Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1.CC(C)([O-])C.[K+].[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20]>>[NH2:1][C:2]1[N:7]=[C:6]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1
Reactant: Nc1nc(Cl)cc(CCl)n1
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOc1cc(CCl)nc(N)n1
Temperature: 50 °C

Procedure:
3,56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine and 2.24 parts of potassium t-butoxide were dissolved in 60 parts of n-butanol at room temperature then the solution was heated at 50° C. for 2 hours, with stirring. After this time, the solution was cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase was separated and washed three times with water then dried (MgSO4). Evaporation of the solvent gave the crude product which was purified by chromatography on silica (Merck Kieselgel 60) eluted with ether to give 2-amino-4-n-butoxy-6-chloromethylpyrmidine as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH:13](=[C:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>O.C1(C)C=CC=CC=1>[CH:13](=[C:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)[CH:14]([CH3:16])[CH3:15]
Reactant: COCc1ncnc(Cl)c1OC
Reactant: CC(C)C=C1CCC(N)CC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCc1ncnc(NC2CCC(=CC(C)C)CC2)c1OC

Procedure:
3.8 g (20 mmol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine (DE-A 4 116 089), 3.1 g (20 mmol) of 4-iso-butylidene-cyclohexylamine and 3.0 g (30 mmol) of triethylamine were stirred for 3 hours without solvent at 80°-90° C. After cooling, the mixture was taken up in water/toluene, and the organic phase was dried and evaporated on a rotary evaporator. Purification by chromatography (silica gel/ethyl acetate) gave 2.2 g (36% of theory) of a virtually colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:34])[CH2:32]Br)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:32]([C:31](=[O:34])[C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:26][CH:27]=3)=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1cc2cc(Br)ccc2o1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
5-Bromosalicylaldehyde (2.9 g, 14.5 mmol), cesium carbonate (2.5 g, 7.7 mmol) and acetonitrile (40 ml) were combined and heated to reflux for 30 minutes. The mixture was cooled to 0° C. and a solution of 4'-benzyloxy-2-bromoacetophenone (J. Het. Chem., 2, 310 (1965)) (4.7 g, 15 mmol) in acetonitrile (20 ml) was added. The cooling bath was removed, the mixture stirred at room temperature for 2.5 hours and the precipitate collected (4.5 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][C@@H:9]1[CH3:25])=[O:7].C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:37])[CH3:36].O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:35](=[O:37])[CH3:36])[CH2:10][C@@H:9]1[CH3:25])=[O:7]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccccc2)c2ccccc2N1C(=O)c1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccco2)c2ccccc21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of (±)-cis-furan-2-yl-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-methanone (360 mg, 1.0 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (1.9 mL, 10 mmol) followed by acetyl chloride (388 uL, 5 mmol). The mixture was stirred at room temperature over night. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M (aq) NaOH and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (50% hexanes/50% ethyl acetate) to afford the amide (230 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].O[CH2:15][CH:16]([CH2:18]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]2[C:7](=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[N:8]=[CH:18][CH:16]=[CH:15]2)[CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: OCC(O)CO
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: CCOc1cc([N+](=O)[O-])c2ncccc2c1
Yield: 75.1 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4-ethoxy-2-nitroaniline (1.0 g, 5.49 mmol), glycerol (1.6 g, 17.0 mmol) and 3-nitrobenzenesulfonic acid sodium salt (1.6 g, 7.14 mmol) gave the title compound (900 mg, 75%) which was used in the next step without purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10]2)(=[O:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2cc(S(=O)(=O)Cl)ccc12
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
5-(Acetylamino)naphthalene-2-sulfonyl chloride (280 mg, 0.987 mmol) was added to benzylamine (127 mg, 1.19 mmol) and triethylamine (0.17 ml, 1.22 mmol) dissolved in tetrahydrofuran (3.0 ml), and the mixture was stirred at room temperature for 1 hour. Water (10 ml) was added to the reaction solution, and after the mixture was stirred for 10 minutes, the resulting solid was collected. The solid was washed with water and isopropyl ether to give the title compound as a light pink solid (296 mg, 84.6%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.C(N(CC)CC)C.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][N:27]=[C:28]=[O:29])[CH3:23]>C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][NH:27][C:28]([C:3]1[C:4](=[O:14])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=2)=[O:29])[CH3:23]
Reactant: Cc1cc2oc(=O)cc(O)c2cc1C
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(C)c(C)cc2oc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
4-Hydroxy-6,7-dimethyl-chromen-2-one (500 mg, 2.4 mmol), triethylamine (368 uL, 2.64 mmol) and methylene chloride (4 mL) were placed together in a dry flask. Isocyanato-acetic acid ethyl ester (283 uL, 2.52 mmol) was added and the reaction was stirred overnight (24 h) at room temperature. The crude reaction mixture was purified using silica gel chromatography (SGC) (1% Methanol in Methylene Chloride) to provide the title compound in 85% yield. MS ESI(−) m/e: 318.33 (M−1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:15])=[CH:8][CH:7]=1.[BrH:16]>O>[Br:16][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48%) over 5 min at 0° C. The mixture was stirred for 20 minutes and was then pipetted into an ice cold solution of CuBr (22.0 g, 0.210 mol) in HBr (48%, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off and was treated with saturated NaHCO3. The mixture was extracted with ethyl acetate (20 mL×3). The organic layer was dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[N:8]=2)[CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:33]([CH3:37])[C:34](O)=[O:35])[CH:24]=[CH:25][C:26]=1[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:20][C:21]1[CH:22]=[C:23]([CH:33]([CH3:37])[C:34]([NH:14][CH2:13][C:12]2[C:7]([C:3]3[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=3)=[N:8][C:9]([C:15]([F:16])([F:18])[F:17])=[CH:10][CH:11]=2)=[O:35])[CH:24]=[CH:25][C:26]=1[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Reaction time: 48 h
Yield: 0 %

