Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][N:10]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:9]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:37])[C:34]([CH3:36])=[CH2:35].O>C(Cl)Cl.CO>[C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][N:10]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:37])[C:34]([CH3:36])=[CH2:35]
Reactant: C=C(C)C(=O)Cl
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc(N)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1ccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
A solution of tert-butyl (2-(((3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (0.150 g, 0.000338 mol) in DCM (3 mL) was cooled to 0° C. TEA (0.068 g, 0.000677 mol) and methacryloyl chloride (0.042 g, 0.000406 mol) were added and the reaction mixture stirred for 15 mins at 0° C. The reaction was poured into water (25 mL) and extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (30 mL), dried over sodium sulphate and concentrated under vacuum. The residue was purified by SGC using DCM:MeOH (0%-5%) as eluent to obtain tert-butyl (2-(((3-(4-methacrylamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (0.080 g, Yield: 45%). ESI-MS: m/z=512.3 [M+1]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:13]([NH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:2]([O:1][C:16](=[O:18])[CH3:17])[CH2:3][CH2:4]2)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1cccc2c1CC(O)CC2
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2c1CC(OC(C)=O)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (3 g, 15 mmol), acetic anhydride (2 g, 200 mmol) in pyridine (50 mL) was stirred at room temperature for 18 h. Solvent was removed by rotoevaporation and the residue was purified by column chromatography on silica gel (1:1 ethyl acetate:hexane as eluant) to give the product (2.2 g) as a tan solid in 59% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.CN(C=O)C.S(Cl)(Cl)=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C(Cl)Cl>[CH:38]1([NH:41][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH:18]=4)[N:13]=[CH:12]3)[CH:4]=2)[CH2:40][CH2:39]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
To a stirred slurry of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.2 g) and DMF (0.05 ml) in methylene chloride (4 ml) at 35° C. was added thionyl chloride (0.019 ml). The resultant yellow solution was stirred at 35° C. for 2.5 hours. The reaction mixture was concentrated to give a yellow/orange solid. The solid was stirred in methylene chloride (4 ml) at room temperature and cyclopropylamine (0.37 ml) was added, stirred for 10 minutes and concentrated. The resultant solid was partitioned between ethyl acetate (5 ml) and a saturated NaHCO3 solution (2.5 ml). The aqueous layer was separated and the organic layer washed with brine (5 ml). The organic phase concentrated to give a yellow foam and white solid. The mixture was triturated with toluene (5 mL) and filtered to remove the inorganic residues. The toluene solution was concentrated to give a yellow gum which was dissolved in methylene chloride and concentrated (3 times) to give the title compound as a yellow foam (171 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 2.13 (s, 3H), 2.24 (s, 3H), 2.48 (m, 4H), 2.86 (m, 1H), 3.29 (m, 4H), 7.48 (d, 1H), 7.53 (d, 1H), 7.64 (m, 2H), 7.82 (d, 1H), 7.90 (m, 1H), 8.09 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[CH2:32][C@@H:19]4[O:20]C(C5C=CC(OC)=CC=5)[O:22][CH2:23][C@@H:18]4[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.COC1C=C(OC)C=CC=1CN.CC(O)=O>O.C1COCC1>[NH2:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[CH2:32][C@H:19]([OH:20])[C@H:18]([CH2:23][OH:22])[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(NCc6ccc(OC)cc6OC)ncnc54)C[C@@H]3O2)cc1
Agent: COc1ccc(CN)c(OC)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnc2c1ccn2[C@@H]1C[C@@H](CO)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (123 mg, 0.238 mmol, prepared following the procedure described in Example 1a-f using 2,4-dimethoxybenzylamine in step c) and AcOH (1.00 mL, 17.6 mmol) in water (0.500 mL) and THF (0.500 mL) were stirred at rt overnight. The reaction mixture was concentrated in vacuo and purification by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (43.0 mg, 73%). LC/MS: Rt=0.15 min, ES+ 249 (FA standard).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34](Cl)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH3:39]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:39])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
A suspension of the compound prepared in Example 204 (50.0 mg) in acetonitrile (20 ml) was cooled to 0° C. and thereto was added ammonia water (28%, 5.0 ml) dropwise and the mixture was stirred for another ten minutes. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (42.0 mg). UPLC/MS 531 (M+H)/0.87 min. (measurement condition 9)
Reaction SMILES: [CH3:1][NH2:2].[C:3]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.C[Si]([C:13]#[N:14])(C)C>>[CH3:1][NH:2][C:3]1([C:13]#[N:14])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)C#N
Reactant: CN
Reactant: O=C1CCCC1
Product: CNC1(C#N)CCCC1
Reaction time: 3 h

