Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][OH:22]>>[CH2:2]([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([O:22][CH3:21])=[CH:16][N:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1cnc(C2CCN(Cc3ccccc3)C2)nc1
Reactant: CO
Agent: [Na]
Product: COc1cnc(C2CCN(Cc3ccccc3)C2)nc1
Temperature: 110 °C
Yield: 27.2 %

Procedure:
Sodium (362 mg, 15.75 mmol) was added portionwise to methanol (15 mL) at 22° C. until a homogeneous solution was obtained. The solution was then treated with 2-(1-benzyl-pyrrolidin-3-yl)-5-bromo-pyrimidine (1 g, 3.15 mmol) and heated in a sealed tube at 110° C. for 24 h. The mixture was cooled, concentrated in vacuo. The residue was purified by column chromatography to afford 2-(1-benzylpyrrolidin-3-yl)-5-methoxypyrimidine (230 mg 27.2%) as a yellow oil.
Reaction SMILES: NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(C3C=NC(N)=NC=3)C=12.[C:37]([N:40]1[CH2:45][CH:44]=[C:43]([C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49](=[O:56])[O:48][C:47]=2[CH:57]([N:59]2[C:63]3=[N:64][CH:65]=[N:66][C:67]([NH2:68])=[C:62]3[C:61](I)=[N:60]2)[CH3:58])[CH2:42][CH2:41]1)(=[O:39])[CH3:38].[F:70][C:71]1[CH:72]=[C:73](B(O)O)[CH:74]=[C:75]([OH:77])[CH:76]=1>>[C:37]([N:40]1[CH2:45][CH:44]=[C:43]([C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49](=[O:56])[O:48][C:47]=2[CH:57]([N:59]2[C:63]3=[N:64][CH:65]=[N:66][C:67]([NH2:68])=[C:62]3[C:61]([C:73]3[CH:74]=[C:75]([OH:77])[CH:76]=[C:71]([F:70])[CH:72]=3)=[N:60]2)[CH3:58])[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: CC(=O)N1CC=C(c2c(C(C)n3nc(I)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)nc2)c2c(N)ncnc21
Product: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(O)cc(F)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Yield: 43.5 %

Procedure:
The title compound was mane in a similar way as that or the compound of example 51 from 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one (Intermediate D12, 1.08 g, 1.941 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (0.605 g, 3.88 mmol), to give the title compound (456 mg, 43.5%) as a pale grey solid.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.[F:10][C:11]1[CH:12]=[C:13]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[C:23]2[CH:24]=[C:25]([C:40](O)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH:14]=[C:15]([F:17])[CH:16]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.CNC>CN(C=O)C>[F:17][C:15]1[CH:14]=[C:13]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[C:23]2[CH:24]=[C:25]([C:40]([N:3]([CH3:4])[CH3:2])=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH:12]=[C:11]([F:10])[CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
DIPEA (0.046 mL, 0.26 mmol) was added to a suspension of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (60 mg, 0.13 mmol) in DMF (1 mL) followed by TSTU (43.5 mg, 0.14 mmol) at room temperature under nitrogen and stirred overnight. Dimethylamine (2N in THF) (0.131 mL, 0.26 mmol) was then added and the mixture was stirred for another hour. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was taken up in a minimum of DCM, diluted with petroleum ether, stirred for 3 h, collected by filtration and dried to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (43 mg, 68%) as a white solid.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.F[C:16]1[N:21]=[C:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[O:33][CH3:34])[N:23]=2)[CH:19]=[CH:18][CH:17]=1.CN(C)C(N(C)C)=N>CS(C)=O.O>[CH3:34][O:33][C:28]1[CH:27]=[C:26]([O:35][CH3:36])[CH:25]=[C:24]2[C:29]=1[C:30](=[O:32])[NH:31][C:22]([C:20]1[N:21]=[C:16]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]3)[CH:17]=[CH:18][CH:19]=1)=[N:23]2
Reactant: COC(=O)CCN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 85 °C
Yield: 66.5 %

