilled off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([Cl:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1cc(Cl)cc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cc(Cl)cc(Cl)c1

Procedure:
According to the procedure of Example 10, Step C, 10g (27.9 mmole) of N-(3,5-dichlorophenyl)aniline, 42 mL of 1.93M phosgene in toluene and 25 mL of toluene at a bath temperature of 105° C. for 4.5 hr gave 10.98 g of a yellow oil, which by 1H NMR was 40 mol % (46 wt %) product, the remainder being starting material.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[F:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: Fc1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(F)ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-fluoro-4-(o-chlorophenyl)quinoline is reacted with hydrazine hydrate at reflux to give 6-fluoro-4-(o-chlorophenyl)-2hydrazinoquinoline.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2cncn2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:27]([O-])(=[O:29])[CH3:28].[Na+].O>C(OC(=O)C)(=O)C>[C:27]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=2)[C:13]1=[O:26])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Cl)ccc3ncc21
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 80 mg, 0.22 mmol) and sodium acetate (27.06 mg, 0.33 mmol) was heated at 50° C. in acetic anhydride (2 ml) for 3 hours. Reaction mixture was cooled to RT. Water was added and extracted with chloroform. Chloroform layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 26 mg (29%); 1H NMR (CDCl3, 300 MHz): δ 9.796 (s, 1H), 8.039-8.070 (d, 1H, J=9.3 Hz), 7.764-7.792 (d, 2H, J=8.4 Hz), 7.499-7.537 (m, 3H), 6.861-6.868 (d, 1H, J=2.1 Hz), 2.822 (s, 3H), 1.83 (s, 6H); MS: m/z 405 (M+).
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:17])[CH2:15][CH3:16])([CH2:10][O:11][CH3:12])[CH2:6][CH2:5]1.O(CC)CC.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>C(N(CC)CC)C>[CH3:12][O:11][CH2:10][C:7]1([N:13]([C:14](=[O:17])[CH2:15][CH3:16])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([O:1][C:35](=[O:38])[CH2:36][CH3:37])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:5][CH2:6]1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(O)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)OC(CN1CCC(COC)(N(C(=O)CC)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.8 %

Procedure:
To a stirred solution of 8.4 parts of N-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide in 52.5 parts of 1,1'-oxybisethane are added 2.15 parts of propanoyl chloride and 3.8 parts of N,N-diethylethanamine. The whole is stirred for 5 hours at reflux. The reaction mixture is cooled to room temperature, poured onto water and the layers are separated. The organic phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the ethanedioate salt in 2-propanol. The solvent is evaporated. The oily residue solidifies on triturating in boiling 4-methyl-2-pentanone. The salt is filtered off and crystallized from 2-propanol. The product is filtered off and dried, yielding 4.6 parts (36.8%) of [2-{4-(methoxymethyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinyl}-1-phenylethyl]propanoate sesquiethanedioate; mp. 171.2° C.