Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].OS(O)(=O)=O>>[F:5][C:6]1[CH:16]=[C:15]([F:17])[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reaction time: 2 h

Procedure:
Conc. HNO3 (8 mL) was added dropwise to a mixture of ethyl 2,4-difluorobenzoate (10.0 g; 53.7 mmol) in cone. H2SO4 (8 mL) at 0° C. After 2 h at 0° C., the mixture was poured onto ice and extracted with EtOAc. The organic extracts were washed with saturated NaHCO3 solution (aq) and concentrated to give the sub-title compound. Yield: 11.8 g (95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][NH:12][CH2:11]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:12]2[CH2:13][CH:14]([CH3:16])[CH2:15][CH:10]([CH3:9])[CH2:11]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1CNCC(C)C1
Product: CC1CC(C)CN(c2cc(Cl)ncn2)C1
Reaction time: 5 h
Yield: 66 %

Procedure:
0.3 g of 4,6-dichloropyrimidine and 0.34 g of 3,5-dimethylpiperidine (cis/trans diastereomer=about 3/1) were mixed and left for 5 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.3 g of 4-chloro-6-(3,5-dimethylpiperidino)pyrimidine. This compound had the cis/trans diastereomer originated two methyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 3.1/1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O.[OH-].[Li+].Cl>CO.O>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:11][CH2:12]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoate (80.0 mg, 0.19 mmol) and lithium hydroxide monohydrate (16.0 mg, 0.37 mmol) in methanol (3.0 mL) and water (1.0 mL) was stirred at RT for 4 h. The mixture was adjusted with 1N HCl to pH=5. The volatiles were removed under reduced pressure, and dried in-vacuo to give a crude product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=415.0.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8](OC(=N)C(Cl)(Cl)Cl)[O:7][CH:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:53])[C:37]=1[NH:38][C:39]1[C:48]2[C:43](=[C:44]([OH:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=2)[O:42][C:41](=[O:52])[CH:40]=1>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:51][C:44]2[C:45]([O:49][CH3:50])=[CH:46][CH:47]=[C:48]3[C:43]=2[O:42][C:41](=[O:52])[CH:40]=[C:39]3[NH:38][C:37]2[C:36]([Cl:53])=[CH:35][N:34]=[CH:33][C:32]=2[Cl:31])[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Solvent: CC#N
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron trifluoride•OEt2 (54 μL, 0.43 mmol) was added to a suspension of (3R,4S,5S,6R)-2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.168 g, 0.341 mmol), 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (60 mg, 0.17 mmol, Example 29), and anhydrous acetonitrile (2 mL) at −40° C. under N2. After 2 h at −40° C., the reaction was allowed to warm to rt and stirred overnight. The mixture was concentrated and purified by reverse-phase HPLC to give (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate: 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.83 (s, 2H), 8.03 (d, 1H), 7.25 (d, 1H), 5.34 (m, 2H), 5.08 (m, 1H), 4.98 (m, 1H), 4.67 (s, 1H), 4.12 (m, 1H), 3.99 (m, 2H), 3.91 (s, 3H), 2.06 (s, 3H), 1.98 (m, 6H), 1.94 (s, 3H); MS (ESI): 682.8.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][CH:11]=[C:12]([CH3:16])[C:13]([OH:15])=[O:14].[CH2:20](Br)[C:21]#[CH:22]>>[CH2:22]([O:14][C:13](=[O:15])[C:12]([CH3:16])=[CH:11][CH:10]=[CH:9][CH2:8][CH:7]([CH3:17])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:18])[CH3:19])[C:21]#[CH:20]
Reactant: COC(C)(C)CCCC(C)CC=CC=C(C)C(=O)O
Reactant: C#CCBr
Product: C#CCOC(=O)C(C)=CC=CCC(C)CCCC(C)(C)OC

Procedure:
Utilizing the procedure of Example 15, 11-methoxy-2,7,11-trimethyl-2,4-dodecadienoic acid and propargyl bromide are reacted. After chromatography on Kieselgel, using diethyl ether/petroleum ether (1:3 parts by volume) as the eluant, there is obtained 11-methoxy-2,7,11-trimethyl-2,4-dodecadienoic acid propargyl ester in pure form; boiling point 110°C/0.002 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4]=1[C:14]([F:17])([F:16])[F:15].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:14]([F:16])([F:15])[F:17]
Reactant: COc1ccc2c(C)cccc2c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)cccc2c1C(F)(F)F
Yield: 106.5 %

