Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=CC=Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccccc1C=CC=CC(=O)O
Temperature: 0 °C
Yield: 85.5 %

Procedure:
A stirred mixture of 0.85 g (2.7 mmol) of methyl 5-[2-(tert-butoxycarbonylaminomethyl)phenyl]-2,4-pentadienoate, 1.17 g (11 mmol) of sodium carbinate, 15 ml of water and 15 ml of methanol was heated at reflux for 2 hours. After the produced methanol was distilled off, the solution was cooled to 0° C. and carefully acidified with 1N hydrochloric acid. The resulting mixture was extracted with methylene chloride and the extracts were washed with brine, dried (Na2SO4) and concentrated. Recrystallization of the residue from 1:3 methylene chloride:hexane gave 0.7 g (86%) of the product as crystals, mp 179°-182° C. (dec).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]#[N:42])=[CH:35][C:34]=2[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]#[N:42])=[CH:35][C:34]=2[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(O)c(Cc3ccccc3)c2)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
0.90 ml (0.90 mmol, 3 eqv) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 164.3 mg (0.30 mmol) 3-(3′,3″-Dibenzyl-2-isobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (27) in 7 ml dry CH2Cl2 at 0° C. via syringe. After that, the solution was stirred for 2 h at 0° C. and then for 4 h at rt. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (2+1)) yielded 137.5 mg (0.26 mmol, 86%) 28 as a colorless oil: Rf (Hexanes/EtOAc (2+1)) 0.35; 1H NMR (500 MHz, CDCl3) δ 0.67 (d, 6H, J=6.62 Hz), 1.61 (m, 1H), 2.40 (d, 2H, J=7.09 Hz), 2.58 (t, 2H, J=7.41 Hz), 2.91 (t, 2H, J=7.41 Hz), 3.89 (s, 2H), 3.93 (s, 2H), 5.57 (s, 1H), 6.74 (d, 1H, J=8.04 Hz), 6.90 (m, 2H), 6.99-7.26 (m, 16H); LRMS (EI) m/z 536 (19), 535 (46), 501 (10), 446 (9), 369 (21), 91 (100), 78 (12), 76 (10); HRMS (EI) Calcd. for C39H37NO: 535.287514. Found: 535.287420.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.CN.Cl.[C:17]([BH3-])#[N:18].[Na+]>CO.O1CCOCC1>[CH3:17][NH:18][CH2:12][C:10]1[O:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2cccnc2)o1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CNCc1ccc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a solution 23 (104 mg, 0.60 mmol) was added a solution of methylamine (2.0 M, 1.8 mL, 3.6 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.3 mL, 1.2 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (38 mg, 0.6 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 48 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 10/90, Rf=0.1) to afford the title compound 41 (94 mg, 84% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.89 (m, 1H), 8.46 (m, 1H), 7.91 (m, 1H), 7.28 (m, 1H), 6.67 (d, J=3.2 Hz, 1H), 6.31 (d, J=3.2 Hz, 1H), 3.82 (s, 2H), 2.49 (s, 3H), 2.14 (br s, 1H); LRMS (ESI) m/z calcd for C11H13N2O [M+H]+ 189. found 189; m/z calcd for C10H8NO [M−NH(CH3)]+ 158. found 158; HRMS (ESI) m/z calcd for C11H13N2O [M+H]+ 189.1028. found 189.1041; HPLC>95% (tR=8.74 min, 60 (A):40 (B): 0.02 (C); tR=3.69 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([OH:26])[CH:28]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccccc1
Yield: 65.9 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.18 g, 18.4 mmol), (prepared as described for the starting material in Example 4), DMF (1 ml) and thionyl chloride (70 ml) was heated at reflux under argon for 2 hours. The mixture was allowed to cool, excess thionyl chloride was removed by evaporation and the residue azeotroped to dryness with toluene. The resulting crude 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride was suspended in isopropanol (50 ml) and 3-hydroxy4-methylaniline (2.60 g, 21.1 mmol) added. The mixture was heated at reflux for 3 hours and then allowed to cool. The precipitated product was collected by filtration, washed with isopropanol and dried to give 7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazoline (4.7 g, 60%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]2[CH2:11][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:33][C:28]5=[N:29][CH:30]=[CH:31][CH:32]=[C:27]5[O:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:14][C:15]=2[N:16]=1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[O:26]1[C:27]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[O:33][C@@H:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:12]3[CH2:13][CH2:14][C:15]4[N:16]=[C:8]([NH2:7])[S:9][C:10]=4[CH2:11]3)=[CH:23][CH:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)Nc1nc2c(s1)CN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)CC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nc2c(s1)CN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl}-carbamic acid tert-butyl ester (prepared from Intermediate N according to General Method K) (50 mg, 0.10 mmol) in DCM (2 mL) with several drops MeOH is added 4M HCl in 1,4-dioxane (1.0 mL, 4.0 mmol) and the reaction stirred at rt for 16 h. The reaction is concentrated, suspended in Et2O and filtered to give the title compound 258. (LC/MS method 16: ES+ m/z 381.4 [M+H]+, Rt=0.36 m)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 69.2 %

