Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[Cl-].[NH4+].[N+:6]([C:9]1[C:10]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)([O-])=O>[Fe].O>[NH2:6][C:9]1[C:10]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(Nc2ncccc2N)cc1
Yield: 91.8 %

Procedure:
To phenol (22.92 g) were added 2-chloro-3-nitropyridine (13.22 g) and potassium iodide (0.42 g), and the mixture was stirred at 100° C. for 10 min. Ethyl 4-aminobenzoate (13.2 g) were added, and the mixture was stirred at 100° C.-150° C. for 6 hr. The reaction mixture was poured into ice water, and 4N aqueous sodium hydroxide solution (63 mL) and ethyl acetate (100 mL) were added. The precipitated solid was collected by filtration, and recrystallized from ethanol to give ethyl 4-(3-nitropyridin-2-ylamino)benzoate (15.48 g). Then, to a solution of ethanol (186 mL) and water (46 mL) were added ammonium chloride (1.12 g) and iron (8.1 g), the mixture was stirred at 60° C.-70° C., and the obtained ethyl 4-(3-nitropyridin-2-ylamino)benzoate (10.67 g) was added. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g). To the obtained ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g) was added triethyl orthoformate (87 mL), and the mixture was stirred with heating under reflux for 4 hr. The solvent was evaporated from the reaction mixture, and toluene (35 mL) and a small amount of p-toluenesulfonic acid hydrate were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated from the organic layer, and to the residue were added ethylether and hexane, and the precipitated solid was collected by filtration to give the title compound (7.926 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[H-].[Na+].CI.[C:47](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH3:47])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto is added sodium hydride (63%,11 mg) under ice-cooling, and the mixture is stirred at 0° C. for 30 minutes. Methyl iodide (23 μl) is added thereto, and the mixture is stirred for 2 hours under ice-cooling. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (120 mg). MS (m/z): 614 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)=[CH:10][C:9]=1[CH3:34])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)=[CH:10][C:9]=1[CH3:34])([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 4 h

Procedure:
0.070 g (0.140 mmol) of the above prepared 2-methyl-2-(2-methyl-4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester was dissolved in 0.84 ml of THF/EtOH=1/1, treated with 0.42 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness to yield 0.057 g of the title product as light yellow foam.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[C:12]([O:21][CH3:22])[N:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[CH3:17][O:16][C:14]1[C:13]([N+:18]([O-:20])=[O:19])=[C:12]([O:21][CH3:22])[N:11]=[C:10]([N:6]2[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[N:15]=1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Reactant: COC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1nc(N2CCC(OC)CC2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
4-Methoxypiperidine (1.31 g, 11 mmol, 1 equiv) was added via syringe to a mixture of 2-chloro-4,6-dimethoxy-5-nitropyrimidine (2.5 g, 11 mmol) and diisopropylethylamine (5.97 mL, 34 mmol, 3 equiv) in THF (60 mL). The reaction mixture was stirred at RT for 1 h, and then additional 4-methoxypiperidine (0.6 g, 5 mmol, 0.47 equiv) was added via syringe. The mixture was stirred for another 1 h and then diluted with water and extracted with ethyl acetate (2×). The organic extracts were dried over sodium sulfate, filtered and concentrated. The crude material was purified using a Biotage Isolera One (SiO2, 80 g, 0-80% EtOAc in heptane gradient) to afford 2.99 g (88%) of 4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)-5-nitropyrimidine as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.14 (ddd, J=13.2, 7.5, 3.9 Hz, 2H) 3.99 (s, 6H) 3.63 (ddd, J=13.2, 8.5, 3.8 Hz, 2H) 3.51 (tt, J=7.4, 3.6 Hz, 1H) 3.40 (s, 3H) 1.86-1.96 (m, 2H) 1.61-1.70 (m, 2H). LCMS m/z=299.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[CH2:5]2.[CH3:12][C:13]([CH3:15])=O.N>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2=[C:13]([CH3:15])[CH3:12]
Reactant: O=C1Cc2cc(O)ccc2N1
Reactant: CC(C)=O
Agent: N
Solvent: CCO
Product: CC(C)=C1CNc2ccc(O)cc21
Yield: 94 %

