Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[NH:8][CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([N:26]2[CH:30]=[CH:29][N:28]=[N:27]2)[N:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>C(Cl)Cl>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:8]2[C@H:1]3[C@H:6]([CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]3)[CH2:7]2)=[O:22])=[C:19]([N:26]2[CH:30]=[CH:29][N:28]=[N:27]2)[N:18]=1
Reactant: Cc1ccc(C(=O)O)c(-n2ccnn2)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2C[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]32)c(-n2ccnn2)n1
Yield: 98 %

Procedure:
To a mixture of Intermediate 24 (570 mg, 2.69 mmol), 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid (603 mg, 2.95 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1200 mg, 2.69 mmol) in DCM (15 mL) was added TEA (1.1 mL, 8.06 mmol). The resulting mixture was stirred for 5 h at ambient temperature at which time water (30 mL) was added. The aqueous layer was extracted with DCM (15 mL) three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by FCC (SiO2, ethyl acetate/hexanes, 0-40%) to yield (1S,6R)-tert-butyl 8-(6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.05 g, 98%). MS (ESI) mass calcd. for C20H26N6O3, 398.2; m/z found, 399.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.48-8.38 (m, 1H), 7.82-7.79 (m, 1H), 7.77-7.64 (m, 1H), 7.33-7.23 (m, 1H), 4.53-4.27 (m, 2H), 4.06-3.89 (m, 1H), 3.80-3.36 (m, 4H), 3.01-2.90 (m, 1H), 2.62-2.58 (m, 3H), 2.03-1.76 (m, 2H), 1.53-1.42 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1.NC1C=CC=CC=1>C(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1ccccc1N
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
2-Methoxyaniline (o-anisidine) (15 g, 0.122 mol) was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (50 g, 0.122 mol) by dissolving the aniline in 250 ml of methylene chloride, chilling the solution to -10°, and slowly adding and brominating agent, keeping the temperature below -5°. The reaction was allowed to warm at room temperature, and then washed with 2N sodium hydroxide (2×75 ml), then washed with water (2×25 ml), dried over magnesium sulfate, and evaporated to dryness. The product was purified on a silica gel column, eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether). Anal. Calcd for C7H8BrNO: C, 41.61; H, 3.99; Br, 39.55; N, 6.93. Found: C, 41.59; H, 3.99; Br, 39.49; N, 6.92.
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1CCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1CCl

Procedure:
A solution of ammonia (5.2 ml) in tetrahydrofuran (250 ml) at -70° was contacted rapidly with a solution of 2-(chloromethyl)benzenesulfonyl chloride (21.8 g) in tetrahydrofuran (125 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed under vacuum. The residue was contacted with ethyl acetate and a small volume of water. The organic layer was dried (MgSO4) and evaporated to give 19.8 g of white solid, m.p. 156°-157.5°. Recrystallization from toluene/ethyl acetate gave a sample with m.p. 157°-160°. 1H nmr δ(CD3)2COTMS 8.16-7.35 (m), 6.75 brds), 5.20 (s), 3.08 (s).
Reaction SMILES: CN(C)[C:3](=O)[CH3:4].[Cl:7][C:8]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9]=1[NH2:22].C(C(CC)(CC)C([O-])([O-])[O-])C.C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[Cl:7][C:8]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]2[C:9]=1[N:22]=[C:3]([CH3:4])[N:15]2[CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(=O)N(C)C
Reactant: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(Cl)nc(N)nc2n1C1CCOCC1
Temperature: 160 °C
Yield: 75 %

