Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[N:13]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([C:17](OC)=[O:18])[N:16]=1.Cl.O>O1CCCC1>[Br:11][C:12]1[N:13]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH:17]=[O:18])[N:16]=1
Reactant: COC(=O)c1nc(Br)n(CC=C(C)C)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C=O)nc(Br)n1CC=C(C)C
Temperature: -65 °C

Procedure:
Under an argon atmosphere 35 ml (35 mmol) diisobutylaluminium hydride (1 mol/l in toluene) were added dropwise at −65° C. within 20 minutes to a solution of 9.00 g (12.18 mmol) dimethyl 2-bromo-1-(3-methyl-2-buten-1-yl)-1H-imidazole-4,5-dicarboxylate in 140 ml of tetrahydrofuran. After 1 hour at −65° C. another 5 ml (5 mmol) diisobutylaluminium hydride (1 mol/l in toluene) was added dropwise. The mixture was stirred for a further hour at −65° C. and then 20 ml of a 1:1 mixture of hydrochloric acid (1 mol/l) and tetrahydrofuran were added dropwise. After heating to ambient temperature approx. 100 ml of water was added, and the mixture was extracted three times with 70 ml of ethyl acetate. The extracts were dried over sodium sulphate, evaporated down, and the crude product thus obtained was purified by column chromatography (silica gel; eluant: cyclohexane/ethyl acetate 3:1->1:2).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17]C2C=C3C(=CC=2)N(C)C(=O)C=C3)[CH:11]=1)([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CI>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:2]([CH3:1])([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(CC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Solvent: CI
Product: CCOC(=O)C(C)(CC)c1cccc(OC)c1

Procedure:
The ethyl 2-(3-hydroxyphenyl)-2-methylbutyrate used as a starting material was obtained using the procedures described in the portion of Example 1 which is concerned with the preparation of starting materials except that methyl iodide was used in place of ethyl iodide in the second alkylation step. The intermediate so obtained, ethyl 2-(3-methoxyphenyl)-2-methylbutyrate, gave the following characteristic NMR signals: 0.84 (t, 3 H), 1.19 (t, 3 H), 1.5 (s, 3 H), 1.85-2.15 (m, 2 H), 3.8 (s, 3 H), 4.13 (q, 2 H), 6.72-6.92 (m, 3 H), 7.21 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.B1(C=C)OB([CH:26]=[CH2:27])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([CH:26]=[CH2:27])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Temperature: 90 °C
Yield: 52.8 %

Procedure:
A solution of 8-chloro-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.2 g, 2.71 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (0.784 g, 3.26 mmol), tetrakis(triphenylphosphine)palladium (0.157 g, 0.136 mmol) and Na2CO3 (0.575 g, 5.43 mmol) in toluene (30 mL) and water (0.5 mL) was purged with nitrogen and heated at 90° C. for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through diatomaceous earth (Celite®). The EtOAc layer was washed with brine and water. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using EtOAc-hexane as the eluent to afford 8-chloro-4,6-dimethyl-9-vinylbenzo[c][2,7]naphthyridin-5(6H)-one (0.6 g, 1.43 mmol, 68% yield)) as brown gummy solid. LC/MS (ESI) m/e 285.0 [(M+H)+, calcd for C16H14ClN2O, 285.1]; LC/MS retention time (method B): tR=2.25 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:7][C:8]=1[CH3:9].[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][C:4]2[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[S:7][C:8]=2[CH3:9])=[CH:25][CH:24]=1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-(2-hydroxy-ethyl)-5-methyl-2-(4-trifluoromethyl-phenyl)thiazole (Example 3, 288 mg, 1.0 mmol) in THF (3 mL) add 4-hydroxy-benzoic acid methyl ester (167 mg, 1.1 mmol) followed by triphenylphosphine (288 mg, 1.1 mmol). To this solution, add, dropwise, diethyl azodicarboxylate (174 μL, 1.1 mmol). On complete addition, stir the resulting red solution for 20 min. concentrate under reduced pressure and purify the residue by flash chromatography (elute with 15% ethyl acetate/15% dichloromethane in heptane) to give the title compound as a white solid. (410 mg).
Reaction SMILES: CS(O[CH:6]1[CH2:9][CH:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]4[N:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]5=[N:27][CH:26]=4)=[O:24])[CH:16]=3)[N:11]=2)[CH2:7]1)(=O)=O.[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:34]1([CH:6]2[CH2:9][CH:8]([C:10]3[O:14][N:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]5[N:29]6[CH:30]=[CH:31][CH:32]=[CH:33][C:28]6=[N:27][CH:26]=5)=[O:24])[CH:16]=4)[N:11]=3)[CH2:7]2)[CH:38]=[CH:37][CH:36]=[N:35]1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(-c2noc(C3CC(OS(C)(=O)=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(C3CC(n4cccn4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 60 °C