Procedure:
A mixture of 20 g. 5-hydroxyindolinone, 80 ml. acetone and 80 ml. ethanol is saturated with gaseous ammonia and heated under reflux for 3 hours. After evaporation, the reaction mixture is filtered off with suction. There are obtained 27.7 g. of the title compound (94% of theory); m.p. 235° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[C:22]([O:21][CH3:20])=[N:23][C:24]([O:31][CH3:32])=[CH:25][CH:26]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ccc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 67.4 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,6-dimethoxypyridine-3-boronic acid (176 mg, 0.96 mmol) were reacted. After purification the title compound (124 mg, 67% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J=4.8 Hz, 1H), 8.51 (m, 1H), 7.73 (t, J=9.1 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 2.93 (m, 1H), 0.70(m, 4H). MS APCI, m/z=384.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:51]([F:58])=[C:52](O)[C:53]([F:56])=[CH:54][CH:55]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][C:52]4[C:53]([F:56])=[CH:54][CH:55]=[C:50]([Cl:49])[C:51]=4[F:58])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reactant: Oc1c(F)ccc(Cl)c1F
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4c(F)ccc(Cl)c4F)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E9 and 3-chloro-2,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.23 min, ES+: 831.38.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>CCO>[Br:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Product: Cc1cc(Nc2nc(Br)cn3ccnc23)n[nH]1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
Example 8 was then prepared as follows. 6,8-Dibromoimidazo[1,2-a]pyrazine (278 mg, 1 mmol) and 5-methyl-1H-pyrazol-3-amine (196 mg, 2 mmol) was suspended in EtOH (2 ml). The mixture was heated with microwave at 120° C. for four hours. The mixture was then purified with HPLC to give (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a solid (96 mg). 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H) 7.98 (s, 1H) 7.70 (s, 1H) 6.48 (s, 1H) 2.27 (s, 3H). [M+H] calc'd for C10H9BrN6, 293; found, 293.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].COCCOC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B2OCCCO2)=[CH:24][CH:23]=1.[F-].[Cs+]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: Clc1ccc(B2OCCCO2)cc1
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)cc(N)c1OC
Temperature: 110 °C
Yield: 44 %