Procedure:
A suspension of 2-methoxy-5-methyl-1-(trifluoromethyl)naphthalene (1.2 g, 5.0 mmol), N-bromosuccinimide (1.07 g, 6.0 mmol) and benzoyl peroxide (20-30 mg) in carbon tetrachloride (10 mL) was heated at reflux for 1.5 hr. The residual solid in the reaction mixture was removed by filtration, and the collected solid on the filter was washed with methylene chloride. The combined filtrates were washed with water, dried (MgSO4) and evaporated to give 1.7 g of 5-(bromomethyl)-1-(trifluoromethyl)-2-methoxynaphthalene (IX, R=CH3 and R1 =CH2Br) which was used in the next step without purification. Crystallization of a sample from hexane furnished pure 5-(bromomethyl)-1-trifluoromethyl-2-methoxynaphthalene having mp 97°-99° C.; nmr (CDCl3) δ 3.95 (s, 3H), 4.85 (s, 2H), 7.7 (m, 5H); ir (CHCl3) 1265, 1125 cm-1 ; uvλmax (MeOH) 339 nm (ε3,510), 326 (3,280), 300 (7,230), 288 (7,150), 229 (44,150); anal Calcd for C13H10BrF3O: C, 48.93% H, 3.16%; Found: C, 48.88% H, 3.14%.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)CCC>[CH:3]1([CH2:2][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1c[nH]cn1
Reactant: BrCC1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1cn(CC2CCCCCC2)cn1
Reaction time: 7 h

Procedure:
Bromomethylcycloheptane (5.3 g, 0.0278 mol) was added dropwise to a stirred solution of potassium t-butoxide (3.1 g, 0.0277 mol) and imidazole (1.9 g, 0.0279 mol) in dry n-butanol (50 ml) maintained at 100° and under dry nitrogen. After the addition (~20 mins) the temperature of the reaction mixture was raised to boiling. The reaction mixture was then stirred and boiled for 7 h and then cooled.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)[CH3:2].C([Li])(CC)C.[CH3:22][S:23]SC>C1COCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][C:6]=1[S:23][CH3:22])[CH3:16]
Reactant: CCCc1ccc(C(=O)N(CC)CC)cc1
Reactant: CSSC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)N(CC)CC)c(SC)c1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a stirring solution of N,N-diethyl-4-propylbenzamide (2.0 g, 9.3 mmol) and N,N,N′N′-tetramethylethylenediamine (1085 mg, 9.4 mmol) in dry THF (93 mL) at −78° C. under Ar was added 0.78 M s-butyllithium in hexanes (12 mL). The reaction was stirred for 30 min and then methyl disulfide (1936 mg, 12.1 mmol) was added. The reaction was stirred for 5 min and then quenched with MeOH (1 mL) and brine. The reaction was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and conc in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0-30% EtOAc in hexanes) to yield 2.1 g (86%) of the product as a yellow oil. MS (ESI) 266 (M+H).
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:21]=[CH:20][N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2C1CCCCO1)[CH2:9][CH:10]([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N>O>[CH2:1]([N:8]([C:13]1[N:21]=[CH:20][N:19]=[C:18]2[C:14]=1[NH:15][CH:16]=[N:17]2)[CH2:9][CH:10]([CH3:12])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN(Cc1ccccc1)c1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Agent: N
Solvent: O
Product: CC(C)CN(Cc1ccccc1)c1ncnc2nc[nH]c12
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 17.0 g. (47 mmole) 6-[N-benzyl-N-(2-methylpropyl)-amino]-9-tetrahydropyran-2-ylpurine (compound of Example 1) in 200 ml. saturated ethanolic hydrogen chloride solution is heated under reflux for 10 minutes. After standing overnight, the reaction mixture is diluted with water, adjusted to pH 7 with aqueous ammonia solution and the precipitate filtered off with suction. After recrystallization from aqueous propan-2-ol, there are obtained 10.5 g. of the title compound (80% of theory); m.p. 160°-162° C.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([O:14][P:15]([CH:22](O)[C:23]1[CH:45]=[CH:44][C:26]([CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[C:10]([O:14][P:15]([CH:22]([F:7])[C:23]1[CH:45]=[CH:44][C:26]([CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117 %