Procedure:
A stirring mixture of 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl methanesulfonate (81) (25 mg, 0.0535 mmol), 1H-pyrazole (7 mg, 0.0802 mmol) and cesium carbonate (26 mg, 0.107 mmol) in anhydrous DMF (1 mL) was heated at 60° C. for 1 hour. Then, the reaction was cooled to room temperature and filtered. The crude product was purified by reverse phase preparative HPLC to give N-(5-(5-(3-(1H-pyrazol-1-yl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F45). 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 9.54-9.51 (m, 1H), 8.71 (s, 1H), 8.10 (dd, J=1.6, 7.2 Hz, 1H), 7.89-7.85 (m, 3H), 7.70-7.66 (m, 1H), 7.54-7.50 (m, 2H), 7.33-7.29 (m, 1H), 6.28-6.25 (m, 1H), 5.04-4.96 (m, 1H), 3.82-3.73 (m, 1H), 3.10-2.85 (m, 4), 2.37 (s, 3H). MS m/z 440.18 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH:8][C:10](=[O:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ncc1Br
Product: CC(=O)Nc1cc(C)c(Br)cn1
Temperature: 110 °C

Procedure:
5-bromo-4-methylpyridin-2-amine (0.578 mmol) was dissolved in acetic anhydride (5.78 mmol) and heated at 110° C. for 30 minutes. The reaction was quenched with ice. The aqueous reaction mixture neutralized with sodium hydroxide solution was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over sodium sulfate. The organic layer was evaporated to dryness. The crude material was purified (silica column, MeOH/CHCl3). 1HNMR (300 MHz, DMSO-d6): 10.53 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 2.30 (s, 3H), 2.05 (s, 3H); MS (m/z): 231 (M+2)+.
Reaction SMILES: C(OC(=O)C(C)(C)CC1C=CC(S)=CC=1)C.[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([C@@:34]([OH:40])([CH3:39])[C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:18]
Reactant: CCc1ccccc1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CCOC(=O)C(C)(C)Cc1ccc(S)cc1
Product: CCc1ccccc1S(=O)(=O)c1ccc([C@](C)(O)C(F)(F)F)cc1

Procedure:
Using the methods described above in Example 12, but substituting 2-ethylbenzenethiol for 3-(4-mercaptophenyl)-2,2-dimethylpropionic acid ethyl ester in step a, 2-[4-(2-ethylbenzenesulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol was prepared. 1H NMR (CDCl3, 400 MHz) δ 8.19 (dd, J=1.3 Hz, 8.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.56 (m, 1H), 7.40 (m, 1H), 7.32 (d, J=7.6 Hz 1H), 3.03 (s, 1H), 2.58 (q, J=7.4 Hz, 2H), 1.77(s, 3H), 1.03 (t, J=7.5 Hz, 3H). The racemic product was resolved by chiral HPLC. The flow rate was 20 mL/min on a Chiralcel OD-H 20 mm i.d.×250 mm, 5μ column (Daciel Chemical Industries LTD), using isopropyl alcohol/hexanes (7/93) as the eluent.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.[CH3:20][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([Sn](C)(C)C)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3S(C2C=CC=CC=2)(=O)=O)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:22].C1(S)C=CC=CC=1>CN(C=O)C>[NH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:38]3[CH:37]=[C:36]4[C:32]([CH:33]=[N:34][NH:35]4)=[C:31]([NH:30][C:28]([C:27]4[N:23]([CH:21]([CH3:20])[CH3:22])[N:24]=[CH:25][CH:26]=4)=[O:29])[CH:39]=3)[C:3]=2[CH:4]=[N:5]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(Br)cccc21
Reactant: CC(C)n1nccc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]ncc23)cc2[nH]ncc12
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indazole (61 mg) in DMF (0.4 ml) was added to 1-(1-Methylethyl)-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-5-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight, then heated to 60° C. for 2 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 15 mg.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH2:37]([O:39][C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1)=[O:41])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:41])[C:42]1[CH:49]=[CH:48][C:45](/[CH:46]=[C:15](/[C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=3[CH:8]=2)\[CH3:16])=[CH:44][CH:43]=1)[CH3:38]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonylbenzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid ethyl ester of melting point 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH:15]2[O:16][CH2:17][CH:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH:14]2[O:13][CH2:12]1>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH:15]3[O:16][CH2:17][CH:18]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH:14]3[O:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C1COC2C(Nc3nc(Cl)ncc3Cl)COC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.45 g, 7.9 mmol) in MeOH (40 mL) were added triethanamine (970 mg, 9.6 mmol) and 2-(6-aminohexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (crude product from above step). The mixture was stirred at room temperature overnight, Then concentrated in vacuo, the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/3) to give the desired compound as a white solid (450 mg, 13.5% three steps).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CO.[H][H]>[C].[Pd].O1CCCC1>[NH:16]1[CH2:15][CH2:14][CH:13]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:12]=3)[CH:8]=[CH:9]2)[CH2:18][CH2:17]1
Reactant: [H][H]
Reactant: NC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Temperature: 25 °C

