Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(=O)C(C)C.C(N(CC)CC)C.[BH4-].[Na+]>O>[CH2:4]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH2:13][CH2:14]1)[CH:1]([CH3:3])[CH3:2]
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNCC4CC4)CC3)ccnc2c1
Agent: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CNCCCN1CCN(CCCNc2ccnc3cc(Cl)ccc23)CC1
Reaction time: 3 h

Procedure:
To a solution of N4-3-[4(3-aminopropyl)piperazine]propyl-7-chloroquinolin-4-amine (Intermediate of example 12) (150 mg, 0.41 mmol) in CH2C2 (4 mL) isobutyraldehyde (62 μL, 0.46 mmol), triethylamine (26 μL, 0.16 mmol) and 3 Å molecular sieves are added. The reaction media is stirred for 3 h and cooled before NaBH4 (78 mg, 2.05 mmol) is added portionwise over 30 min. Stirring is left for 1.5 h, water (10 mL) is added and the media is filtered. Compound is extracted with CH2Cl2 (3×20 mL). Combined organic layers are dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH:90/10/1.4).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](N(CC)CC)[CH3:34].ICC>CN(C)C=O.CO.CS(C)=O>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:24]#[C:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH2:32]2)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCN1CCNCC1)cn2COCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CO
Solvent: CCI
Product: CCCCc1nc(N)c2c(n1)c(C#CCN1CCN(CC)CC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.1 %

Procedure:
To a solution of 5-((benzyloxy)methyl)-2-butyl-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (38 mg, 0.088 mmol) in anhydrous N,N-dimethylformamide (1 mL) at room temperature was added triethylamine (25 μL, 0.179 mmol) and iodoethane (10 μL, 0.125 mmol). The reaction was stirred at room temperature for 5 hours. The reaction was evaporated in vacuo to yield a pale yellow oil. The oil was dissolved in MeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method B). The appropriate fraction was evaporated in vacuo to yield the title compound as a pale yellow oil (28 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[C:20]([CH2:34][O:35][CH2:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[C:20]([CH2:34][O:35][CH2:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate (prepared as described in Parts A-C of Example 397, 21.0 g, 41.6 mmol) and concentrated hydrochloric acid (13 mL) in ethanol (100 mL) was heated at reflux for 1 hour. The solution was allowed to cool to room temperature and a precipitate formed that was isolated by filtration to yield 12.10 g of 4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-1-amine dihydrochloride as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23]6(OCC[O:24]6)[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ncn3cc4c(cc23)CCCC2CC3(CCC42Cc2ccccn2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCC2(Cc3ccccn3)c3cn4cnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
rac-(4aR,13bS)-9-(4-Fluorophenyl)-13b-(pyridin-2-ylmethyl)-1,2,4,4a,5,6,7,13b-octahydro spiro[benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridine-3,2′-[1,3]dioxolane] (148, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.380 g, 0.786 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was treated with 6 N hydrochloric acid (0.52 mL, 3.1 mmol) then stirred at rt for about 4 h. Water (1 mL) was added and the mixture was stirred for about 12 h. Sat. aq. NaHCO3 (˜10 mL) and EtOAc (20 mL) were added to the mixture then the layers were separated. The organic layer was washed with brine (˜15 mL) then dried over MgSO4, filtered and concentrated to yield rac-(4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridin-3(2H)-one (149, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.323 g, 94%); LC/MS, method 3, Rt=2.30 min, MS m/z 440 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.38-8.36 (m, 1H), 8.18 (s, 1H), 7.96-7.90 (m, 3H), 7.75 (s, 1H), 7.43-7.39 (m, 1H), 7.27-7.19 (m, 2H), 7.08-7.04 (m, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.70 (d, J=13.6 Hz, 1H), 3.45-3.38 (m, 2H), 3.20-3.02 (m, 2H), 2.69-2.62 (m, 1H), 2.29-1.87 (m, 7H), 1.72-1.63 (m, 1H), 1.46-1.32 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:37][CH2:38][CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]([CH2:37][CH2:38][CH3:39])=[N:10][C:11]=3[CH:16]=2)=[CH:34][CH:33]=1)#[N:36]
Reactant: CCCc1nc2cc(N(Cc3ccc(C#N)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccc(C#N)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Cyano-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 4H), 7.48 (m, 4H), 7.16 (m, 2H), 6.78 (m, 1H), 4.92 (s, 2H), 4.33 (s, 2H), 2.65 (t, 2H), 1.71 (m, 2H), 0.95 (t, 3H). MS calculated for C26H23FN4O4S+H: 507, observed: 507.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:29])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[C:8]2[NH:7][C:6]=1[CH3:30])=[O:4].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:29])[N:20]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[C:8]2[N:7]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:6]=1[CH3:30])=[O:4]
Reactant: COC(=O)C1=C(C)Nc2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
Intermediate 6 (100 mg, 0.24 mmol), 3-trifluoromethylphenylboronic acid (95 mg, 0.5 mmol), Et3N (250 μl, 1.8 mmol), and copper (II) acetate (50 mg, 0.4 mmol) were dissolved in DCM (10 mL), and stirring at RT was continued for 48 hours. The reaction mixture was filtered to remove the solid and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-15% MeOH in DCM. Appropriate fractions were combined and concentrated in vacuo and the resulting residue further purified using preparative HPLC system 2 to yield the title compound as a white solid (20 mg).
Reaction SMILES: F[CH:2](F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1>CO.[Pd]>[C:3]1([CH3:2])[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(-c4ccc(C(F)F)cc4)oc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3o2)cc1
Yield: 72.8 %