Procedure:
To DAST (0.15 mL, 1.1 mmol) in anhydrous CHCl3 (0.6 mL) at -78° C. was slowly added compound 9 (536 mg, 1.0 mmol) in CHCl3 (2.0 mL). After 10 minutes, the reaction mixture was warmed to ambient temperature and stirred (20 minutes). The mixture was slowly diluted with brine (10 mL) then extracted with CHCl3 (2×10 mL) and the combined extracts dried (MgSO4) and evaporated under reduced pressure to yield crude 20 (629 mg). Purification by silica gel chromatography afforded pure 20 as a syrup (295 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[C:19]([N:27]=1)=[N:20][CH:21]=[C:22]([N+:24]([O-])=O)[CH:23]=2.O.O.Cl[Sn]Cl>C(O)C>[NH2:24][C:22]1[CH:23]=[C:18]2[NH:17][C:16]([C:3]3[CH:4]=[C:5]([NH:8][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[O:10])[CH:6]=[CH:7][C:2]=3[Cl:1])=[N:27][C:19]2=[N:20][CH:21]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2nc3ncc([N+](=O)[O-])cc3[nH]2)c1)c1ccco1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)[nH]c2c1
Yield: 54.3 %

Procedure:
To a suspension of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)furan-2-carboxamide (3.9 g, 10.16 mmol, 1.00 equiv) in ethanol (50 mL) was added SnCl2.2H2O (3.4 g, 15.04 mmol, 1.48 equiv) and heated to reflux overnight. The reaction mixture was concentrated under vacuum and diluted with H2O. The pH value of the mixture was adjusted to 9 with sodium carbonate (sat.). The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/PE (3/1) to give 1.95 g (54%) of N-(3-[6-amino-1H-imidazo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide as a yellow solid. 1H-NMR: (CD3OD, 400 MHz): 8.16 (d, J=2.4 Hz, 1H), 7.97-8.10 (m, 2H), 7.78 (d, J=0.8 Hz, 1H), 7.65 (d, J=20.0 Hz, 1H), 7.31-7.41 (m, 2H), 6.68 (dd, J=3.6, 2.0 Hz, 1H. MS (M+H)+=354.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][CH:6]=2)[CH2:3][CH2:2]1.[Cl:16]N1C(=O)CCC1=O>C(#N)C>[Cl:16][C:6]1[N:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:9][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: c1cncc(-c2ncc(NC3CC3)s2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Clc1nc(-c2cccnc2)sc1NC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine (1.00 g, 4.60 mmol) in acetonitrile (2 mL) was added 1-chloropyrrolidine-2,5-dione (645 mg, 4.83 mmol) and the mixture stirred at 0° C. for 1 h. The mixture was filtered and the filtrate was treated with excess HCl (4M in dioxane) to give 4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine as a brown solid: mp 56-60° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[S:18][C:19]([C:29]([NH2:31])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:21]=3)[C:13]=2[CH:32]=1)C1C=CC=CC=1.ClCCl>O>[Cl:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:17]([N:14]3[C:13]4[CH:32]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[N:16]=[CH:15]3)[S:18][C:19]=2[C:29]([NH2:31])=[O:30])[CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a mixture of 3.2 g (6.96 mmole) of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.25c) and 50 mL of dichloromethane at 0 degrees was added, dropwise, 5.86 mL (56 mmole) of boron trifluoride-dimethylsulfide complex. The mixture was stirred at ambient temperature for 1 hour and then 50 mL of water was added. The mixture was stirred vigorously for 1 hour. The precipitate was collected by filtration to give 2.6 g of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:7]=3[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)ccc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.96 g, 5.58 mmol) was dissolved in DMF (20 mL), and sodium hydride (60% weight dispersion in mineral oil, 330 mg, 8.37 mmol) was added. After 30 minutes, methyl iodide (0.52 mL, 8.4 mmol) was added, and the reaction stirred for a further 2 h. The mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (1.75 g, 86%) as a white powder: 1H NMR (500 MHz, CD3OD) δ 7.41 (d, J=1.5 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 4.60 (br s, 2H), 3.73 (br s, 2H), 3.59 (s, 3H), 2.76 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 22.5 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (21 mg, 23% over 2 steps) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.36 (s, 1H), 8.27 (dd, J=8.8, 1.9 Hz, 1H), 8.24 (d, J=2.7 Hz, 2H), 8.06 (d, J=8.8 Hz, 1H), 7.90 (dd, J=9.4, 2.6 Hz, 1H), 7.27 (m, 2H), 7.08 (d, J=9.4 Hz, 1H), 4.16 (p, J=6.2 Hz, 1H), 4.05 (dd, J=11.9, 6.5 Hz, 1H), 3.88 (dt, J=10.8, 7.5 Hz, 1H), 3.79 (dt, J=10.5, 3.3 Hz, 2H), 2.81 (p, J=6.0 Hz, 1H), 2.61 (dq, J=13.3, 6.6 Hz, 1H), 2.33 (td, J=13.4, 5.3 Hz, 1H), 1.20 (m, 4H); ESI MS m/z 518 [C28H25ClFN5O2+H]+; HPLC 99.4% (AUC), tR=10.02 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:32][O:31][C:27]1[CH:26]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[O:13][N:12]=[C:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:28]=1[O:29][CH3:30]
Reactant: Clc1nccc(Nc2cc(C3CCCCC3)no2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2nccc(Nc3cc(C4CCCCC4)no3)n2)cc(OC)c1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(3-cyclohexylisoxazol-5-yl)-4-pyrimidineamine (Step C) and 3,4,5-trimethoxyaniline. MS (MH+)=426.5; Calc'd for C22H27N5O4— 425.49.
Reaction SMILES: [C:1]([S:20][C@@H:21]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]1[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[C:1]([S:20][C@@H:21]1[O:29][C@H:28]([CH2:30][O:31][S:33]([CH3:32])(=[O:35])=[O:34])[C@@H:26]([O:27][S:33]([CH3:32])(=[O:35])=[O:34])[C@H:24]([O:25][S:33]([CH3:32])(=[O:35])=[O:34])[C@H:22]1[O:23][S:33]([CH3:32])(=[O:35])=[O:34])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1OS(C)(=O)=O
Reaction time: 22 h

