Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:24][CH2:23][C:25](=[O:26])[CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(CNCc2ccc(Cl)cc2Cl)C1
Solvent: ClC(Cl)Cl
Product: CC(=O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Yield: 81.4 %

Procedure:
To a solution of 3-[(2,4-dichlorobenzylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 0.58 mmol) in CHCl3 (3 mL) is added methyl vinyl ketone (0.12 mL, 1.45 mmol). The reaction is refluxed under N2 overnight and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH4OH)/chloroform to yield 196 mg (81%) of 3-{[(2,4-dichlorobenzyl)-(3-oxo-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CD3OD) δH: 7.46-7.44 (2H, m), 7.35-7.32 (1H, m), 3.95-3.91 (2H, m), 3.7 (2H, s) 3.5-3.45 (2H, m), 2.9-2.75 (3H, m), 2.74-2.65 (4H, m), 2.1 (3H, s), 1.46 (9H, s). Mass spectrum (ion spray): m/z=415.2 (M+H).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:30]([NH:29][C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])=[O:31])=[CH:10][C:9]=2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 4-(2-(azetidin-1-yl)ethoxy)-3-(1-methyl-1H-pyrazol-5-yl)benzenamine (40.1 mg, 0.147 mmol) in CH2Cl2 (2 mL) was added 2,4-difluorophenyl isocyanate (18 μL, 0.152 mmol) and stirred for two hours. The crude reaction mixture was purified by SiO2 column chromatography (Eluent: methanol/CH2Cl2=1/6) to afford the title compound (50.4 mg, 80%). LCMS m/z (%)=428 (MH+, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.96 (bs, 1H), 8.47 (bs, 1H), 8.09-7.98 (m, 1H), 7.45-7.39 (m, 2H), 7.36 (d, J=2.71 Hz, 1H), 7.34-7.26 (m, 1H), 7.06 (d, J=8.94 Hz, 1H), 7.06-6.98 (m, 1H), 6.23 (d, J=1.85 Hz, 1H), 3.89 (t, J=5.49 Hz, 2H), 3.67 (s, 3H), 2.98 (t, J=6.92 Hz, 4H), 2.60 (t, J=5.47 Hz, 2H), 1.86 (quintet, J=6.99 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]#[C:29][Si](C)(C)C)[CH:26]=[CH:27][C:21]=2[N:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]#[CH:29])[CH:26]=[CH:27][C:21]=2[N:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nc(C3CCCN3C(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Potassium carbonate (144 mg) was added to 2-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.52 mmol) in 6 ml methanol. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(6-ethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (121 mg, yield 75%). LCMS-ESI−: calc'd for C18H21N3O2: 311.38; Found: 311.8 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[S:8][CH:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25]3)C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[N:6]=[C:5]1[O:35]C)(=[O:3])[NH2:2].B(Br)(Br)Br>C(Cl)Cl.CO>[F:34][C:33]1[C:28]([C:24]2([CH2:23][NH:15][C:12]3[N:13]=[N:14][C:9]([CH:7]4[N:6]=[C:5]([OH:35])[CH:4]([C:1]([NH2:2])=[O:3])[S:8]4)=[CH:10][CH:11]=3)[CH2:25][CH2:26][CH2:27]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC1=NC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)SC1C(N)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C1SC(c2ccc(NCC3(c4ncccc4F)CCC3)nn2)N=C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31060.1 %

