Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)(=O)=O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH2:15]([NH:22][CH2:6][CH:7]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CNCc2ccccc2)CO1
Yield: 84.7 %

Procedure:
A solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (1.70 g, 7.58 mmol) in benzylamine (10 mL, 92 mmol) was stirred at 80° C. and monitored by TLC. After 2 h the reaction was complete therefore concentrated in vacuo. The residue was diluted with toluene (containing a small amount of ethyl acetate) and washed with water, dried and concentrate in vacuo. Column chromatography on silica eluting with ethyl acetate afforded N-benzyl(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (1.51 g, 85% yield) as a yellow oil. 13C NMR (CD3OD) δ 140.8, 129.4 (2XCH), 128.1, 99.3, 64.0 (2XCH2), 54.7, 33.7, 25.6, 23.0
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:12]1[N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:14]=[C:15]2[CH2:19][CH2:18][CH2:17][C:16]=12)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([N:13]2[C:12]([CH:5]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:4][OH:3])=[C:16]3[CH2:17][CH2:18][CH2:19][C:15]3=[N:14]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.8 %

Procedure:
A solution of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid ethyl ester (500 mg, 1.2 mmol) in THF (25 ml) was added within 20 min to an ice cold suspension of lithium aluminium hydride (66 mg, 1.7 mmol) in THF (25 ml). The solution was stirred at 0° C. for 45 min, filtered over Speedex and the filtrate was brought to dryness under reduced pressure. The residue was taken up in ice water/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was extracted one more time with iPrOAc. The combined extracts were dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (336 mg, 0.97 mmol; 79%) as yellow oil which was used in the next step without further purification. MS: m/e=345.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>O.C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1cnc(Cl)c(Cl)c1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: OCc1cnc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 5,6-dichloro-pyridin-3-yl-methanol (10.0 g, 56.2 mmol), phenylboronic acid (7.5 g, 61.5 mmol), K2CO3 (20.0 g, 145 mmol) in H2O (140 mL) and dimethoxyethane (140 mL, 0.4 M), is degassed and treated with tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) and warmed to a gentle reflux under nitrogen for 4 h. After cooling to room temperature, ethyl acetate (100 mL) is added and the solids are filtered and washed with ethyl acetate (20 ml). The filtrate is extracted with ethyl acetate (100 mL) and the organic layer is washed with H2O (200 mL), saturated aq NaCl (200 mL) and dried over Na2SO4. The product is purified by MPLC (30-90% ethyl acetate in n-heptane) to provide 5-chloro-6-phenyl-pyridin-3-yl-methanol as a light yellow solid (12.0 g, 97%): Rf 0.24 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.47 (br s, 1 H), 7.78 (br s, 1 H), 7.70-7.65 (m, 2 H), 7.50-7.40 (m, 3 H), 4.67 (s, 2 H); ESI-LCMS m/z calcd for C12H10ClNO: 219.0; found 220.0 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][C:12](=[O:14])[CH3:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+].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.O>[N+:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:3]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccncc2)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: O
Product: CC(=O)Nc1c(-c2ccncc2)cccc1[N+](=O)[O-]
Yield: 55.2 %

Procedure:
A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (XCI) (2.59 g, 10 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (XCII) (2.05 g, 10 mmol, 1.3 eq), Na2CO3 (2.12 g, 20 mmol, 2 eq) and Pd(PPh3)4 (1.16 g, 1 mmol, 0.1 eq) in a mixed solvent of DME (30 mL) and H2O (10 mL) was heated to reflux under nitrogen overnight, the mixture was poured onto water (40 ml) and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, purification the resultant residue was purified by column chromatography (EtOAc:PE=1:4→100% EtOAc) to afford N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (XCIII) (1.42 g, 5.52 mmol, 55% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.92 (s, 3H), 7.46 (d, J=5.6 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.80 (dd, J=7.6 Hz, J=1.2 Hz, 1H), 8.06 (dd, J=8 Hz, J=1.6 Hz, 1H), 8.73 (d, J=6 Hz, 2H), 9.96 (s, 1H); ESIMS found for C13H11N3O3 m/z 258 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Cl)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:11]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(OC)c1
Temperature: 0 °C

Procedure:
3-Methoxy-phenol (43.4 ml, 400 mmol) is dissolved in acetone (800 ml) and after addition of chloro-acetic acid ethyl ester (42.6 ml, 400 mmol) and K2CO3 (111 g, 800 mmol) the mixture is refluxed for 22 h. After cooling down to 0° C., the mixture is filtrated and the filtrate is evaporated under reduced pressure. The residue is diluted in ethyl acetate, cooled to 0° C. and washed with aqueous NaOH solution. The organic layer is dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[C:11]([CH:19]([O:22][CH3:23])[O:20][CH3:21])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:11]1[CH:10]=[C:9]([CH:1]([OH:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(OC)c1cc(C(=O)c2ccccc2)ccc1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cc(C(O)c2ccccc2)ccc1NC(C)=O
Yield: 50.8 %

