Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: Cc1noc(N)c1Cl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccccc2)c1Cl
Yield: 74 %

Procedure:
N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 10 from 5-amino-4-chloro-3-methylisoxazole and 2-biphenylsulfonyl chloride in 74% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes give a crystalline solid, m.p. 132-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([OH:25])=O)[N:22]=[C:11]2[CH2:10][N:9]=1.S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([Cl:28])=[O:25])[N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Product: O=C(Cl)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
An amount of 3.63 g (0.010 mole) of 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid is refluxed with 60 ml of thionyl chloride for two hours. The clear yellow solution is concentrated at 40° in vacuo and, to effect the total removal of thionyl chloride, the residue dissolved in 50 ml of abs. toluene and again concentrated by evaporation to obtain as residue crude 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carbonyl chloride. It can be optionally recrystallised from dioxane and has then a M.P. of 196°-198° (decomposition).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:30]2[C:31]3[C:26](=[C:25]([Cl:24])[CH:34]=[CH:33][CH:32]=3)[CH:27]=[CH:28][CH:29]=2)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 5-chloronaphthalenecarboxylic acid (186 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (136 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8]>CO.[Ni]>[Cl:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][C:3]=1[F:13]
Reactant: CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CNc1cc(Cl)c(F)cc1N

Procedure:
A stifled solution of 5-chloro-4-fluoro-N-methyl-2-nitroaniline (8; 1.5 g, 0.0078 mol) in MeOH (20 ml) was hydrogenated using Raney Ni for 6 h at room temperature. The reaction was filtered through CELITE® and the filter bed was thoroughly washed with MeOH. The resulting solution was concentrated to provide 5-chloro-4-fluoro-N1-methylbenzene-1 2-diamine as a brownish solid. 1H NMR (400 MHz, DMSO-d6), δ: 6.49-6.47 (d, 11.6 Hz, 1H), 6.30-6.28 (d, J=7.6 Hz, 1H) 4.96 (bs, 2H), 4.74 (bs, 1H), 2.67 (s, 3H). MS (M+1): 175.1.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[N:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(Cl)(=O)C>C1C=CC=CC=1>[CH2:9]([N:8]1[C:7]2=[N:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]2[N:25]=[C:23]1[CH3:24])[CH3:10]
Reactant: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CC(=O)Cl
Product: CCn1c(C)nc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 15 °C

Procedure:
2-Chloro-3-ethylamino-5,6-diphenylpyrazine, (3.10 g, 0.01 moles) is dissolved in benzene (50 ml) and then triethylamine (1.29 g, 0.013 moles) and acetyl chloride (1.00 g, 0.013 moles) are added. The solution is refluxed 41/2 hours, cooled to 15°C and filtered. The filtrate is diluted with ethanol (3ml), warmed briefly at 50°C and then all volatile materials evaporated. The resultant brown oil is treated with liquid ammonia (17 g) in ethanol (60 ml) in a bomb at 165°C for 12 hours. The solution is diluted with water (200 ml), cooled and the yellow precipitate filtered off. The solid is triturated with boiling 50% aqueous methanol, filtered, and the filtrate chilled. The product is collected by filtration. Yield 0.45 g (14%). It is recrystallized from benzene-heptane, m.p. 178.5°-180°C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(N(CC)CC)C.[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>CCOCC>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[N:15]=[C:1]=[S:2]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(N=C=S)c(F)c1F
Temperature: 20 °C
Yield: 77.2 %

