Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:42]([C@:50]([C@@H:58]([CH:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[OH:61])[OH:59])([OH:57])[C:51]([F:56])([F:55])[C:52](O)=[O:53])[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:52]([C:51]([F:56])([F:55])[C@@:50]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])([C@@H:58]([CH:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[OH:61])[OH:59])[OH:57])=[O:53]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 34.3 %

Procedure:
To a solution of 0.77 g (5.0 mmol) of 6-chloropurine in 50 ml of tetrahydrofuran was added 1.31 g (5.0 mmol) of triphenylphosphine and 0.87 g (5.0 mmol) of diethyl azodicarboxylate. To this solution was added a solution of 1.99 g (5.0 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose in tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 60 hours and an additional 0.66 g (1.7 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose was added to the reaction mixture. The mixture was stirred for an additional 6 hours at room temperature. The solvent was evaporated under vacuum and the residue was stirred in a small amount of diethyl ether overnight. The precipitated solid was removed by vacuum filtration and the filtrate was concentrated under vacuum to dryness. The residue was chromatographed over 70 g of silica and eluted with chloroform. Fractions containing the major component were combined and the solvent was evaporated therefrom to provide 1.0 g of 1-(6-chloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. The structure of the product was verified by NMR. Mass spec.=477 [534-(t-butyl)]
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH:24]C(OC(C)CC)=O)[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]([CH2:23][NH2:24])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CCC(C)OC(=O)NCC(C)C(=O)N(Cc1cc(Cl)c2c(c1)OCCCO2)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above (±)-2-Methyl-3-(methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide was dissolved in dichloromethane (3 ml) and treated with trifluoroacetic acid (3 ml). After stirring for two hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (10 mL) and aq. sodium carbonate (sat., 10 mL). The aqueous layer was extracted with dichloromethane (10 ml×2). After washing with brine, the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to yield a resin: MS (m+1)=355.5.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(OCC)(OCC)OCC>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1ccccc1CN
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: COc1ccccc1CNCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (66.17 mmol) 2-nitrobenzaldehyde, 9.08 g (66.17 mmol) 2-methoxybenzylamine and 100 mL triethyl orthoformate in 100 mL dichloromethane were stirred for approx. 24 hours at room temperature. The residue obtained after evaporation was dissolved in 190 mL ethanol and mixed by portions with a total of 5.02 g NaBH4 while stirring at room temperature. After approx. 1 hour, the mixture was poured into water, extracted three times with dichloromethane; the combined organic phases were dried with MgSO4, filtered and concentrated until dry; 18.36 g yellow oil. ESI-MS [M+H+]=273.15.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[O:15][N:14]=[C:13]([CH2:16]O)[CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1(C)C=CC=CC=1>[Cl:3][CH2:16][C:13]1[CH:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:15][N:14]=1
Reactant: OCc1cc(-c2ccccc2)on1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: ClCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Thionyl chloride (7.55 ml) was added to a solution of (5-phenyl-3-isoxazolyl)methanol (12.1 g) in toluene (50 ml) and stirred at 80° C. for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(chloromethyl)-5-phenylisoxazole (11.8 g, yield 88%) as pale-yellow crystals. m.p. 46-47° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH:27][C:28](=O)[CH3:29])[C:5]2=3)[CH:14]=1.CO>C1COCC1>[CH2:28]([NH:27][CH2:26][CH2:25][O:24][C:6]1[C:5]2[C:4]3[C:12]4=[C:13]([O:15][CH2:16][CH:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:11]4[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:14]=[C:2]([CH3:1])[CH:3]=3)[CH3:29]
Reactant: CC(=O)NCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Solvent: CO
Solvent: C1CCOC1
Product: CCNCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 72.3 %

