Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:34][C:35]1[O:39][C:38](B(O)O)=[CH:37][CH:36]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:34][C:35]1[O:39][C:38]([C:2]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:8]=3)[N:3]=2)=[CH:37][CH:36]=1
Reactant: O=C(Nc1cccnc1)c1cc(Cl)nc2ccc(-c3ccccc3)cc12
Reactant: Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)Nc3cccnc3)c3cc(-c4ccccc4)ccc3n2)o1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a round-bottomed flask under argon atmosphere was added 2-chloro-6-phenyl-N-(pyridin-3-yl)quinoline-4-carboxamide (0.100 g) in 1,4-dioxane (3 ml), and the vessel was purged with argon under stirring for 5 minutes. After 5 minutes, a 2N solution of potassium carbonate in water (11 eq) was added and the flask was purged with argon under stirring for 5 minutes. (5-methylfuran-2-yl)boronic acid (1.5 eq) was then added and the tube was purged with argon under stirring for 15 minutes. Finally, palladium(0)tetrakis triphenylphosphine (0.05 eq) was added under argon and the flask was affixed to a reflux condenser and heated to 90° C. for 5 hours. The completion of the reaction was monitored on TLC using ethyl acetate:hexanes as a mobile phase. After completion of the reaction, reaction mixture was diluted with ethyl acetate (100 ml) and then washed with water (5*100 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out and the crude was subjected to purification by silica gel column chromatography to provide 0.01 g of 2-(5-methylfuran-2-yl)-6-phenyl-N-(pyridin-3-yl)quinoline-4-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (s, 1H), 8.97 (s, 1H), 8.41 (m, 1H), 8.39 (s, 1H), 8.30 (m, 1H), 8.19 (m, 3H), 7.78 (m, 2H), 7.55 (m, 2H), 7.48 (m, 1H), 7.44 (m, 2H), 6.43 (broad s, 1H), 2.48 (s, 3H); m/z 406.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([OH:29])[CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([O:29][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:5]=[CH:4][N:3]=3)[CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Oc1cccc2ccc(Cl)nc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4ccc(Cl)nc34)ncn2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (259 mg, 1 mmol) and 2-chloro-quinolin-8-ol (Example 2(a), Method B), (180 mg, 1 mmol) in 2 mL of DMF was added potassium carbonate (276 mg, 2 mmol). The reaction was stirred in a 90° C. oil bath for 2 h. EtOAc and brine were added, and the aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuum. Purification by flash chromatography by silica gel chromatography 1:4 of EtOAc/hexanes as eluent gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 402 (M+1). Mp: 171.5–173.0° C. Anal. Calcd for C20H11ClF3N3O: C, 59.79; H, 2.76; N, 10.46. Found: C, 60.01; H, 2.80; N, 10.50.
Reaction SMILES: [C:1]1([C:7]2([CH:14]=[O:15])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2([CH2:14][OH:15])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2ccccc2)CCC=CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccccc2)CCC=CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-1-phenylcyclohept-4-enecarbaldehyde (22 mg, step C) in methanol (1 mL) was added sodium borohydride (8 mg), and the resulting mixture was stirred at room temperature for 1 h. Methanol was removed in vacuo, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 1.91 (2H, m), 2.20 (6H, m), 3.55 (2H, s), 5.68 (2H, m), 7.35 (5H, m). 13C NMR (CDCl3, 100 MHz) δ 24.0, 32.9, 47.3, 71.7, 126.3, 127.4, 128.6, 131.2, 144.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[CH3:21][C:22]1([CH3:32])[O:26][C:25](=[CH:27][C:28](Cl)=[O:29])[C:24](=[O:31])[O:23]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:28](=[O:29])[CH:27]=[C:25]1[C:24](=[O:31])[O:23][C:22]([CH3:21])([CH3:32])[O:26]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: Clc1ccc(CNCCCc2ccccc2)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CC(=O)N(CCCc2ccccc2)Cc2ccc(Cl)c(Cl)c2)O1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred mixture of (3,4-dichloro-benzyl)-(3-phenyl-propyl)-amine; hydrochloride (330 mg, 1.0 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (206 mg, 1.08 mmol) in CH2Cl2 (10 mL) at room temperature was added diisopropylethylamine (386 μL, 2.2 mmol). After 30 min, the reaction mixture was diluted with ether (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the desired amide (447 mg, 100% yield) as a viscous oil. 1H NMR (300 MHz, CDCl3) δ: 7.41–6.94 (8H, m), 6.08 (0.66H, s), 6.01 (0.34H, s), 4.53 (1.33H, s), 4.48 (0.67H, s), 3.41 (0.67H, t, J=7.5 Hz), 3.26 (1.33H, t, J=7.8 Hz), 2.61 (2H, t, J=7.3 Hz), 1.95–1.85 (2H, m), 1.71 (6H,s). MS calcd for C23H23Cl2NO4Na (M+Na): 470.09. Found: 470.09.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][CH2:18]3)=[CH:13][CH:12]=2)[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([CH:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:9]#[N:10])=[CH:12][CH:13]=3)[CH2:18]2)(=[O:29])=[O:28])[N:24]=[CH:23]1
Reactant: N#CC(Cc1ccccc1)c1ccc2c(c1)CNCC2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(C#N)Cc4ccccc4)cc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of 0.135 mmol 3-phenyl-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanenitrile in 2 ml CH2Cl2 were added 0.203 mmol DMAP and 0.162 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride. The mixture was stirred at room temperature for 3 h. Additional 0.162 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride were added and the mixture was stirred for 3 d. The mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated NaHCO3 and H2O. The combined aqueous layers were extracted with CH2Cl2. The combined organic phase was dried over MgSO4 and filtered. Evaporation of the solvent gave 90 mg of the crude material. The material was purified by flash chromatography to yield 53 mg of a white solid (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:23]([O-])=O)=[C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([O:19][CH3:20])[C:13]([O:21][CH3:22])=[CH:12]3)[CH:8]=1>C(OCC)(=O)C.[Pd]>[NH2:23][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH3:20])[C:13]([O:21][CH3:22])=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c(-c2ccc3cc(OC)c(OC)cc3c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(-c2ccc3cc(OC)c(OC)cc3c2)c1
Yield: 72.4 %

