Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15]2[N:19]3[N:20]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH2:3]1.N(C1C=NC=CC=1N1CCC[C@H](N[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])C1)=C=S.FC1C(C2N=NC(NN)=CC=2)=NC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[F:30][C:29]1[C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([NH:14][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:8]=4[N:4]4[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:3]4)=[N:16][N:17]=3)[N:20]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H]1CCCN(c2ccncc2Nc2nnc3ccc(-c4ncccc4F)nn23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=C=S)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NNc1ccc(-c2ncccc2F)nn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2Nc2nnc3ccc(-c4ncccc4F)nn23)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
N-(4-((3S)-3-amino-1-piperidinyl)-3-pyridinyl)-6-(3-fluoro-2-pyridinyl)[1,2,4]triazolo[4,3-b]pyridazin-3-amine. A mixture of (S)-tert-butyl (1-(3-isothiocyanatopyridin-4-yl)piperidin-3-yl)carbamate (193 mg, 0.58 mmol, Preparation XI) and 3-(3-fluoropyridin-2-yl)-6-hydrazinylpyridazine (113 mg, 0.551 mmol) in ACN (2 mL) was heated at 85° C. for 30 min. After the reaction mixture was cooled to RT, it was treated with DCC (125 mg, 0.60 mmol) and heating was resumed at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-10% MeOH in EtOAc) to provide (S)-tert-butyl (1-(3-((6-(3-fluoropyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (250 mg, 90% yield) as a dark green crystalline solid. MS (ESI, pos. ion) m/z: 506.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10](C([O-])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:20](=O)([O-:22])[O-:21].[Na+].[Na+]>>[C:20]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)([O:22][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:21]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C([O-])Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isonipecotic acid (5 g) was dissolved in 10% sodium carbonate (100 ml) and cooled to 0° C. Then benzylformate (6.6 ml) was added dropwise and stirred at 0° C. for 30 minutes. The reaction mixture was then removed to an ice bath and stirred for 18 hours. The reaction mixture was then poured into 2 M hydrochloric acid (100 ml). Ethyl acetate (300 ml) was added and the organic layer taken and washed with hydrochloric acid (2×100 ml) and saturated sodium chloride (75 ml). The organic layer was dried over magnesium sulphate, filtered and the solvent evaporated to form CBZ-isonipecotic acid.
Reaction SMILES: O1CCOC1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)OC(C)(C)C)=[C:9]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[CH2:31][CH2:30]3)[C:25]([N+:40]([O-:42])=[O:41])=[CH:24][N:23]=2)[CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[NH:21][C:22]1[N:27]=[C:26]([NH:28][C@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=[O:39])[CH2:31][CH2:30]2)[C:25]([N+:40]([O-:42])=[O:41])=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1
Solvent: ClCCl
Solvent: C1COCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1

Procedure:
A solution of 1,3-dioxolane of (R)-tert-butyl 4-fluoro-2-(5-nitro-4-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-ylamino)pyrimidin-2-ylamino)phenylcarbamate (145 mg) and TFA (2.5 mL) in CH2Cl2 (5 mL) was stirred at room temperature for 1 h. Volatiles were removed in vacuo and the crude (120 mg) was subjected to the next step without further purification.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.S(=O)(=O)(O)O.[N+:15]([C:18]1[C:19]([CH3:30])=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)C(O)=O)([O-:17])=[O:16].[N-:31]=[N+]=[N-].[Na+]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[N+:15]([C:18]1[C:19]([CH3:30])=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[NH2:31])([O-:17])=[O:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C(=O)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1c(N)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 45 °C
Yield: 86 %

