Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=N1.[CH2:31]([NH:33][NH2:34])[CH3:32]>>[CH2:31]([N:33]1[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[CH:6]=[N:34]1)[CH3:32]
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CCNN
Product: CCn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting ethyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H), 8.23 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1 H), 7.85 (d, J=7.4 Hz, 1H), 7.83 (s, 1 H), 7.74 (m, 2 H), 7.57 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 2 H), 7.14 (d, J=9.1 Hz, 2 H), 7.04 (m, 2H) 5.42 (s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H); MS: (M+H m/z=407.3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=O)=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].N[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(O)C>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:16][C:13]1[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]2[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:15][N:14]=1
Reactant: NCCCCCO
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCCCCO)[nH]c2=O)cnc1C

Procedure:
5-(5,6-Dimethyl-3-pyridylmethyl)-2-nitroamino4-pyrimidone is reacted with 5-aminopentanol in refluxing ethanol to give 2-(5-hydroxypentylamino)-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone which is reacted with cyanamide and hydrogen chloride to give 2-[5-(O-isoureido)pentylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: OCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(CO)cc1
Reaction time: 18 h
Yield: 28.3 %

Procedure:
To a solution of 4-hydroxybenzyl alcohol (7.5 g, 60 mmol) and 8.4 mL of triethylamine (8.4 mL, 60 mmol) in 100 mL of ethyl acetate, cooled in an ice bath, was added, via canula over 15 min, a solution of acetyl chloride (4.7 mL, 66 mmol) in 50 mL of ethyl acetate. The mixture was stirred in the same bath, which was left to come to room temperature on its own. After 18 h, the precipitate was removed by filtration. It was rinsed with 50 mL of ethyl acetate in small portions. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel, using 3:2 hexanes:ethyl acetate as the eluent, to afford 60 (2.853 g, 17 mmol, 29%) as an oil. 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 4.69 (d, J=5.8 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].CO[CH:9]([O:15]C)[CH2:10][CH2:11][CH2:12][CH:13]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][CH3:6])=[CH:13]/[CH2:12][CH2:11][CH2:10][CH:9]=[O:15])([O-:3])=[O:2]
Reactant: CCC[N+](=O)[O-]
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 55.1 %

Procedure:
Prepared according to the general procedure A from 1-nitropropane 112c (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 55% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.II>S([O-])([O-])(=O)=O.[NH4+].[NH4+].CO>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[N:5]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:13])[CH:3]=1
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: II
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCCCn1c(N)cc(=O)n(Cc2ccccc2)c1=O
Temperature: 110 °C
Yield: 39.8 %

Procedure:
6-Amino-1-butyl-1H-pyrimidine-2,4-dione (1.72 g, 9.4 mmol), 1,1,1,3,3,3-hexamethyldisilazane (30 mL), and ammonium sulfate (0.03 g, 0.2 mmol) were heated under nitrogen at reflux for 24 h. After cooling to room temperature the 1,1,1,3,3,3-hexamethyldisilazane was removed under vacuum to give a light brown oil to which was added benzylbromide (1.1 mL, 1.58 g, 9.2 mmol) and a crystal of iodine. The resulting mixture was heated in a 110° C. oil bath for 1 h. The mixture was cooled in as ice bath while methanol was cautiously added. After concentration and trituration with chloroform and cooling to −20° C. freezer, the solid product was isolated by filtration. This material was passed through a pad of silica gel 60 (35–70 mesh) eluted with 9:1 chloroform/methanol to give 1.0 g of pure 6-amino-3-benzyl-1-butyl-1H-pyrimidine-2,4-dione. LRMS, m/z(M+H)=274.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[NH2:35])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH:35][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COc1ccc(N)cc1OCCN1CCOCC1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN1CCOCC1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxdiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-morpholin-4-ylethoxy)-4-methoxyaniline (D13) using a similar procedure to Example 1 (58%) mp 58°-63° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: NN
Reactant: Clc1cc(N2CCCCC2)ncn1
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CCCCC2)ncn1

