Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.5 ml), 4-fluoro aniline (14.2 ml) and sodium carbonate (5.3 g) was heated at 180° for 3 h. The reaction mixture was cooled to room temperature, then diluted with DCM, washed with water (50 ml), brine (2×50 ml) dried and evaporated under vacuum to give the crude compound (22.6 g), which was purified by flash chromatography with CH-EA 4/1 to give the title compound as an orange solid (12.35 g) M.p. 115°-6° T.l.c. (CH-EA (10:1), Rf 0.52.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-7-hydroxytetralin (400 mg) was dissolved in 8 ml of N,N-dimethylformamide, 3.16 g of cesium carbonate and 650 μl of ethyl 4-bromobutyrate were added to the solution, and the mixture was stirred at room temperature for 1.5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=1/1) to give 488 mg of ethyl (S)-4-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]butyrate having a meltin(point of 96 to 98° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1.[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]O)[CH2:32][C@@H:31]1[CH3:39])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:24][C:21]2[CH:20]=[CH:19][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH2:10][CH2:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:23][CH:22]=2)[CH2:32][C@@H:31]1[CH3:39])(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCN(CCO)C[C@@H]1C
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)C[C@@H]1C
Yield: 41 %

Procedure:
Obtained in 41% yield by an analogous method to Example 51, starting from 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol and (S)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (obtained by an analogous method to the R enantiomer as described in Example 51, preparation of starting materials).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[S:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:15]2[CH2:16][CH2:17][S:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCSCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCSCC1
Temperature: 80 °C
Yield: 50.8 %