Procedure:
Methylamine was bubbled into a refrigerated mixture of cyclopentanone (0.252 g, 3 mmol) and trimethylsilyl cyanide (0.396 g, 4 mmol) until the volume doubled. The mixture was stirred 3 h and then concentrated to dryness to obtain 31a (0.372 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:9])[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1nc(O)ncc1F
Product: CCOC(=O)n1cc(F)c(N)nc1=O
Yield: 25.6 %

Procedure:
Using the procedure of Example 2, 4-amino-5-fluoro-pyrimidin-2-ol (0.25 g, 1.9 mmol), BSA (1.41 mL, 5.8 mmol) and ethyl chloroformate (0.277 mL, 2.9 mmol) were reacted, and the resulting material was purified via reverse phase chromatography (gradient, CH3CN/H2O) to give ethyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.098 g, 25.6%) as a white solid: mp 190-193° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.04-8.01 (m, 2H), 4.27 (q, J=7.25 Hz, 2H), 1.26 (t, J=7.25 Hz, 3H); ESIMS m/z 200 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O(CCCCCO)C1C=CC=CC=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>>[O:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCCCCCOc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: OCCCCCOc1ccccc1
Agent: [K+]
Product: c1ccc(OCCCCCOc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(5-phenoxypentyl)oxy]pyrazine (2.06 g, 7.03 mmol; obtained according to the procedure of example 50, step 1, starting from 5-phenoxy-1-pentanol*), piperazine (1.88 g, 21.8 mmol) and K2CO3 (0.97 g, 7.03 mmol). The yield of the title compound was 1.15 g (48%) which was obtained as a white solid. Purity 100% (HPLC). MS m/z 343 (M+H)+. HRMS m/z calcd for C19H26N4O2 (M)+ 342.2056, found 342.2054. *Described in. J. Org. Chem. 1968, 33, 2271-2284.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH:20]1([SH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: SC1CCCCC1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSC3CCCCC3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and cyclohexylmercaptan.
Reaction SMILES: [Br-:1].[Br-:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:22]1[C:30]2[CH2:29][CH2:28]O[CH2:26][C:25]=2[CH:24]=[CH:23]1>C(#N)C>[Br:1][CH2:28][CH2:29][C:30]1[S:22][CH:23]=[CH:24][C:25]=1[CH2:26][Br:2]
Reactant: [Br-]
Reactant: c1cc2c(s1)CCOC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCCc1sccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 9.5 g of triphenylphosphine dibromide dissolved in 50 mL of acetonitrile, 2 g of 6,7-dihydro-4H-thieno[3,2-c]pyrane obtained in Example 14 was added, and the resulting mixture was refluxed for 8 hours. The reaction product solution was concentrated by evaporation under reduced pressure. To the residue, 5 mL of ethyl acetate and then 15 mL of n-hexane were added. The resulting mixture was stirred for 1 hour at room temperature and 2 hours at below 5° C., filtered, and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to obtain 3.3 g (yield of 80%) of the title compound as a yellowish oil, of which analysis data were the same as obtained in Example 7.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 95 °C
Yield: 57.4 %