Procedure:
To a stirred solution of 25.6 parts of intermediate 65, namely N-[4-benzoyl-2-(dimethoxymethyl)phenyl]acetamide, in 119 parts of methanol were added portionwise 10.72 parts of sodium tetrahydroborate. Stirring was continued for a while at 60° C. and over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane (2×) and the combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH3COOC2H5 /hexane 50:50→60:40). The eluent of the desired fraction was evaporated, yielding 13.1 parts (50.8%) of N-[2-(dimethoxymethyl)-4-(hydroxyphenylmethyl)phenyl]acetamide (interm. 66).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12](NC(OCC2C=CC=CC=2)=O)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCCN(NC(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCCNC1

Procedure:
20% Pd(OH)2 on carbon (1 g) was added to a solution of benzyl 3-(tert-butoxycarbonylamino-methyl)-piperidine-1-carbamate (5 g, 14.3 mmol) in EtOH (50 ml) and EtOAc (50 ml), and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The reaction mixture was filtered and the filtrate was concentrated.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([F:17])([F:16])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:16][CH:11]([F:17])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 53.2 %

Procedure:
4-Cyanophenol (0.12 G, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 75°-80° C. for 0.3 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed twice with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a colorless solid (0.09 g, 53%). mp 34°-35° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH2:33]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[CH3:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[C@H:35]([CH2:33][CH3:34])[CH2:39][O:38][C:37]5=[O:40])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 85.7 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (519 mg) described in Preparation Example 179 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (474 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH2:13]O.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: Sc1ccccc1Br
Reactant: COc1cc(OC)c(CO)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Yield: 8.9 %

Procedure:
To a solution of 30.8 g (2,4,6-trimethoxyphenyl)methanol (155.4 mmol) and 29.2 g 2-bromobenzenethiol (155.4 mmol) in 150 ml DCM at 0° C. was added dropwise 1.3 eq TFA. The reaction was stirred 15 minutes at room temperature before saturated NaHCO3 was added until neutral. The organic volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3×150 ml). The organic layer was collected, washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure afforded a yellowish solid. The solid was washed with ethyl acetate to yield 51.3 g white solid (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (13.9 mmol, 89% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.Br[C:20]1[CH:47]=[CH:46][CH:45]=[CH:44][C:21]=1[CH2:22][N:23]1[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[N:25]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:32]=2)[C:24]1=[O:43]>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([N:25]2[C:26](=[O:30])[C:27]([CH3:29])([CH3:28])[N:23]([CH2:22][C:21]3[CH:44]=[CH:45][CH:46]=[CH:47][C:20]=3[NH:2][C:3]3[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)[C:24]2=[O:43])=[CH:32][C:33]=1[C:39]([F:40])([F:42])[F:41])#[N:36]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Br
Reactant: COC(=O)C(Cc1ccc(N)cc1)C(=O)OC
Agent: Cl
Product: COC(=O)C(Cc1ccc(Nc2ccccc2CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1)C(=O)OC