Procedure:
Reference Example 1 Thiophosgene (1.4 g) was dissolved in 25 ml of ether, 2.0 g of triethylamine was added thereto with ice cooling and stirring (at not higher than 20° C.), then a mixture of 1.4 g of 2,3,4-trifluoroaniline and 3 ml of ether was gradually dropped thereinto at the same temperature, and the mixture was stirred for one hour at the same temperature. Then it was filtered off, the filtrate was concentrated, the residue was extracted with n-hexane, insoluble matters were removed by filtration, the resulting hexane-soluble matters were subjected to a silica gel column chromatography (Wacogel C-200 in the amount of 15 g) and eluted with n-hexane to give 1.39 g of 2,3,4-trifluorophenyl isothiocyanate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1([F:37])[O:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33](B(O)O)[C:27]=2[O:26]1>>[F:37][C:25]1([F:24])[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[C:30]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[C:28]=2[O:29]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc5c4OC(F)(F)O5)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (Apollo, Cheshire, United Kingdom, 26 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: tR 2.95 min (Method A); M+H=450 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.18-8.13 (m, 1H), 8.08 (s, 1H), 7.97-7.91 (m, 1H), 7.88-7.84 (m, 1H), 7.441-7.38 (m, 2H), 7.36-7.29 (m, 1H), 3.85 (s, 3H), 3.58 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:12])[CH2:5][CH2:4][C@@H:3]1[NH:13][CH2:14][CH2:15][CH3:16].I[CH2:18][CH2:19][CH3:20].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(#N)C>[CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:12])[CH2:5][CH2:4][C@@H:3]1[N:13]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16]
Reactant: CCCN[C@H]1CCc2cccc(Br)c2[C@H]1C
Reactant: CCCI
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CC#N
Product: CCCN(CCC)[C@H]1CCc2cccc(Br)c2[C@H]1C
Temperature: 50 °C
Yield: 19.6 %

Procedure:
To a solution of cis-1-Methyl-2-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.47 gm, 5.2 mMol) in acetonitrile (30 mL) were added 1-iodopropane (0.59 mL, 5.8 mMol) and proton sponge (2.2 gm, 10.4 mMol), and the mixture was stirred at 50° C. for eighteen hours. The colorless suspension was filtered and the filtrate concentrated in vacuo to give a light yellow oil. Purification by flash chromatography (20% diethyl ether in hexane+tr. NH4OH) gave the desired compound as a colorless glass (330 mg, 20%).
Reaction SMILES: [OH:1][CH:2]([CH3:23])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)=[O:11])[CH2:6][CH2:5]1.[C:24]([Cl:27])(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+].Cl>ClCCl.CO.C(N(CC)CC)C>[ClH:27].[C:24]([O:1][CH:2]([CH3:23])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)=[O:11])[CH2:6][CH2:5]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C

Procedure:
0.5 Gram of 6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 0.3 ml of triethylamine were dissolved in 10 ml of dichloromethane, the mixture was stirred at a room temperature, 0.15 g of acetyl chloride was added slowly thereto and further stirred at a room temperature for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution then dried with anhydrous sodium sulfate. The solvent was removed by distillation under a reduced pressure and the residue obtained was treated by means of a silica gel column chromatography, then the objective product was dissolved in methanol and converted into the hydrochloride by adding a concentrated hydrochloric acid. Recrystallized from water-acetone to obtain 0.22 g of 6-[4-(2-acetoxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Melting point: 239°-241° C. (decomposed)
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C(=O)CC2C=CC=CC=2)=CC=1.[C:22]1([C:28](=[O:35])[CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.BrC1C=CC([F:43])=CC=1>>[F:43][C:25]1[CH:26]=[CH:27][C:22]([C:28](=[O:35])[CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:23][CH:24]=1
Reactant: O=C(Cc1ccsc1)c1ccccc1
Reactant: Fc1ccc(Br)cc1
Agent: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Product: O=C(Cc1ccsc1)c1ccc(F)cc1
Yield: 45 %

Procedure:
Followed the procedure described in synthesis of Intermediate 14 using N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (prepared in Step 1 of Intermediate 2) and 1-bromo-4-fluorobenzene to give Intermediate 54, (260 mg, 45%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1.[H][H].S([O-])([O-])(=O)=O.[Mg+2]>[Ni].O1CCCC1>[NH2:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC1Cc2cccc([N+](=O)[O-])c2O1
Reactant: [H][H]
Agent: [Ni]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC1Cc2cccc(N)c2O1