Procedure:
A mixture of 6-phenyl-2-oxindole (41 mg, 0.19 mmol)-5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 49 mg (56%) of the title compound as an orange crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][P:22](=[O:25])([O-:24])[O-:23].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[C:16]([NH:19][CH2:20][CH2:21][P:22]([OH:25])([OH:24])=[O:23])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCP(=O)([O-])[O-]
Reactant: Nc1ncnc2c1nc(Br)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ncnc2c1nc(NCCP(=O)(O)O)n2Cc1ccccc1
Temperature: 110 °C

Procedure:
A mixture of N9-benzyl-8-bromoadenine (1 mmol), aminoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at 110° C. under nitrogen. After 24 h the cooled reaction mixture was purified through preparative HPLC to give N9-benzyl-8-(2-phosphonoethylamino)adenine (3.1). Exact mass calculated for C14H17N6O3P+H+: 349.1178. Found: 349.1180.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1>CCO>[O:23]=[C:15]1[NH:14][C:22]2[C:17](/[C:16]/1=[CH:1]\[C:3]1[CH:11]=[C:10]3[C:6]([C:7]([C:12]#[N:13])=[N:8][NH:9]3)=[CH:5][CH:4]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: N#Cc1n[nH]c2cc(C=O)ccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1n[nH]c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Temperature: 75 °C
Yield: 81.9 %

Procedure:
To a mixture of 6-formyl-1H-indazole-3-carbonitrile (1.10 g, 6.4 mmol) and 2-oxindole (871 mg, 6.5 mmol) in EtOH (25 mL) was added piperidine (0.1 mL, 1 mmol). The resulting mixture was refluxed (oil temp. 75° C.) for 90 min, then cooled to rt. The resulting precipitate was collected by suction filtration and dried to give the title compound as an orange solid (1.5 g, 82%) 1H NMR (400 MHz, DMSO-d6) δ 14.6 (s, 1H), 10.66 (s, 1H), 8.09 (s, 1H), 8.01 (d, J=8.5 Hz, 1H) 7.78 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.83 (t, J=7.8 Hz, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20](=[O:25])[CH2:19]4)(=O)=O)=CC=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[CH2:27]([NH:34][CH2:12][C@@H:13]1[O:26][C:17]2=[C:18]3[C:22](=[CH:23][CH:24]=[C:16]2[O:15][CH2:14]1)[NH:21][C:20](=[O:25])[CH2:19]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2O[C@@H](CNCc2ccccc2)CO3)N1
Reaction time: 18 h
Yield: 101.4 %