Procedure:
To a stirred suspension of methyl 3-(piperazin-1-yl)propanoate dihydrochloride (0.358 g, 1.46 mmol) and 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.220 g, 0.73 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.336 g, 2.92 mmol). The resulting mixture was heated at 85° C. for 5 h. After that time the reaction was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give methyl 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoate (0.220 g, 66%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.85 (d, J=7.42 Hz, 1H), 7.62-7.70 (m, 1H), 6.79-6.85 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H), 3.59-3.67 (m, 4H), 2.75-2.83 (m, 2H), 2.54-2.66 (m, 6H); ESI MS m/z 454 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3](/[CH:10]=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:2]1.[C:21]([O-])(=[O:23])[CH3:22].[K+]>C(OC(=O)C)(=O)C>[C:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3](/[CH:10]=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:2]1)(=[O:23])[CH3:22]
Reactant: O=C1Nc2ccccc2/C1=C/c1c[nH]c2ncccc12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1cc(/C=C2\C(=O)Nc3ccccc32)c2cccnc21
Yield: 65 %

Procedure:
A mixture of (Z)-3-[(7-azaindol-3-yl)methylen]-2-oxindole (2.61 g, 0.010 mol), potassium acetate (0.98 g, 0.010 mol) and acetic anhydride (10 ml) is heated at reflux temperature for 15 h and then concentrated under vacuum. The residue is taken up with ethyl acetate and water, the organic phase separated, washed with water, dried over Na2SO4 and evaporated under vacuum. The residue is crystallized from ethanol to give pure title compound in 65% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCN(C)CC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.30 g, 0.44 mmole) in DMSO (2 mL) was added 1-methylpiperazine (0.903 g, 1.00 mL, 9.02 mmole) and the reaction was stirred at 85° C. for 3 h. The mixture was poured onto ice-water (100 mL) and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2 CH3OH—with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which was taken on to the next step. HPLC retention time 6.00 mins.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:18])[CH:12]3[CH:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:18])[CH:12]3[CH:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:43])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S(=O)c3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.6 %