Procedure:
Chloroform (38 ml.) was added carefully to a stirred mixture of oleum (16.9 ml.: 20% free sulphur trioxide) and concentrated sulphuric acid (3.8 ml.) followed by 3,5-dinitro-2-methylbenzoic acid (10.0 g.). The mixture was warmed to 45°C. and sodium azide (3.28 g.) was added in small portions over 20 minutes, the temperature of the reaction mixture being kept between 45° and 50°C. by means of intermittent cooling. After the addition was complete, the mixture was stirred and heated under reflux for 1 hour on the steam bath and then the chloroform was removed by decantation and the residue was poured into ice-water (300 ml.). The yellow precipitate was filtered off, washed with water and dried, to give crude 3,5-dinitro-2-methylaniline (8.8 g.), m.p. 169°-171°C. The crude product was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then with water and the solvent was removed in vacuo. Trituration with petroleum ether (b.p. 40°-60°C.) gave 3,5-dinitro-2-methylaniline (7.5 g.), m.p. 172.5°-174.5°C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].Cl.COC(=O)CN>C(Cl)Cl>[Br:7][CH2:1][CH:2]([OH:6])[CH2:3][C:4]([NH:13][CH2:12][C:11]([O:10][CH3:9])=[O:14])=[O:5]
Reactant: COC(=O)CN
Reactant: C=C1CC(=O)O1
Reactant: BrBr
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)CC(O)CBr
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
0.76 ml Diketene is dissolved in 3.5 ml methylene chloride. The solution is cooled to -30° C. and a solution of 0.5 ml bromine in 3.5 ml methylene chloride is added slowly dropwise, after which stirring is continued at -30° C. for 10 mins. This solution is added quickly dropwise to a solution of glycine methyl ester prepared by suspending 1.25 g glycine methyl ester hydrochloride in 20 ml methylene chloride containing 2.8 ml triethylamine, stirring for 30 min and cooling to -30° C. The temperature is allowed to return to ambient with continued stirring. After filtering, and evaporating in vacuo at ambient temperature, the oil remaining is dissolved in 20 ml ethanol, cooled to 0° C. and treated with 100 mg NaBH4. After 5 min the excess hydride is destroyed with dilute acid, the ethanol is evaporated and the residue taken up with ethyl acetate; the solution is washed with brine, dried, evaporated, and purified by chromatography on silica, eluting with ethyl acetate. The title compound is obtained as a white powder, m.p. 60°-61° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2].C(OP([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a mixture of 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl (2E)-3-{1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (0.51 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[CH2:13]([SH:16])[CH2:14][CH3:15].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([S:16][CH2:13][CH2:14][CH3:15])=[CH:5][C:3]=1[NH2:4].[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:3]=1[NH2:4]
Reactant: Sc1ccccc1
Reactant: CCCS
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCSc1cc(N)c(Cl)cc1[N+](=O)[O-]
Product: Nc1cc(Sc2ccccc2)c([N+](=O)[O-])cc1Cl

Procedure:
Similarly, 2.5-dichloro-4-nitroaniline is allowed to react with n-propyl mercaptan and thiophenol in dimethylformaldehyde at 100° C. in the presence of potassium carbonate to afford 2-chloro-4nitro-5-n-propylthioaniline, m.p. 125°-127° C., and 2-chloro-4-nitro-5-phenylthioaniline, m.p. 163°-166° C.
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[CH2:38]([N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][C@H:16]1[C@@H:20]([NH:22][C:23]1[N:28]=[C:27]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[CH:30]2)[CH:26]=[CH:25][N:24]=1)[CH3:21])[CH3:39]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCN(C(=O)Nc2cccc3ccccc23)C[C@H]1[C@H](C)Nc1nccc(-n2cnc3ccccc32)n1

Procedure:
The title compound was prepared from (S,S)-2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yi)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 9 mg), acetaldehyde (5 mg), and sodium cyanoborohydride (2.3 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 521.5 (M+1).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]N(C)C=O.IC>[Cl-].[Na+].O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([CH3:32])[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1c2ccccc2CN(C(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone of Example 6 (0.97 g) was added to sodium hydride (2 equivalents, 60% in oil, washed with hexane) and N,N-dimethylformamide (25 mL). Iodomethane (0.45 g) was added and after overnight stirring, the mixture was poured into brine. The precipitate was collected, redissolved in dichloromethane and the solution filtered through a short column of Magnesol®. The column was rinsed with several volumes of dichloromethane, and the combined eluate refluxed with the gradual addition of hexane until incipient crystallization. Cooling and filtration provided the title compound (0.89 g), m.p. 198-201° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2ccsc12
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccsc12