Procedure:
To a mixture of N-{2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide (0.212 g, 0.53 mmol) in THF (10 mL) is added borane-methylsulfide complex (0.15 mL, 1.6 mmol). The mixture is refluxed at 85° C. for 16 hours. After cooling, methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added then removed. The residue is dissolved in CH2C2/CH3OH (1:5, 15 mL). Conc. HCl is added and the mixture is heated at 65° C. for 1 h. The mixture is removed from heat, neutralized with aqueous potassium carbonate and then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica gel) using CH3OH/CH2C2 (5:95) as eluent gave 0.148 g (70%) of N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (TLC: MeOH/CH2C2, 5/95, Rf=0.38); conversion to the maleic acid salt and recrystallizing from absolute ethanol gave 0.0223 g of N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine, maleic acid salt.
Reaction SMILES: S(=O)(=O)(O)O.FC(F)(F)C(O)=O.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+]>O>[N:18]([C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)=[N+:25]=[N-:26]
Reactant: Nc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Prepared in analogy to J. Org. Chem. (1989) 54:5938-5945. To a solution of sulfuric acid (40 mL) and trifluoroacetic acid (200 mL) was added 4-fluoroaniline (22.1 mL, 0.23 mol) dropwise. Then under ice-cooling a solution of sodium nitrite (20.6 g, 0.3 mol) in water (200 mL) was added over 30 min at 15-18° C. The solution was then stirred for 30 min while kept in the ice bath. A solution of sodium azide (25.42 g, 0.39 mol) in water (150 mL) was added dropwise over 30 min. Mixture was foaming and temperature went up to 10° C. while cooling with an ice bath. Reaction mixture was stirred without cooling for 1 h, then extracted with diethyl ether. The combined organic layers were washed with water two times. Then the combined organic layers were diluted with saturated aqueous sodium carbonate solution (500 mL) until the mixture became basic. The organic phase was separated and washed with brine, extracted again with diethyl ether. The organic layers were dried over sodium sulfate and evaporated at 40° C., minimum 50 mbar (already distillation of product), to afford the title product (30.42 g, 96%) as a brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:19](=[S:21])=[S:20]>CO>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([SH:21])=[S:20])[CH2:15][CH2:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: S=C=S
Solvent: CO
Product: COc1cc(N2CCN(C(=S)S)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
In a nitrogen atmosphere, 1.9 g of 1-(3,4,5-trimethoxyphenyl)piperazine wasdissolved in 10 ml of methanol. To the solution was dropwise added under chilling with ice 0.46 ml of carbon disulfide. After the addition was complete, the mixture was stirred at room temperature for 2 hours. Precipitated crystals were collected by filtration to give 1.9 g of the desired compound as a gray-brown powder, m.p. 183°-190° C. (decomp.), yield 77.7%.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH2:4][CH2:3][C@@H:2]1[CH2:15][OH:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][C@H:2]2[CH2:3][CH2:4][C:5]3[C:10](=[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]4=[CH:7][CH:6]=3)[O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCc2ccc3ccccc3c2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ccccc4c3O2)cc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
To a solution of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol (0.90 g, 4.22 mmol) in dichloromethane (50 mL) is added p-toluenesulfonyl chloride (1.61 g, 8.44 mmol), 4-(dimethylamino)pyridine (0.10 g, 0.84 mmol), and N,N-diisopropylethylamine (1.20 g, 9.28 mmol) and the reaction mixture is heated to 50° C. for 12 h. The reaction mixture is quenched by the addition of water (100 mL). The aqueous layer is separated and extracted with dichloromethane (100 mL). The combined organic extracts are washed with aqueous hydrogen chloride (1.0 M, 100 mL), water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) provides 1.20 g (77%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethyl 4-methylbenzenesulfonate as a white solid. [α]D25=−10.23 (c 10.16 in chloroform, 50% ee); Rf=0.68 (silica, ethyl acetate:hexanes 2:3); mp 107-111° C.; Anal. Calcd. for C21H20O4S: C, 68.46; H, 5.47. Found: C, 68.10; H, 5.27.
Reaction SMILES: [CH3:1][C:2]([NH2:12])([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:3].C=O.[C:15](=O)([O-])O.[Na+]>>[CH2:15]=[N:12][C:2]([CH3:1])([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:3]
Reactant: CC(C)(N)c1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Product: C=NC(C)(C)c1cc(Cl)cc(Cl)c1
Reaction time: 7 h

Procedure:
1-Methyl-1-(3,5-dichlorophenyl)ethylamine (7.5 g) was added slowly to formalin (aqueous 37% HCHO solution) (4.6 g) at room temperature. This was allowed to react as it was for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was then extracted with ether. After it was washed with saturated saline, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the captioned compound (8.6 g) as white crystals.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[O:17])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[O:17][CH2:4]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(F)cc1)c1ccccc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(C2(c3ccccc3Cl)CO2)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethylsulphoxide (DMSO; 30 ml). A solution of o-chlorophenyl p-fluorophenyl ketone (0.025 mol) in DMSO (10 ml) was added dropwise at room temperature. The solution was then heated at 50° for 11/2 hours, cooled to room temperature and poured into water. The solution was extracted with diethyl ether (100 ml), washed with water (3×100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-o-chlorophenyl-1-p-fluorophenyl ethylene oxide (90%) as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](Br)[CH:3]=1.[S:10]1[C:14]([CH:15]=O)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2>>[S:10]1[C:14]([CH2:15][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: Clc1cc(Br)cc(Br)c1
Product: Clc1cc(Br)cc(Cc2cc3ccccc3s2)c1

Procedure:
1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([CH3:14])([OH:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)CCl
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccccc1Br
Temperature: 90 °C
Yield: 0.6 %