Procedure:
Crude 6-(5-methoxy-2-nitrophenyl)-2,3-dimethoxynaphthalene 30 (100 mg, approximately 90% pure) was hydrogenated overnight in ethyl acetate (40 mL) at 40˜45 lb./sq. in. using 10% palladium on carbon (30 mg) as catalyst. The reaction solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 mL×3). Concentration in vacuo gave the crude product. The residue was chromatographed using a 50:50 mixture of hexanes:ethyl acetate to give 33 (66 mg); mp 158-160° C.; IR (KBr) 3408, 3354, 2936, 1633, 1499, 1249, 1166 cm−1; 1H NMR (CDCl3) δ3.57 (2H, s), 3.79 (3H, s), 4.01 (3H, s), 4.03 (3H, s), 6.77-6.84 (3H, m), 7.15 (1H, s), 7.16 (1H, s), 7.45 (1H, dd, J1=8.3, J2=1.8), 7.75-7.79 (2H, m); 13C NMR δ56.34, 56.42, 106.59, 106.85, 114.80, 116.35, 117.41, 125.99, 126.81, 127.32, 128.73, 129.42, 129.82, 135.75, 137.89, 150.19, 150.32, 153.25; HRMS (EI) calcd for C19H19NO3 m/z: 309.1365; found: 309.1375.
Reaction SMILES: [CH3:1][CH:2]([CH2:27][CH3:28])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1COCC1>[CH3:1][CH:2]([CH2:27][CH3:28])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[S:38]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(C)/C=C/C(=O)N1CCN(c2ccnc3cc(C(F)(F)F)ccc23)CC1
Solvent: C1CCOC1
Product: CCC(C)/C=C/C(=S)N1CCN(c2ccnc3cc(C(F)(F)F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-4-methyl-1-[4-[7-(trifluoromethyl)-4-quinolyl]piperazin-1-yl]hex-2-en-1-one (20 mg, 0.049 mmol) was dissolved in THF (1 ml), Lawesson's reagent (20 mg, 0.051 mmol) was added in one portion and the resulting mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 5.4 mg (0.013 mmol, 25%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:5]=2[C:6]([CH3:9])([CH3:8])[CH:7]=1.CC1C2C=C(Br)C=CC=2SC(C)=C1C.[H][H]>C(OCC)(=O)C.[Pd]=S>[CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]2[C:4](=[CH:13][CH:12]=[C:11]([Br:14])[CH:10]=2)[S:3]1
Reactant: [H][H]
Reactant: CC1=CC(C)(C)c2cc(Br)ccc2S1
Agent: S=[Pd]
Agent: CC1=C(C)C(C)c2cc(Br)ccc2S1
Solvent: CCOC(C)=O
Product: CC1CC(C)(C)c2cc(Br)ccc2S1