Procedure:
To a stirred solution of (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (3.5 g, 13.143 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (5.415 g, 19.715 mmol) in tetrahydrofuran (102 mL) was added 1-hydroxybenzotriazolhydrate (1.834 mL, 13.143 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.213 g, 13.143 mmol) and N-ethyldiisopropylamine (6.676 mL, 39.429 mmol). The reaction mixture was stirred for 48 h. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: ethyl acetate/cyclohexane 2:1) to afford a white solid (2.65 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1cccc2cc[nH]c12
Product: CN1CC=C(c2c[nH]c3c(Cl)cccc23)CC1
Yield: 81.1 %

Procedure:
Beginning with 0.50 gm (3.3 mMol) 7-chloro-1H-indole and 0.81 mL (6.6 mMol) 1-methyl-4-piperidone, 0.66 gm (81%) of the title compound were recovered as a white solid.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[C:12](Br)=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)C(=O)C(F)(F)F)[CH:2]=[CH2:3].[Cl-].C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.[Cl-].[Cl-].[Cl-].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:14]1[N:13]=[C:12]2[C:2]([CH3:3])=[CH:1][NH:4][C:11]2=[CH:16][CH:15]=1
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccc(OC)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[NH3+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]cc(C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of N-allyl-N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.54 g, 16.3 mmol), palladium acetate (147 mg, 0.65 mmol), tetra(n-butylammonium) chloride (4.99 g, 17.9 mmol) and triethylamine (3.72 g, 26.8 mmol) in anhydrous DMF (35 mL) is stirred at 10° C. under N2 for an hour. DMF is evaporated off, and the residue is mixed with water (20 mL) and stirred at rt overnight. EtOAc (50 mL) is added. The organic layer is separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 30-70% EtOAc in heptane to afford 5-methoxy-3-methyl-1H-pyrrolo[3,2-b]pyridine (2.62 g) as a solid. 1H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H), 4.05 (s, 3H), 6.62 (s, H), 7.12 (s, H), 7.54 (d, H), 7.94 (br, N—H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:21])[CH3:20])[S:16]2)[C@@H:12]([OH:22])[C@@H:11]1[OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:20])[CH3:21])[S:16]2)[C@@H:12]([O:22][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:11]1[O:23][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(CBr)cc1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1 g, 2.76 mmol) in DMF (20 mL) was added sodium hydride (568 mg, 16.6 mmol, 70%) at 15° C., and followed by addition of 1-(bromomethyl)-4-methoxybenzene (2.22 g, 11.0 mmol). The resulting solution was stirred for 3 h at room temperature, quenched by addition of cold water (50 mL), and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by silica gel column, eluted with 10-25% ethyl acetate in petroleum ether to give compound 9 as a yellow oil (1.2 g, 64%). (ES, m/z): [M+H]+ 603.1; 1H NMR (300 MHz, CDCl3) δ 7.22-7.35 (m, 4H), 6.84-6.92 (m, 4H), 6.27-6.29 (d, J=6.6 Hz, 1H), 4.60-4.76 (m, 4H), 4.36-4.43 (m, 2H), 4.10-4.17 (m, 2H), 3.81 (s, 6H), 3.72 (m, 1H), 3.61 (m, 1H), 2.99 (s, 6H), 0.83 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: C([N:9]1[CH2:22][C:21](=[O:23])[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=O)C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+]>>[O:23]=[C:21]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10][NH:9][CH2:22]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=C(c1ccccc1)N1CC(=O)N2CCc3ccccc3C2C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: O=C1CNCC2c3ccccc3CCN12
Yield: 91 %

