Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CC#N>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Clc1nc2ccccc2s1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: c1ccc2sc(Oc3ccc4cc[nH]c4c3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.9 %

Procedure:
To a suspension of 6-hydroxyindole (5.0 g, 37.6 mmol) and Cs2CO3 (36.7 g, 112.8 mmol) in MeCN (75 mL) was added 2-chlorobenzthiazole (6.4 g, 4.7 mL, 37.6 mmol) and the resulting suspension was stirred (rt, 2 d). The reaction mixture was partitioned with brine and EtOAc (200 mL each) and the aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, washed with brine (300 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using EtOAc:hexane (0-40%) to afford the title compound as a tan solid (6.1 g, 61%). MS (ESI): mass calcd. for C15H10N2OS, 266.3; m/z found, 267.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (s, 1H), 7.72 (dd, J=8.4, 0.6, 1H), 7.65-7.63 (m, 2H), 7.39-7.35 (m, 2H), 7.27-7.22 (m, 1H), 7.19-7.18 (m, 1H), 7.08 (dd, J=8.4, 2.1, 1H), 6.55-6.53 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]4[N:23]([CH3:24])[C:22](=[O:25])[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][C:20]=5[CH3:26])[N:15]=4)=[CH:10][CH:9]=3)=[O:7])=[CH:29][CH:30]=2)=[CH:45][CH:46]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccc(OCc6ccccc6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 78.1 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (309 mg), 4-benzyloxybenzyl chloride (224 mg) and potassium carbonate (295 mg) in DMF (5 ml) was stirred at room temperature for 14 hours. This reaction mixture was concentrated and the residue was dissolved in chloroform. The solution was washed with water, dried, and concentrated. The residue was recrystallized from chloroform-ethyl acetate to provide the title compound as colorless solid (355 mg).
Reaction SMILES: [C:1]1([NH:7]/[CH:8]=[CH:9]/[CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12](OC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=O)C>CO>[O:13]=[C:12]1[C:11]([C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=[CH:8][N:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=C/C=C/Nc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of (E)-dimethyl 2-(3-(phenylamino)allylidene)malonate (130 mg, 0.50 mrnol) in methanol (8 mL) at rt was added NaH (50 mg of the 60% NaH in oil, 1.2 mmol) and the mixture was stirred at rt for 3 h. Acetic acid (0.3 mL) was added to the mixture, concentrated to a volume of 4 mL, and purificationof the reaction mixture by preparative HPLC provided the desired product (105 mg, 92%) as a yellow solid. 1H NMR (CD3OD) δ 8.30 (dd, 1H, J=7.2, 2.2 Hz), 7.87 (dd, 1H, J=6.6, 1.7 ), 7.57-7.38 (m, 5H), 6.53 (t, 1H, J=7.0 Hz), 3.84 (s, 3H); MS(ESI+) m/z 230.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:20]=[CH:21][C@@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])O>C(O)C>[CH2:1]([NH:19][CH:30]1[O:31][C@H:22]([CH2:21][OH:20])[C@@H:24]([OH:25])[C@H:26]([OH:27])[C@H:28]1[OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
20 g of octadecylamine are dissolved in 120 ml of ethanol and the solution is warmed to 70° C. 11 g of anhydrous D-glucose are added. Stirring is continued for a further 15 minutes at 70° after a clear solution has been formed. The mixture is cooled to 10° and allowed to stand for 15 minutes. The resulting mash of crystals is filtered off with suction, washed twice with ethanol and dried in vacuo.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=[O:10].C(=O)=O.CC(C)=O.Cl>C(Cl)Cl>[CH3:16][O:15][C:13]1[C:12]([O:17][CH3:18])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([OH:6])[CH:14]=1
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: Cl
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A solution of boron trichloride (50 mL, 1.0 M solution in CH2Cl2) was slowly added to a solution of 2,4,5-trimethoxybenzaldehyde (3.92 g, 20 mmol) in CH2Cl2 (200 mL) at −78° C. (dry ice/acetone bath). The mixture was warmed to room temperature and stirred for three hours. 10 mL of HCl (37%) aqueous solution was poured into the resulting solution at 0° C. and extracted with CH2Cl2 (150 mL×3). The combined organic layer was washed with saturated aqueous NaCl (200 mL×2), water (100 mL×1), dried over MgSO4, and evaporated to afford 3.72 g of a light brown solid (3.72 g, 99%): 1H-NMR (400 MHz, CDCl3) δ3.88 (s, 3H), 3.94 (s, 3H), 6.47 (s, 1H), 6.91 (s, 1H), 9.70 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:34]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: COc1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(OC)ccc1CO
Temperature: 100 °C
Reaction time: 7 h
Yield: 64.4 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol), 1-bromodocosane (16.6 g, 42.7 mmol) and potassium carbonate (14.8 g, 107 mmol) were mixed with DMF (150 ml), and the mixture was stirred at 100° C. for 7 hr. Chloroform (400 ml) and 1N hydrochloric acid (300 ml) were added to the reaction mixture, and the mixture was washed. The organic layer was washed successively with 1N hydrochloric acid and saturated brine. The organic layer was concentrated and slurry-washed with methanol. The precipitate was collected by filtration and dried under reduced pressure. The obtained dried crystals were dissolved in THF (150 ml), sodium borohydride (3.7 g) was added, and the mixture was stirred at 40° C. for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated. The mixture was extracted with chloroform, and washed successively with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated. The obtained residue was washed with acetonitrile, and the precipitate was collected by filtration and dried under reduced pressure to give 2-docosyloxy-4-methoxybenzyl alcohol (9.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:48][C@H:49]5[CH2:50][O:51]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CCOCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol (0.21 g, 0.5 mmol, 1.0 eq.) and Cs2CO3 (0.49 g, 1.5 mmol, 3.0 eq.) in DMF (2 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2R)-(−)-glycidyl tosylate (0.17 g, 0.75 mmol, 1.5 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][CH2:30][S:31]([NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:36])(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.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.O>[OH:27][CH2:28][CH2:29][CH2:30][S:31]([NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=2)=[CH:39][C:38]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:36])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccnc1
Reactant: CC(C)Oc1cc(B(O)O)ccc1C(=O)NS(=O)(=O)CCCO
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 80 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (331 mg) in 1,4-dioxane (3.3 ml) were added [4-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3-isopropoxyphenyl]boronic acid (325 mg), tetrakis(triphenylphosphine)palladium (91 mg) and aqueous solution of sodium carbonate (2M, 1.4 ml), and the mixture was stirred at 80° C. for 3 hours under nitrogen. The mixture was portioned into a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/methanol=100/3) to give tert-butyl [2-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-isopropoxy-4-biphenylyl]-ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (108 mg).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:19][NH2:20].O>C(O)C>[CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:19][NH2:20])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NN
Reactant: CCCCCCOc1ccc(C(=O)OC)cc1
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(C(=O)NN)cc1
Yield: 98 %

