Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31]CC1C=CC(OC)=CC=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:15]=[C:10]2[N:9]=[C:8]1[NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:31][C:30]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:15]=[C:10]3[N:9]=[C:8]2[NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a stirred solution of ethyl (3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (2.50 g, 4.61 mmol) in dichloromethane (100 mL) at 0° C. was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0° C. After 2 h, the mixture was treated with 2M potassium carbonate solution to adjust the pH to ˜9. The basic mixture was extracted with 1:1 methanol/dichloromethane solution (2×50 mL). The combined organic phases were washed with brine (2×50 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.80 g (93%) of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].FC(F)(F)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O>>[F:20][C:19]([F:22])([F:21])[CH2:18][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Yield: 83.1 %

Procedure:
Analogous to the preparation of intermediate 49, 5-hydroxy-2-pyridinecarboxylic acid methyl ester (0.253 mL, 2.122 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.739 mL, 3.18 mmol) were combined to afford the title compound (390 mg, 1.764 mmol, 83%) as a white solid. MS m/z=222.1 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]2[C:21]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([N+:30]([O-:32])=[O:31])[C:19](Br)=[N:18]2)[N:12]=[C:11](Br)[C:10]=1[N+:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1(OB(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]2[C:21]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([N+:30]([O-:32])=[O:31])[C:19]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:18]2)[N:12]=[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccccc2)nn(CCCn2nc(-c3ccccc3)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1
Yield: 81.8 %

Procedure:
3.7 g of 1,3-bis-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propane from step 5.2 in 40 ml 1,2-dimethoxyethane are mixed under nitrogen with 3.8 g phenyl boric acid, 1.2 g of tetrakis(triphenylphosphin)palladium (0) and a solution of 8.3 g of potassium carbonate in 30 ml water. The resulting reaction mixture is subsequently heated under reflux under nitrogen. After five hours the reaction mixture is heated over silica gel (hyflo super-gel of Celite Co.), filtered and the filtrate cooled in an ice bath. The precipitate coming down is filtered, washed with water and recrystallized from 50 ml ethanol. After drying in vacuum at 60° C. one obtains 1.5 g of a yellow product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.[CH3:11][C:12]1([CH3:19])[O:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].BrC1C=CC=CC=1CCN1C(=O)CN(C)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][N:14]1[C:13](=[O:18])[C:12]([CH3:19])([CH3:11])[O:16][C:15]1=[O:17]
Reactant: CC1(C)OC(=O)NC1=O
Reactant: OCCc1ccccc1Br
Agent: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Product: CC1(C)OC(=O)N(CCc2ccccc2Br)C1=O

Procedure:
2-Bromophenethyl alcohol (402 mg, 2 mmol) and 5,5-dimethyl-oxazolidine-2,4-dione (361 mg, 2.8 mmol) were treated as described in the preparation of compound 436. Purification was done by flash chromatography (petroleum ether/ethyl acetate 4:1) to provide the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:14])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][Cl:14])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCC=Cc1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCC=Cc1cncc(Br)c1
Yield: 76 %

Procedure:
A solution of 3-(5-bromo-3-pyridinyl)prop-2-en-1-ol (0.85 gms, 3.97 mmol) is diluted with methylene chloride (20 mls). Thionyl chloride (0.27 mls, 97%, leq) is added at room temperature. After one hour a second equivalent of thionyl chloride is added. The reaction is neutralized with saturated aqueous NaHCO3 after an additional hour and extracted with methylene chloride. The organic layer is dried over Na2SO4 and evaporated to yield 0.70 gms of an oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.90 (s,1H), 8.70 (s,1H), 8.40 (s,1H), 6.70 (m,2H), and 4.30 (d, J=3.8 Hz, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([O-])([O-])=O.[K+].[K+].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:14]=1[C:15]#[N:16]>C(Cl)(Cl)Cl>[C:15]([C:14]1[C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH3:5])#[N:16]
Reactant: COC(=O)Cl
Reactant: COc1ccc(N)c(C#N)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(OC)c(OC)c1C#N
Yield: 50.2 %

Procedure:
Methyl chloroformate (18.6 g, 19.7 mmol) was added to a suspension of K2CO3 (2.71 g, 19.6 mmol) and 2-amino-5,6-dimethoxybenzonitrile (7.0 g, 39.3 mmol) in 70 ml of CHCl3. The resulting mixture was heated at reflux for 2 hours before using filtered and evaporated to a residual solid. Recrystallization of the crude material from MeOH yielded 4.64 g (50.2% of product in good purity.
Reaction SMILES: [CH2:1]([C:4]1[C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[C:29]([OH:31])[C:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][C:26]=2[CH2:39][CH3:40])=[CH:18][CH:17]=[CH:16][C:5]=1[S:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:46]>C(Cl)Cl>[CH2:1]([C:4]1[C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[C:29]([OH:31])[C:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][C:26]=2[CH2:39][CH3:40])=[CH:18][CH:17]=[CH:16][C:5]=1[S:6]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:46])[CH2:2][CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Sc1ccccc1C(=O)O
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1S(=O)c1ccccc1C(=O)O
Yield: 82.4 %

