Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]1[O:19][C@H:17]1[CH3:18].C(Cl)Cl.CO>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H]1CO1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
1-(4-Nitro-phenyl)-piperazine (2.0 g, 0.0096 mol) was dissolved in Methanol (50.0 mL) and the reaction mixture was placed in a sealed tube. (S)-(−)-Propylene Oxide (0.841 g, 0.0145 mol) was then added at room temperature and the reaction was allowed to stir overnight. The mixture was then reduced en vacuo and the product was isolated by Isco flash column chromatography (DCM/MeOH) to afford 1.63 grams of (S)-1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-propan-2-ol as a yellow solid. (M+H)=266.20.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[N:11]1([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: FC(F)(F)c1ccc(NN2CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccc(NN2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
A mixture of (4-benzylpiperazin-1-yl)-(4-trifluoromethylphenyl)amine prepared in Reference Example 108 and 10% palladium/carbon (0.53 g) in ethanol (50 ml) was stirred at room temperature under an atmospheric pressure of hydrogen for 6 hours, and then at 60° C. for 10 hours. After the catalyst was removed by filtration through Celite, 10% palladium/carbon (0.53 g) was added to the filtrate, and the mixture was stirred at 60° C. under an atmospheric pressure of hydrogen for 8 hours. After the catalyst was removed by filtration through Celite, the filtrate was concentrated under reduced pressure. The resulting solid was dried in vacuo to afford piperazin-1-yl-(4-trifluoromethylphenyl)amine (1.76 g, yield 90%) as a colorless crystalline powder.
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[N:16][C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[S:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: c1nc[nH]n1
Reactant: S=c1c(Br)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2nc[nH]n2)oc2ccccc12
Temperature: 0 °C
Yield: 80.5 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, 1,2,4-triazole (138 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and recrystallized from benzene/hexane to give the titled compound (92.6 mg; yield=80.8%) as white needle crystals. Melting point: 232° C. 1H-NMR(DMSO-d6, δ ppm): 7.70 (s, H3), 8.35 (dd, H5), 7.66 (t, H6), 7.80 (t, H7), 7.99 (d, H8), 8.40 (s, H3'), 9.63 (s, H5').
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:41])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]3[CH2:27][CH2:26][N:25](CC4C=CC=CC=4)[CH2:24][C:22]=3[N:23]=2)=[CH:13][CH:12]=1.C1CC=CCC=1>[Pd].C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:41])[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[N:19]=[C:20]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:21]3[CH2:27][CH2:26][NH:25][CH2:24][C:22]=3[N:23]=2)=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc3c(c(-c4ccccc4)n2)CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc3c(c(-c4ccccc4)n2)CCNC3)cc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of N-(2,6-dimethylphenyl)-4-{[4-phenyl-7-(phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl]amino}benzamide (60 mg, 0.11 mmol), prepared as described in Example 249, 1,4-cyclohexadiene (11 μL, 0.11 mmol) and 10% palladium on carbon (8 mg) in ethanol (2 mL) were heated to 80° C. overnight. Upon cooling to rt, the reaction mixture was filtered through celite and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-(2,6-dimethylphenyl)-4-[(4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino]benzamide (31 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H), 9.52 (s, 1H), 7.96 (m, 4H), 7.62 (m, 2H), 7.52 (m, 3H), 7.11 (m, 3H), 3.75 (m, 2H), 3.05 (m, 2H), 2.79 (m, 2H), 2.17 (s, 6H). MS (EI) for C28H27N5O: 450.2 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH2:21])[CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:26][C:25]=1[C:40](Cl)=[O:41].C(N(CC)CC)C>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]([NH:21][C:40]([C:25]3[CH:26]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=4)[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[O:41])[CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COCC(N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COC[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC
Yield: 78.7 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide (45 mg) was prepared from 1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-methoxy-ethylamine hydrochloride salt (35 mg, 0.1 mmol) and 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl chloride (32 mg, 0.1 mmol) in presence of triethyl amine (41 mg, 0.41 mmol) according to the general procedure M.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[NH:19][CH:20]=[CH:21]3)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a mixture of 5-indolylboronic acid (670 mg, 4.19 mmol) in water (5 mL) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol). The resulting reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the catalyst. The filtrate was partitioned between water (50 mL) and methylene chloride (50 mL), and the layers were separated. The aqueous layer was further extracted with methylene chloride (50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl ester (347 mg, 36%) as a light brown oil: EI-HRMS m/e calcd for C23H25NO2 (M+) 347.1885, found 347.1887.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:39][CH2:40][CH3:41])[C:5]1[CH:6]=[C:7]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:35](OC)=[O:36])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)[CH:8]=[CH:9][CH:10]=1)[CH3:2].C(OC(OCC)C1C=C(C2C(C3C=CC=C(C(OCC)OCC)C=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)C=CC=1)C.O.[NH2:85][NH2:86]>CO>[CH2:40]([O:39][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:85][NH:86][C:35](=[O:36])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[CH:22]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:41]
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2cccc(C(OCC)OCC)c2)c1
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1cccc(C(OCC)OCC)c1)C(c1cccc(C(OCC)OCC)c1)N2
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (370 mg, 0.59 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL) was stirred at 40° C. for 2 hr. The mixture was cooled to room temperature and filtered to give 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (250 mg, yield 77%) as a light yellow solid. LC-MS (ESI) m/z: 544 (M+1)+.
Reaction SMILES: C(O)(=O)C.C[O:6][C:7]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([S:23]([N:26](C(OCC(C)C)=O)[C:27]3[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:8].N(C([O-])=O)=NC([O-])=O.[K+].[K+]>C(COC)OC>[C:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([S:23]([NH:26][C:27]3[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)([OH:8])=[O:6]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CCC(=O)O)cc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
A 1M solution of acetic acid in dimethoxyethane (5.6 ml) was added dropwise over 3 hours to a mixture of 2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) and potassium azodicarboxylate (1.4 g) in dry dimethoxyethane (20 ml) at 45° C. The mixture was heated at 45° C. for 18 hours. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was eluted through a pad of silica gel with ethyl acetate/hexane (1:3 v/v) and the resulting solid (230 mg) was dissolved in a mixture of tetrahydrofuran (16 ml) and methanol (4 ml). A solution of lithium hydroxide (118 mg) in water (4 ml) was added and the solution was stirred for 18 hours. Volatile material was removed by evaporation and the residue was dissolved in water (15 ml). The solution was washed with ethyl acetate (2×15 ml) and acidified with 20% aqueous citric acid. The mixture was extracted with ethyl acetate (2×15 ml) and the extracts were washed with water (10 ml) and saturated sodium chloride solution (50 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with ether to give 2-[4-(2-carboxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (42 mg), m.p. 166-168° C.; 1H NMR (CDCl3): 2.25 (s, 3H), 2.6 (t, 2H), 3.0 (t, 2H), 3.8 (s, 3H), 7.2-7.3 (m, 5H), 7.45-7.55 (m, 1H), 8.65 (d, 1H), 8.8 (d, 1H), 10.25-10.5 (br, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1
Reactant: COc1cc(CO)ccc1Sc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1Sc1ccccc1
Reaction time: 1 h