Procedure:
A solution of Methyl 4-n-hexyloxybenzoate (2.00 g) and hydrazine hydrate (4.24 g) in ethanol (10 ml) was refluxed for 6 hours. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration, washed with water and dried over P2O5 under reduced pressure to give N-(4-n-hexyloxybenzoyl)hydrazine (1.96 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[CH2:9][O:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:8]([NH2:7])[CH2:9][O:10][CH3:11])[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]=2[CH:23]=1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of [(R)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]carbamic acid tert-butyl ester (0.227 g, 0.59 mmol) in DCM (4.5 mL) was added TFA (2.5 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a colourless oil (110 mg, 65%). LCMS (Method B): RT 1.90 min [M+H]+ 286.0.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH2:20].C(Cl)(Cl)Cl.Cl>C(O)C.C(OCC)C>[ClH:1].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH:20][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: COc1ccccc1C(O)CCl
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CCNCC(O)c2ccccc2OC)cc1OC
Yield: 41.1 %

Procedure:
A mixture of 3.7 g of α-chloromethyl-2-methoxybenzylalcohol (crude oil) and 10.9 g of 3,4-dimethoxyphenethylamine is heated at 130° to 140° C. for 2 hours. After cooling, chloroform is added to the reaction mixture, and said mixture is washed with water. The mixture is dried and evaporated to remove solvent. 30 ml of ethanol are added to the residue obtained. Then, hydrochloric acid-containing diethylether is added to the ethanol mixture, and crystalline precipitates are collected by filtration. 3.0 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-methoxybenzylalcohol hydrochloride are obtained as crystals. M.p. 142°-143° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[N:31](C2CCCCO2)[N:30]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[NH:31][N:30]=[C:29]([CH3:28])[CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(CO)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 41 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 39.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 41.1) to afford a beige lyophilizate. HPLC (Condition 7) tR=5.488 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=448.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3H) 2.56-2.69 (m, 1H) 3.46 (d, J=6.26 Hz, 2H) 3.51-3.57 (m, 2H) 3.79 (t, J=8.6 Hz, 2H) 6.16 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.83-7.90 (m, J=9.00 Hz, 2H) 8.01 (d, J=2.35 Hz, 1H) 8.70 (d, J=2.35 Hz, 1H) 10.20 (br.s, 1H), 12.04 (br.s, 1H).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[CH2:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.C(Cl)(Cl)Cl>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[CH2:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
H2O2 (70%, 0.18 mL, ca. 3.6 mmol) was added dropwise to a stirred solution of TFAA (0.51 mL, 3.6 mmol) in DCM (6 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 207 (100 mg, 0.36 mmol) and TFA (0.06 mL, 0.78 mmol) in CHCl3 (6 mL) at 0° C. and the solution stirred at 20° C. for 4.5 h. The solution was cooled to 0° C., made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×10 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-16%) of MeOH/DCM to give 1,4-dioxide 208 (56 mg, 53%) as an orange solid: mp 186-189° C.; 1H NMR δ 8.13 (t, J=1.6 Hz, 1H, H-9), 7.48 (br s, 2H, H-5, NH), 4.81 (t, J=8.3 Hz, 2H, H-7), 3.62 (t, J=6.0 Hz, 2H, CH2N), 3.37 (dt, J=8.3, 1.6 Hz, 2H, H-8), 2.62 (t, J=8.3 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2]; 13C NMR δ 167.2, 149.9, 140.6, 132.0, 117.9, 93.8, 87.9, 73.4, 57.5, 45.2 (2), 38.8, 28.5. HRMS (FAB+) calcd for C13H18N5O3 (MH+) m/z 292.1410, found 292.1409.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]([C:9]([OH:11])=O)[NH:3]1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1>CN(C)C=O>[O:1]=[C:2]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]([C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])[NH:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C1CCSCC(C(=O)O)N1