Procedure:
232 was obtained by reacting compound 232.2 with compound 1.2 under conditions as described for the preparation of compound I. Molecular weight 622.20 (C32H29F3N4O6); retention time Rt=2.21 min. [B]; MS (ESI): 623.21 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][N:30]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][N:30]([CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1)[CH:36]1[CH2:37][CH2:38][N:39]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:40][CH2:41]1
Reactant: CN(C1CCNCC1)C1CCOC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4CCOC4)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (72 mg, 0.19 mmol), methylpiperidin-4-yl(tetrahydrofuran-3-yl)amine (42 mg, 0.23 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 389 as a white solid (55 mg, 53%). LCMS (Method G): RT 4.96 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.07 (m, 1 H); 7.73-7.69 (m, 1 H); 7.29-7.24 (m, 2 H); 4.35 (m, 4 H); 3.96 (m, 1 H); 3.92-3.80 (m, 8 H); 3.83-3.71 (m, 4 H); 3.43 (m, 1 H); 3.02-2.90 (m, 4 H); 2.52 (m, 1 H); 2.26 (s, 3 H); 2.16 (m, 2 H); 2.03 (m, 1 H); 1.90 (m, 1 H); 1.77 (s, 3 H) and 1.59 (m, 2 H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:16]3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(C3CCCCC3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 119.4 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), cyclohexyl aldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (116 mg, 59.6% yield) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=S)[NH:6][C:7]=1[CH3:8].ClCC(O)=[O:14]>O>[CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:14])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1C
Reactant: O=C(O)CCl
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1C
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 5,6-dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (14.4 g, 0.09 mol, Step A) and chloroacetic acid (100.0 g, 1.06 mol) in water (43 mL) was refluxed overnight, cooled down to ambient temperature and quenched with water (500 mL). The formed precipitate was collected by filtration and dried to yield 10.3 g (79.7%) of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.70 (s, 3H) 2.02 (s, 3H) 10.56 (s, 1H) 10.86 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7](=[O:18])[CH2:6][CH2:5]1)[CH3:2].[Li].[Cl-].[NH4+].[Cl-].[Na+].[O:24]1CCCC1>CCCCCC.C1COCC1>[C:12]1([S:9]([N:8]2[CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([OH:24])[C:7]2=[O:18])(=[O:10])=[O:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1CCOC1
Reactant: CCOC1CCC(=O)N1S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCCCCC
Product: CCOC1CC(O)C(=O)N1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g of 5-ethoxy-1-benzenesulfonylpyrrolidin-2-one in 300 cm3 of anhydrous tetrahydrofuran, cooled to -78° C., 0.037 moles of a solution of lithium bis-trimethylsylylamide in a mixture of hexane-tetrahydrofuran (1-1) is added drop by drop at a temperature of -78° C. This mixture is agitated for 1 hour at -78° C., then 14.55 g of 2-sulfonyloxaziridine is added. The mixture is then agitated at -78° C. for 2 hours, brought to -5° C., then cooled to -30° C., after which 130 cm3 of an aqueous solution of saturated ammonium chloride is added, while the temperature is maintained at approximately -30° C. The temperature is brought to 20° C., then 130 cm3 of an aqueous solution of saturated sodium chloride is added. The organic phase is separated and the aqueous phase is extracted with chloroform. The organic phases are combined, dried, and the solvent is evaporated under reduced pressure, then the residue is chromatographed on silica, using an ethyl acetate-hexane (2-1) mixture as eluent. The product is dissolved in isopropyl ether, and 250 g of the expected product is obtained, m.p. 108°-116° C. (mixture of cis and trans isomers in which the trans isomer predominates).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Mg].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>BrCCBr.C(OCC)C.O1CCCC1.C(OCC)(=O)C>[O:19]=[C:13]([C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Fc1cc(Br)c2occc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1cc(F)cc2ccoc12
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 1.01 gm (4.72 mMol) 5-fluoro-7-bromobenzofuran, 0.15 gm (6.14 mMol) magnesium(0), and 2 drops of 1,2-dibromoethane in 1 mL diethyl ether was stirred at room temperature until initiation of the Grignard formation had occurred (about 5–10 minutes). The mixture was then diluted with 8 mL of diethyl ether and heated at reflux for 30 minutes. This mixture was then added dropwise to a solution of 1.38 gm (9.44 mMol) diethyl oxalate in 3 mL tetrahydrofuran at −10° C. Once the addition was complete the reaction mixture was allowed to warm to room temperature and was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with 20 volumes of ethyl acetate and was washed sequentially with 1N hydrochloric acid, water, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.894 gm (80%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([O:10]C)[CH:9]=1)([O-:3])=[O:2].Cl.N1C=CC=CC=1.Cl>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:13])([F:14])[F:15])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Temperature: 210 °C

Procedure:
5-Nitro-2-trifluoromethylanisole (10.7 g, 48.5 mmol) and pyridine hydrochloride (44.9 g, 388 mmol) were combined in a round-bottom flask and heated at 210° C. for 2 h. The reaction was cooled to RT and dissolved into 6 N HCl and EtOAc. The layers were separated, and the organic layer was washed 4× with 2 N HCl and once with brine, dried over Na2SO4, filtered, and concentrated in vacuo, to yield the title compound as a dark red solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:28]3[CH:29]=[CH:30][C:26]([CH3:25])=[N:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: Cc1cc[nH]n1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)n1
Yield: 27.8 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (371 mg, 1.0 mmol), 3-methyl-1H-pyrazole (164 mg, 2.0 mmol) and DMAP (367 mg, 3.0 mmol) in MeCN (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 116 mg (28%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.39-1.57 (m, 4 H), 1.59 (s, 9 H), 2.17 (s, 3 H), 2.23-2.33 (m, 1 H), 3.27-3.36 (m, 2 H), 3.88 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 6.31 (d, J=2.54 Hz, 1 H), 7.88-7.99 (m, 2 H), 8.18 (d, J=2.73 Hz, 1 H), 8.28 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=416.8.