Procedure:
2,6-Dichloro-3-nitropyridine (0.500 g, 2.59 mmol), tetrahydro-2H-thiopyran-4-amine (0.304 g, 2.59 mmol) and DIEA (0.91 mL, 5.19 mmol) were taken up in ethanol (2.0 mL) and heated to 80° C. for 18 h in a sealed tube. The reaction solution was chilled to form a precipitate. The precipitate was collected by vacuum filtration to give the title compound (0.360 g) LCMS m/z=274.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.70-1.85 (m, 2H), 2.20-2.35 (m, 2H), 2.60-2.90 (m, 4H), 3.90-4.10 (m, 1H), 5.84 (d, J=10.0 Hz, 1H), 8.24 (d, J=9.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:10][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)=[CH:12][CH:13]=1
Reactant: Cc1cncc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Product: Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 24.9 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 3-bromo-5-methylpyridine, (prepared as described in PREPARATION 1), (196 mg, 1.14 mmol) and 1-ethynyl-4-fluorobenzene (150 mg, 1.25 mmol) to give the title compound (60 mg, 25%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[C:12]=2[CH3:20])[N:7]1[C:21](=[O:24])[CH2:22]Cl)=O)C.[NH3:25]>CO.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:8]2[N:7]3[C:21](=[O:24])[CH2:22][NH:25][C:4](=[O:3])[C@@H:6]3[CH2:10][CH2:9]2)=[C:12]([CH3:20])[C:13]=1[CH3:19]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1C(=O)CCl
Reactant: N
Solvent: O
Solvent: CO
Product: COc1ccc([C@@H]2CC[C@H]3C(=O)NCC(=O)N32)c(C)c1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of the crude cis-1-(2-chloroacetyl)-5-(4-methoxy-2,3-dimethyl-phenyl)pyrrolidine-2-carboxylic acid ethyl ester (˜16.56 mmol) and ca. 7 M NH3 in MeOH (50 mL) is stirred in a sealed flask at room temperature for 2.5 days. The mixture is then diluted with water (ca. 200-300 mL). The resulting suspension is cooled to 0° C. and stirred well. The mixture is then filtered and the solid thoroughly washed with water followed by Et2O. Drying affords cis-6-(4-methoxy-2,3-dimethylphenyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as a slightly off-white powder. 1H NMR (CDCl3, 400 MHz): 6.70 (br, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.38 (d, J=8.8 Hz, 1H), 4.29 (dd, J=10.8, 6.4 Hz, 1H), 4.10, 3.93 (ABXq, JAB=16.8 Hz, JAX=1.0 Hz, JBX=4.8 Hz, 2H), 3.77 (s, 3H), 2.43-2.31 (m, 1H), 2.26 (s, 3H), 2.24-2.11 (m, 2H), 2.16 (s, 3H), 1.85 (dd, J=12.2, 5.8 Hz, 1H). Electrospray MS: m/z 289 [M+1].
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][C:8]=1[S:13]([CH3:16])(=[O:14])=[O:15]
Reactant: CC(N=[N+]=[N-])c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 4-(1-azidoethyl)-1chloro-2-(methylsulfonyl)benzene (2.1 g, 7.7 mmol), THF (20 mL), triphenylphosphine (2.4 g, 8.5 mmol) and water (0.6 mL, 34.2 mmol) at 0° C. and the reaction was stirred at room temperature over night. The solvents were removed and the residue was dissolved in MTBE and 20% HCl in dioxane was added dropwise at 0° C. The resulting salt was collected and washed with EtOAc. The salt was then neutralized with 6N NaOH and extracted with CH2Cl2. The combined organic layers were concentrated under reduced pressure to get the title compound as a very thick oil. 1H NMR (400 MHz, CDCl3): 8.14 (d, 1H, J=2.0 Hz), 7.63 (dd, 1H, J=8.4, 2.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 4.24 (q, 1H, J=6.4 Hz), 3.28 (s, 3H), 1.40 (d, 3H, J=6.4 Hz).
Reaction SMILES: CC1C=CC(S(O[C@H:12]2[CH2:15][C@@H:14]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[O:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[NH:29][C:28]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[O:36]=[C:28]1[N:29]([C@H:12]2[CH2:13][C@H:14]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:15]2)[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:35]2[O:27]1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](NC(=O)OCc3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1C[C@H](n2c(=O)oc3cccnc32)C1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of cis-3-(((benzyloxy)carbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (0.25 g, 0.666 mmol) in dry dimethylformamide (1.332 ml) was added oxazolo[4,5-b]pyridin-2(3H)-one (0.091 g, 0.666 mmol) and potassium carbonate (0.230 g, 1.665 mmol). The resulting mixture was heated at 50° C. for 14 hours, 100° C. for 3 hours, then 110° C. for an additional 20 hours. The mixture was diluted with dichloromethane and washed with water and brine then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was advanced directly to next step.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH2:7]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
A reaction mixture having the molar composition 0.303 Na2O:0.0052 Al2O3 :SiO2 :XH2O is first prepared by adding 83.5 parts by weight of soda waterglass (27% of SiO2, 8.43% of Na2O and 0.24% of Al2O3 to 149 parts of water. Thereafter, some of a filter-moist crystalline sodium silicate from a previous experiment (71% weight loss as a result of heating to 1,200° C.; only the amount of water was taken into account in calculating the molar composition) is added. 4.93 parts of 96% strength sulfuric acid are then added slowly, while stirring. The reaction mixture then has the following molar composition: 0.174 Na2O:0.0052 Al2O3 :SiO2 :0.129 Na2SO4 :30 H2O.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CO>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C@@H:25]([OH:27])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([C@H](C)O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
56.36 g of boran complex of (3aR,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2c][1,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0° C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]propoxy}-3-methoxy-phenyl)-ethanone (Iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0° C.±2° C. After the addition is complete, the mixture is stirred at 0° C. for 20 hours. The reaction mixture is then poured into precooled methanol (0-5° C.) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50° C. and an additional hour at 0° C. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50° C. The title compound is obtained (white crystals).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[H-].[Na+]>C1COCC1>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1ccc(-c2csc(NCc3cccs3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2csc(N(CC(=O)OC(C)(C)C)Cc3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a THF solution of [4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amine (80 mg, 0.25 mmol) and tert-butyl bromoacetate (41 μL, 0.28 mmol) was added NaH (15 mg, 60%, 0.38 mmol) and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with brine and extracted with ethyl acetate (3×5 mL). Combined ethyl acetate extracts were dried over sodium sulfate, concentrated and purified on silica gel column to afford 2-{thiophen-2-ylmethyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}acetic acid tert-butyl ester (75 mg). LCMS m/z: 430 (M+1)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCN(C(C)=O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([OH:31])[CH:25]=2.[C:32]([C@@H:36]1[CH2:41][CH2:40][C@H:39](O)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33].C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:32]([C@H:36]1[CH2:41][CH2:40][C@H:39]([O:31][C:26]2[CH:25]=[C:24]3[C:29]([CH:30]=[C:21]([CH3:20])[N:22]=[CH:23]3)=[CH:28][CH:27]=2)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1cc2ccc(O)cc2cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2cn1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (5.14 g, 19.6 mmol) was added to a solution of 3-Methylisoquinolin-7-ol (2.08 g, 13.1 mmol) and cis-4-tert-butylcyclohexanol (3.06 g, 19.6 mmol) in Toluene (60 mL, 600 mmol). The mixture was stirred for 15 minutes then Diisopropyl azodicarboxylate (3.86 mL, 19.6 mmol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under vacuum. The crude product was dissolved in methylene chloride, adsorbed onto silica gel and purified by flash chromatography to give the title compound in 2.01 g (52%) yield. ESI-MS (M+H+): 298.46.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]2[O:14]CCO2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])=[CH2:2].[CH2:15]1CCCCC1.CCOC(C)=O>>[CH3:15][C:1]1([C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=2)[CH:10]=[O:14])[CH2:2][CH2:3]1
Reactant: C=C(C)c1cccc(C2OCCO2)c1
Reactant: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(C=O)c2)CC1

Procedure:
The title compound was prepared following a procedure described in J. Am. Chem. Soc. 2007, 127, 12440-12441, starting from 2-(3-isopropenyl-phenyl)-[1,3]dioxolane and was obtained as a light yellow oil: TLC (cyclohexane-EtOAc 80:20) Rf=0.52; HPLC RtG2=1.35 min; 1H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.51 (m, 2H), 1.40 (s, 3H), 0.89 (t, 2H), 0.81 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=1)([O-])=O>CO.[Pd]>[N:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnn(Cc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(Cc2ccncc2)c1
Yield: 93.9 %