Procedure:
17.7 ml (18.2 g, 364.2 mmol) hydrazine hydrate are added dropwise to a solution of 6.0 g (30.4 mmol) 4-chloro-6-piperidin-1-ylpyrimidine in 50 ml ethanol at RT, while stirring. The reaction solution is subsequently stirred at 80° C. for 16 h. For working up, the mixture is concentrated in vacuo, the residue is stirred in water, the solid which has precipitated out is filtered off, the residue on the filter is washed twice with 150 ml water each time and twice with 100 ml diethyl ether each time and the product is dried in vacuo.
Reaction SMILES: Br[C:2]1[CH:34]=[N:33][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:32])[N:14]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:15]4[CH:20]([C:21]=3[OH:22])[CH:19]3[CH2:23][CH:16]4[CH2:17][CH2:18]3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd]>[O:11]=[S:9]1(=[O:10])[C:4]2[CH:3]=[CH:2][CH:34]=[N:33][C:5]=2[NH:6][C:7]([C:12]2[C:13](=[O:32])[N:14]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C@@H:15]3[C@H:20]([C:21]=2[OH:22])[C@@H:19]2[CH2:23][C@H:16]3[CH2:17][CH2:18]2)=[N:8]1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)C2C3CCC(C3)C2N1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1C(C2=NS(=O)(=O)c3cccnc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
5-(7-Bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 62, 0.07 g, 0.128 mmol) was dissolved in methanol (8 mL). Ammonium formate (0.2 g, 3.17 mmol) followed by 10% palladium on carbon (wet, 0.1 g) were added. The mixture stirred at 50° C. for 3 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in water (5 mL) and ethyl acetate (50 mL). The mixture was shaken and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to a clear oil. Flash column chromatography (Merck silica gel 60, 40-63 μm; 20 to 40% ethyl acetate in hexanes) afforded the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.0441 g, 0.094 mmol, 74%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.11-1.61 (6H, m), 2.51 (1H, s), 2.63 (1H, s), 2.99 (1H, d, J=9.4 Hz), 3.54 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=8.6 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.4 Hz), 7.51 (1H, dd, J1=7.8 Hz, J2=4.5 Hz), 8.34 (1H, d, J=7.6 Hz), 8.68 (1H, dd, J1=4.6 Hz, J2=1.7 Hz). LC-MS (ESI) calcd for C23H21FN4O4S 468.13, found 469.4 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>O.COCCOC>[CH3:15][C:4]1[C:3]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2c3ccccc3nn2c1Cl
Reactant: Cc1ccc(B(O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(C(=O)OC)c1c(C)nc2c3ccccc3nn2c1-c1ccc(C)cc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a sonicated solution of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)pentanoate (0.252 g; 0.74 mmol) and 4-methylphenylboronic acid (0.201 mg; 1.48 mmol) in a mixture of water/DME (⅓, 3 mL) were added palladiumtetrakistriphenylphosphine (0.128 mg; 0.11 mmol) and diisopropylethylamine (0.368 mL; 2.22 mmol). The solution was stirred for 20 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with a 1N hydrochloric acid solution, a 1N sodium hydrogenocarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1-40%) in dichloromethane furnished 0.264 g (90%) of methyl 2-(2-methyl-4-p-tolylpyrimido[1,2-b]indazol-3-yl)pentanoate as an oil. ESI/APCI(+): 388 (M+H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:38][CH2:37][C:12]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:34][CH2:33][CH2:32][C@H:31]5[CH3:35])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[F:36])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:36][C:19]1[CH:20]=[C:21]([CH:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH3:35])[CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:14][CH2:13][C:12]2([CH2:11][CH2:10][NH:9][CH2:38][CH2:37]2)[C:16]1=[O:17]
Reactant: C[C@@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCNCC4)C3=O)c(F)c2)CC1