Procedure:
S-Trityl-1-thio-β-D-glucopyranose (3.6 g.) was dissolved in 50 ml. dry pyridine, cooled to 0° while 5 ml. (7.5 g.) of methylsulfonyl chloride was added. The solution was placed in the refrigerator for 22 hours until thin layer chromatography showed only traces of starting material or partially reacted products remaining. The solvent was removed at reduced pressure. The oily residue was dissolved in chloroform (200 ml.) and was washed with dilute hydrochloric acid and brine. Evaporating the dried organic extract yielded a product which was chromatographed over a silica dry-column using 20% ethyl acetate-80% chloroform eluant. Pure S-trityl-2,3,4,6-tetra-O-methylsulfonyl-1-thio-β-D-glucopyranose was obtained from ether.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[Cl:37])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[Cl:37])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: OC1CCOC1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (1.76 grams; 0.02 mole), toluene (50 ml) and triethylamine (2.0 grams; 0.02 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (7.60 grams; 0.02 mole) in toluene (10 ml) was slowly added with stirring. After the addition was completed, stirring was continued overnight. After this time, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The dried solution was then stripped of solvent under reduced pressure leaving a brown oil. This oil was purified by silica gel chromatography using toluene and ethyl acetate/toluene mixtures as the eluant. The purified oil was triturated in ethanol to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoate as a white solid, melting point at 55° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:25])[CH2:15][S:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:25])[CH2:15][S:16]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CS(=O)Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CS(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylmethanesulfinyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[NH2:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)OC>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[N:25]=[CH:26]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(Cc2ccccc2)CC1
Yield: 629.2 %

Procedure:
The crude material from step 2 (130 g) was stirred in 300 mL trimethylorthoformate containing 4-toluenesulphonic acid (8 g) at 90° C. for one hour, and collecting the methanol distillate. The reaction was cooled and filtered to give 108 g 1-(1-benzylpiperidin-4-yl)-5-methylsulphonyl-1H-benzimidazole as a brown solid.