Procedure:
A mixture of 81 g of 1B, 400 ml of tetrahydrofuran (THF) and 3 g of activated Raney nickel catalyst was shaken under 35 p.s.i.g. hydrogen pressure at room temperature for 4 hours. The resulting mixture was treated with 20 g of magnesium sulfate, filtered and the solvent was evaporated from the filtrate, to give 7-amino-2,3-dihydro-2-methylbenzofuran (1C), as an amber syrup.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCCCC.O>C1COCC1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[B:14]([OH:15])[OH:13])#[N:5]
Reactant: N#Cc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Dissolve 2-bromobenzonitrile (melt in water bath at 65° C. before use, 6.733 kg, 37.0 mol, 1 eq) in THF (52.5 L) in a cryogenic reactor and cool to −78° C. Add triisopropylborate (13.96 kg, 74 mol, 2 eq). Allow the mixture to cool to −78° C. again. Add hexyllithium (2.5M in hexane, 15.38 kg, 55.5 mol, 1.5 eq) over a period of 2 h (max internal temp=69° C.). After the addition, stir for 1 h at −75° C. Add the mixture (−74° C.) to water (48 L, 5° C.) over a period of 15 min with stirring to give a slightly yellow emulsion (−1° C.). Warm the mixture to 23° C. and stir at this temperature for 90 min. Separate the layers. Extract the aqueous layer with isopropyl acetate (24 L). Combine the organic layers and re-extract with brine (22 L). Combine the aqueous layers and acidify to pH 1 with 1M sulfuric acid (31 L). Extract the product twice with isopropyl acetate (41 L and 39 L). Combine the organic layers and stir overnight with brine (21 L) at 2° C. Collect the organic solution (90 L) and distill under reduced pressure at 50-60° C. to reduce the volume to 10 L. Strip the suspension with isopropyl acetate (11 L). Add methylcyclohexane (20 L) at 25° C. Cool the suspension to -7° C. Collect the precipitated product by filtration. Wash the filter cake with a mixture of isopropyl acetate (2 L) and methylcyclohexane (4 L). Dry the filter cake on the rotovap at reduced pressure at 50° C. to obtain 2.997 kg of title compound as a white powder; 55% yield (poor yield due to some material sticking to the reactor wall). 1H NMR (solvent-dx): § 7.53 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.62 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.73 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([CH:13]=1)[O:8][CH2:9][C@H:10]1[CH2:12][O:11]1.C(N(C(C)C)C(C)C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:26](=[O:28])[CH3:27])=[C:7]([O:8][CH2:9][C@H:10]2[CH2:12][O:11]2)[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([N+](=O)[O-])c(OC[C@H]2CO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(C)=O)c(OC[C@H]2CO2)c1
Reaction time: 0.67 h
Yield: 23.8 %

Procedure:
A mixture of (2R)-2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (620 mg, 2.75 mmol), Pd on charcoal (10%) (250 mg), N-ethyldiisopropylamine (0.941 mL), acetic anhydride (0.52 mL, 5.5 mmol) in ethyl acetate (25 mL) was hydrogenated at normal pressure for 40 min. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum spirit) to give the subtitled compound (155 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][C:5]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].[Cl:27]N1C(=O)CCC1=O>C(#N)C>[Cl:27][C:6]1[C:5](/[N:18]=[CH:19]/[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1Cc1c[nH]c2ncccc12
Solvent: CC#N
Product: CCn1nc(/N=C/c2ccc(F)cc2)c(Cl)c1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine (P-0165, 10.1 mg, 0.0289 mmol, prepared as described in Example 105, Scheme 162) in acetonitrile (8.0 mL) was added N-chloro-succinimide (4.18 mg, 0.0318 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0166, 1.1 mg). MS (ESI) [M+H+]+=382.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][C:51]3[C:50]4[CH2:49][C:48]([CH3:55])([CH3:54])[CH2:47][C:46]=4[S:45][C:44]=3[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].C([O-])(=O)C.[Na+].[O-]P([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].O.C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][C:51]3[C:50]4[CH2:49][C:48]([CH3:55])([CH3:54])[CH2:47][C:46]=4[S:45][C:44]=3[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[N:13]([N:12]=2)[CH2:18][C:17]([CH3:20])([CH3:19])[O:16][CH2:15]3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Reactant: Cn1nc(Cl)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(C)(C)OC4)c(=O)n(C)n2)ccnc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 95 °C
Yield: 24.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 330h (133 mg, 0.43 mmol), 330c (178 mg, 0.43 mmol), sodium acetate (71 mg, 0.86 mmol), K3PO4 (182 mg, 0.86 mmol), Pd(dppf)Cl2 (35 mg, 0.043 mmol), acetonitrile (15 mL), and water (0.5 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, the reaction mixture was heated at 95° C. for 3 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 330i as a yellow solid (69 mg, 25%). MS-ESI: [M+H]+ 644.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[OH-].[K+].[C:17](=S)=[S:18]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:17]([SH:18])=[N:14][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: S=C=S
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine (18 g, 94.7 mmol) in ethanol (230 mL) and water (63 mL) was added KOH (5.63 g, 100 mmol), followed by CS2 (12 mL, 198 mmol). The mixture was stirred and heated to reflux for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1 N aqueous sodium hydroxide and the insolubles were filtered off. The filtrate was acidified to pH 2-3 with 1 N aqueous HCl. The resulting precipitate was collected, washed with water, and dried in vacuo to provide 17.7 g of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (80.5% yield): 1H NMR (DMSO-d6) δ 3.95 (s, 3H), 7.73 (d, 1H), 8.13 (s, 1H), 8.16 (d, 1H), 8.53 (s, 1H), 14.7 (s, 1H); MS (m/z) 233 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:9][CH2:10][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)NCC2