Procedure:
The title compound was prepared in the same manner as Example 17 by using hydrochloric acid in dioxane to hydrolyze 2-{2-fluoro-4-[4-((R)-2-methyl-pyrrolidin-1-yl)-cyclohexyl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[CH:27][C:28]([N+:40]([O-:42])=[O:41])=[C:29]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:30]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:13][C:12]([O:19][C:25]2[CH:26]=[CH:27][C:28]([N+:40]([O-:42])=[O:41])=[C:29]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH:30]=2)=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C(C)(C)C)cc1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(OCc3ccccc3)cc2C(C)(C)C)ccc1[N+](=O)[O-]
Yield: 103.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-benzyloxy-2,5-di-t-butylphenol (4.3 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (3.51 g), sodium hydride (55 wt. %, 0.72 g) and anhydrous N,N-dimethylformamide (15 ml) and the reaction mixture was purified to give the title compound (7.1 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25]>>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH2:18][N:12]([C:4]2[CH:3]=[C:2]([NH:25][CH2:24][CH2:23][NH2:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:13][CH2:14]1
Reactant: Clc1cc(N2CCOc3ccccc3C2)nc2ccccc12
Reactant: NCCN
Product: NCCNc1cc(N2CCOc3ccccc3C2)nc2ccccc12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The mixture of 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) and 1.6 mL of ethane-1,2-diamine was heated with stirring in a 5 mL microwave process vial for 3 hours at 150° C. under microwave irradiation. The mixture was concentrate in vacuo to give a residue which was purified by preparative HPLC to give 31 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 335. 1H NMR (400 MHz, CD3OD) δ ppm 8.61 (s, 1 H), 7.90 (d, J=7.6 Hz, 1 H), 7.60-7.51 (m, 3 H), 7.23 (brs, 2 H), 7.09-6.98 (m, 2 H), 6.05 (s, 1 H), 4.89 (s, 2 H), 4.27 (s, 2 H), 4.25 (s, 2 H), 3.61 (s, 2 H), 3.15 (s, 2 H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)[C:20]([NH:22][CH2:23][CH:24]2[CH2:29][CH:28]3[CH2:30][CH:25]2[CH:26]=[CH:27]3)=[O:21])C=CC=CC=1.CN(C)C=O.[H-].[Na+]>CCOCC>[CH:28]12[CH2:30][CH:25]([CH:24]([CH2:23][NH:22][C:20]([NH:12][S:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])=[O:21])[CH2:29]1)[CH:26]=[CH:27]2
Reactant: O=C(NCC1CC2C=CC1C2)N(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(NCC1CC2C=CC1C2)NS(=O)(=O)C=Cc1ccccc1

Procedure:
To a solution of 1.8 g. of 2-phenylethenesulfonamide and 4.8 g. of 1,1-diphenyl-3-(bicyclo[2.2.1]hept-2-en-5-ylmethyl)urea in 20 ml. of N,N-dimethylformamide, is added, with stirring 0.64 g. of a 56.6% dispersion of sodium hydride in mineral oil. The mixture is stirred at ambient temperature overnight, during which time a heavy precipitate forms. To the reaction mixture is then added 200 ml. of ether. After stirring for 15 minutes, the precipitate is filtered off. It is dissolved in 50 ml. of water, and then the crude product is precipitated by acidification usng concentrated hydrochloric acid. It is filtered off and recrystallized from aqueous acetone. The yield is 1.9 g. (56%) of a solid, m.p. 161°-163.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:11])[CH3:10].[Br:12]N1C(=O)CCC1=O>C(#N)C>[CH:9]([C:4]1[CH:5]=[C:6]([Br:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:11])[CH3:10]
Reactant: COc1ccccc1C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)cc1C(C)C
Yield: 82 %

