Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(S(N)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of benzenesulfonamide-4-boronic acid pinacol ester (23 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA14 (2.2 mg, 10% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.1.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26][C:27]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:28][C:27]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])([C:29]1[CH:30]=[CH:31][C:32]([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:33][CH:34]=1)[CH3:26]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {1-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (93 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (0-50% ethyl acetate in hexanes) gave the product (56 mg, 80%). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.09-8.00 (m, 1H), 7.95 (dd, 1H, J=7.8, 1.4 Hz), 7.55-7.48 (m, 2H), 7.38-7.32 (m, 3H), 7.31-7.19 (m, 5H), 7.17-7.07 (m, 3H), 6.91-6.77 (m, 1H), 6.70-6.59 (m, 1H), 1.50 (br s, 6H), 1.41-1.05 (m, 9H). LCMS: 544 [M+H].
Reaction SMILES: [CH2:1]([C@H:8]1[C:12](=[O:13])[O:11][C@@H:10]([CH2:14][S:15]C(=O)C)[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[BH4-].[Na+].[C:21](O)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:1]([C@@H:8]1[CH2:9][C@H:10]([CH2:14][S:15][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:11][C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCC[C@@H]1C[C@H](CSC(C)=O)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC[C@@H]1C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the product of Example 13 in 100 mL of methanol, cooled to 0° C., was added 2.69 g (0.071 mol) of solid sodium borohydride in portions over 15 minutes. The reaction was then concentrated in vacuo, acidified with 10% HCl solution and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude thiol was dissolved in 50 mL of trifluoroacetic acid and 5.98 g (0.023 mol) of trityl alcohol was added. After stirring at room temperature for 1 h the reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:50) to provide 5.26 g (61%) of the desired product as a colorless oil. CI Mass Spec: 473.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@H:10]([O:12]C1CCCCO1)[CH3:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@H:10]([OH:12])[CH3:11]
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C(=O)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
In ethanol (3 ml) was dissolved (2R)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (121 mg), to which was added pyridinium p-toluenesulfonate (25 mg), and the mixture was stirred for one hour at 55° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). The solution was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=5:1) to give (2R)-2',4'-difluoro-2-hydroxypropiophenone (62 mg) as a pale yellow oily product. [α]D +68.7 (c=1.8 in chloroform)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:33]1[C@@H:38]2[CH2:39][CH2:40][CH2:41][N:37]2[CH2:36][C@H:35]([CH2:42]O)[O:34]1>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:42][C@@H:35]4[O:34][CH2:33][C@@H:38]5[CH2:39][CH2:40][CH2:41][N:37]5[CH2:36]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: OC[C@H]1CN2CCC[C@H]2CO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CN2CCC[C@H]2CO1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6) and [(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][CH2:31][OH:32])=[CH:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>CN(C)C(=O)C>[S:34](=[O:36])(=[O:35])([O:32][CH2:31][CH2:30][C:28]1[CH:27]=[CH:26][C:25]2[C:18]3[C:17]([NH:16][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)=[C:2]([Cl:1])[CH:3]=4)=[N:22][CH:21]=[N:20][C:19]=3[S:23][C:24]=2[CH:29]=1)[NH2:37]
Reactant: NS(=O)(=O)Cl
Reactant: OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To a solution of 2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}[1]benzothieno[2,3-d]pyrimidin-7-yl)ethanol (35 mg, 0.08 mmol, 1 equiv) in N,N-Dimethylacetamide (2 mL) was added chlorosulfonamide (87 mg, 0.76 mmol, 10 equiv) under nitrogen. The reaction mixture was stirred at rt for 15 h. The solvent was concentrated in vacuo. The crude material was separated by pre-HPLC to give a white solid (18.6 mg, 43%) as product. 1H-NMR (DMSO-d6) δ 9.0 (broad s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.54 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.03 (s, 1H), 7.88 (t, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.54 (m, 2H), 7.37 (t, 1H), 7.26 (d, J=8.7 Hz, 1H), 5.32 (s, 2H), 4.36 (t, 2H), 3.19 (t, 2H); LCMS RT=3.08 min, [M+H]+=542.10
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>C1COCC1>[I:46][CH2:20][CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:3]2[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:15]1
Reactant: II
Reactant: COc1cc(N2CCC(CCO)CC2)c(C)cc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N2CCC(CCI)CC2)c(C)cc1[N+](=O)[O-]
Yield: 90.1 %

Procedure:
To 2-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}ethanol (32.6 g, 111 mmol), triphenylphosphine (32.0 g, 122 mmol), and imidazole (8.29 g, 122 mmol) in THF (554 mL) was added iodine (30.9 g, 122 mmol) in one portion, slowly due to observable exotherm. The reaction mixture was filtered through Celite® and washed with DCM. Purification by flash chromatography provided the crude title compound which was washed with saturated Na2SO3 to remove any residual iodine. The aqueous layer was back extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and rotovapped down to give the title compound of step G (40.6 g, 100 mmol, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=0.5 Hz, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.33 (t, J=7.5 Hz, 2H), 3.26 (d, J=12.4 Hz, 2H), 2.63-2.74 (m, 2H), 2.17 (s, 3H), 1.78 (q, J=7.1 Hz, 4H), 1.46-1.61 (m, J=7.2, 7.2, 7.1, 3.8 Hz, 1H), 1.30 (qd, J=12.0, 3.6 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C2(c3cccc([N+](=O)[O-])c3)CC12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C23CC2C(=O)NC3=O)c1