Procedure:
The 1-hydroxymethyl-3-methoxy-4-phenylthiobenzene obtained above is dissolved in methylene chloride (372 ml), and thereto is added with strring thionyl chloride (9.12 ml) under ice cooling. The mixture is stirred for one hour, and the reaction mixture is washed with ice water (500 ml×2), and thereto is added ethyl acetate (500 ml). The mixture is washed in order with 5% aqueous sodium hydrogen carbonate solution (20 ml), water (200 ml) and saturated aqueous sodium chloride solution (200 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-chloromethyl-3-methoxy-4-phenylthiobenzene.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[H-].[Na+].Cl[C:25]1[N:29]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:28]2[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=2[N:26]=1>CN(C)C=O>[CH2:33]([O:32][CH2:31][CH2:30][N:29]1[C:28]2[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=2[N:26]=[C:25]1[O:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:3]1)[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C[C@@H]1Cc1ccccc1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1c(O[C@@H]2CCN(C(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 118.7 %

Procedure:
(±)-1,1-dimethylethyl trans-4-hydroxy-2-(phenylmethyl)-1-piperidinecarboxylate (25.6 g) was dissolved in N,N-dimethylformamide (256 ml). Sodiumhydride (4.24 g) was added and the mixture was stirred at RT for 1.5 hours. 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazol (24.8 g) was added and the mixture was stirred at 70° C. for 18 hours. The solvent was evaporated, the residue taken up in water and CH2Cl2 and the layers were separated. The organic layer was dried, filtered and the solvent evaporated, yielding 50 g (100%) of (±)-1,1-dimethylethyl trans-4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]oxy]-2-(phenylmethyl)-1-piperidine-carboxylate (interm 27).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:3]([NH:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[C:7]([O:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:30]([N:29]([CH3:34])[CH3:28])(=[O:32])=[O:31])[CH2:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.5 g) in methylene chloride (20 ml) and pyridine (1.2 ml) was added dimethylsulfamoyl chloride (1 ml), and the mixture stirred overnight at room temperature. The mixture was partitioned between methylene chloride and water, and after the organic layer was dried over magnesium sulfate, solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-45% ethyl acetate/hexane, to give (R)-N-tert-butoxy-2-dimethylaminosulfonamido-3-(4-phenoxyphenylsulfonyl)-propionamide (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N#Cc1c(N)cccc1OCC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (75%). MS 329 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]3[CH2:24][CH3:25])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[C:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[CH2:24][CH3:25])(=[O:28])[NH2:27]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Temperature: 100 °C
Yield: 82.6 %