Procedure:
43 g of benzyl 4-(6-carbamoyl-1H-indol-1-yl)piperidin-1-carboxylate was suspended in a mixed solution consisting of 400 ml of methanol and 600 ml of tetrahydrofuran. Thereafter, 3.3 g of 10% palladium carbon was added thereto. This suspension was substituted by hydrogen, and it was then stirred at room temperature. After completion of the reaction, 10% palladium carbon was filtered off from the reaction solution, and the reaction solution was then concentrated under a reduced pressure. Tetrahydrofuran was added to the residue, and the obtained mixture was concentrated again under a reduced pressure. Tetrahydrofuran was added to the generated residue, followed by stirring, so as to solidify the subject compound. Thereafter, tetrahydrofuran and ether were added thereto, followed by cooling on ice. The solidified subject compound was collected by filtration. The generated filtrate was concentrated, and thus, the subject compound was obtained in the same above manner. The total amount of the subject compounds was 25.2 g.
Reaction SMILES: P(OCC)(OCC)OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21](O)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[NH:21][C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1
Reactant: CCCc1c(-c2ccc(Br)cc2)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1O
Agent: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
The triethyl phosphite (0.9 mL, 5.33 mmol) was added to a solution of (S)-tert-butyl 2-(4-(4-bromophenyl)hydroxy-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.776 mmol) in DMF (2 mL) and stirred for 18 hours at 80° C. Add second 0.8 mL and the reaction was continued an additional 8 hours, cooled, and taken up in ethyl acetate (400 mL) and washed with water and brine. Apply in CH2Cl2 to a 25 (M) Biotage silica gel column. Gradient elution, 15-100%, over 750 mL (A=Hexanes; B=ethyl acetate) gave (S)-tert-butyl 2-(4-(4-bromophenyl)-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 585 mg (76%). 1H NMR (500 MHz, DMSO-d6) δ 7.55-7.53 (m, 4H), 4.80-4.69 (m, 1H), 3.53-3.51 (m, 1H), 3.38-3.32 (m, 1H), 2.71 (t, J=7.0 Hz, 2H), 2.24-2.11 (m, 1H), 2.0-1.79 (m, 1H), 1.89-1.79 (m, 2H), 1.63-1.59 (m, 2H), 1.41/1.17 (s, 9H). 0.91 (t, J=7.6 Hz, 3H). RT=1.8 min, (Condition 1) LRMS: Anal. Calcd. for C21H28BrN3O2 434.14; found: 434.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c2cc1OC
Yield: 83.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) using the procedure in Example 182 to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea (119 mg, 0.25 mmol, 82%). 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 7.68-7.62 (m, 4H), 7.61-7.55 (m, 2H), 7.44-7.37 (m, 2H), 7.28 (d, 1H), 6.95 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 485 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH3:18]>CN(C=O)C>[CH2:17]([N:8]1[C:6]2=[N:7][C:2]([F:1])=[CH:3][CH:4]=[C:5]2[CH:10]=[CH:9]1)[CH3:18]
Reactant: Fc1ccc2cc[nH]c2n1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc2ccc(F)nc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a stirred solution of 6-fluoro-1H-pyrrolo[2,3-b]pyridine (15.00 g, 110.19 mmol) in DMF (100 mL), under a nitrogen atmosphere, is added potassium carbonate (22.84 g, 165.3 mmol), followed by ethyl bromide (12.36 mL, 165.3 mmol). The reaction is heated to 70° C. for 4 h. Further ethyl bromide (3.00 mL, 27.6 mmol) is added and the reaction kept at 70° C. overnight. After cooling further potassium carbonate (8.00 g, 57.9 mmol) and ethyl bromide (3.00 mL, 27.6 mmol) are added, and the reaction heated at 70° C. for 4 h. The reaction is cooled, poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 70% DCM in hexane to give the title compound as a light yellow oil (16.38 g, 99.77 mmol). MS (m/z): 165 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12](C(OC(C)(C)C)=O)[C:11]([CH3:25])=[C:10]2[C:26](=[O:40])[N:27]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH3:28])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[NH:12][C:11]([CH3:25])=[C:10]2[C:26]([N:27]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH3:28])=[O:40])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)Nc3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 1.5 h