Procedure:
N,N-Dimethylacetamide (8 mL) containing 0.2% (v) glacial acetic acid was added to 6-chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,5-triamine (preparation Route A) (400 mg, 1.64 mmol), followed by triethylorthoacetate (0.8 mL, 5.32 mmol, 3.2 equiv.), and the reaction mixture was heated at 160° C. in a closed vial for two days. The mixture was then poured into water, and the pH was brought to basic using a saturated solution of sodium bicarbonate. Multiple extractions with methylene chloride, washing of the combined organic layers with water, and evaporation of the solvent in vacuo gave a dark brown residue, which was purified by column chromatography (silica gel, gradual elution with 2% methanol in 4/2/1 hexanes/methylene chloride/ethyl acetate to 3% methanol in 4/2/1 hexanes/methylene chloride/ethyl acetate) to give 330 mg (75% yield) of desired product as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 4.67-4.57 (m, 1H), 4.11 (dd, J=11.5, 4.6 Hz, 2H), 3.61 (td, J=12.0, 1.5 Hz, 2H), 2.91-2.76 (m, 2H), 2.72 (s, 3H), 1.86 (br dd, J=12.5, 2.4 Hz, 2H); MS (EI) m/z 268.1 (MH)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]1[C:11](=[O:12])[C:10](=[CH:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[NH:9][C:8]1=[O:23].C([Li])CCC.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:38]([N:9]1[C:10](=[CH:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:11](=[O:12])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=2)[C:8]1=[O:23])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C1NC(=Cc2c[nH]c3ccccc23)C(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1C(=Cc2c[nH]c3ccccc23)N(Cc2ccccc2)C(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of the compound of Example 2 (0.5 g) in dry tetrahydrofuran (20 ml) was cooled to -78° C. and n-butyl lithium (0.72 ml of a 1.6M solution in hexanes) was added with stirring. After 15 minutes benzyl bromide (0.14 ml) was added. The solution was allowed to warm to room temperature then heated to reflux for 3 hours, cooled and poured into saturated ammonium chloride solution (20 ml). This mixture was extracted with ethyl acetate and the organic layers dried (MgSO4). The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give the title compound, mp 154°-156° C.; found: C, 61.66; H, 4.05; N, 7.64; C28H21F6N3O2 requires: C, 61.65; H, 3.88; N, 7.70.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1.[ClH:20]>C(Cl)Cl.O1CCOCC1>[ClH:20].[C:2]1(=[O:1])[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1NCCCC12CCNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To the stirred solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (3.0 g, 11.19 mmol) in DCM (60 mL) was added 4N HCl in dioxane (20 mL) and the mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and triturated with diethyl ether (2×5 mL) to yield the title compound as a solid (2.2 g, 96%). Note: The product is moisture sensitive. [1H-NMR (DMSO-d6, 300 MHz): δ 9.25-8.68 (m, 2H), 7.43 (s, 1H), 7.20-6.25 (m, 2H), 3.61-2.90 (m, 5H), 2.12-1.95 (m, 2H), 1.76-1.49 (m, 5H); LCMS RtA=0.326, [M+H]+=169.0].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Temperature: 78 °C
Yield: 74.8 %

Procedure:
N-[4-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.330 g, 1.12 mmol) and ethyl formate (0.269 mL, 3.37 mmol) were dissolved in anhydrous ethanol (3.80 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.09 mL, 5.61 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.272 g, 0.838 mmol, 75%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([C:10]1([C:13](OCC)=[O:14])[CH2:12][CH2:11]1)#[N:9]>COC1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:8]#[N:9])[C:13]2=[O:14])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)C1(C#N)CC1
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: Cn1ccc(N2CCC(C#N)C2=O)n1
Temperature: 120 °C
Reaction time: 30 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (223 mg) in cyclopentyl methyl ether (5.0 mL) was added ethyl 1-cyanocyclopropanecarboxylate (0.90 ml). The reaction mixture was stirred at 120° C. for 30 hr, and diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (237 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc2N1
Yield: 29 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 29% of theory; LC (method 5): tR=0.98 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17](N)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:29].[Li+].N(OCCC(C)C)=O.[Cl-].[NH4+]>C(#N)C.[Cu](Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([Cl:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-3-amino-1-(4-methoxyphenyl)-1H-pyrazole (4.0 g), lithium chloride (2.28 g), and copper(II) chloride (2.90 g) in acetonitrile (50 ml) was stirred at ambient temperature for 10 minutes. To this mixture was added isoamyl nitrite (2.52 g), and the mixture was stirred at ambient temperature for 1.5 hours. To the reaction mixture was added a mixture of ethyl acetate and saturated aqueous ammonium chloride solution. The mixture was stirred at ambient temperature for a while, and partitioned. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 20% AcOEt/n-hexane. The pure fractions were collected and concentrated in vacuo to give 5-[4-(benzyloxy)phenyl]-3-chloro-1-(4-methoxyphenyl)-1H-pyrazole (2.81 g) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)(=O)=O>CN(C=O)C>[O:33]1[CH2:34][CH2:35][C@H:31]([N:12]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]3[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:11]2)[CH2:32]1
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc([N+](=O)[O-])cc1)nn2[C@H]1CCOC1
Reaction time: 3 h

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((S)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[I:13]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:13][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[CH3:1]
Reactant: II
Reactant: Cc1cc(=O)c2ccccc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2ccccc2c(=O)c1I
Temperature: 60 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
2-Methyl-4H-thiochromen-4-one (1.0 mmol, 176 mg), iodine (1.2 mmol, 305 mg) and ceric ammonium nitrate (1.1 mmol, 603 mg) were dissolved in acetonitrile (4.0 mL), and the solution was stirred under a nitrogen atmosphere at 60° C. for 4 hours. After the disappearance of the starting materials was confirmed by thin-layer chromatography, the reaction solution was poured into a solution of a 10% saturated aqueous sodium thiosulfate solution under ice-cooling to terminate the reaction. The organic substances were extracted with methylene chloride, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.79 mmol, 238 mg) was obtained in a 79% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[N-:11]=[N+:12]=[N-:13].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:11]=[N+:12]=[N-:13]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1