Procedure:
A solution of 4-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine (247 mg, 1.21 mmol) in methanol (10 mL) is hydrogenated over 10% palladium on carbon (30 mg) under balloon pressure for 3 h. The mixture is filtered through Celite and the filtrate is concentrated. The residue is purified by flash column chromatography using a gradient of 0-10% methanol in CH2Cl2 to afford the title compound as a brown oil (198 mg, 94%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.[OH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([N:11]4[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[CH2:12]4)[C:10]=3[C:2]([C:34]3[CH:35]=[C:30]([CH2:29][OH:28])[CH:31]=[CH:32][CH:33]=3)=[CH:3]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(CO)c3)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Temperature: 150 °C
Yield: 146.6 %

Procedure:
A mixture of 5-bromo-7-[(4-methylphenyl)sulfonyl]-4-[(3S)-3-methylpiperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (C15) (0.225 g, 0.501 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.104 g, 0.684 mmol), sodium carbonate (0.159 g, 1.50 mmol) and dichlorobis(triphenylphosphine)palladium(II) (36 mg, 51 μmol) in acetonitrile (2 mL) and water (2 mL) was heated to 150° C. under microwave irradiation for 15 minutes. The reaction was concentrated in vacuo to afford the product (0.35 g, >100%), which was used directly in the following step without additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncc(C(=O)O)cc1Cl
Product: Nc1ncc(C(=O)Cl)cc1Cl

Procedure:
6.3 g (36 mmol) of 5-chloro-6-amino-nicotinic acid are heated under reflux in 60 ml of thionyl chloride for 4 hours. After the volatile constituents have been distilled off, 50 ml of toluene are added to the residue and the mixture is evaporated. 6.9 g of 5-chloro-6-amino-nicotinoyl chloride are obtained as crystals of melting point: >250° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])P(Cl)(Cl)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](O)=[O:14]>COCCOC>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([N:2]([CH3:7])[CH3:1])=[O:14]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN(C)P(=O)(Cl)Cl
Solvent: COCCOC
Product: COc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 54.3 %

Procedure:
N,N-Dimethylphosphoramidodichloridate (1.8 mL, 15.22 mmol) was added to a solution of 3-methoxy-4-nitrobenzoic acid (300 mg, 1.52 mmol) in anhydrous 1,2-dimethoxyethane (15 mL) and the resulting mixture was heated at reflux for 110 hours ca. The reaction mixture was then cooled and poured into ice-water (50 mL); the resulting mixture was extracted with diethyl ether (50 mL), the organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic extracts were concentrated under reduced pressure; the residue was dissolved in dichloromethane and washed with water (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The tan liquid residue was purified by flash chromatography (DCM/MeOH, 98/2) to give 185 mg of 3-methoxy-N,N-dimethyl-4-nitro-benzamide as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCOCC2)c2nn[nH]c2n1

Procedure:
A mixture of 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (49.0 mg, 128 μmol) and TFA (1000 μL) was refluxed for 8 h under N2 atmosphere. The reaction mixture was concentrated in vacuo to afford crude to 5-tert-butyl-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:8]1[N:7]([CH2:17][CH2:18][O:19][CH3:20])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[CH3:15]
Reactant: CCOC(=O)Cc1nc(C(C)(C)C)n[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nc(C(C)(C)C)nn1CCOC
Temperature: 55 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
Ethyl (3-tert-Butyl-1H-1,2,4-triazol-5-yl)acetate (Preparation 116, 27.4 g, 0.13 mol) and 1-bromo-2-methoxyethane (13.7 mL, 0.143 mol) was dissolved in DMF (400 mL). K2CO3 (90.0 g, 0.65 mol) was added and the reaction mixture was stirred for 6 hours at 50-60° C. The reaction was cooled to room temperature, diluted with water (400 mL), and extracted with Et2O (3×100 mL). The combined organic extracts were washed with brine (3×200 mL), dried with Na2SO4, and evaporated to afford a mixture of alkylated triazole residues. The mixture was separated using HPLC (Luna 10 u 018(2), 100 A, 21.2×250 mm, H2O/acetonitrile 30-40%) to afford ethyl[3-tert-Butyl-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl]acetate (23.14 g, 66%).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>C(Cl)(Cl)Cl.CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([NH2:7])[CH:9]=1
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(N)c1
Reaction time: 8 h

Procedure:
To a chilled solution of methanol (100) was added thionyl chloride (21.25 ml, 0.29 mol). The solution was stirred for a further 30 minutes after which time m-aminobenzoic acid (10 g, 73 mmol) was added. The reaction was allowed to proceed overnight at room temperature and the solvents were then removed under reduced pressure. The product was obtained on tituration of the residue with diethyl ether. Yield 12.2 g (89%), m.p. 216°-218° C. The product was judged homogeneous by tlc in chloroform/methanol (4:1) (Rf 0.688) or chloroform/methanol (1:1) (Rf 0.597). (Found: C, 50.16; H, 5.27; N, 7.29. C8H10O2N1Cl1 requires C, 50.26; H, 5.23; N, 7.33%).