Procedure:
A 25 mL, flask is charged with [(2R)-8-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate (1.00 g, 2.7 mmol) and DMSO (8.0 mL). Nitrogen gas is bubbled through the solution for 10 min, benzylamine (0.73 mL, 6.7 mmol) is added and nitrogen is bubbled through the mixture for another 15 min. The flask is immersed in an 85° C. oil bath and stirred for 18 h. The solution is cooled, water (24 mL) is added and the resulting solution is extracted with MTBE (3×15 mL). The combined organic extracts are washed successively with water (10 mL), saturated NH4Cl (10 mL) and saturated NaHCO3 (10 mL), and are evaporated to give the crude title compound (0.85 g, 101%) as a red syrup. LCMS (Basic Method): 1.84 min, 311 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.4 (br s, 1H), 7.35-7.27 (m, 5H), 6.73 (d, J=8.3 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 4.37-4.35 (m, 1H), 4.25 (dd, J=2.2, 11.5 Hz, 1H), 4.03 (dd, J=7.3, 11.5 Hz, 1H), 3.88 (s, 2H), 3.44 (s, 2H), 2.97-2.88 (m, 2H), 8.9 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([O:24]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[N:38]=1.CS(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:43][C:39]4[N:38]=[N:37][CH:42]=[CH:41][CH:40]=4)(=[O:22])=[O:24])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1cccnn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
A RBF was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.68 g, 1.199 mmol) and pyridazin-3-amine (0.137 g, 1.438 mmol). DMSO (2.2 ml) was added to give a solution which was then diluted with THF (7.14 ml). The flask was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (2.64 ml, 2.64 mmol) was added dropwise, slowly over 2 min. After 15 min, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 10-70% of a 3:1 EtOAc/EtOH solution in heptane with 10% DCM as additive). Fractions containing pure product were combined and concentrated to give 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (0.25 g, 0.523 mmol, 43.6% yield) as an off-white solid. m/z (ESI) 478.0 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][C:43](O)=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:43](=[O:44])[CH2:42][CH:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:36])=[N:2]1
Reactant: COc1ccc(-c2ccc(CNCCCNc3nsc4ccccc34)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
N1-(Benzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg, 0.25 mmol), 2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (68 mg, 0.34 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboduimide hydrochloride (58 mg, 0.30 mmol) were dissolved in anhydrous methylene chloride (10 mL). Diisopropylethylamine (52 μL, mmol) added to the mixture. The reaction was allowed to stir overnight at room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 3:1 hexanes:ethyl acetate yielded tert-butyl 2-(2-((3-(benzo[d]isothiazol-3-ylamino)propyl)((4′-methoxybiphenyl-4-yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate as a solid (30 mg). 1H NMR (300 MHz, CDCl3): 7.90-7.95 (m, 1H), 7.75-7.85 (m, 1H), 7.35-7.55 (m, 6H), 7.19-7.25 (m, 2H), 6.95-7.00 m, 2H), 4.90-5.00 (m, 1H), 4.55-4.65 (m, 2H), 4.19-4.25 (m, 1H), 3.85 (s, 3H), 3.55-3.65 (m, 2H), 3.30-3.35 (m, 2H), 3.10-3.19 (m, 1H), 2.35-2.45 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.90 (m, 4H), 1.50 ppm (s, 9H). MW=615 confirmed by LC-MS, tr=5.12 min (Method B) MH+=614-616.
Reaction SMILES: Br.[OH:2][C:3]1[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1.[C:18]([Br:21])(=[O:20])[CH3:19]>FC(F)(F)C(O)=O>[BrH:21].[C:18]([O:2][C:3]1[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Br
Reactant: CS(=O)(=O)c1cc2c(cc1O)CCNCC2
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1cc2c(cc1S(C)(=O)=O)CCNCC2

Procedure:
A mixture of 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.2 g, 0.01 m) in trifluoroacetic acid (25 ml) is stirred at 25° and treated with acetyl bromide (1.4 g, 0.011 m). The mixture is stirred at 25° and concentrated in vacuo to give 8-acetoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1>CO.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(/C=C/C(=O)OC(C)(C)C)ccn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccn1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
tert-Butyl (E)-3-(2-methyl-4-pyridyl)-2-propenoate (4.4 g, 20 mmol) was dissolved in methanol (100 ml), and 10% palladium-carbon (0.45 g) was added thereto. The mixture was stirred under hydrogen atmosphere for 3 hrs. Palladium-carbon was filtered off, and the filtrate was concentrated to give the titled compound (4.4 g, 99%).
Reaction SMILES: [C:1]([C:4]1[S:27][C:7]2[S:8](=[O:26])(=[O:25])[CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CO.C(Cl)(Cl)Cl.[BH4-].[Na+]>O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15](=[O:17])[CH:16]=[C:11]3[CH2:10][CH2:9][S:8](=[O:26])(=[O:25])[C:7]4[S:27][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]=4[C:12]3=[N:13]2)=[CH:19][CH:20]=1
Reactant: CC(=O)c1cc2c(s1)S(=O)(=O)CCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)c1cc2c(s1)S(=O)(=O)CCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of 0.5 g of 9-acetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7,7-dioxide obtained in Example 48 in a mixed solvent of 40 ml of methanol and 30 ml of chloroform is added 0.1 g of sodium borohydride under ice-cooling and the mixture is stirred for 30 minutes at room temperature. After the completion of reaction, to the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting crystals are recrystallized with ethanol to give 0.25 g of 2-(4-chlorophenyl)-9-(1-hydroxyethyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7,7-dioxide as white crystals, melting at 233°-235° C.