Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Oc3ccccc3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of the compound obtained in step 1 (0.50 g), phenol (0.21 g), potassium carbonate (0.76 g) and DMF (5 mL) was stirred at 100° C. for 3 days. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-benzyl-8-phenoxy-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.42 g, 66%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:18][O:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[N:7]([CH:8]([CH2:18][O:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]1)[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)COCC1COC(C)(C)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C(COCc1ccccc1)COCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of [2-Benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-carbamic acid tert-butyl ester (1.26 g, 3.18 mmol) in DMF (10 mL) was added sodium hydride (60%, 0.19 g, 4.78 mmol) at 0° C. in one portion. The reaction was stirred at 0° C. for 0.5 h then MeI (1.36 g, 9.56 mmol) was added. The reaction mixture was then stirred at 0° C. for 3 h at which time the LC-MS showed the reaction was complete. The reaction was quenched with saturated aq. NH4Cl solution and extracted with EtOAc (2×100 mL). The organic layer was then washed with water, brine and dried over Na2SO4. The organic layers were concentrated to give [2-benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.25 g, 96%). LRMS (M−Boc+H+) m/z 310.1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(OC(=O)C)C>CS(C)=O>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Temperature: 55 °C
Reaction time: 43 h
Yield: 87.3 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzonitrile (300 mg, 1.59 mmol) in DMSO (5.0 mL) was added piperidine (675 mg, 7.93 mmol), and the mixture was stirred for 43 hours at 55° C. After the mixture was cooled to room temperature, ethylacetate was added and washed with water then brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane:ethylacetate=10:1) to afford 3-piperidin-1-yl-4-(trifluoromethyl)benzonitrile (353 mg, 88% yield).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]2[NH:7][C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=3[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13]3)[C:5]=2[CH:4]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:28]=[CH:27][C:6]2[NH:7][C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=3[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:33])[C@@H:14]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13]3)[C:5]=2[CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Temperature: 25 °C

Procedure:
Add (S)-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.167 g, 0.399 mmol), formaldehyde (40.8 mg, 0.499 mmol, 37%), and sodium triacetoxyborohydride (0.127 g, 0.598 mmol) in dichloromethane (3 mL). Stir at ambient temperature over night. Dilute the mixture with water and extract with dichloromethane. Wash the organic with brine twice, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):433.08 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc(Br)cc1CBr
Yield: 69.7 %

Procedure:
A mixture of 4-bromo-1-chloro-2-methylbenzene (5.0 g, 24.0 mmol), N-bromosuccinimide (4.4 g, 25.0 mmol), and benzoyl peroxide (700 mg, 2.9 mmol) in anhydrous carbon tetrachloride (85 mL) was stirred at reflux for 4 hours. Dichloromethane (50 mL) was added. The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% EtOAc/hexanes), affording 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g, 70% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine from General Procedure B-3 (500 mg), isopropylsulfonyl chloride (0.26 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 2-chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine.
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([O:10][C:11](=[O:27])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][CH2:24][OH:25])[CH:20]=[CH:19][C:18]=1[Cl:26])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>O.CC(C)=O>[C:6]([O:10][C:11]([N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]([OH:1])=[O:25])[CH:20]=[CH:19][C:18]=1[Cl:26])[CH:13]1[CH2:14][CH2:15]1)=[O:27])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Conc. H2SO4 (98%, 5.80 mL) was carefully added to a suspension of CrO3 (6.70 g, 67.0 mmol) in water (12.5 mL). Water was slowly added up to a total volume of 22.5 mL, at which stage the mixture was a clear sol. This sol. was added dropwise to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (13.0 g, 39.9 mmol) in acetone (140 mL) at 0° C. When the addition was complete, the mixture was stirred at 0° C. for 30 min. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with aq. 1M HCl. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (12.2 g, 90%) that was used further without purification. LC-MS: tR=0.95 min; ES+: 325.35.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:7][CH:6]=1)=[O:4].[C:27](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(CNCC2CCCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN(C)CC2CCCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 72 h
Yield: 50.5 %