Procedure:
To a stirring mixture of t-butyl 6-(5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (60 mg, 0.12 μmol) in CH2Cl2 (2 mL) was added BBr3 (140 μL, 1.2 mmol). The reaction was stirred at rt for 2 h and then at 60° C. for 15 min. The reaction was cooled to rt and carefully diluted with methanol (2 mL). The reaction was concentrated, diluted with ethyl acetate (20 mL), and saturated sodium bicarbonate (10 mL) was added. The mixture was agitated and then filtered. The subsequent crude solid was then purified using reverse phase chromatography to give 15 mg of 2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxamide as a yellow solid (M+H=401.3)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][NH:15][CH3:16].O.ON1C2C=CC=CC=2N=N1.CN(C=O)C>>[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][N:15]([CH3:16])[C:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CNCC(OC)OC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN(C)C(=O)[C@H]1CC[C@H](O)CC1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (1.00 g, 6.94 mmol), 2,2-dimethoxy-N-methylethanamine (0.909 g, 7.63 mmol), and 1-Hydroxybenzotriazole hydrate (1.17 g, 7.63 mmol) in DMF (25 mL, 320 mmol) was added N-(3-Dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (1.46 g, 7.63 mmol) at ambient temperature, and the solution was stirred at ambient temperature overnight. Most of the DMF was evaporated in vacuo, and the residue was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (4×25 mL), saturated with NaCl, and extracted again with EtOAc (5×25 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as yellow oil that was used without further purification in the next step. 1H NMR (400 MHz, CDCl3): δ=4.48 (t, J=5.4 Hz, 1H, major rotamer), 4.39 (t, J=5.4 Hz, 1H, minor rotamer), 3.70-3.61 (m, 1H), 3.45-3.42 (m, 2H), 3.43 (s, 6H, minor rotamer), 3.40 (s, 6H, major rotamer), 3.11 (s, 3H, major rotamer), 2.97 (s, 3H, minor rotamer), 2.56 (tt, J=11.6, 3.8 Hz, 1H, minor rotamer), 2.46 (tt, J=11.8, 3.4 Hz, 1H, major rotamer), 2.11-2.00 (m, 2H), 1.86-1.74 (m, 2H), 1.71-1.55 (m, 3H), 1.36-1.23 (m, 2H). MS (ES+): m/z=268.11 (87) [MNa+], 246.15 (42) [MH+], 214.13 (100) [MH+−MeOH]. HPLC: tR=2.36 min (polar—5 min, ZQ3).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:10](N)=[O:11]>>[CH:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:11]
Reactant: NC=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: O=CN[C@@H](CC(=O)O)C(=O)O

Procedure:
The process of claim 6 in which a slurry of L-aspartic acid in formamide is heated to form N-formyl-L-aspartic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C.C(OC(C)C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Solvent: CC(C)OC(C)C
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Yield: 94.8 %

Procedure:
17.7 g of 4-methyl-7-nitro-1H-indazole [Chem. Ber. 37: 2556 (1904)] and 68.0 g of tertbutoxybis(dimethylamino)methane are heated to 80° C. for 45 minutes, combined with diisopropyl ether, suctioned off, and washed with diisopropyl ether, thus producing 22.0 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine, mp 255° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
2-(4-Butoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared following an analogous procedure to the preparation described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with 1-bromobutane. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.71 (s, 1H), 8.28 (d, 1H), 7.43 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.75 (s, 1H), 6.69 (d, 1H), 6.54 (br, 2H) 3.95 (t, 2H), 3.16 (t, 2H), 3.04 (t, 2H), 2.47 (s, 3H), 2.30 (s, 3H), 1.69-1.77 (m, 2H), 1.43-1.54 (m, 2H), 0.97 (t, 3H). LRMS [M+H]=400.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromobenzenesulfonyl chloride (3.19 g, 12.5 mmol) was added to a solution of 4-amino-2-chloropyridine (642 mg, 5 mmol) in pyridine (5 ml) and dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue suspended in 2M NaOH (25 ml) and heated at 60° C. for 1 h. The reaction mixture was extracted with ethyl acetate (2×25 ml). The extracts were washed, dried and evaporated. The residue was suspended in methanol and filtered. Evaporation of the filtrate and trituration with diethyl ether afforded the title compound (D3), 1H NMR (DMSO) δ: 6.54 (1H, d), 6.62 (1H, s), 7.60-7.63 (4H, m), 7.66 (1H, d).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:26])[C:10](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccccc3)n2C)n(CCC)c1=O
Yield: 84.2 %

Procedure:
Compound 1 obtained in Example 1 (2.00 g, 5.90 mmol) was dissolved in 65 ml of N,N-dimethylformamide. To the solution were added 2.04 g (14.8 mmol) of potassium carbonate and then 0.74 ml (11.8 mmol) of methyl iodide, and the mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble substances were removed by filtration, and 500 ml of water was added to the filtrate. The mixture was extracted three times with chloroform, and the combined organic layers were washed twice with water and twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20% ethyl acetate/hexane), followed by recrystallization from ethanol/water to give 1.75 g (yield: 84%) of Compound 2 as white needles.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl.Cl[CH2:18][C:19]1[N:20]=[CH:21][S:22][CH:23]=1>>[S:22]1[CH:23]=[C:19]([CH2:18][N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[N:20]=[CH:21]1
Reactant: ClCc1cscn1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Agent: Cl
Product: N#Cc1ccc2c(ccn2Cc2cscn2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole hydrochloride: MS (ES) m/z 308 (M+1).
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[C:10]([CH:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](OCC)=[O:15])(=O)[CH3:11]>CCO>[CH3:7][C:6]1[NH:9][C:14](=[O:15])[C:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:11])[N:8]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nc(C)[nH]c1=O