Procedure:
A solution of 500 mg (1.9 mmol) of 2,4,4-trimethyl-6-bromo-(4H)-1-benzothiopyran (Compound 50) in 5 ml of ethyl acetate was treated with 500 mg of 10% palladium sulfide on carbon and then shaken under an atmosphere (30 psi) of hydrogen in a Parr apparatus for 24 hours. The mixture was filtered through celite and the solvent was removed in-vacuo. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 1.21 (3 H, s), 1.33 (3 H, d, J=6.6 Hz), 1.36 (3 H, s), 1.64-1.89 (2 H, M), 3.37-3.50 (1 H, m), 7.10 (1 H, dd, J=8.4 Hz, 2.1 Hz), 7.19 (1 H, d, 8.4 Hz), 7.20 (1 H, d, 2.1 Hz)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.Cl.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1
Reactant: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 78 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
2-[4-(3-Bromopropoxy)phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (20.47 g, 60 mmol), (R)-2-methylpyrrolidine hydrochloride (7.663 g, 63 mmol) and dry, pulverized K2CO3 (24.96 g, 180 mmol) were mixed in dry CH3CN (650 mL). After stirring for 12 h at 78° C. under a nitrogen atmosphere, the reaction mixture was cooled and further (R)-2-methylpyrrolidine hydrochloride (10.0 g, 82 mmol) was introduced and heating at 78° C. was continued for 24 h. The reaction mixture was cooled, filtered and the filtrate was evaporated. Chromatography on silica gel, eluting initially with CH2Cl2, then with a mixture of CH2Cl2/EtOH/aq. NH3 (290:10:1) and later with a (90:10:1) and (40:10:1) mixture of these solvents provided the title compound (17.44 g, 84%). The material crystallized on seeding. A sample was converted into a hydrochloride salt, m.p. 212-214° C.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:33][N:34]=2)[N:31]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:33][N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nnc2ccc(Cl)nn12
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 70 °C
Yield: 26.1 %

Procedure:
5.15 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 3.6 g of ethyl 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate were dissolved in 70 ml of N,N-dimethylformamide; 5.48 ml of N-ethyldiisdpropylamine was added, followed by stirring under heating at an external temperature of 70° C. for 4 hours. After cooling, cold saline was added; the reaction mixture was extracted with tetrahydrofuran and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; half of the precipitated crystal was recrystallized from ethanol-ethyl acetate (1:1), collected by filtration, and dried, to yield 2.13 g of the title compound.
Reaction SMILES: C(CC1C=CC(CC[C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=CC=1)#N.S(=O)(=O)(O)O>[OH-].[Na+]>[CH:18]1[N:17]=[CH:16][N:15]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=12
Reactant: N#CCc1ccc(CCc2cccc3cncn23)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccn2cncc2c1

Procedure:
A solution of 5-[p-(cyanomethyl)phenethyl]imidazo[1,5-a]pyridine (1.0 g) in 2N sodium hydroxide (30 ml) is heated under reflux for 15 hours, acidified with concentrated sulfuric acid and filtered to yield 5-[p-carboxymethyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(Cl)cncc2Cl)cc1
Temperature: 80 °C

