Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:13][CH:14]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4ccc(C)cc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(OCCNc4ccc(C)cc4)cc3)c2cc1OC
Yield: 21 %

Procedure:
N1-(4-Methylphenyl)-2-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenoxy}acetamide (54 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A borane-tetrahydrofuran complex (1.0 M solution: 0.60 ml) was then added to the solution, and the mixture was heated under reflux for 3 hr. 1 N Hydrochloric acid was added thereto, and the mixture was further heated under reflux for 30 min. A 5% aqueous sodium hydroxide solution was added to the reaction solution, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (11 mg, yield 20%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:38]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH:39]([CH3:41])[CH3:40]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:45]3[CH2:46][CH2:47][N:42]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:43][CH2:44]3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)CN1CCNCC1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)cc1
Reaction time: 0.67 h
Yield: 84.2 %

Procedure:
4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid (16.5 g) was dissolved in a mixture of chloroform (150 ml) and triethylamine (15.3 ml). To this mixture was added diphenylphosphinic chloride (11.5 ml) while being cooled with ice. After being stirred for 40 minutes, the mixture, with 1-isobutylpiperazine (7.83 g) added thereto, was stirred for 1.5 hours at room temperature. This reaction mixture was washed with saturated sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform: methanol=50:1) and the resulting solid was recrystallized (from n-hexane), thereby yielding 19.6 g of the aimed compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]([C:14]([O:16]CC)=O)=[N:4]1)[CH3:2].[OH-].[NH4+:20]>>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]([C:14]([NH2:20])=[O:16])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(CCS(C)(=O)=O)n(CC)n1
Reactant: [NH4+]
Agent: [OH-]
Product: CCn1nc(C(N)=O)cc1CCS(C)(=O)=O

Procedure:
The method described in Part C of Example 10 was used to treat ethyl 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxylate (4.6 g, 17 mmol) with ammonium hydroxide (100 mL). The solid was isolated by filtration and washed with water to provide 3.0 g of 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxamide as a white powder, which was mixed with material from another run.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 4-methoxybenzenemethanamine (72.7 g) and triethylamine (83.6 ml) in CH2Cl2 (750 ml) was cooled on an ice-bath. Phenylchloroformate (91.4 g) was added dropwise and the reaction mixture was stirred at RT. The reaction mixture was washed three times with water and the precipitate was filtered off. The organic layer was separated, washed three times with a 5% aqueous NaHCO3 solution, dried (MgSO4), filtered and the solvent was evaporated. The precipitate was stirred in boiling diethyl ether (300 ml), filtered off and dried, yielding 84.4 g (65.5%) of phenyl [(4-methoxyphenyl)methyl]carbamate (interm. 2).
Reaction SMILES: [CH2:1]1COC[CH2:2]1.C([Mg]Cl)=C.[Cl:10][C:11]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].Cl>C#C>[Cl:10][C:11]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[C:1]#[CH:2]
Reactant: CC(C)c1cccc(C=O)c1Cl
Reactant: C1CCOC1
Agent: C#C
Agent: C=C[Mg]Cl
Agent: Cl
Product: C#CC(O)c1cccc(C(C)C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
30 ml of absolute THF is saturated under a nitrogen blanket at from 0°-10° C. with acetylene. While passing in further acetylene, 81.7 ml of vinylmagnesium chloride solution (1.47 molar) is dripped in and the mixture is stirred for 30 minutes at 0° C. Subsequently, 18.5 g of 2-chloro-3-isopropylbenzaldehyde is dripped in. The mixture is stirred for 15 hours at room temperature and then poured into 300 ml of ice water. The mixture is acidified with dilute hydrochloric acid and extracted by shaking three times with ether. The combined ether extracts are washed with water, dried and concentrated. There is obtained 22 g of crude product. Purification by column chromatography over silica gel with toluene/acetone (95/%) as eluant gives 9 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:9](O)=O.Br[C:21]1[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:8]([C:9]2[NH:28][C:23]3[C:24]([N:27]=2)=[N:25][CH:26]=[CH:21][CH:22]=3)[CH:7]=1
Reactant: O=C(O)c1cc(O)cc(OCc2ccccc2F)c1
Reactant: Nc1cc(Br)cnc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Oc1cc(OCc2ccccc2F)cc(-c2nc3ncccc3[nH]2)c1