Procedure:
A solution of 1,1-dimethylethyl 2-((4-(methoxycarbonyl)phenylmethylamino)methyl)-1-piperidinecarboxylate (0.7 g, 2 mmol) in dichloroethane (10 mL) was treated with acetic acid (180 mg, 3 mmol) and formaldehyde (37% solution in water). After the addition of sodium triacetoxyborohydride (487 mg, 2.3 mmol) the reaction was stirred for 3 days. The reaction was poured into water and extracted with methylene chloride (2×). The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 0.38 g of 1,1-dimethylethyl 2-(((4-(methoxycarbonyl)phenylmethyl)(methyl)amino)methyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].[O:34]1CCC[CH2:35]1.CN(CCS(O)(=O)=O)C.[OH-].[Na+]>C(Cl)Cl>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([CH:35]=[O:34])[C@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: C1CCOC1
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CN(C)CCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C=O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1.17 h
Yield: 93 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (109.5 mg, 0.24 mmol) was added to a tetrahydrofuran solution (7.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (39.6 mg, 0.24 mmol) at room temperature and the resulting mixture was stirred for 70 minutes. Methylene chloride was added to the reaction mixture and the resulting mixture was poured into a 2 N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (107.9 mg, 93%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O-])(O)=[O:17].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([N:13]=[C:16]=[O:17])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])O
Reactant: COc1ccc(C2CCCCC2)cc1N
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCCCC2)cc1N=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5-cyclohexyl-2-methoxy-phenylamine (106 mg, 0.49 mmol), CH2Cl2 (10 mL) and saturated NaHCO3 (5 mL) was added a 20% solution of COCl2 in toluene (0.39 mL) directly to the organic layer. The mixture was stirred for 15 min at RT, diluted with CH2Cl2 and extracted with water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 4-cyclohexyl-2-isocyanato-1-methoxy-benzene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[CH:13]=1>>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]([CH2:11][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH:17]=[CH:16][N:15]=2)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: NC(=O)C1CCNCC1
Product: COc1cc(-c2cc(CN3CCC(C(N)=O)CC3)ccn2)cc(OC)c1OC

Procedure:
Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) were condensed by the same method as described in Example 2 to give the title compound as white needles.
Reaction SMILES: B.O1CCCC1.[C:7]1([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:7]1([NH:13][CH2:14][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 57 mL, 57 mmol) was added to a stirred, cooled (0° C.) solution N-phenyl-1-t-butoxycarbonylpiperidine-4-carboxamide (5.78 g, 19 mmol) in tetrahydrofuran (95 mL) and the mixture was stirred at room temperature for 18 h. Methanol (10 mL) was added and the solvent was evaporated under reduced pressure. Potassium carbonate (13.13 g, 95 mmol) and methanol (150 mL) were added and the mixture was heated under reflux for 1 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (100 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (20:80) to give the title compound as a colorless solid (5.08 g, 92%), δH (250 MHz, CDCl3) 7.18 (2H, t, J 7.6 Hz), 6.69 (1H, t, J 7.6 Hz), 6.59 (2H, d, J 7.6 Hz), 4.14 (2H, m), 3.73 (1H, br s), 3.03 (2H, d, J 6.2 Hz), 2.69 (2H, m), 1.79-1.55 (3H, m), 1.46 (9H, s), and 1.20 (2H, m).
Reaction SMILES: O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39](C=O)[CH:38]=2)=[N:29][N:30]([CH3:36])[C:31]=1[O:32][CH:33]([F:35])[F:34]>ClCCl>[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH:19]([O:22][CH3:23])[O:24][CH3:25])[CH:38]=2)=[N:29][N:30]([CH3:36])[C:31]=1[O:32][CH:33]([F:34])[F:35]
Reactant: COC(OC)OC
Reactant: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: COC(OC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g of montmorillonite K10 were added to a solution of 16 ml of trimethyl orthoformate in 80 ml of dichloromethane. A solution of 6.4 g (20 mmol) of 4-chloro-3-(4-chloro-3-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 20 ml of dichloromethane was added dropwise at 5° C. to this mixture. The mixture was then stirred at room temperature overnight. The solids were then separated off and the clear reaction solution which remained was concentrated. Yield: 6.7 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([O:23][C:24]([C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28])=[O:25])[CH3:22].C(N(CC)CC)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[C:24]([O:23][CH2:21][CH3:22])=[O:25])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol), o-ethoxycarbonylaniline (150 μL, 1 mmol), and triethylamine (280 μL, 2 mmol) in dichloromethane (3 mL) was added N,N-bis(2-oxo-3-oxazolydinyl)phosphinic chloride (254 mg, 1 mmol) at 0° C. The mixture was stirred overnight at room temperature and 0.2N hydrochloric acid was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residual solid was rinsed with diethyl ether and dried in vacuo to give 290 mg of the title compound (58%): mp>265°~267° C.; 1H NMR (270 MHz, DMSO-d6) δ12.05 (bs, 1H), 10.55 (s, 1H), 8.14 (d, 1H, J=8.1 Hz), 7.89 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J=2 Hz), 7.22 (t, 1H, J=8.1 Hz), 7.16 (d, 1H, J=2 Hz), 5.14~5.26 (m, 1H), 4.29 (q, 2H, J=7.2 Hz), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.62~2.76 (m, 2H), 2.18 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC(=O)OC(C)C)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2-methyl-phenol (see example 13) (150 mg, 0.44 mmol, 1.0 eq) in DMF (2 mL) was added Cs2CO3 (214 mg, 0.66 mmol, 1.5 eq) and the reaction mixture was stirred for 1 h. Isopropyl 2-bromoacetate (80 mg, 0.44 mmol, 1.0 eq) was then added and the reaction was stirred for a further 1 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound as a colourless oil (130 mg, 80%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C([N:18]([CH:21]([CH3:23])[CH3:22])CC)(C)C.C1(N)CC1>C(O)C>[CH:21]1([NH:18][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:23][CH2:22]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Agent: NC1CC1
Solvent: CCO
Product: CC(C)n1cnc2c(NC3CC3)nc(F)nc21
Yield: 70.4 %