Procedure:
To a solution of indole-5-carboxaldehyde (2.00 g, 13.8 mmol) in dimethylformamide (50 mL) were added sodium hydride (60% oil dispersion; 828 mg, 20.7 mmol) and p-toluenesulfonyl chloride (3.16 g, 16.6 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 13 h at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5:1 hexane/ethyl acetate) to afford 1-(4-methylphenyl)sulfonylindole-5-carboxaldehyde (2.86 g, 69%).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=O)=[CH:13][CH:12]=1>C(OCC)C>[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH2:4])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Product: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
An equivalent of methyl magnesium bromide/diethyl ether solution is reacted with 4,4′-dimethoxybenzophenone (24.2 g, 0.1 mol) dissolved in anhydrous diethyl ether over a 60 minute period at ambient temperature. The reaction mixture is poured onto ice and extracted with ether. The ether is removed by distillation and replaced with ethyl acetate (100 mL). The ethyl acetate solution is refluxed for one hour over anhydrous magnesium sulfate. Methylene chloride (300 mL) is added and the magnesium sulfate removed by filtration. The solvent is distilled leaving 16.9 g of the title compound as a white solid melting at 137° C. whose structure is consistent with 1Hnmr and mass spectrometry.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH2:11]([C:13]1[C:18]([CH2:19][NH2:20])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][C:18]2[C:13]([CH2:11][CH3:12])=[N:14][CH:15]=[N:16][CH:17]=2)[N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CCc1ncncc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1ncncc1CNc1ncc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a mixture of 2,4-dichloropyrimidine-5-carbonitrile (1.0 equiv. 61.4) and (4-ethylpyrimidin-5-yl)methanamine (1.0 equiv.) in isopropanol (0.2 M) was added DIEA (2.0 equiv.). The mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with a solution of ammonium chloride and concentrated under vacuum to give crude product, which was purified by silica gel chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (11.4% yield) as brown solid. 1H-NMR (400 MHz, CD3OD) δ (ppm) 9.95 (d, J=3.2 Hz, 1H), 8.64 (d, J=12.0 Hz, 1H), 8.58 (d, J=19.6 Hz, 1H), 4.70 (d, J=20.4 Hz, 2H), 2.97-2.87 (m, 2H), 1.33-1.27 (m, 3H); MS (ESI) m/z 275.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-(5-Fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (3.1 g, 12.5 mmol), tert-butyl-1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO (50 mL) at 80° C. overnight. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. Yield 4.6 g (86%); 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9 H), 2.0 (br s, 2 H), 3.01 (s, 3 H), 3.28 (s, 3 H), 3.3-3.8 (br, 8 H), 6.64 (d, J=8.1 Hz, 1 H), 6.74 (d, J=4.8 Hz, 1 H), 8.09 (d, J=8.1 Hz, 1 H); MS (ESI+) for C18H28N4O6S m/z 428.1709 (M+) (calc. 428.1730).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]=[C:17]2[N:21]3[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:29][C@H:20]3[CH2:19][S:18]2)[S:14][CH:15]=1)=[O:6].[ClH:30].C(OCC)C>C(O)C>[ClH:30].[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]=[C:17]2[N:21]3[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:29][C@H:20]3[CH2:19][S:18]2)[S:14][CH:15]=1)([OH:6])=[O:4]
Reactant: COC(=O)CCCCc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)CCCCc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Temperature: 20 °C