Procedure:
To a vial containing 4-aminophenol (2.185 g, 20.0 mmol, 1 equiv.) in 60 mL DMF was added t-BuOK (2.468 g, 22.0 mmol, 1.1 equiv.) followed by 3,4,5-trichloropyridine (3.653 g, 20.0 mmol, 1 equiv.). The flask was fitted with a condenser and the mixture was stirred at 80° C. under nitrogen. After the reaction mixture was cooled, diluted with ethyl acetate (600 mL) and washed with water (3×150 mL) and brine. The organic layer was dried over Na2SO4, filtered and solvent was removed under vacuum. The crude material was absorbed onto silica gel and purified by flash column (7.5×12 cm silica) using 2500 mL 1:1 hexanes:ethyl acetate giving 4.6348 g (91%) of product as a light yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
Ethyl 5-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (4.95 g) was dissolved in absolute tetrahydrofuran (50 mL), and sodium hydride (60% in oil, 1.20 g) was added under ice-cooling. The mixture was stirred at room temperature for 15 min, and benzenesulfonyl chloride (5.30 g) was added dropwise. The reaction mixture was stirred at room temperature for 18 hr, ice water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2) to give the title compound as a solid (yield 2.75 g, 35%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][N:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1)#[N:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]=[N:5]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1cc(C#N)nn1
Product: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1

Procedure:
1.3 g (7.5 mmol) of the compound from Example 4A and 1.4 ml (1.2 g, 8.2 mmol) of N,N-dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For work-up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried under reduced pressure. Yield: 1.5 g (86% of theory)
Reaction SMILES: [C:1]1([CH:7]2[CH2:19][C:18](=O)[C:10]3[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][O:13][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[NH:24](/[N:25]=[C:18]1\[CH2:19][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[O:13][CH:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]\1=2)[C:21]([NH2:23])=[NH:22]
Reactant: O=C1CC(c2ccccc2)Cc2occ(C(F)(F)F)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccccc2)Cc2occ(C(F)(F)F)c21
Temperature: 900 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To 6-phenyl-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.13 g) and aminoguanidine hydrochloride (51 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.04 ml), and the mixture was stirred at 900° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether and dried to give (E)-4-guanidinoimino-6-phenyl-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 50) (0.12 g).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33](=[O:35])[NH2:34])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>ClCCl>[CH2:36]([N:38]([CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33]([NH2:34])=[O:35])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: CCNCC
Reactant: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Solvent: ClCCl
Product: CCN(CC)Cc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 58 mg of [1-(5-carbamoyl-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (compound A1) in 4 ml of dichloromethane were added 146 mg of diethylamine, and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated to dryness under vacuum and the residue was dissolved in acetonitrile/water and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)). After lyophilization the title compound was obtained.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[CH2:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[C:4](=[O:13])[CH2:5][CH2:6]2)[CH:10]=1)=[O:21]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1CCc2cccc3c2N1CC3
Product: O=C(CCCCCBr)c1cc2c3c(c1)CCN3C(=O)CC2

Procedure:
Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (3.00 g) and 6-bromohexanoyl chloride (2,91 ml) according to the same method as that of Reference Example 1, the title compound (3.94 g) was obtained as white crystals having a melting point of 97 to 98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.[CH3:21][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([OH:12])[CH3:21])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(C=O)c21
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carbaldehyde (600 mg, 1.689 mmol) in tetrahydrofuran (10 mL) at −78° C. was added methylmagnesiumbromide (3M in diethyl ether, 1.13 mL, 3.38 mmol). After 5 min, the ice bath was removed and stirring continued for 30 min. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The mixture was poured into diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 575 mg (92%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 5.92 (d, J=11.6, 1H), 5.80 (d, J=11.6, 1H), 5.56 (m, 1H), 3.46 (m, 2H), 3.26 (s, 1H), 1.64 (d, J=6.4, 3H), 0.80 (m, 2H), −0.11 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 136.2, 133.5, 130.8, 128.1, 126.9, 122.9, 114.8, 80.3, 66.5, 64.6, 23.0, 17.8, −1.4.