Procedure:
6-Chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclopropylamine (0.2 g, 2.66 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (232 mg, 70.5%) δH (CDCl3, 500 MHz) 0.63-0.55 (2 H, m, CHHCHH of Cp), 0.85-0.78 (2 H, m, CHHCHH of Cp), 1.54 (6H, d, J 7.5, CH[CH3]2), 2.97 (1 H, s, br, CH of Cp), 4.73-4.62 (1 H, m, CHMe2), 6.72 (1 H, s, br, NH) 7.7 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.29 (C), 157.63 (C), 156.8 (C), 156.64 (C), 137.69 (CH), 47.35 (CH), 22.6 (2×CH3), 21.06 (CH), 7.28 (2×CH2); m/z 236.2 (M+H)
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=1.IC1C=CC=CC=1>>[CH3:38][O:37][C:33]1[N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: COc1cccc(Br)n1
Agent: Cl
Solvent: Ic1ccccc1
Product: COc1cccc(-n2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cc2=O)n1

Procedure:
4-[3-(6'-Methoxy-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-6-methoxypyridine for the iodobenzene in Step 3.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([Br:11])=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:5]=2[N:6]=1.N1C=CC=CC=1.[CH3:20][C:21]1[S:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1>ClCCl>[Br:11][C:10]1[C:4]2[S:3][C:2]([NH:1][C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:27])=[N:6][C:5]=2[C:7]([O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-7-bromo-4-methoxybenzothiazol (2.33 g, 9 mmol) is dissolved in dichloromethane (100 ml) and at 0° C. treated with pyridine (2.2 ml, 27 mmol) and 5-methyl-thiophene-2-carbonyl chloride (2.2 g, 13.5 mmol). The reaction mixture is allowed to warm to room temperature and after stirring for additional 18 h quenched with water (100 ml). After separation of the phases, the aqueous phases are extracted twice with ethyl acetate. The combined organic layers are then washed with brine, dried and avaporated to dryness. Flash chromatography on silica (eluent ethyl acetate/cyclohexane 1:1 to 4:1) and final recrystallization from ethyl acetate affords the product as off-white solid. (34 mg, 69%). MS: m/e=384 (M+).