Procedure:
5 N Aqueous sodium hydroxide (20 cc) is added to a solution of (S)-3-{[4-(4-methoxycarbonylbutyl)-thiazol-2-yl]imino}-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (7.4 g) in ethanol (60 cc). The mixture is heated under reflux for 2 hours. After cooling to 20° C., it is acidified by adding 12 N hydrochloric acid (d=1.19; 10 cc). Diethyl ether (30 cc) is added and the mixture is cooled to 0° C. The resulting precipitate is filtered off, washed with water (4×15 cc), ethanol (2×10 cc) and diethyl ether (2×30 cc) and crystallised by dissolving it in boiling propan-2-ol (200 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with propan-2-ol (20 cc) and diethyl ether (50 cc) and dried at 45° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-{[4-(4-carboxybutyl)thiazol-2-yl]imino}-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline hydrochloride (4.9 g), m.p.=214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=3[CH3:25])[N:10]=2)[CH:6]=[N:7][CH:8]=1.CC1C(NC2N=C(C3C=NC=C(N4CCCC4)C=3)C=CN=2)=CC(N)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=3[CH3:25])[N:10]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(-c2ccnc(Nc3cc([N+](=O)[O-])ccc3C)n2)c1
Agent: Cc1ccc(N)cc1Nc1nccc(-c2cncc(N3CCCC3)c2)n1
Product: COc1cncc(-c2ccnc(Nc3cc(N)ccc3C)n2)c1

Procedure:
N3-[4-(5-Methoxy-pyridin-3-yl)-pyrimidin-2-yl]-4-methyl-benzene-1,3-diamine 14 is prepared by hydrogenation of 13 using a similar protocol for the preparation of 10. 1H NMR (400 MHz, d6-DMSO) δ 8.90 (d, J=1.6 Hz, 1H), 8.71 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H), 8.01 (dd, J=2.0, 3.2 Hz, 1H), 7.43 (d, J=5.2 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.38 (dd, J=2.4, 8.0 Hz, 1H), 4.87 (s, 2H), 3.95 (s, 3H), 2.12 (s, 3H). MS (m/z) (M+1)+: 308.1
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][CH:28]=1.Cl>O1CCOCC1>[N:27]1([C:2]2[N:3]=[C:4]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[CH:28]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CCN(Cc2cc3nc(-n4cnc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]dimethylamine (50 mg, 0.13 mmol), benzimidazole (32 mg, 0.27 mmol) and concentrated HCl (53 μL, 0.64 mmol) in 1,4-dioxane (1 mL) was subjected to microwave irradiation at 150° C. for 40 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (2 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10) to afford 110 as a white solid (38 mg, 63%). LCMS (Method F): RT=5.12 min, [M+H]+ 478.2. 1H NMR (CDCl3, 400 MHz): δ 9.04 (s, 1 H); 8.61-8.57 (m, 1 H); 7.86-7.82 (m, 1 H); 7.43-7.31 (m, 2 H); 7.27 (s, 1H); 4.07 (t, J=4.8 Hz, 4 H); 3.92 (t, J=4.8 Hz, 4 H); 3.82 (s, 2 H); 3.08-2.99 (m, 2 H); 2.30 (s, 6 H); 2.20-2.10 (m, 3 H); 1.88-1.78 (m, 2 H); 1.66-1.54 (m, 2 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of the 6-methoxy-2-(4-nitropheyl)benzothiazbles 5 (22 mg, 0.077 mmol) and tin (II) chloride dihydrate (132 mg, 0.45 mmol) in boiling ethanol was stirred under nitrogen for 4 hrs. Ethanol was evaporated and the residue was dissolved in ethyl acetate (10 mL), washed with 1 N sodium hydroxide (2 mL) and water (5 mL), and dried over MgSO4. Evaporation of the solvent gave 19 mg (97%) of the product 6 as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18](O)=[O:19])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][CH2:18][OH:19])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(-c2nc(CC(=O)O)c[nH]2)ccc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nc(CCO)c[nH]2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.45 g (5.23 mmol) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid are dissolved in 36 ml THF and cooled to 0° C. and combined with 10 ml (18 mmol) borane-THF complex (1.8 mol/V). After 1 h the mixture is heated to 20° C. and stirred for 16 h. Water is added until the development of gas has ended. Then the mixture is extracted twice with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phases are combined, dried and freed from the solvent in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30][CH2:31][CH3:32])[C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CO.[OH:35]OS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30]([CH2:31][CH3:32])=[O:35])[C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(SCC)cc3n2COCCOC)c1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)CC)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 44 h
Yield: 45 %