Procedure:
To a solution of 2-bromophenol (3.0 g, 1.745 mmol, Aldrich) and 1-chloro-2-methylpropan-2-ol (2.8 g, 6.397 mmol, Spectrochem) in DMF (15 mL) was added sodium carbonate (1.23 g, 11.63 mmol). The reaction mixture was heated at 90° C. for 12 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material that was purified by combiflash silica gel column chromatography (column size: 12 g; elution: 0-5% ethyl acetate in hexane) to yield 1-(2-bromophenoxy)-2-methylpropan-2-ol (2.7 mg, 64.2%) as a transparent liquid. m/z (ESI) 243.3 (M+H)+.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22]C#N)[CH2:16]1>>[OH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: N#CCCN1CCC[C@@H](O)C1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@@H](O)C3)cc12
Yield: 6.5 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (1.41 g) and (R)-3-(3-hydroxypiperidin-1-yl)propionitrile (1.44 g), (R)-3-[2-(3-hydroxypiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (147 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=C([CH:30]=[C:31]([F:33])C=1)C#N>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[C:31]([F:33])[CH:30]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: N#Cc1cc(F)cc(Br)c1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-5-fluorobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=367.9 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:28]=2[CH2:27][CH2:26]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:36][C:33]2[CH:34]=[CH:35][C:28]3[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH2:31][CH2:30][C:29]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC#N)n3)cc2CC1

Procedure:
The title compound was prepared from [2-(2,5-dichloropyrimidin-4-ylamino)-3-fluorophenoxy]-acetonitrile and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 930 to afford a yellow foam (48 mg, 55%). Mp: 68-74° C. LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.35 (m, 1H), 7.14 (s, 1H), 7.09-6.94 (m, 3H), 6.90 (m, 1H), 6.51 (s, 1H), 4.71 (s, 2H), 3.58 (m, 2H), 3.38 (s, 3H), 2.87 (m, 2H), 2.80-2.65 (m, 8H).
Reaction SMILES: [C:1](O)(=[O:3])C.[C:5]([O:9][C:10](=[O:32])[N:11]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([CH2:30][NH2:31])[N:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[C:5]([O:9][C:10](=[O:32])[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])[C:23]1[CH:28]=[CH:27][C:26]2[NH:29][C:1](=[O:3])[NH:31][CH2:30][C:25]=2[N:24]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)O
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3)c(OC)c1
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester acetate salt (1.3 g, 2.56 mmol) and N,N-diisopropylethylamine (890 μL, 5.12 mmol, 2 equiv) in THF (20 mL) was added a solution of 1,1′-carbonyldiimidazole (622 mg, 3.84 mmol, 1.5 equiv) and the reaction mixture was stirred overnight. The solvent was evaporated and the crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 50-100%) to afford (2,4-dimethoxy-benzyl)-(2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (464 mg). MS: [M+H]+=415
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21]O.C(N(CC)CC)C.CS([Cl:46])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21][Cl:46]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (510 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (250 μL, 1.8 mmol ) was added to the mixture followed by methanesulfonyl chloride (100 μL, 1.3 mmol). Mixture was stirred at room temperature for 1.5 hours. Mixture was diluted with dichloromethane then washed once with water, twice with 1N hydrochloric acid, and once with brine. Organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 91% yield. MS m/e (M+H)+=491.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.C(N(CC)CC)C>[CH:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: [H][H]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNc1ccccc1
Yield: 98 %

Procedure:
A solution of phenyl isocyanate (1.2 g.; 0.01 mole in 100 ml. anhydrous 1,4-dioxane containing two drops of anhydrous triethylamine was mixed with 500 mg. of 10% Pd-on-carbon and shaken at a pressure of 50 p.s.i. of hydrogen on a Parr low pressure hydrogenator. The uptake of hydrogen was complete in 5 minutes. The catalyst was collected and washed with 50 ml. of 1,4-dioxane. The solvent was evaporated to give 1.2 g. (98% yield) of slightly yellow oil which slowly crystallized. The product was confirmed to be formanilide by ir, nmr and glc analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:15]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. After reaction completion (the reaction being complete when 3 mole equivalents of hydrogen have been reacted), the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline as a white solid (120.6 g, 98%); NMR Spectrum (CDCl3): 2.11 (s, 3H), 2.50 (s, 3H), 6.51 (d, 1H), 6.58 (s, 1H), 6.75 (d, 1H), 6.98-7.03 (m, 2H), 8.18 (s, 1H); Mass spectrum: MH+ 215.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:15]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.710 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.636 g, 90%). MS=328 (MH)+. 315b) 7-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.630 g, 1.92 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.605 g, 2.31 mmol) in a manner analogous to Example 311b to give product (0.750 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 3.85 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H): MS=554 (MH)+.