Procedure:
Reaction of 3-(2-fluorobenzyloxy)-5-hydroxybenzoic acid (3.9 g, 15 mmole, 1.0 eq.) with 5-bromo-2,3-diaminopyridine (5.6 g, 30 mmole, 2 eq.), HBTU (11.3 g, 30 mmole, 2 eq.) and TEA (5.2 mL) in DMF (40 mL) over 18 h gave the amide intermediate (LC/MS calculated and found (M+2H+)=434 and 416 final product). This intermediate was isolated by pouring the reaction mixture into 400 g of ice water and filtering the subsequent white solid which formed. After the solid was thoroughly dried to 6.2 g, the material was brought through to the next step. The solid (2 g) was dissolved in 10 mL of ethyl alcohol and 10 mL of glacial acetic acid and put in the microwave at 180° C. for 30 min. This was repeated two more times to bring all 6.2 g through to the final product. This product crashed out of solution and was isolated as a brown solid after cooling the mixture to 0° C. for 10 h. The light tan solid (5.6 g) had an LC/MS with a calculated and found (M+H+)=416.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@:19]([OH:35])([C@H:26]([N:28]1[CH:32]=[C:31]([CH2:33][OH:34])[N:30]=[N:29]1)[CH3:27])[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@:19]([OH:35])([C@H:26]([N:28]1[CH:32]=[C:31]([CH:33]=[O:34])[N:30]=[N:29]1)[CH3:27])[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: C[C@@H](n1cc(CO)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](n1cc(C=O)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
Dimethylsulfoxide (1.08 ml) was added dropwise at -78° C. to a solution of oxalyl chloride (1 ml) in dichloromethane (30 ml), followed by stirring for 10 minutes. To the mixture was added dropwise over the period of 5 minutes a solution of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (2 g) in dichloro-methane (30 ml), followed by stirring for 15 minutes at -78° C. and then for 1 hour at -45° C. To the mixture was added triethylamine (5 ml), followed by stirring for 20 minutes at 0° C. To the mixture was added a saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted with dichloromethane (40 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: ethyl acetate/dichloromethane=3:1) to give Compound 71 (1.49 g), which was crystallized from diisopropyl ether to yield a colorless crystalline powder.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][N:14]([CH3:19])[CH2:15][C:16](O)=[O:17].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl.O.OC1C2N=NNC=2C=CC=1>[CH3:13][N:14]([CH2:15][C:16]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:17])[CH3:19]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)CN(C)C)CC1
Reaction time: 18 h

Procedure:
4.6 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added, at 20° C., under an argon atmosphere, to a solution of 2.3 g of N,N-dimethylglycine, 3.2 cm3 of ethyl 4-piperidinecarboxylate, 3.4 cm3 of triethylamine and 0.27 g of hydroxybenzotriazol hydrate in 100 cm3 of dichloromethane. After stirring for 18 hours, the reaction mixture is washed with twice 100 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 4.6 g of ethyl 1-(dimethylaminoacetyl)piperidine-4-carboxylate are obtained in the form of a yellow oil.
Reaction SMILES: F[C:2]1C=C(F)C=C[C:3]=1[O:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[CH:13]=[C:9]2[N:8]=[C:7]([CH3:15])[C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1.[OH-].[Na+].O>C(O)C>[CH2:3]([O:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[CH:13]=[C:9]2[N:8]=[C:7]([CH3:15])[C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][NH:24][C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5cc(C)nn5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1c(-c2cn(C)c(=O)c3[nH]ccc23)c(C)nc2cc(C)nn12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A suspension of 4-[7-(2,4-difluorophenoxy)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (29.1 mg, 50.6 μmol) in ethanol (1.0 mL) was treated with a 3.0 M solution of sodium hydroxide in water (0.254 mL, 0.762 mmol), then warmed to 55° C. and stirred at that temperature for 30 min. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (6 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (br s, 1H), 7.28 (d, J=2.8 Hz, 1H), 7.24 (s, 1H), 6.39 (s, 1H), 6.03 (d, J=2.7 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 3.55 (s, 3H), 2.42 (s, 3H), 2.24 (s, 3H), 1.07 (t, J=7.1 Hz, 3H); LCMS calculated for C18H20N5O2 (M+H)+: m/z=338.2. found: 338.1.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.Cl>C(O)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 91.4 %