Procedure:
Intermediate 48 (45 mg, 0.14 mmol) dissolved in MeOH (10 ml) and added Pd/C (5%) (100 mg). This mixture was stirred under 60 Psi hydrogen pressure for 15 h in an autoclave. After completion of the reaction, reaction mixture filtered through a bed of celite and celite was washed with MeOH. Combined MeOH layers were removed on rotavapour to obtain the residue. Residue was triturated with petether to obtain the titled compound (40 mg) as an off-white solid. MS (m/z): 393.2 [M+H]+.
Reaction SMILES: ClC1C=CC([C@H:8]2[C@H:13]([O:14]CC3C=CC=CC=3)[C@@H:12]([O:22]CC3C=CC=CC=3)[C@H:11]([O:30]CC3C=CC=CC=3)[C@@H:10]([CH2:38][O:39]CC3C=CC=CC=3)[O:9]2)=CC=1CC(=N)NN.C(C=O)=[O:53]>CCO>[CH2:38]([OH:39])[C@H:10]1[O:9][C:8](=[O:53])[C@H:13]([OH:14])[C@@H:12]([OH:22])[C@@H:11]1[OH:30]
Reactant: N=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)NN
Reactant: O=CC=O
Solvent: CCO
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
2-(2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)acetimidohydrazide (compound 45, crude 1 g from step 1) in EtOH (30 ml) reacted with glyoxal (5 ml, 30% in water) at 0° C., and allowed to warm up at room temperature. After the reaction mixture was stirred for 3 hours, it was evaporated under reduced pressure to remove volatile compounds. The residue was purified with silica gel (Hx/EtOAc=⅓) to provided title compound (324 mg, 60% overall yield form intermediate 2).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nc[nH]c1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Yield: 69.6 %