Procedure:
To a vial charged with (3R,4R)-tert-butyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate from Step 1 of Example 125 (349 mg, 0.748 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (467 mg, 2.245 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (61.1 mg, 0.075 mmol) were added dioxane (5.0 ml) and a 2M solution of potassium phosphate (1.1 ml, 2.245 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 1 hr. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated. The residue was partitioned between ethyl acetate (50 ml) and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield (3R,4R)-tert-butyl 4-((3-carbamoyl-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (288 mg, 0.618 mmol, 83% yield) as a white solid. LCMS (Method K) m/z 468.4 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH2:29][O:30][CH3:31])[C:4]([C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9](=[O:21])[N:10]2[N:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[C:11]=12)=[O:5])[CH3:2].Cl.C(OCC)(=O)C>CO>[CH2:1]([N:3]([CH2:28][CH2:29][O:30][CH3:31])[C:4]([C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9](=[O:21])[N:10]2[NH:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[C:11]=12)=[O:5])[CH3:2]
Reactant: CCN(CCOC)C(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccc(Cl)cc3c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CCOC)C(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CN2

Procedure:
from N-ethyl-10-chloro-N-(2-methoxyethyl)-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide in methanol/glacial acetic acid (10:1), but without the addition of saturated methanolic hydrochloric acid, there is obtained N-ethyl-10-chloro-6,7-dihydro-N-(2-methoxyethyl)-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide of m.p. 184°-185° (ethyl acetate);
Reaction SMILES: [ClH:1].C([NH:5][CH:6]([CH2:10][C:11]#[C:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17])[C:7]([OH:9])=[O:8])(=O)C.Cl>N1C=CC=CC=1>[ClH:1].[ClH:1].[NH2:5][CH:6]([CH2:10][C:11]#[C:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17])[C:7]([OH:9])=[O:8]
Reactant: CC(=O)NC(CC#CCNC(=N)CF)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: N=C(CF)NCC#CCC(N)C(=O)O

Procedure:
Ex-8i) A sample of (±)-2-Acetylamino-6-(1-imino-2-fluoroethylamino)-hex-4-ynoic acid hydrochloride (3 g) is treated with concentrated HCl and then pyridine to afford (±)-2-Amino-6-(1-imino-2-fluoroethylamino)-hex-4-ynoic acid dihydrochloride.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([O-])([OH:10])=[O:9]>C1C=CC=CC=1>[N+:8]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
Phenol dissolved in benzene is nitrated continuously by means of 58% nitric acid and the organic layer containing the mixture of ortho- and para-nitrophenol is separated from the residual nitric acid by decantation. The acid organic layer is successively neutralised by means of an aqueous solution of sodium sulphite, distilled until the benzene is removed and treated with steam in order to remove ortho-nitrophenol by steam distillation. An aqueous distillation residue of para-nitrophenol is thus obtained, the composition of which is substantially as follows:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC[O-].[Na+].[CH2:10]([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:11]=[CH2:12]>CCO>[CH2:10]([C:13]1[C:19]([OH:20])=[N:4][C:3]([NH2:5])=[N:2][C:14]=1[OH:15])[CH:11]=[CH2:12]
Reactant: N=C(N)N
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCc1c(O)nc(N)nc1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Guanidine hydrochloride (27 g, 0.28 mol) was added to cold absolute EtOH (200 mL) and NaOEt (30% in ethanol) (200 mL), and the mixture was stirred at 0° C. for 10 min. After this time, diethyl allylmalonate (55 g, 0.28 mol) was added. The reaction mixture was then stirred at room temperature for 18 h. Acidification with 3N HCl precipitated the crude product (pH=6). The solid was collected by filtration and washed with ethanol. Recrystallization from water afforded 29 g (62%) of pure 5-allyl-2-amino-4,6-dihydroxypyrimidine (CXLIII). LCMS (ESI) m/z=168 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[CH2:2][CH2:3][CH3:4].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:17]=1[C:18]#[N:19])([O-:15])=[O:14]>>[CH2:1]([NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[C:17]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCCCNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 215c from N-butyl-3-hydroxy-2,2-dimethylpropanamide (Example 228c) and 2,6-dinitrobenzonitrile in 66% yield. MS 320 (MH+).