Procedure:
7 g of 7-methylbenzo[b]thiophene, 8,5 g of N-bromosuccinimide and a spatula tip of α,α'-azoisobutyronitrile are refluxed together for 6 hours in 50 ml of carbon tetrachloride. The resulting mixture is cooled, filtered and concentrated by evaporation. The resulting raw title compound can be directly employed in the next step. M.p. when isolated=57° (isopropanol)
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]=1.Cl.[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C>[CH3:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[CH:11][C:2]1[N:3]2[N:14]=[N:15][N:16]=1
Reactant: Cc1cccc2nc(Cl)cnc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2c1ncc1nnnn12
Reaction time: 6 h
Yield: 91 %

Procedure:
A solution was made of 0.5 g. of 2-chloro-5-methylquinoxaline, 10 ml. of 0.1N HCl and 0.6 g. of sodium azide in 35 ml. of denatured ethanol. The reaction mixture was stirred for 6 hours at reflux temperature. When the mixture was allowed to cool, the product, 6-methyltetrazolo[1,5-a]quinoxaline, crystallized in 91 percent yield and was separated by filtration. The product had a melting point of 160°-62° C., and was identified by nuclear magnetic resonance analysis and elemental microanalysis, the results of which were as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[OH:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:33]=[N:32]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cnn(CCO)c2)c1
Temperature: 95 °C

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 181 mg, 0.5 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (193 mg, 0.600 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), K2CO3 (138 mg, 1 mmol), water (2 mL) and dioxane (10 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 95° C. 7 h. The RM was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 25 g, EtOAc). The purified intermediate was treated with 5 M HCl in MeOH (5 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from Et2O/EtOAc afford the title compound as a beige powder. UPLC-MS (Condition 2) tR 0.92 min, m/z=393.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.78 (q, J=5.47 Hz, 2H) 4.19 (t, J=5.47 Hz, 2H) 4.96 (t, J=5.08 Hz, 1H) 7.40 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (s, 1H) 8.38 (s, 1H) 8.43 (d, J=1.17 Hz, 1H) 8.88 (s, 1H) 9.03 (s, 1H) 10.63 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[N:10]=[C:9]([C:11]2[N:15](C(OC(C)(C)C)=O)[C:14]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:13]=3[N:12]=2)[C:8]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:7][CH:6]=1.CCN(CC)CC.[S:50](Cl)([CH3:53])(=[O:52])=[O:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:8]1[N:7]=[CH:6][C:5]([C:4]#[C:3][CH2:2][NH:1][S:50]([CH3:53])(=[O:52])=[O:51])=[N:10][C:9]=1[C:11]1[NH:15][C:14]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:13]=2[N:12]=1
Reactant: Cc1ccc2nc(-c3nc(C#CCN)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3nc(C#CCNS(C)(=O)=O)cnc3N)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 3.6 %