Procedure:
To a solution of 200 mg of 3-phenylthio-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 15 mL of methylene chloride at -50° under nitrogen was added 90 mg of m-chloroperbenzoic acid in 3 mL of methylene chloride. The solution was stirred at -40° for 45 min and then warmed to room temperature over a 45 min period. The mixture was partitioned between methylene chloride and aqueous sodium sulfite. The organic layer was washed twice with bicarbonate, then brine, then dried over sodium sulfate and evaporated to dryness. The crude reaction product was purified by preparative thin layer chromatography two 20×20×0.2 cm silica gel plates, eluting with 5% methanol in methylene chloride, to afford 144 mg (69.6%) of 3-phenylsulfinyl-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]-hept-2-en-2-carboxylic acid, diphenylmethyl ester, a diastereomeric mixture, as a colorless glass. IR (Nujol mull): 1780, 1710, 1600, 3400 cm-1 ; NMR (220 MHz; CDCl3 indicative of a 3:1 mixture of diastereoisomers at sulfur): δ 1.15 (3H, d, J=6.5, major isomer), 1.30 (3H, d, J=6.5, minor isomer), 2.3-3.0 (3H, m), 3.3-3.6(1H, m), 3.93 (1H, m, major isomer), 4.02 (1H, m, minor isomer), 4.52 (1H, m, minor isomer), 4.68 (1H, m, major isomer), 6.95 (1H, s), and 7.2-7.7 (15H, m). ##STR25##
Reaction SMILES: ClC1C(C(OCC)=O)=[N:4]N2C=1CCOC1C=CC(I)=CC2=1.C([C@]1(O)CCN(C)C1=O)#C.[Cl:32][C:33]1[C:34]([C:57]([O:59]CC)=O)=[N:35][N:36]2[C:42]=1[CH2:41][CH2:40][O:39][C:38]1[CH:43]=[CH:44][C:45]([C:47]#[C:48][C@:49]3([OH:56])[CH2:53][CH2:52][N:51]([CH3:54])[C:50]3=[O:55])=[CH:46][C:37]2=1>>[Cl:32][C:33]1[C:34]([C:57]([NH2:4])=[O:59])=[N:35][N:36]2[C:42]=1[CH2:41][CH2:40][O:39][C:38]1[CH:43]=[CH:44][C:45]([C:47]#[C:48][C@:49]3([OH:56])[CH2:53][CH2:52][N:51]([CH3:54])[C:50]3=[O:55])=[CH:46][C:37]2=1
Reactant: CCOC(=O)c1nn2c(c1Cl)CCOc1ccc(I)cc1-2
Reactant: CCOC(=O)c1nn2c(c1Cl)CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)c(Cl)c2CCO3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic ethyl 3-chloro-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of (R)-ethyl 3-chloro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) the titled compound was obtained after purification by prep HPLC.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][CH3:19])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>ClCCl>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine dihydrochloride salt (2.0 g, 6.09 mmol) in dichloromethane (50 mL). Add triethylamine (3.39 mL, 24.4 mmol), and benzenesulfonylchloride (854 μL, 6.69 mmol). Stir at ambient temperature for 18 hr. Add dichloromethane and aqueous 1 N HCl solution. Separate the organic layer and extract the aqueous layer twice with dichloromethane. Combine the organic layers and dry (magnesium sulfate), filter, and concentrate. Purify via SCX chromatography, followed by silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate) to give the title preparation (1.88 g, 78%). MS (ES): m/z=396 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCCC1[O:43][CH2:44][CH2:45][OH:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][CH:8]=2)[O:43][CH2:44][CH2:45][OH:46])[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of Intermediate 95a (1.2 g, 5.2 mmol) and triphenyl phosphine (2.72 g, 10.4 mmol) in THF (30 mL), under an atmosphere of argon was treated with 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.05 mL, 7.78 mmol), followed by the dropwise addition of diisopropylazodicarboxylate (1.64 mL, 10.4 mmol). The reaction mixture was then stirred at RT for 1 h. The reaction mixture was eluted on a SCX-2 cartridge using MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure and the product was purified by FCC, using EtOAc/DCM 0-60% to afford the title compound as a brown gum (1.0 g, 80%). LCMS (Method 3): Rt 2.27 min, m/z 276 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]2.NC1C=CC2C(=CC=C(CN3CCNCC3=O)C=2)N=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[S:45][C:44]=2[CH:52]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46]([S:48]([N:6]3[CH2:5][CH2:4][N:3]([CH2:8][C:9]4[CH:10]=[C:11]5[C:16](=[CH:17][CH:18]=4)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]5)[C:2](=[O:1])[CH2:7]3)(=[O:50])=[O:49])[S:45][C:44]=2[CH:52]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: O=C1CNCCN1Cc1ccc2[nH]c(=O)ccc2c1
Agent: Nc1ccc2cc(CN3CCNCC3=O)ccc2n1
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2[nH]c(=O)ccc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 101,using 6-(2-oxopiperazin-1-ylmethyl)-1H-quinolin-2-one, minor product from EXAMPLE 67, Part D, and 6-chlorobenzo[b]thiophene-2-sulfonyl chloride, EXAMPLE 1. The crude product is triturated in CH2Cl2 and filtered to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ11.72 (bs, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.07 (d, 1H), 7.78 (d, 1H), 7.58 (dd, 1H), 7.45 (s, 1H), 7.30 (dd, 1H), 7.18 (d, 1H), 6.46 (d, 1H), 4.52 (s, 2H), 3.86 (s, 2H), 3.43 (m, 2H), 3.31 (m, 2H). MS (ion spray) m/z 488, 490, (M+H), Cl pattern.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]1([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC1CCCC1
Yield: 46.8 %

Procedure:
2-Nitrophenol (83.5 g, 0.60 mole), cyclopentyl bromide (98.0 g, 0.66 mole), anhydrous potassium carbonate (82.9 g, 0.60 mole) and dry acetone (600 cc) were refluxed for 72 hrs., and filtered to remove the potassium bromide. The residue was washed with acetone and the solvent was removed by rotary evaporation. The residue was partitioned between 200 cc of dichloromethane and water. The dichloromethane layer was washed with 200 cc of 10% potassium hydroxide, separated and the solvent was removed by rotary evaporation. The crude product was fractionally distilled at 144°-146° C. at 1.0 mm. Hg to yield 58.2 g of product (46.8%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.CN(C)[CH:24]=[O:25]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]([F:21])[C:15]=1[CH:24]=[O:25]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Br)cc1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame-dried 250 mL round-bottomed flask equipped with an addition funnel and magnetic stirrer, a mixture of diisopropylamine (4.82 mL, 34.66 mmol) in 100 mL of anhydrous THF was cooled to −78° C. and treated with 2.5N n-butyllithium (13.86 mL, 34.66 mmol) in THF, dropwise. After stirring for 10 minutes a mixture of 3,5-dibromo-1-fluorobenzene (8.0 g, 31.51 mmol) in 16 mL of THF was added dropwise and stirring was continued for an additional 30 minutes. At this point, N,N-dimethylformamide (DMF) (2.68 mL, 34.66 mmol) was added dropwise and stirring continued another 10 minutes at −78° C. The reaction was quenched with saturated aqueous ammonium chloride and the solvent removed on a rotary evaporator. The residue was dissolved in ether, washed with saturated brine and dried over calcium sulfate, filtered and concentrated to an oil, 7.36 g. Purification by flash chromatography using ethyl acetate-hexanes (1:99) gave the title product as a white solid.
Reaction SMILES: Cl.[Cl:2]C1C=C(C(C2(O)CCN(C)CC2)CN2CCNCC2)C=CC=1Cl.[CH2:26]([NH:33][C:34](=O)[CH:35]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)[C:36]1([OH:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[ClH:2].[CH2:26]([NH:33][CH2:34][CH:35]([C:36]1([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccccc1)C(c1ccc(Cl)c(Cl)c1)C1(O)CCCCC1
Reactant: CN1CCC(O)(C(CN2CCNCC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Product: OC1(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2 4-[1-(3,4-dichlorophenyl)-2-piperazin-1-ylethyl]-1-methylpiperidin-4-ol hydrochloride was prepared from N-benzyl-2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. HRMS: calcd for C21H25Cl2NO.HCl, 413.1080; found (ESI_FT), 378.13864.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19]O.Cl>N1C=CC=CC=1>[C:2]1([C:1]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:12])[O:13][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=c1onc(-c2ccccc2)c2ccccc12