Procedure:
A mixture of NaOEt (0.069 mol) in EtOH (prepared from 1.6 g of Na in 100 mL of EtOH), acetamidine hydrochloride (6.5 g, 0.069 mol), and diethyl 2-acetylsuccinate (15.0 g, 0.069 mol) was heated under reflux for 16 h. The mixture was concentrated, taken up in water (50 mL), and acidified with 2N HCl (12 mL). The aqueous mixture was extracted with CH2Cl2, and the extracts were dried (MgSO4) and concentrated. Trituration with either gave 3.9 g (27%) of product as a white solid, mp 175°177° C.
Reaction SMILES: [C:1]([C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:5][CH2:4]1)#[N:2].[NH2:29]N>CO>[C:1]([C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH2:29])[CH2:5][CH2:4]1)#[N:2]
Reactant: NN
Reactant: N#CC1(c2ccccc2)CCN(CCCc2cccc3c2C(=O)NC3=O)CC1
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(CCCN)CC1
Yield: 96 %

Procedure:
To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide (112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added and the mixture was stirred and refluxed for 20 hours. It was cooled, the white solid formed was filtered and washed with more methanol (200 mL). Solvent was evaporated from the filtrate and residue was dried under vacuum for 4 hours. Chloroform (500 mL) was added to this, stirred for 1 hour and filtered. The white solid was washed with more chloroform (200 mL), the solvent was evaporated from the combined filtrates to leave the product as an oil (70 g, 96%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH:14]([O:22][C:23]2[CH:37]=[CH:36][C:26]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=O)=[CH:25][CH:24]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:16]1([CH2:15][CH:14]([O:22][C:23]2[CH:37]=[CH:36][C:26]([CH2:27][NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1ccncc1)c1ccc(OC(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(CC(Cc2ccccc2)Oc2ccc(CNc3ccncc3)cc2)cc1