Procedure:
Following the procedure of Example 1, 600 mg of 1-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione are dissolved in 30 ml of ethanol and reduction is carried out with hydrogen in the presence of 60 mg of 5% palladium/carbon. When the hydrogenation is complete, the mixture is diluted with ethanol and the catalyst is removed by filtration over HYFLO-Super-Cel®. The solvent is stripped off in vacuo and the residue is recrystallised from a mixture of ethyl acetate/petroleum ether, affording the title compound in the form of pale pink crystals with m.p. 135°-137° C. and an Rf value of 0.47 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1), or 0.52 in methylene chloride/methanol/glacial acetic acid (40:5:1).
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH2:16])=[O:15]>C(OCC)(=O)C>[CH3:6][O:5][C:3]([C:2]1[O:15][C:14]([C:13]2[CH:12]=[C:11]([CH3:10])[CH:19]=[CH:18][CH:17]=2)=[N:16][C:7]=1[CH3:9])=[O:4]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: Cc1cccc(C(N)=O)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1oc(-c2cccc(C)c2)nc1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
Heat to 120° C. a neat mixture of methyl 2-chloroacetoacetate (914 mL, 7.5 mmol) and 3-methyl-benzamide (676 mg, 5 mmol) and stir at this temperature for 12 hrs. Cool the reaction mixture to room temperature and dilute it with ethyl acetate, wash with saturated sodium bicarbonate solution (3 times), water (twice) and brine, Dry the organic extract over MgSO4 and concentrate. Purify the resulting residue by flash chromatography (elute with 10% ethyl acetate in heptane) to give the title compound as a yellow oil (492 mg).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([CH:18]=[CH:19][CH:20]=2)[N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:15]=1.[Cl:21]N1C(=O)CCC1=O>O1CCCC1>[ClH:21].[Cl:1][C:18]1[N:11]2[N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:15]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[C:10]2=[CH:20][CH:19]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cccn21
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CN1C(=O)CN=C(c2ccccc2F)c2ccc(Cl)n21
Yield: 55.7 %

Procedure:
A solution containing 5-(2-fluorophenyl)-1-methyl-1H-pyrrolo[1,2-b][1,2,5]triazepin-2(3H)-one hydrochloride (3.3 g, 12.9 mmol) and N-chlorosuccinimide (1.87 g, 14 mmol) in 100 ml of dry tetrahydrofuran was refluxed under N2 for 3 hours. The resultant solution was evaporated and the residual oil was taken up in 200 ml of EtOAc, washed with H2O, dried (MgSO4), filtered, and evaporated to an oil. This oil was purified by flash chromatography (silica, 4:7 hexane-ether) to given an oil (2.1 g). This oil was treated with ethereal HCl and the resultant solid was recrystallized from isopropanol-ether to give 2.36 g (55%) of powder, m.p. 218° dec.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[C:28]1[S:29][CH:30]=[CH:31][N:32]=1.CS(C)=O>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2]
Reactant: Brc1nccs1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (350 mg, 1.2 mmol), potassium carbonate (363 mg, 2.63 mmol), 2-bromothiazole (431 mg, 2.63 mmol), and dimethyl sulfoxide (10 mL) was heated at 135° C. overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C.O1CCOCC1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Temperature: 60 °C

Procedure:
12.6 g of 4'-chloro-3'-chlorosulfonylacetophenone were introduced, while stirring, in a mixture of 5.6 g of aniline, 7.5 g of triethyl amine and 100 ml of dioxane. The mixture was allowed to dwell over night at 20° C., it was heated to 60° C. during 30 minutes while stirring and the separated triethylamine-hydrochloride was separated. The filtrate was concentrated under reduced pressure and the residue was crystallized under water. Colorless crystals (from isopropanol/active charcoal), melting point: 142° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[N:16]=2)=[CH:11][CH:10]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[F:23][C:20]([F:21])([F:22])[C:17]1[N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([NH2:6])=[CH:14][CH:13]=2)[NH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
8.9 g (39.7 mmol, 4 eq.) of tin(II) chloride dihydrate were added to a solution of 2.7 g (9.9 mmol) of 5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole in 110 ml of ethanol, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was poured into ice-water, and sodium bicarbonate was added carefully until a pH of 8 had been reached. The mixture was filtered through a filter layer and the residue was washed with ethyl acetate. After phase separation, the aqueous phase was washed twice with ethyl acetate. The combined organic phases were washed with aqueous sodium chloride solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. Yield: 1.9 g (79% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[Br:14]Br>C(Cl)Cl>[Br:14][C:8]1[C:7]([O:12][CH3:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc2nc(Cl)ccc2c1Br
Reaction time: 14 h
Yield: 101.7 %