Procedure:
To a solution of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]thiophenoxy]benzoic acid (450 mg, 0.803 mmol) in methylene chloride (10 mL) at −78° C. was added a solution of 85% m-chloroperoxybenzoic acid (138 mg) in methylene chloride (2 mL). After 40 minutes the mixture was concentrated in vacuo. Purification of the residue via silica gel chromatography (95% chloroform/4.5% methanol/0.5% acetic acid) provided 380 mg (80%) of the title product as an off-white solid: mp >100° C. (dec); NMR (CDCl3) 8.53 (d, J=8 Hz, 1H), 8.14 (d, J=8 Hz, 1H), 7.93 (t, J=8 Hz, 1H), 7.63 (t, J=8 Hz, 1H), 7.43 (m, 2H), 7.13 (m, 2H), 6.94-7.06 (m, 2H), 6.88 (d, J=8 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 7.46 (s, 1H), 6.38 (bs, 1H, —OH), 4.15 (m, 4H), 3.32 (m, 1H), 3.08 (m, 1H), 2.57 (q, J=7.5 Hz, 2H), 2.29 (quintet, J=6 Hz, 2H), 1.75 (m, 2H), 1.17 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H); MS (high resolution) calc 577.202642 (MH+), found 577.203800; IR (CHCl3, cm−1) 2969, 1708, 1497, 1455, 1266, 1146, 1018.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)NCc2ccccc2)c1
Reaction time: 1.5 h

Procedure:
A sample of the product of step (a), 8.8 g, was dissolved in 100 ml of methanol and hydrogenated with 0.4 g of 10% palladium on carbon and 50 PSI hydrogen. After 90 minutes, the mix was filtered and evaporated. The solid residue was slurried in ethyl ether, and filtered to provide crude N-phenylmethyl-3-aminobenzamide, mp 95°-100° C., m.s. (M+H)+ =227
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.CN1CC[O:16][CH2:15]C1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.Cl.Cl.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:15]([O:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:16])[CH2:43][CH2:42]2)=[CH:39][CH:40]=1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CN1CCCN(CCO)CC1
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)OCCN3CCCN(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
2-(4-methylhomopiperazin-1-yl)ethanol from the previous step (2.77 g, 17.5 mmol) was dissolved in DCM (25 mL) and cooled to 0° C. NMM (2.00 mL, 18.4 mmol) and p-nitrophenyl chloroformate (3.71 g, 18.4 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. A solution of 4-(4-methylphenyl)piperazine dihydrochloride (2.84 g, 11.4 mmol) and DIPEA (5.50 mL, 33.3 mmol) in DMF (40 mL) was then added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1 M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 85:15 mixture of DCM:MeOH) followed by reverse phase HPLC (Advanced Chromatography Technologies ACE-122-1030 RP silica 100×30 mm column, packed with Ace 5 C8 (5 μm), Pore Size 100 Å, 30 mL/min, gradient of actonitrile in water, with 0.1% trifluoroacetic acid in each solvent, 8-38%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give 2-(4-methyl-1,4-diazepan-1-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (184 mg, 3.0%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:24][CH2:23][CH2:22][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ClCCCN1CCCC1
Reactant: CCOc1ccc(C2=NNC(=O)SC2CC)cc1OC
Product: CCC1SC(=O)N(CCCN2CCCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
of 5-(3-methoxy-4-ethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-3-pyrrolidinopropane:
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxyphenyl]-ethanone as a beige solid, m.p.=118-120° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)[N:16]=1
Reactant: Clc1cccc(Cl)n1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(-n2ccc(-c3ccccn3)c2)n1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(1H-pyrrol-3-yl)pyridine (432 mg, 3.0 mmol) in DMF (15 mL) at 50° C. was added NaH (3.15 mmol, 60% suspension in oil). After 10 min, 2,6-dichloropyridine (1.33 g, 9.0 mmol) was added, and the reaction was warmed to 120° C., stirred for 18 h, then quenched with water (100 mL) and partitioned with EtOAc (100 mL). The aqueous layer was washed with additional EtOAc (2×75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by liquid chromatography on SiO2 eluting with 1:1 hexanes:EtOAc to afford 2-chloro-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine as a tan solid. H-NMR (CDCl3, 500 MHz) δ 8.60 (d, 1H), 8.13 (dd, 1H), 7.66-7.79 (m, 2H), 7.57-7.61 (m, 2H), 7.31 (d, 1H), 7.16 (d, 1H), 7.11 (dd, 1H), 6.88 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[NH:26][CH:25]=[N:24][CH:23]=1>>[NH:24]1[C:23]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:22][N:26]=[CH:25]1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Ic1cnc[nH]1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cnc[nH]2)c1)c1ccccc1
Yield: 46 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodo-1H-imidazole were reacted to give the title compound as a white foam (24 mg, 46%).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:27][C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=4)=[CH:26][CH:25]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Fc1ncccc1C1CCCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCOC3)cc2)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), 4-(pyridin-2-ylamino)phenol (0.26 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 348.1 (M+1). IC50 (uM) 0.012.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[CH2:18]([NH2:20])[CH3:19]>CO>[CH2:18]([NH:20][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)=[O:16])[CH3:19]
Reactant: CCN
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Solvent: CO
Product: CCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
A mixture of 200 g (0.86 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 1000 ml methanol and 200 g (4.4 mole) of ethylamine was heated at 100° C. in a pressure reactor for 17.2 hours. The reaction mixture was cooled and the excess ethylamine and methanol were removed under reduced pressure. The residue was taken up in dichloromethane and washed with 3×150 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 104.6 g of N-ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 97°-99° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=O)[CH2:7]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl>C(O)C>[ClH:23].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[CH2:7]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccco1)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccco1)C2
Yield: 95.5 %