Procedure:
Ethyl 5-methyl-4-1H-imidazolecarboxylate (6.16 g) in toluene (100 ml), triphenylmethyl chloride (11.12 g) and triethylamine (5.6 ml) were heated at reflux for 18 h. Toluene was removed under reduced pressure and the residue was dissolved in dichloromethane (100 ml), washed with water (4×50 ml) dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using 1% methanol in dichloromethane as eluant with a trace of triethylamine. This afforded the title compound (11 g), m.p. 188°-190° C. δH (250 MHz, CDCl3) 1.38-1.42 (3 H, t, J=6.5 Hz, CH3), 1.86 (3 H, s, CH3), 4.36-4.40 (2 H, q, J=7.2 Hz, CH2), 7.10-7.46 (16 H, m, ArH); m/z (NoM+), 243 (Ph3C+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[CH:29][O:30][CH3:31])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC([O-])(C)C.[Na+].C(OC1C=C(C2[N:54]=C(C3CC(=O)C3)N3C=CN=C(Cl)C=23)C=CC=1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[CH:29][O:30][CH3:31])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:54])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Reactant: O=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Temperature: 70 °C

Procedure:
1-(3-Benzyloxy-phenyl)-8-chloro-3-(3-methoxymethylene-cyclobutyl)-imidazo[1,5-a]pyrazine: To a solution of Ph3PCH2OMeCl (2.6 g, 7.44 mmol) in benzene (37 mL) a solution of sodium tert-amylate (819.0 mg, 7.44 mmol) in benzene (9.0 mL) was added at rt. The dark red solution was allowed to stir at rt for 10 min. at which point a solution of 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone in benzene (30.0 mL) was added dropwise at rt. The reaction mixture was then heated to 70° C. for 4 h. The reaction was then quenched with NH4Cl sat. Aq. and extracted with diethyl ether (3×). The organic layers were washed with H2O (1×), brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. Purification via HPFC using a 50 g Jones silica gel column (30% EtOAc:Hex) to yield the desired product as a light yellow solid; 1H NMR (CDCl3, 400 MHz) δ 3.29-3.33 (m, 4H), 3.59 (s, 3H), 3.90 (q, 1H, J=8.2 Hz), 5.14 (s, 2H), 5.93 (s, 1H), 7.26-7.66 (m, 11H); MS (ES) 432.05 (M+1), 434.01 (M+3), 435.02 (M+4).
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[O:15]=[S:12]1(=[O:16])[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([C:22]3[CH:21]=[CH:20][C:19]([C:33]4[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=4)=[C:18]([F:17])[CH:23]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: O=S1(=O)CCC(Oc2ncccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3cccnc3OC3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-((3-bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=1.3, 2H), 8.21 (dd, J=4.9, 1.8, 1H), 7.90 (dd, J=7.4, 1.8, 1H), 7.64 (m, 1H), 7.58 (dd, J=12.4, 1.5, 1H), 7.53 (dd, J=8.0, 1.7, 1H), 7.16 (dd, J=7.4, 4.9, 1H), 6.89 (s, 2H), 5.42 (dd, J=6.3, 3.0, 1H), 3.21 (dd, J=14.5, 8.0, 2H), 3.09-3.01 (m, 2H), 2.34-2.24 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:13][NH:14][CH3:15]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: CNC
Solvent: CO
Product: CN(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
5-Bromo-6-chloropyridine-3-sulfonyl chloride (1.455 g, 5 mmol) in methanol (20 mL) was treated with 2.0 N dimethylamine (6.25 mL, 12.50 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed, and the solid was washed with water several times. The solid was then purified by chromatography on silica gel eluting with 15% ethyl acetate in hexanes to give 0.8 g of the title compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>O1CCCC1.O>[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COc1ccccc1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccccc1OCC(C)C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.92 g of 60% sodium hydride was suspended in 30 mL of tetrahydrofuran, to which 5.0 mL of ethyl diethylphosphonoacetate was added dropwise over 5 minutes at room temperature, and this mixture was stirred for 30 minutes at 40° C. Then, after 3.40 g of 2-isobutoxybenzaldehyde dissolved in 20 mL of tetrahydrofuran was added to the mixture dropwise over 20 minutes at room temperature, this mixture was stirred for one hour at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=9:1] to yield 4.30 g of ethyl (E)-3-(2-isobutoxyphenyl)-2-propenoate as light yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH:17]([Br:19])[CH3:18].O>CN(C=O)C>[Br:19][CH:17]([CH3:18])[CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Br)COc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a stirring solution of 4-iodophenol (15 g, 70 mmol) and K2CO3 (12.4 g, 90 mmol) in DMF (30 mL) was added 1,2-dibromopropane (7.8 mL, 90 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. Water (500 mL) was added and the reaction mixture was extracted with dichloromethane, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. Purified on silica gel chromatography, eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (10 g, 29 mmol).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9](OC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].CO>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: COC(=O)c1nc(C(C)C)cs1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1csc(CO)n1
Yield: 5 %