Procedure:
To a solution of sodium metal (0.9 g, 39.13 g.a.) in absolute ethanol (50 mL) is added dropwise under nitrogen a solution of 4-hydroxybenzaldehyde (5 g, 40.94 mmole) in absolute ethanol (50 mL). The mixture is gently refluxed for 1 hour and then treated dropwise with a solution of 2-chloromethylquinoline (free base, 7.24 g, 40.76 mmole), freshly prepared from the HCl salt) in ethanol (50 mL). The mixture is refluxed for 24 hours, the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is washed with 5% NaOH (pH 8), water, brine to neutral and dried (MgSO4). Removal of the solvent yields the title compound as a yellow solid (9.81 g). The crude material is further purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 9:1 to remove less polar impurities and 8:2 to elute the product). Yield: 7.37 g (71.5%), m.p. 82°-83° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](N(CC=C)CC=C)=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[CH2:2][CH3:3].[Cl:26]C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1[N+]([O-])=O.C(O)CC>S(=O)(=O)(O)O.O>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Cl:26])=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[CH2:2][CH3:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: C=CCN(CC=C)c1c([N+](=O)[O-])cc(C(=O)OCCC)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCCO
Solvent: O
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1

Procedure:
According to a preferred form of realization of the process of the present invention n-propyl-4-diallylamino-3,5-dinitro-benzoate may be prepared by reacting 1 mole of 4-chloro-3,5-dinitro-benzoic acid with 1.25 moles of n-propanol at a temperature between 85° C. and 90° C., in the presence of a sulfuric acid catalyst, whereby the water formed is removed by azeotropic distillation with benzene. The distillation of water having been completed (5-7 hours) the reaction mixture, is cooled and the n-propyl-4-chloro-3,5-dinitro-benzoate is isolated. This compound is reacted with a 1.1 molar amount of diallyl amine at a temperature between 70° C. and 80° C., in an aqueous melt in the presence of 0.1 mole of 75% phosphoric acid and 1.05 moles of a 10% sodium hydroxide solution as acid binding agent. The reaction mixture is allowed to sedimentate, the organic phase is poured into water and the crystalline n-propyl-4-diallylamino-3,5-dinitro-benzoate is isolated.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5]1.[CH3:23][O:24][CH2:25]Cl>O1CCCC1>[CH3:23][O:24][CH2:25][N:10]1[C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[N:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5][C:4]1=[O:3]
Reactant: COc1ccc2c(c1)NC(=O)CCN2c1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1C(=O)CCN(c2ccccc2)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 86.8 %