Procedure:
A mixture of 7-(2-furyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (227 mg), aminoguanidine hydrochloride (122 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was refluxed for 2 hours. The reaction solution was cooled, and precipitated crystals were filtered and washed with ethanol to give 7-(2-furyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 69) (305 mg) as colorless crystals.
Reaction SMILES: ClC1C=C(C2OC([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=3[CH3:24])=NC=2)C=CN=1.Cl[C:26]1[O:27][C:28]([C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=2[Cl:38])=[CH:29][N:30]=1.ClC1OC(C2C=CN=C(Cl)C=2)=CN=1>>[Cl:38][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C:28]1[O:27][C:26]([NH:13][C:14]2[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=2[CH3:24])=[N:30][CH:29]=1
Reactant: CCOCc1ccc(C)c(Nc2ncc(-c3ccnc(Cl)c3)o2)c1
Reactant: Clc1ncc(-c2c(Cl)cncc2Cl)o1
Agent: Clc1cc(-c2cnc(Cl)o2)ccn1
Product: CCOCc1ccc(C)c(Nc2ncc(-c3c(Cl)cncc3Cl)o2)c1
Yield: 81 %

Procedure:
The same procedure outlined above in the preparation of 5-(2-chloropyridin-4-yl)-N-(5-(ethoxymethyl)-2-methylphenyl) oxazol-2-amine was used. However 2-chloro-5-(3,5-dichloropyridin-4-yl)oxazole was used instead 2-chloro-5-(2-chloropyridin-4-yl)oxazole. Yield=81%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:25])([CH3:24])[CH3:23]>O>[CH:22]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of isopropylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 5.90 g of N-isopropyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([S:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=Cc1ccc(SCc2ccccc2)cc1

Procedure:
Title product was prepared from benzyl mercaptan (145 mmol, 17.9 g) and 4-bromobenzaldehyde according to the method of Preparation 1 yielding 4 g of purified product following chromatography on silica gel using 9:1 hexane:ethyl acetate as eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17](NC)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4](F)[CH:3]=1.CN.NC1C=CC(OC2C3C(=CC(OC)=C(C(NC)=O)C=3)N=CC=2)=CC=1[F:52].CN1CCC[C:55]1=[O:59]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([O:59][CH3:55])=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:23][C:24]=1[F:52]
Reactant: CNC(=O)c1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OC
Reactant: CNC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Reactant: CN1CCCC1=O
Agent: CN
Product: COC(=O)c1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OC
Yield: 62 %

Procedure:
Similar to the synthesis of compound 46a, from compound 49b (50.5 mg), 40% aqueous methylamine solution (500 μL), and N-methylpyrrolidin-2-one (500 μL), compound 49c was yielded (31.2 mg, yield: 62%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O=S(Cl)[Cl:12]>C1COCC1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1
Solvent: C1CCOC1
Product: O=C(Cl)c1cccnc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of nicotinic acid (2 g, 16.2 mmol) in anhydrous THF (30 mL) was added SOCl2 (2.4 mL, 32.5 mmol). After stirring at 80° C. for 2 hours, the mixture was concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:15][C:16]=3[Br:17])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:24][CH:25]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:26]([O:28]C)=[O:27].[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:15][C:16]=3[Br:17])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:24][CH:25]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3nc(-c4ccccc4)sc3Br)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3nc(-c4ccccc4)sc3Br)ccc2c1Br
Yield: 51.9 %

Procedure:
A mixture of methyl 2-{[1-bromo-6-(5-bromo-2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}-3-phenylpropanoate (134 mg, 0.215 mmol), prepared in the previous step, and 1 N NaOH (323 μL, 0.323 mmol) in 10 mL of THF plus 10 mL of methanol plus 5 mL of water was refluxed under nitrogen 2 h. The reaction was filtered, acidified with 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (68 mg, 52%) as a yellow solid, mp 221-223° C. Elemental Analysis for C28H19Br2NO3S Calc'd: C, 55.19; H, 3.14; N, 2.30. Found: C, 56.17; H, 3.45; N, 2.05.