Procedure:
A mixture of o-benzoyl benzoic acid (0.01 mol) and hydroxylamine hydrochloride (0.01 mol) is refluxed in pyridine (40 ml) for 3 hours, is cooled, and is poured over ice-cold dilute-HCl. The separated solid is filtered off, is dried and is crystallized from ethanol to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 83.3 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.027 g, 0.12 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 6 (0.051 g, 0.10 mmol, 81%) as a white solid. LCMS m/z (%)=503 (M+H79Br35Cl, 78), 505 (M+H81Br35Cl, 100), 507 (M+H81Br37Cl, 28). 1H NMR (400 MHz, acetone-d6) δ: 8.52 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.14 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[SH:16]>>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[S:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1S
Reactant: Ic1ccccc1
Product: Cc1cccc(C)c1Sc1ccccc1

Procedure:
The general procedure was used to convert iodobenzene and 2,6-dimethylthiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (409 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.1–6.98 (m, 5H; Hc, Hc, Hd, Hd′, He), 6.93–6.86 (m, 1H; Hb), 6.77 (d, J=7.16, 2H; Ha, Ha′) 2.34 (s, 6H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 143.86 (C2, C6), 137.98 (C9), 130.43 (C1), 129.22 (C4), 128.86 (C10, C14), 128.40 (C1, C13), 125.59 (C3, C5), 124.57 (C12), 21.82 (C7, C8). Anal. Calcd. for C14H14S: C, 78.45; H, 6.58; S, 14.96; Found C, 78.58; H, 6.71; S, 14.98.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:12])=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].OC1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([CH3:22])[C:16]([CH3:24])([CH3:23])[CH2:15]1>>[CH3:1][C:2]1[O:3][C:4]([CH3:12])=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH:10]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([CH3:22])[C:16]([CH3:24])([CH3:23])[CH2:15]1)=[O:8]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)c1c(C)oc(C)c1C
Product: Cc1oc(C)c(C(=O)OC2CC(C)(C)N(C)C(C)(C)C2)c1C

Procedure:
If methyl 2,4,5-trimethylfuran-3-carboxylate and 4-hydroxy-1,2,2,6,6-pentamethylpiperidine are reacted by the method given in Example 1, the product obtained is a virtually colorless oil of boiling point 138°-140° C./0.4 mm; this solidifies to a solid of melting point 55°-56° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.OO.S(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Fc1cccnc1Cl
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: [O-][n+]1cccc(F)c1Cl
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloro-3-fluoropyridine (11.8 g, 0.10 mol) and 11.4 ml of 30% hydrogen peroxide in acetic acid, 70 ml, is stirred at 75° C. for 4 hours. Additional 30% hydrogen peroxide, three 5 ml portions, is added over 24 hours followed by 3 ml of a saturated sodium bisulfite solution. The reaction mixture is concentrated to approximately 25 ml under reduced pressure at 55°-60° C., diluted with water, 30 ml, and made basic with potassium carbonate. The crude N-oxide is extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography over silica gel and elution with 2% MeOH- 98% CHCl3 (v/v) mixture gives 2-chloro-3-fluoropyridine N-oxide as a liquid.