Procedure:
A solution of 2-methoxyisopropyl-benzene (2 g) and N-bromosuccinimide (2.6 g) in acetonitrile (20 mL) was stirred at ambient temperature for 18 h. The reaction was concentrated in vacuo, slurried in carbon tetrachloride and filtered. The filtrate was concentrated in vacuo. The residue was flash chromatographed (5% dichloromethane/hexanes) to afford the title compound as an oil (2.5 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC1CCCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., a solution of 25.0 g (215 mmol) of tetrahydro-2H-pyran-2-ylmethanol (racemate) in 500 ml of THF was slowly added dropwise to a suspension of 9.47 g (237 mmol, 60% in mineral oil) of sodium hydride in 500 ml of THF, and after the addition had ended, the mixture was stirred at 0° C. for another 30 min 25.7 ml (215 mmol) of benzyl bromide were then added, and the mixture was stirred at 0° C. for another 30 min and at room temperature for another 1 h. The reaction was terminated by addition of 200 ml of saturated aqueous ammonium chloride solution, and the phases were separated. The aqueous phase was extracted twice with 200 ml of methyl tert-butyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 340 g silica cartridge, flow rate 100 ml/min), giving the title compound. Yield: 41.9 g (94% of theory)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+].OOS([O-])=O.[K+]>O1CCOCC1.CCOC(C)=O.O.S(=O)(=O)(O)[O-].[Na+]>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([OH:14])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Clc1nccc2ccc(Br)cc12
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: O=S([O-])OO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc2ccnc(Cl)c2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
7-Bromo-1-chloroisoquinoline (2.0 g, 8.25 mmol), bis(pinacolato)diboron (2.20 g, 8.66 mmol), potassium acetate (2.43 g, 24.7 mmol) and PdCl2(dppf)DCM adduct (0.337 g, 0.412 mmol) were combined under nitrogen in dioxane (40 mL) and heated in an oil bath at 100° C. for 24 h. The reaction mixture was cooled, diluted with EtOAc (100 mL) and washed with 10% aqueous KHSO4. The organic phase was dried over Na2SO4, filtered and concentrated to an oil. The oil was dissolved in acetone (100 mL) and a solution of OXONE (5.07 g, 8.25 mmol) in water (20 mL) added over 2 min. The reaction mixture was stirred for 10 min, diluted with aqueous sodium bisulfate solution and stirred for an additional 20 min. and then concentrated to remove acetone. The resulting mixture was filtered to give the title compound (1.4 g) which was used without further purification. LRMS (M+H)+=180.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Si:33]([O:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[N:7][CH:6]=1)[CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Br)nc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 1-(6-bromopyridin-3-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethanol (1.58 g) and 2,6-lutidine (0.83 mL) in dichloromethane (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.31 mL) was added dropwise, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.79 g, yield 84%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:19, volume ratio).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.Br.[CH2:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH2:10][CH3:11].[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>C(#N)C>[Cl:18][CH:19]([Cl:23])[C:20]([N:15]1[CH2:16][CH2:17][N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]1)=[O:21]
Reactant: CCCN1CCNCC1
Reactant: O=C(Cl)C(Cl)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(C(=O)C(Cl)Cl)CC1
Yield: 96.2 %

Procedure:
21 g (0.15 mol) of potassium carbonate were added in portions to a suspension of 14.5 g (0.05 mol) of 1-n-propyl-piperazine dihydrobromide in 200 ml of acetonitrile. 7.4 g (0.05 mol) of dichloroacetyl chloride were added dropwise to this mixture at room temperature, while stirring. The mixture was subsequently stirred at 20° C. for 5 hours and working up was then effected by a procedure in which the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from a mixture of toluene and petroleum ether. 11.5 g (96% of theory) of 1-dichloroacetyl-4-n-propyl-piperazine were obtained in the form of beige-colored crystals of melting point 88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21])=[CH:6][CH:7]=1
Reactant: Fc1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=S(CCCCl)c1ccc(F)cc1

Procedure:
Prepared by Procedure S and Scheme AA using 3-chloropropyl 4-fluorophenyl sulfide and 1 eq m-CPBA: 1H NMR (400 MHz, CDCl3) δ 7.65–7.62 (m, 2H), 7.28–7.21 (m, 2H), 3.65 (m, 2H), 2.94 (m, 2H), 2.28 (m, 1H), 2.06 (m, 1H); ESMS m/e: 220.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=S)[CH:14]([CH3:16])[CH3:15]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:18]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CC(C)CN=C=S
Solvent: CCOC(C)=O
Product: CC(C)CNC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 150 °C
Yield: 41.7 %

Procedure:
A mixture of 2-amino-4-chlorobenzenesulfonamide (5.0 g, 24.18 mmol) and isobutyl isothiocyanate (10 ml, 83.6 mmol) was heated at 150° C. for 3 h. The mixture was allowed to cool and then stirred with 50 ml of ethyl acetate for 30 min. The precipitate was isolated by filtration and recrystallised from ethanol to give 2.9 g (42%) of the pure title compound; m.p. 298-301° C.; 1H-NMR (DMSO-d6): δ 0.91 (d, 6H, CH(CH3)2), 1.83 (m, 1H, CH(CH3)2), 3.05 (t, 2H, CH2), 7.2-7.4 (m, 3H, ArH+NH), 7.67 (d, 1H, ArH), 10.5 (br.s, 1H, NH); MS: m/e 287/289 (M+); (C11H14N3Cl1O2S1) calc. C, 45.91; H, 4.90; N, 14.60; found C, 45.90; H, 5.04; N, 14.66.