Procedure:
A stirred mixture of 3,4-dichlorobenzyl chloride (12.6 g, 64.5 mmol) and sodium azide (7.0 g, 0.11 mole) in absolute ethanol (70 ml) was refluxed for 4.75 hours, cooled and filtered to provide a solution of 3,4-dichlorobenzyl azide. Separately, 2-cyanoacetamide (5.5 g, 65 mmol) was added to a 35° C. solution of sodium (1.5 g, 65 mmol) in absolute ethanol (125 ml), and to the resulting suspension was added the above azide solution dropwise over 10 minutes. The combined mixtures were refluxed for 1 hour, kept 16 hours at ambient temperature and 1 hour at 5° C., and filtered. The crude product was dried under vacuum, dissolved in boiling ethanol (290 ml), filtered hot, and cooled to 0° C. The solid was collected by filtration and dried under vacuum to provide 12.4 g (67%) of 1-(3,4-dichlorobenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 221°-222° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.O>CS(C)=O.[Cu]I.CCOCC>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: Clc1ccc(I)cc1
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: C=CCN(C)CCCCOc1ccc2c(ccn2-c2ccc(Cl)cc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
260 mg (1 mmol) Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine in 2.5 ml DMSO were treated with 280 mg (2 mmol) powdered K2CO3 and 480 mg (2 mmol) 1-chloro-4-iodobenzene at 130° C. for 1 h. 19.1 mg (0.1 mmol) CuI were added and the mixture was stirred for additional 2 h at 130° C. At RT, water and ether were added, and the organic phase was washed with water, dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1 yielded 75 mg (20%) Allyl-{4-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine as orange oil, MS: 369 (MH+, 1Cl).
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[CH:20][C:19]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].II>CN(C)C=O.C(O)(C)(C)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[CH:20][C:19]=1[CH3:29]
Reactant: Cc1cc(C(CN)CN)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: Cc1cc(C2CN=C3c4ccccc4NC(=O)N3C2)ccc1N
Temperature: 75 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
A flask was charged with (2-formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-amino-3-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL). The mixture was stirred at 70-80° C. for 3 h. To the stirred, cooled (40-50° C.) mixture were added anhydrous potassium carbonate (16.6 g) and iodine (20.3 g). The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion. The cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL). The filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH2Cl2 (2×180 mL) and the separated organic layers were concentrated to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane. A Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield).
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].C([O-])(=O)C.[Na+]>C(O)=O>[CH3:22][O:23][C:24]([CH2:25][N:26]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH2:7][CH2:6][N:5]1[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]2[C:1]1=[O:20])=[O:27]
Reactant: CC(=O)CCC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)Cn1c(C)ccc1CCN1C(=O)c2ccccc2C1=O

Procedure:
82 g (0.03 mol) of 7-phthalimido-2,5-heptanedione, 5.0 g (0.04 mol) of glycine methyl ester hydrochloride and 3.3 g (0.04 mol) of sodium acetate are stirred in 150 ml of formic acid at 60° C. for 4 hours and the mixture is worked up as in Example 27.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C1C=CN=CC=1)C.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:3]([CH2:2][CH:1]=[O:7])[C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COC(CC=O)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of succinic anhydride (10 g, 0.1 mol) in CH3CN (200 mL) were added (4-methoxyphenyl)methanol (69.0 g, 0.5 mol) and DMAP (12.2 g, 0.1 mol). The reaction mixture was stirred for 3 h at about 30° C. and then diluted with water (700 mL). The resulting mixture was adjusted to pH=10 with saturated Na2CO3 solution and washed with ethyl acetate (300 mL×4) to remove an excess of (4-methoxyphenyl)methanol. The aqueous phase was adjusted to pH=2 with saturated citric acid solution and then extracted with ethyl acetate (200 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated to give product (21.0 g. 88% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13](=[O:30])[NH:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:13](=[O:30])[N:12]2[CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)C1C1CCOCC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(C2CCOCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 0 °C

Procedure:
At 0° C. 0.16 g (3.7 mmol) sodium hydride was added to 1.30 g (3.3 mmol) tert-butyl 5-(3,5-difluorophenyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (isomer mixture 2) in 20 ml DMF. After 20 min 0.36 ml (3.7 mmol) methyl bromoacetate were added dropwise while cooling with an ice bath. Then the mixture was stirred for 30 min in the ice bath and for 5 h at RT. The reaction mixture was poured onto water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.