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CSCCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.3 g (0.03 mole) of 5-oxo-perhydro-(1,4)-thiazepine-3-carboxylic acid and 6.1 g (0.03 mole) of N,N'-carbonyl-diimidazole are stirred in 15 ml of dimethylformamide at 50° c. for 15 minutes. After addition of 4.9 g (0.03 mole) of 6-(4-amino-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, the mixture is stirred at room temperature for 12 hours and the product is filtered off with suction and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: C1CCNC1
Product: O=C(c1cccc(F)c1)N1CCCC1

Procedure:
3-Fluorobenzoyl chloride was reacted with pyrrolidine using General Method E1 or E2 to produce N-(3-fluorobenzoyl)pyrrolidine.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12]>O1CCCC1>[CH2:1]([NH:7][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[I:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CCCCCCN
Solvent: C1CCOC1
Product: CCCCCCNC(=O)c1ccccc1I
Yield: 76.4 %

Procedure:
Solutions of 12.2 g hexylamine and 8.0 g o-iodobenzoyl chloride in a total of 20 ml tetrahydrofuran were reacted for 10 minutes. The tetrahydrofuran was removed by heating on a water bath at 65° for 10 minutes and 50 ml of water were added to precipitate the crude product. The precipitate was recovered as in Example 1 and recrystallized from a benzene/hexane mixture as white crystals, to yield 7.6 g of N-hexyl-o-iodobenzamide, m.p. 104°-105°, Rf 0.78.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (5 g, 0.019 mol) in methanol was treated with sodium hydroxide (1.50 g, 0.037 mol) and water, heated to 65° C., stirred for 3 h and concentrated under reduced pressure. The resultant residue was dissolved in water and acidified with concentrated HCl. The resultant precipitate was removed by filtration and dried under vacuum overnight to provide 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (82.0%). 1H NMR-(400 MHz, DSMO-d6): 7.96 (d, J=8 Hz, 2H), 7.91 (m, J=9 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.52 (m, J=6 Hz, 2H), 4.65 (s, 2H). LCMS (ESI+) 253 (M+H). A portion of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (5.0 g, 0.020 mol) was dissolved in dichloromethane, cooled to 0° C., treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.50 g, 0.023 mol), 1-hydroxybenzotriazole (HOBT) (3.21 g, 0.024 mol), and diisopropylethylamine (6.41 g, 0.049 mol), stirred at room temperature for 30 min, cooled to 0° C., treated with a solution of 3-pyrrolidinol (1.89 g, 0.021 mol) in dichloromethane, stirred at room temperature for 24 h and diluted with water. The phases were separated and the organic phase was washed sequentially with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over sodium sulfate and concentrated to dryness under reduced pressure to provide [4-(1H-benzoimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 7.47 (s, 4H), 7.38 (d, J=7.6 Hz, 2H), 4.87 (s, J=4.2 Hz, 1H), 4.21 (d, 2H), 3.48 (m, 4 H), 1.85 (m, 2H). LCMS (ESI+) 322 (M+H).
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH3:3]>C1COCC1.C(OCC)(=O)C>[CH2:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:1])(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH3:3]
Reactant: N
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1ccc(Oc2ccc(S(N)(=O)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Conc. NH3 (5.0 mmol; 0.28 mL) was slowly added to a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (1.0 mmol; 344 mg) in THF (5 mL), under argon at 0° C. The reaction was stirred overnight with slow warming to room temperature. Diluted with ethyl acetate (5 mL), the mixture was washed with HCl (1N), and sat. NH4Cl. The organic phase was dried over MgSO4, concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate gradient) to yield the title compound as an off-white solid (108 mg; 0.33 mmol; 33%).