Procedure:
To a mixture of 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (EXAMPLE 95, product from Step A) (0.501 g, 1.14 mmol) and methanol (5.7 mL) was added a solution of Oxone®/potassium peroxymonosulfate (1.47 g, 2.40 mmol) in water (5.7 mL). The mixture was stirred for 44 h at 23° C. EtOAc (50 mL) and water (30 mL) were added and the biphasic mixture was stirred. The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-80% EtOAc/hexanes) to yield the tiled compound (0.260 g, 48% yield, 5:2 mixture of regioisomers) and 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.232 g, 45% yield, 2:1 mixture of regioisomers). MS (ESI/CI): mass calcd. for C13H23ClN4O6S, 470.1; m/z found, 471.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.91 (d, J=0.6 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.82 (s, 1H), 6.21 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72-3.67 (m, 2H), 3.53-3.42 (m, 4H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.30 (t, J=7.4 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([O:12][CH2:14][CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: COCCBr
Reactant: Oc1cc(I)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(I)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 3-iodo-5-(trifluoromethyl)phenol (5 g, 17.36 mmol, 1.00 equiv), 1-bromo-2-methoxyethane (3.6 g, 25.90 mmol, 1.49 equiv) and potassium carbonate (7.2 g, 52.09 mmol, 3.00 equiv) in N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 h. The resulting mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 5.1 g (85%) of 1-iodo-3-(2-methoxyethoxy)-5-(trifluoromethyl)benzene as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 7.63-7.60 (m, 2H), 7.28 (s, 1H), 4.21-4.18 (m, 2H), 3.66-3.64 (m, 3H), 3.33 (s, 3H) ppm. LCMS (method D, ESI): RT=1.67 min.
Reaction SMILES: C1(C2C=CC(C(=O)C[Cl:13])=CC=2)CCCCC1.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[CH2:20][Mg:21]Cl>CCOCC>[Mg:21].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[CH2:20][Cl:13]
Reactant: O=C(CCl)c1ccc(C2CCCCC2)cc1
Reactant: Cl[Mg]Cc1ccc(Cl)cc1Cl
Solvent: CCOCC
Product: ClCc1ccc(Cl)cc1Cl
Product: [Mg]

Procedure:
A solution of 47.3 g (0.2 mol) of 4-cyclohexylphenacyl chloride in 200 ml of ether is added dropwise to a solution of 0.4 mol of 2,4-dichlorobenzyl magnesium chloride, obtained from 10.6 g (0.44 mol) of magnesium and 78 g (0.4 mol) of 2,4-dichlorobenzyl chloride in 150 ml of ether. The reaction mixture is poured onto aqueous ammonium chloride solution and the ether phase is separated off, washed with water, dried over sodium sulphate and evaporated. 79.5 g (99% of theory) of 2-(4-cyclohexyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol of refractive index nD20 =1.5780 are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.C1N2CCN(CC2)C1.[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1.C(#N)C>>[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23]([NH:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:25])=[O:24])[CH:22]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: Nc1cccnn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1cccnn1)c1cc(Cl)c(F)cc1F
Reaction time: 18 h
Yield: 24.9 %

Procedure:
Pyridazin-3-amine (1.00 g, 10.5 mmol) and triethylenediamine (1.18 g, 10.5 mmol) was added concurrently to a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (2.60 g, 10.5 mmol) in acetonitrile (50 mL, 1000 mmol). The reaction mixture was stirred for 18 h then concentrated. The residue was dissolved in ethyl acetate (30 mL), washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified on automated silica gel chromatography (chloroform to 50% of 10% methanol in chloroform) to give 800 mg of the desired product as a yellow solid.