Procedure:
g. of 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline is boiled with 20 ml. concentrated potassium hydrogen sulfate solution for 48 hours. The solution is subsequently extracted with chloroform, and the organic phase is dried with sodium sulfate and evaporated. 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline of m.p. 119°-120° C. is obtained in a yield of 91%.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](OS(C)(=O)=O)[CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[C:14]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]2=3)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1)[CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]1=2)=[N+:33]=[N-:34]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(C(N)=O)nc2)CCN(C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
Methanesulfonic acid-1-(6-carbamoyl-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl ester (300 mg, 0.678 mmol) was dissolved in 5 mL DMF, and sodium azide (88 mg, 1.357 mmol) was added, and the mixture heated at 100° C. for 1 h. The reaction mixture was monitored by LCMS. After completion of reaction, the reaction mixture was cooled to RT and diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (4×40 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to yield 5-[1-azido-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylic acid amide (135 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (dd, 1H), 8.1 (t, 1H), 7.9 (t, 1H), 7.33 (dd, 1H), 7.26 (s, 1H), 7.06 (t, 1H), 5.3 (t, 1H), 4.7 (dd, 1H), 4.42 (dd, 1H), 4.4 (dd, 2H), 4.3 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.34 (dd, 1H), 3.1 (d, 3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers V-22a-b.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[N:23]=[CH:22][CH:21]=[CH:20][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>>[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[C:9]2[N:23]=[CH:22][CH:21]=[CH:20][C:10]=2[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(-c2ccccc2)c2cccnc12
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2cccnc12
Yield: 98.1 %

Procedure:
Using methods described in Example 6, and starting with (R)-tert-butyl 3-methyl-4-(5-phenylpyrido[3,2-d]pyridazin-8-yl)piperazine-1-carboxylate 74 (325 mg, 801 μmol) and trifluoroacetic acid (3.09 ml, 40.1 mmol), yielded (R)-8-(2-methylpiperazin-1-yl)-5-phenylpyrido[3,2-d]pyridazine 75 (240 mg, 98.1% yield). 1H-NMR (400 MHz, CDCl3): δ 9.07 (dd, J=4.3, 2.0 Hz, 1H), 8.31 (dd, J=8.6, 2.0 Hz, 1H), 7.72 (m, 2H), 7.64 (dd, J=8.6, 4.3 Hz, 1H), 7.52 (m, 3H), 5.38 (m, 1H), 4.60 (dt, J=13.3, 2.3 Hz, 1H), 3.64 (ddd, J=13.7, 10.6, 4.7 Hz, 1H), 3.31 (dd, J=12.5, 3.9 Hz, 1H), 3.15 (m, 2H), 2.95 (dd, J=12.5, 1.6 Hz, 1H), 1.43 (d, J=7.0 Hz, 1H). MS 305.2 306.1 (M+H, found).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[C:11]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:28][C:29]2[CH:30]=[N:31][C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:33][CH:34]=2)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1>>[C:11]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH:19]([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:20]([CH2:28][C:29]2[CH:30]=[N:31][C:32]([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[CH:33][CH:34]=2)[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:12]=1
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=CCCc2cccc(-c3ccccc3)c2)C(=O)OC(C)(C)C)cn1
Product: COc1ccc(CSC(CCc2cccc(-c3ccccc3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Yield: 89.9 %