Procedure:
To a solution of methyl 4-amino-6-bromo-3-methoxypicolinate (prepared as in Fields, S. C. et al. U.S. Pat. No. 6,297,197 B1, Oct. 2, 2001; 500 mg, 1.9 mmol) in a 1:1 mixture of DME (4.5 mL) and H2O (4.5 mL) was added 2-(4-chlorophenyl)-1,3,2-dioxaborinane (561 mg, 2.7 mmol), CsF (288 mg, 1.9 mmol) and PdCl2(PPh3)2 (26 mg, 0.1941 mmol). The reaction was heated at 110° C. in a CES microwave for 20 min. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2, then washed with water, satd aq NaHCO3 and satd aq NaCl. The organic layer was dried with Na2SO4 and filtered. The solvent was removed in vacuo. The residue was purified by normal phase chromatography (eluting with 5% Et2O in CH2Cl2 with 0.05% acetic acid (HOAc)) to afford the title compound as a brown oil (245 mg, 44%): 1H NMR (300 MHz, CDCl3) δ 7.90-7.81 (m, 2H), 7.46-7.36 (m, 2H), 7.12 (s, 1H), 4.56 (s, 2H), 4.01 (s, 3H), 3.92 (s, 3H), ESIMS m/z 291 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[N:16]2)[CH:3]=1.COC1C(C)=C2C(C(O[CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)=CC(C3SC=CN=3)=N2)=CC=1>>[CH:20]([C:17]1[CH:18]=[CH:19][N:15]([C:4]2[CH:3]=[C:2]([O:1][CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:16]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Reactant: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinoline (64) and intermediate 26 following the procedure (Step D-F) reported for the preparation of 17-[7-methoxy-8-methyl-2-(thiazol-2-yl)quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29): m/z=630 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:6]#[N:7])[CH3:2].[H-].[Na+].[C:14]([N:19]=[C:20]=[S:21])([CH2:17][CH3:18])([CH3:16])[CH3:15].C(OCC)C>CN(C=O)C.Cl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:10]=1[NH:11][C:20]([NH:19][C:14]([CH3:16])([CH3:15])[CH2:17][CH3:18])=[S:21])[CH3:2]
Reactant: CCc1cc(C#N)ccc1N
Reactant: CCC(C)(C)N=C=S
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C#N)ccc1NC(=S)NC(C)(C)CC
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 3-ethyl-4-aminobenzonitrile (1.35 g, 9.29 mmol) in DMF (10 mL) at room temperature was added sodium hydride (0.28 g, 80%, 9.29 mmol). The mixture was heated to 70° C. for 40 minutes and was then cooled to room temperature. A solution of tert-amyl isothiocyanate (1.0 g, 7.74 mmol) in DMF (1 mL) was added by syringe and the reaction was stirred at 70° C. overnight. The cooled reaction mixture was diluted with 2N HCl and water and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to afford an oil. The crude product was taken up in a minimal amount of diethyl ether and the solution was made turbid by adding petroleum ether. Sonication resulted in the formation of a precipitate which was collected by filtration to afford 1.2 g (56%) of 1-(2-ethyl-4-cyanophenyl)-3-(1,1-dimethyl-propyl)-thiourea as an off-white solid which was used without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[O:25])[NH2:24])=[N:9][C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([NH2:24])=[O:25])=[N:9][C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
53.0 g of t-butyl 4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 160 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for one hour. 1250 ml of a 2 M aqueous sodium hydroxide solution was added drop wise to the reaction solution, and the mixture was stirred at room temperature for one hour and 50 minutes. The resulting white precipitate was collected by filtration. The white solid was washed with water and then with ethanol, and dried at 60° C. overnight to give 42.8 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:17][O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1
Reactant: OCCCSc1cccc2nccn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCSc1cccc2nccn12
Yield: 35.9 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (803 mg, 3.86 mmoles) in tetrahydrofuran (30 ml) was added 60% sodium hydride in oil (0.19 g, 4.6 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 30 minutes. To the reaction mixture was added methyl iodide (0.36 ml, 5.8 mmoles), followed by stirring at room temperature overnight. The reaction mixture was poured into water, which was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 308 mg of the desired product (35.9%, light brown oily product).
Reaction SMILES: [S:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH2:3][C:4]([O:6]C)=O.[H-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[CH3:13][O:12][C:10]([C:9]1[CH2:8][S:1][CH2:2][CH2:3][C:4]=1[OH:6])=[O:11]
Reactant: COC(=O)CCSCCC(=O)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1=C(O)CCSC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A solution of dimethyl 3,3′-thiodipropionate (30.00 g, 144.0 mmol) in ethylene glycol dimethyl ether (200 mL), under nitrogen, was treated with sodium hydride (7.00 g, 145.8 mmol), and the reaction was heated under reflux for 1.5 h. The reaction mixture was then cooled to 25° C. and was slowly treated with a saturated aqueous sodium bicarbonate solution. The solvent was then removed in vacuo, and the resulting residue was diluted with water (500 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were then washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography, performed in two batches, (FLASH 40M, Silica, 9/1 hexanes/diethyl ether) afforded 4-hydroxy-5,6-dihydro-2H-thiopyran-3-carboxylic acid methyl ester (12.89 g, 51.4%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])(=[O:10])[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: C1CCNC1
Product: CS(=O)(=Nc1ccc(Br)cc1)N1CCCC1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and pyrrolidine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=303, 305 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]([C:9]1[S:10][CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:8]>OS(O)(=O)=O>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]([Br:14])[CH:13]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Br)cs1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
The nitrating mixture (HNO3 d=1.42, 2 mL; concentrated H2SO4, 6 mL) was slowly added with stirring, at −5 to −10° C., to 4-Bromothiophene-2-carboxylic acid methyl ester (3 g, 13.57 mmol) dissolved in concentrated H2SO4 (10 mL). After being kept at −5 to −10° C. for 30 min. the mixture was poured over crushed ice. The solid precipitate was separated by filtration and washed with water and dried over P2O5 to give 3.7 g of 4-bromo-5-nitrothiophene-2-carboxylic acid methyl ester as a tan solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>CN(C)C=O.Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:3]([C:4](=[O:7])[CH2:5][CH3:6])[C:2](=[O:8])[CH3:1])=[CH:14][CH:15]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hexane-2,4-dione (5.7 g) in N,N-dimethylformamide (20 mL) was added dropwise over a period of 15 minutes to a stirred suspension of sodium hydride (60% in oil, 2.2 g) in N,N-dimethylformamide (60 mL) at −5° C. The mixture was stirred a room temperature for 30 minutes and then a solution of 1-bromomethyl-4-chlorobenzene (11 g) in N,N-dimethylformamide (20 mL) was added dropwise over a period of 20 minutes. The resulting mixture Was stirred at room temperature for 17 hours and then diluted with 1.0 M aqueous hydrochloric acid (100 mL). The mixture was extracted with diethyl ether and the combined extracts, washed with 1.0 M aqueous hydrochloric acid and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and toluene (1:1 to 1:2 to 0:1 by volume) gave title compound (55:45 mixture of keto-enol tautomers) as a white solid, 2.6 g.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.IC1C=C(NC(=O)C2C=CC(N3CCOCC3)=NC=2)C=CC=1C>>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:22]1
Reactant: FC1(F)CNC1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(N3CC(F)(F)C3)nc2)cc1I
Yield: 40 %

Procedure:
6-(3,3-Difluoro-azetidin-1-yl)-N-(3-iodo-4-methyl-phenyl)-nicotinamide was prepared from 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide and 3,3-difluoroazetidine hydrochloride in a manner similar to the one described in the synthesis of N-(3-Iodo-4-methyl-phenyl)-6-morpholin-4-yl-nicotinamide above. The product was isolated after silica gel column purification with 20-30% EtOAc in hexanes to afford the product (23 mg. Yield: 40%). HRMS m/z calcd for C16H14N3OFI [M+H]+: 430.0223. Found: 430.0224.