Procedure:
Using the procedure of Example 5B, but replacing ethyl 2-isopropyl-4-thiazolecarboxylate with methyl 4-isopropylthiazole-2-carboxylate provided, after silica gel chromatography using 2% methanol in chloroform, the desired compound (Rf 0.3, 5% methanol in chloroform) in 96% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[S:4][N:3]=1.B(F)(F)F.S(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[S:4][N:3]=1
Reactant: COc1ccc(-c2c(-c3c(C)nsc3C)n(C#N)c3ccccc23)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: Cc1nsc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Temperature: 1 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
2-(3,5-dimethylisothiazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile (38 mg, 0.11 mmol) was dissolved in 10 ml DCM and the mixture was cooled in an ice bath. BF3.SMe2 (0.56 ml, 5.29 mmol) was added drop wise and the mixture was stirred at 0-2° C. for 16 h. A few drops MeOH were added followed by NaHCO3 (aq, sat). The layers were separated and the organic layer was concentrated. The crude product was purified by preparative HPLC. 18.0 mg 2-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7])([O-])=O>[Fe]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(N2CCCCC2)cccc1[N+](=O)[O-]
Agent: [Fe]
Product: N#Cc1c(N)cccc1N1CCCCC1

Procedure:
2-Amino-6-(1-piperidinyl)benzonitrile is prepared from 2-nitro-6-(1-piperidinyl)benzonitrile as in Example 9 by iron reduction.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>CO>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:9][CH:10]=1
Reactant: NCCc1ccncc1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCc3ccncc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (220 mg, 0.528 mmol) obtained in Example 54 and 4-(2-aminoethyl)pyridine (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Water was added to the residue thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride=1:30 eluate was concentrated under reduced pressure to give the title compound (114 mg, 0.227 mmol, 43%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10][OH:11])=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.C1COCC1.[CH2:26]([NH2:28])[CH3:27]>C(Cl)Cl.C(Cl)(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]=[C:6]1[C:5]1[CH:12]=[CH:13][C:2]([CH2:27][CH2:26][NH2:28])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CCN
Reactant: O=C(NCCO)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: NCCc1ccc(C2=NCCO2)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of intermediate 4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (0.40 g, 1.6 mmol) in anhydrous DCM (20 mL) added dropwise thionyl chloride (0.29 mL, 4.0 mmol). After stirring 2 h the reaction mixture was diluted with chloroform and concentrated. The resulting yellow oil was diluted cautiously with 2.0 M solution of ethylamine in THF (10 mL, 20 mmol) and heated in a sealed tube at 65° C. After 2 h the reaction mixture was cooled, concentrated and diluted with THF (20 mL). This solution was combined with an aqueous solution of 20% KOH (5 mL) and tetrabutylammonium bromide (20 mg). After stirring rapidly 2 h the mixture was extracted with Et2O (2×100 mL). The combined organic layers were washed with water and brine, dried (MgSO4), concentrated and chromatographed (silica gel, MeOH/DCM, 1:19) to yield [4-(4,5-dihydrooxazol-2-yl)-2-nitrophenyl]ethylamine (0.17 g, 45%) as a yellow solid. TLC (1:19 MeOH/DCM Rf 0.56).