Procedure:
tert-Butyl 2-[6-(3-aminoprop-1-ynyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl]-6-methyl-benzimidazole-1-carboxylate (90 mg, 0.1555 mmol) and Et3N (23.60 mg, 32.51 μL, 0.2332 mmol) were dissolved in DCM (10 mL) and cooled to 0° C. in and ice bath. Mesyl chloride (21.38 mg, 14.45 μL, 0.1866 mmol) as a solution in DCM (1 mL) was added dropwise and the reaction stirred at 0° C. for 20 minutes. The reaction mixture was washed with saturated aqueous NaHCO3 (×1) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was redissolved in DCM (10 mL) and TFA (177.3 mg, 119.8 μL, 1.555 mmol) added. The reaction mixture was stirred at ambient temperature for 1 hour then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (2 mg, 4% Yield). 1H NMR (400.0 MHz, D4-MeOH) δ 1.6 (3H, s), 2.25 (3H, s), 3.25 (2H, s), 6.25 (1H, d), 6.55 (1H, s), 6.7 (1H, d), 7.3 (1H, s); MS (ES+) 357.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:37])[C:3]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41].[OH-].[K+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:37])[C:3]=1[CH2:38][CH2:39][C:40]([OH:42])=[O:41]
Reactant: CCOC(=O)CCc1c(F)cc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1c(F)cc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
That is, ethyl 3-[2,6-difluoro-4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]-propanoate (300 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and ethanol (8 mL). Thereto was added an aqueous solution (5 mL) of 85% potassium hydroxide (100 mg, 1.51 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and crystallized from diethyl ether-hexane to give the title compound (271 mg, yield 94%) as colorless prism crystals.
Reaction SMILES: C(O[C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[C@@H:6]1[OH:25])(=O)C.B(F)(F)F.[CH3:30][CH2:31][O:32]CC.P(Br)(Br)[Br:36]>>[C:31]([O:25][C@@H:6]1[C@@H:5]([Br:36])[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@H:7]1[N:15]1[CH:16]=[N:17][C:18]2[C:24]1=[N:23][CH:22]=[N:21][C:19]=2[NH2:20])(=[O:32])[CH3:30]
Reactant: CCOCC
Reactant: BrP(Br)Br
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OC(C)=O
Agent: FB(F)F
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@H]1Br

Procedure:
This compound is prepared by a in situ acyloxonium ion generated by treating 3',5'-di-O-acetyladenosine with boron trifluoride etherate followed by phosphorus tribromide according to the procedure of Kondo, K., Adachi, T., and Inoue, I. (1977), J. Org. Chem., 42:3967. The title compound can also be formed by treating adenosine with tetraacetoxysilane and phosphorus tribromide in the presence of boron trifluoride etherate.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[F:17][C:18]([F:32])([F:31])[CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[F:17][C:18]([F:31])([F:32])[CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCOc1ccc(OCC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCOc1ccc(OCC(F)(F)F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.70 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-[4-(2,2,2-trifluoroethoxy)phenoxy]ethylamine (0.94 g) and triethylamine (0.40 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH:18]=1>CC(C)=O>[S:21]1[CH:22]=[CH:23][C:19]2[CH:18]=[C:17]([N:16]([C:12]3[S:11][C:2]4[N:10]=[CH:9][CH:8]=[CH:7][C:3]=4[C:4](=[O:5])[N:13]=3)[CH3:15])[CH:25]=[CH:24][C:20]1=2
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNc1ccc2sccc2c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN(c1ccc2sccc2c1)c1nc(=O)c2cccnc2s1
Yield: 17.7 %

Procedure:
The reaction procedure of Example 102 was followed except that 1.669 g of 2-chloronicotinoyl chloride, 722 mg of ammonium thiocyanate, 1.55 g of 5-(methylamino)benzo[b]thiophene and 35 ml of acetone were used. The product was then recrystallized from a mixture of ethanol and ethyl acetate to obtain 546 mg of 2-[N-(benzo[b]thiophen-5-yl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:40]([NH2:42])=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])(OC(C)(C)C)=O.[ClH:43].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:43].[ClH:43].[NH2:33][C@H:34]([C:40]([NH2:42])=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCCC[C@H](N)C(N)=O

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-lysineamide (1,1000 mg, 1.64 mmols) were dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at 60° C. for 3 hours. One-hundred milliliters of diethyl ether were added thereto, and the mixture was filtered. The resulting powder was purified through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio by volume of from 95:5 to 85:15), and was dissolved in a small amount of methanol (10 ml). A mixture of acetonitrile and ethyl acetate was added thereto, and the precipitate obtained was collected by filtration to produce 300 mg (0.554 mmols) of the final product in a yield of 34%.