Procedure:
A solution of 2-chloro-6-methoxyquinoline (4.4 g, 22 mmol) in CH2Cl2 (60 mL) was treated by slow addition of Br2 (3.5 mL, 11 g, 68 mmol). After 14 hours, the mixture was partitioned between NaCl and CH2Cl2. The aqueous layer was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 6.1 g (99%) of 5-bromo-2-chloro-6-methoxyquinoline as a light yellow solid, (M+) 273(100).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([OH:17])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15]O)[CH2:5][CH2:4]1)[CH3:2]>C(O)=O>[CH2:1]([N:3]1[CH2:4][CH2:5][C:6]2([C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:15][O:17]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(O)(c2ccccc2CO)CC1
Solvent: O=CO
Product: CCN1CCC2(CC1)OCc1ccccc12

Procedure:
Treatment of 1-ethyl-4-hydroxy-4-(α-hydroxy2-tolyl)piperidine with formic acid by the method described in Example 17c provides 1,3-dihydro-1'-ethylspiro[isobenzofuran-1,4'-piperidine] as an oil.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:14][C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C>>[Cl:14][C:15]1[C:16]([N:21]2[CH2:22][CH2:23][N:24]([C:2]3[NH:6][C:5]4[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=4[N:3]=3)[CH2:25][CH2:26]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2cc1Cl

Procedure:
The 2,5,6-trichloro-1H-benzoimidazole (0.110 g, 0.5 mmol, Example 25b), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (0.234 g, 1 mmol, Example 3b) and N,N-diisopropylethylamine (0.35 mL, 2 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:14]([CH2:13][CH2:12][CH2:11][Cl:10])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)NS(=O)(=O)CCCCl
Temperature: 120 °C
Yield: 72.5 %

Procedure:
A glass reactor equipped with a stirrer, reflux condenser and gas inlet was charged with hexamethyldisilazane (0.4235 mol, 91.2 ml) and 3-chloropropanesulfonyl chloride (0.4193 mol, 75.0 g). The contents of the reactor were heated. A refluxing liquid was first observed at a temperature of 85°-95° C., and the mixture became clear. The mixture became cloudy at a temperature of about 105 degrees. The temperature of the mixture was maintained at 120° C. for 90 minutes and at 145°-150° C. for 15 minutes. The mixture was then allowed to cool to room temperature, at which time it was filtered, the solids were washed with benzene, and the washing liquid combined with the liquid portion of the mixture. The combined liquids were then heated at 60°-65° C. under reduced pressure to remove volatile materials and then distilled. The fraction boiling from 127°-129° C. under a pressure of from 0.04-0.07 mm. Hg was collected, and was equivalent to a 72.5% yield based on initial reactants. The 1H NMR spectrum was consistent with the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[NH:35][CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][N:44]=[C:45]=[S:46])[CH2:38][CH2:37]2)=[CH:21][CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:45]([NH:44][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][CH:36]([NH:35][C:27]3[N:26]([CH2:25][C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=3)[CH2:37][CH2:38]2)=[S:46])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: Nc1ccccc1NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)Nc4ccccc4NCc4ccc(Cl)c(Cl)c4)CC3)nc3ccccc32)cc1
Yield: 78.9 %

Procedure:
A mixture of 20 parts of N-[(3,4-dichlorophenyl)methyl]-1,2-benzenediamine, 33 parts of 1-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 450 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 40 parts (78.9%) of N-[2-[[(3,4-dichlorophenyl)methyl]amino]phenyl]-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea (199).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:20]([N:24]1[C:29](=[O:30])[C:28]([CH3:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[C:20]([N:24]1[C:29](=[O:30])[C:28]([CH3:31])=[C:27]([O:15][CH2:14][C:11]2[CH:12]=[N:13][C:8]([O:7][CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: OCc1ccc(OCc2ccc(F)cc2)nc1
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(OCc3ccc(F)cc3)nc2)cnn(C(C)(C)C)c1=O
Temperature: 0 °C
Yield: 63.8 %

Procedure:
To a solution of 2.3 g of 6-(4-fluorobenzyloxy)-3-pyridine methanol in 20 ml of N,N-dimethylformamide was added under stirring at 0° C. 0.5 g of 55% sodium hydride (in mineral oil). After stirring for 30 minutes at room temperature, thereto was added dropwise a solution of 2.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for additional 8 hours, poured into 50 ml of ice water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 3.8 g of a crude product. The crude product was separated and purified through thin layer chromatography (on silica gel; benzene) to obtain 2.5 g of 2-t-butyl-5-[{6-(4-fluorobenzyloxy)-3-pyridyl}-methyloxy]-4-methyl-3(2H)-pyridazinone as an oil.