Procedure:
To a mixture of the product obtained from Step C (60 mg, 0.1 mmol) in CH2Cl2 (5.0 mL) at room temperature under N2 was added TFA (5.0 mL). The mixture was stirred for 1.5 h. LC-MS indicated the completion of reaction. Solvent was evaporated, and the mixture was purified by reverse phase HPLC (acetonitrile/water). The desired product was obtained as white solid. LC-MS found: (M+1)+=507.2.
Reaction SMILES: [CH:1]([C@@H:4]1[NH:28][C:27]2[O:29][C:24](=[N:25][N:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[CH:30]=[C:31]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][N:12]=[C:11]3[O:10][C@H:9]2[CH2:32][N:6]([C@H:7]([C:33]([O:35][CH3:36])=[O:34])[CH2:8]2)[C:5]1=[O:37])([CH3:3])[CH3:2].OS(C(F)(F)F)(=O)=O.[I:46]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[I:46][C:14]1[C:15]2[C:31]3=[CH:30][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[O:29][C:27]([NH:28][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:37])[N:6]5[CH2:32][C@H:9]([O:10][C:11]3=[N:12][CH:13]=1)[CH2:8][C@H:7]5[C:33]([O:35][CH3:36])=[O:34])=[N:26][N:25]=4)=[CH:17][CH:16]=2
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCCc1ccc3ccnc(c3c1)O2
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCCc1ccc3c(I)cnc(c3c1)O2
Reaction time: 16 h

Procedure:
To a 0.3 M solution of methyl (3R,5S,8S)-8-isopropyl-7-oxo-2,28-dioxa-6,9,11,12,25-pentaazapentacyclo[17.6.2.13,6.110,13.022,26]noncosa-1(25),10,12,19,21,23,26-heptaene-5-carboxylate (from Step 1) in dry DCM was added triflic acid (2 eq) and N-iodosuccinimide (2 eq) and the mixture was stirred under N2 for 16 h. An additional portion of N-iodosuccinimide (2 eq) was added and the reaction was stirred for additional 24 h. The reaction mixture was poured into saturated NaHCO3 and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude compound was purified on silica gel (20% to 40% EtOAc in PE) to yield the compound as a yellow solid. MS (ES+) C27H32IN5O5 requires: 633. Found: 634 (M+H+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][C:9]1[C:10]([NH:16][CH3:17])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1)=O)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)(C)C>O>[CH2:1]([S:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]1[N:16]([CH3:17])[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[N:8]=1)[CH3:2]
Reactant: CCSc1ccccc1C(=O)Nc1cc(C)cnc1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCSc1ccccc1-c1nc2cc(C)cnc2n1C
Temperature: 82 °C
Yield: 20.5 %

Procedure:
A mixture of 2-ethylsulfanyl-N-(5-methyl-2-methylaminopyridin-3-yl)-benzamide (1.40 g), tripotassium phosphate (1.97 g), and tert-butanol (10 ml) was stirred under reflux at 82° C. for 2 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.27 g of 2-(2-ethylsulfanylphenyl)-3,6-dimethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 39).