Procedure:
Lithium aluminum hydride reduction of 17-8 (1.36 g, 3.3 mmol) as described in Example 14 gave a quant. yield of the product 17-9 as a viscous oil. The hydrochloride melted at 151°-154° C.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=O)[CH2:24][N:25]5[C:29]([CH3:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]5)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:37]>N1C=CC=CC=1>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[S:37])[CH2:24][N:25]5[C:29]([CH3:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]5)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Solvent: c1ccncc1
Product: Cc1cc(C(F)(F)F)nn1CC(=S)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 1, Step B) (235 mg, 0.47 mmol) and phosphorus pentasulfide (104.5 mg, 0.235 mmol) in pyridine (5 ml) was heated under reflux for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was distributed between dichloromethane (10 mL) and water (10 mL). The organic layer was washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4), and concentrated under reduced pressure to give 240 mg of the title product, a compound of the present invention, as a white foam.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH:19]([CH3:21])[CH3:20])[S:5]1(=[O:23])=[O:22].[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=3)=[CH:30][NH:31]2)=[CH:27][CH:26]=1.[I-].[Na+].C(=O)(O)[O-].[Na+]>O>[CH2:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:4]([CH2:3][CH2:2][N:37]3[CH2:38][CH:39]=[C:34]([C:29]4[C:28]5[C:32](=[CH:33][C:25]([F:24])=[CH:26][CH:27]=5)[NH:31][CH:30]=4)[CH2:35][CH2:36]3)[S:5](=[O:23])(=[O:22])[N:6]([CH:19]([CH3:21])[CH3:20])[CH2:7][C:8]=2[CH:13]=1)(=[O:16])=[O:15])[CH3:18]
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCS(=O)(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
1-(2-Chloroethyl)-3,4-dihydro-6-(ethylsulfonyl)-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (1.03 g, 0.0027 mol), 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.706 g, 0.0033 mol), sodium iodide (0.408 g, 0.0027 mol) and sodium bicarbonate (1.586 g, 0.015 mol) were suspended in water (75 ml). The reaction mixture was heated at reflux overnight. The product mixture was then cooled to room temperature. The product was extracted into ethyl acetate (3×50 ml). The organic extracts were combined, washed with water (150 ml), dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-6-ethylsulfonyl-1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. δ(1H NMR, DMSO, ppm): 1.10 (9H, m), 2.50 (2H, m), 2.80 (4H, m), 3.25 (4H, m), 4.10 (3H, m), 4.90 (2H, s), 6.10 (1H, s), 6.90 (1H, dt), 7.20 (1H, dd), 7.35 (1H, d), 7.40 (1H, d), 7.80 (3H, m), 11.20 (1H, s).
Reaction SMILES: [C:1](=[S:7])([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:8]([CH:10](Cl)[C:11](OCC)=O)=[O:9].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:9][CH2:8][C:10]1[S:7][C:1]([CH2:2][CH:3]([CH3:5])[CH3:4])=[N:6][CH:11]=1
Reactant: CC(C)CC(N)=S
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ncc(CO)s1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Isovalerothioamide (6.0 g, 51 mmol) and ethyl formylchloroacetate (Heterocycles 32 (4), 693-701, (1991), 5.0 g, 33 mmol) are dissolved in dry DMF (20 mL), and heated to 95 degrees C. for 4 hours. The reaction is subsequently cooled to 0 degrees C., and cold water (50 mL) is added. The mixture is basified to pH=8 with solid sodium bicarbonate, then extracted with ether (3×35 mL). The combined organic extracts are washed with water, then saline and dried over magnesium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (ethyl acetate/hexanes 4-10% elution) to give the desired product. NMR (CDCl3, 300 MHz) δ 8.27, 4.45-4.30, 3.70-3.50, 3.00-2.80, 2.30-2.10, 1.40-1.20, and 1.10-0.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]#[CH:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][SH:19])=[CH:16][CH:15]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])/[CH:10]=[CH:11]\[CH:18]([S:19][CH:18](/[CH:11]=[CH:10]\[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(O)c(OC)c1
Reactant: COc1ccc(CS)cc1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2ccc(O)c(OC)c2)SC(/C=C\c2ccc(O)c(OC)c2)c2ccc(OC)cc2)cc1

Procedure:
A solution of 3-methoxy-4-hydroxyphenylacetylene (0.02 mol), 4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-hydroxystyryl-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:20]([OH:21])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)Nc1cc(Cl)cnc1N
Solvent: C1CCOC1
Product: CCC(CC)n1c(O)nc2ncc(Cl)cc21
Temperature: 25 °C
Yield: 71 %

Procedure:
To a refluxing solution of 5-chloro-N3-(pentan-3-yl)pyridine-2,3-diamine (1.5 g, 7.0 mmol, 1.0 equiv) in THF (10 mL) was added CDI portionwise until starting material was consumed as judged by TLC (50% EtOAC/Hexanes; UV). Approximately 10 equiv of carbonyldiimidazole were required. The resulting reaction mixture was cooled to room temperature, and the excess carbonyldiimidazole was quenched by the careful addition of water. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with satd. aq. NaHCO3 twice, and brine once. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC provided 6-chloro-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol as a white solid (1.2 g, 71%). m/z=240.1 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[N:10][C:9]2=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=[C:8]2[C:7]=1Cl)=[O:5])[CH3:2].[NH3:26]>CCO.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[N:10][C:9]2=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=[C:8]2[C:7]=1[NH2:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2nn(Cc3ccc(OC)cc3)cc2c1Cl
Reactant: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)nc2nn(Cc3ccc(OC)cc3)cc2c1N
Reaction time: 288 h

Procedure:
A solution of 4,6-dichloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.21 g) in EtOH/THF was saturated with NH3. Then solution was then stirred for 12 days (the solution was resaturated several times during that time). The solvent was removed and the residue was dissolved in EtOAc (250 mL). The solution was washed with aqueous NaCHCO3 and dried. Removal of the solvent gave the product (1 g) as a white solid. LC: 3.84 (Gradient 1); MH+: 347.