Procedure:
N-[2-({1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (36 mg, 0.78 mmol) was dissolved in methanol (1 ml). Sodiumborohydride (12 mg, 0.31 mmol) was added and stirring was continued at room temperature over night. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and 1N aqueous sodium hydroxide solution. The layers were separated and the organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 9 mg.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][CH:14]([P:16]([S:22][CH2:23][CH2:24][CH3:25])(=[O:21])[S:17][CH2:18][CH2:19][CH3:20])[Cl:15].C(Cl)(Cl)(Cl)[Cl:27]>O1CCCC1.CCCCCC.O>[Cl:15][C:14]([P:16]([S:22][CH2:23][CH2:24][CH3:25])(=[O:21])[S:17][CH2:18][CH2:19][CH3:20])([Cl:27])[Cl:13]
Reactant: CCCSP(=O)(SCCC)C(Cl)Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCCSP(=O)(SCCC)C(Cl)(Cl)Cl
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.42 g (0.0047 mole) of diisopropylamine in 10 ml tetrahydrofuran (THF), maintained under inert gas and cooled to -25° C., was added dropwise a solution of n-butyllithium (0.043 mole) in hexane such that the temperature did not exceed -20° C. The solution was stirred at -35° C. for 30 minutes, then cooled to -65° C. A solution of 1.1 g (0.004 mole) of S,S-di-n-propyl dichloromethylphosphonodithioate in 20 ml THF was added dropwise over 20 minutes. After stirring at -65° C. for 60 minutes, a solution of 0.62 g (0.004 mole) of carbon tetrachloride in 10 ml THF was added over 10 minutes. The solution was stirred at -65° C. for 60 minutes, then allowed to warm to room temperature. After cooling in an ice bath, 25 ml of water was added. The reaction mixture was extracted with dichloromethane (2×40 ml) and the combined organic extracts were washed with saturated sodium bicarbonate (2×20 ml), and dried with magnesium sulfate. Evaporation afforded a red oil, the title compound. The structure Tas confirmed by nuclear magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)=[N:4][N:3]=1.C(N(CC)CC)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.C(OCC)(=O)C>[CH3:18][C:14]1([CH3:19])[NH:15][CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:3][N:4]=2)[CH2:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CN(c2nnc(Cl)c3ccccc23)CCN1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-4-(3,3-dimethylpiperazin-1-yl)phthalazine (540 mg, 2 mmol) in 10 mL of dichloromethane was added triethylamine (0.56 mL, 4 mmol, 2 eq), followed by benzoyl chloride (0.26 mL, 2.2 mmol, 1.1 eq). The reaction was stirred at rt for 30 min and diluted with 100 mL of ethyl acetate. The organic layer was washed with 1×10 mL of sat. NaHCO3 solution and 1×10 mL of sat. NaCl solution. Purification by column chromatography (100:2 dichloromethane:methanol) afforded 1-(3,3-dimethylpiperazin-1-yl)-4-phenylphthalazine (BSL-7). 1H-NMR (400 Mhz) δ 1.65 (s, 6H), 3.46 (s, 2H), 3.63 (m, 4H), 7.34 (m, 3H), 7.42 (m, 3H), 7.42 (m, 3H), 7.83 (m, 2H), 8.03 (m, 1H), 8.17 (m, 1H).