Procedure:
A solution of 4-methoxy-α-toluenethiol (0.58 mL, 4.17 mmol) in dry, degassed DMF (2 mL) was treated at room temperature with a catalytic amount of sodium hydride (60% in mineral oil), followed by a solution of tert-butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)pent-2-enoate (1.073 g, 2.08 mmol) in dry, degassed DMF (5 mL). After 20 h at room temperature the reaction mixture was diluted with EtOAc and washed with water three times. The organic layer was dried Na2SO4), concentrated, and subjected to flash chromatography (heptan/EtOAc, 3:1 and toluene/EtOAc 12:1) to give tert-butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]pentanoate (1.251 g, 90%)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([CH3:13])[SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([S:12][S:14][CH2:15][CH2:16][OH:17])[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCS
Reactant: CC(S)Cc1ccc2c(c1)OCO2
Product: CC(Cc1ccc2c(c1)OCO2)SSCCO

Procedure:
5.0 g of the title compound was prepared from 8.4 g of 2-(1,3-benzodioxol-5-yl)-1-methylethanethiol and 2.24 g of.2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br/C(=C\C)/C(O)=O.CNC.ClC1C=C(NC2C3C(=CC=C(N[C:51](=[O:58])[CH:52]=[CH:53][CH2:54][N:55]([CH3:57])[CH3:56])C=3)N=CN=2)C(F)=CC=1Cl>>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:51](=[O:58])[CH:52]=[CH:53][CH2:54][N:55]([CH3:57])[CH3:56])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(I)c3)c2c1
Reactant: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Agent: C/C=C(\Br)C(=O)O
Agent: CNC
Product: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(I)c3)c2c1

Procedure:
A solution of 4-[(3-iodophenyl)amino]-6-aminoquinazoline was reacted with bromocrotonic acid and dimethylamine, as is described hereinabove in Compound 4, to give N-{4-[(3-iodophenyl)amino]quinazoline-6-yl}-4-(dimethylamino)-2-butenamide. MS (m/z): 465 (M+H)+, 509 (M+)+; 1H-NMR (DMSO-d6): δ=4.38 (d, 1H), 4.49 (d, 1H), 6.5 (dd, 1H), 6.94 (dt, 1H), 7.19 (t, 1H), 7.47 (d, 1H), 7.85 (mt, 3H), 8.27 (s, 1H), 8.58 (s, 1H), 8.82 (s, 1H) 10.59 (s, 1H); Anal. Calc: C, 42.46; H, 2.77; N, 11.0. Found: C, 46.52; H, 3.04; N, 12.06. HPLC analysis: C-18 column, 55% acetate buffer/45% acetonitrile, flow=1.0 ml/min; r.t.=26.55 minutes (first peak), 29.99 minutes (second peak).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]#[N:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:7][C:5]1[S:6][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[C:3]([C:8]#[N:9])[N:4]=1
Reactant: Cc1nc(C#N)c(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(C#N)c(C#C[Si](C)(C)C)s1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
5-Bromo-2-methyl-thiazole-4-carbonitrile (4.8 g, 23.6 mmol) was suspended in 50 ml triethyl amine. Trimethylsilylacetylene (4.64 g, 47.3 mmol), triphenylphosphine (186 mg, 0.7 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.83 g, 1.18 mmol) were added and this mixture was evacuated and purged with argon several times to remove oxygen from the solution. Copper(I)iodide (45 mg, 0.24 mmol) was added and the reaction mixture was stirred at 70° C. for 5 hrs. The residue was taken up in water, extracted three times with ethyl acetate and several times with water. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (heptane/ethyl acetate 90:10->1:1 gradient). The desired product was obtained as a black solid (4.1 g, 79%).