Procedure:
Under argon atmosphere, 60% sodium hydride (1.12 g) was suspended in tetrahydrofuran (10 ml), a solution of 2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (5.0 g) in tetrahydrofuran (50 ml) was added thereto under ice-cooling, and the mixture was stirred for 40 minutes at same temperature. After ice bath was removeded, methoxymethyl chloride (2.25 g) was added, the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into ice-water, extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 5.05 g of the titled compound as yellow-brown crystals (Yield: 87%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].[CH2:18]([C@H:20]1[O:22][CH2:21]1)[Cl:19]>C(OCC)(=O)C>[Cl:19][CH2:18][C@@H:20]([OH:22])[CH2:21][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium bromide (1.7 g, 20 mmol) were added to 100 mL ethyl acetate and stirred for 30 minutes. (S)-epichlorohydrin (21 g, 0.23 mol) was then added. The reaction went on at room temperature (32° C.) for 2 hours. Filtered, and the solvent was evaporated to provide 53 g of colorless oil with 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:23])[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:29]O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:23])[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([O:19][CH3:29])=[O:18]
Reactant: COc1ccc(OC)c(C(=O)C=Cc2cccc(C(=O)O)c2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C=CC(=O)c2cc(OC)ccc2OC)c1
Reaction time: 12 h

Procedure:
A solution of 3-[3-(2,5-dimethoxyphenyl)-3-oxo-1-propenyl]-benzoic acid (2.86 g, 9.15 mmol) in methanol (200 mL) is treated with sulfuric acid (0.5 mL) and heated under reflux for 6 hours. After standing at room temperature 12 hours, the resulting solid is collected by filtration and washed with methanol to provide 2.2 g of the title compound; mp 108°-110° C. Additional material (0.7 g) is obtained by concentrating the filtrate and washings under vacuum, partitioning the residue between saturated sodium bicarbonate solution and dichloromethane, and concentrating the dried (MgSO4) organic layer to dryness.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:14][CH3:15])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:51])(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:51])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1
Reactant: CC=C1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-9-cyclopentyl-7-ethylidene-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.01 g, 3.30 mmol) in dry tetrahydrofuran (10 mL) was added to 1:1 molar 2 M lithium diisopropyl amide in tetrahydrofuran and hexamethyl phosphoramide (HMPA) (3.96 mmol each) in tetrahydrofuran (5 mL) at −78° C. After 20 minutes, N-fluorobenzene sulfonimide (2.46 mmol) was added dropwise to it. Continued the reaction at −78° C. for 30 minutes, and then elevated the temperature to 0° C. for 30 minutes. After disappearing the starting material, cooled the reaction flask to −78° C., then quenched with sat. ammonium chloride solution (6 mL). At room temperature, the resultant reaction mixture was taken into ethyl acetate (70 mL), washed with ammonium chloride solution and finally with water, dried over sodium sulphate and evaporated. Purified the product using column chromatography with hexane:ethyl acetate mixtures to give the product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53-2.10 (m, 8 H) 3.38 (s, 3 H) 3.63-3.88 (m, 1 H) 4.12 (m, 1 H) 4.96 (quin, J=8.59 Hz, 1 H) 5.41 (d, J=11.12 Hz, 1 H) 5.49 (dd, J=17.18, 2.02 Hz, 1 H) 6.02 (ddd, J=17.37, 14.72, 10.86 Hz, 1 H) 7.97 (s, 1 H). [M+H] calculated for C15H18ClFN4O, 325; found 325.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]([O:14]CC)=[O:13])=[CH:5]2.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.7 %

Procedure:
A solution of 2.06 g of ethyl 5,6-difluoroindole-2-carboxylate in 90 ml of ethanol was treated with 45 ml of 2N sodium hydroxide solution and stirred at room temperature for 17 hours. The alcohol was evaporated and the residue was treated with 50 ml of 2N hydrochloric acid. The separated crystals were filtered off, washed with water and dried. 1.78 g (98.8%) of 5,6-difluoroindole-2-carboxylic acid were obtained as brown crystals with m.p. 279°-280°.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:30]=[CH:31]/[C:32](O)=[O:33]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32](=[O:33])/[CH:31]=[CH:30]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:28])([F:27])[F:29])[C:20]=3[F:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1F
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3F)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-fluoro-3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[N:8]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 15 %

Procedure:
A solution of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (20 g), 1-bromo-3,3-dimethylbutan-2-one (8.7 mL) and cesium carbonate (21 g) in N,N-dimethylformamide (200 mL) was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (3.8 g, 15%) as a colorless liquid.