Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](=[N:9][C:10]2[C:14]([C:15]#[N:16])=[CH:13][NH:12][N:11]=2)[CH3:8])[CH2:5][CH2:4][O:3]1.O>C(N(CC)CC)C>[C:15]([C:14]1[CH:13]=[N:12][N:11]2[C:2](=[O:1])[C:6]([CH2:5][CH2:4][OH:3])=[C:7]([CH3:8])[NH:9][C:10]=12)#[N:16]
Reactant: CC(=Nc1n[nH]cc1C#N)C1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c2c(C#N)cnn2c(=O)c1CCO
Temperature: 50 °C
Yield: 90 %

Procedure:
(i-1) 15 g of Compound (IV) [R2 =H, R3 =CN], 35 ml of water, and 9.7 ml of triethylamine were mixed and stirred at 50° C. in a warm bath to obtain a brown solution. After heating for about 5 hours, the reacted solution was allowed to stand at room temperature over night. Precipitations of brown crystals was confirmed. The solution was acidified by adding acetic acid. Deposited crystals were collected and recrystallized in dimethylformamide to obtain 13.5 g of 3-cyano-6-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a]pyrimidine-7(4H)-one [R2 =H, R3 =CN in formula (V)] as slight brown crystals having a decomposition temperature of 283° C. at a yield of 90.0%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[N:10]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[C:12]2[CH2:13][CH2:14][N:10]=[CH:11]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: O=Cc1cnccc1Cl
Solvent: CCO
Product: C1=NCCC1=Cc1cnccc1N1CCCC1

Procedure:
A mixture of 4-chloropyridine-3-carboxaldehyde (10 g, prepared according to the method described in J. Het. Chem, 25, 81), pyrrolidine (25 ml) and ethanol (100 ml) was heated under reflux for 5 hours, then concentrated. The residue was purified by flash column chromatography (grade II alumina) eluting first with dichloromethane and then with methanol/dichloromethane (1:200) to give 3-[[4-(pyrrolidin-1-yl)pyridin-3-yl]methylidene]-1-pyrroline (900 mg) as a white solid. NMR (d6DMSO): δ1.8(4H,m); 2.5(2H,m); 3.3(4H,m); 3.95(2H,m); 6.6(1H,d); 7.0(1H,t), 7.9(1H,t), 8.0(1H,d); 8.15(1H,s); m/e 228(M+H)+ ; calculated for C14H17N3 : C, 74.0; H, 7.5; N, 18.5; found C, 74.1; H, 7.7; N, 18.4%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[CH:4][CH:3]=1.[CH3:28][Mg]Br>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]([OH:25])[CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butanal (333 mg, 0.790 mmol) in tetrahydrofuran (8 mL) was added dropwise methylmagnesium bromide (3 M solution in diethyl ether, 0.395 mL, 1.19 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 h. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (192 mg, 0.437 mmol, 55%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[C:6]([CH2:19][O:20]COC)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1>CO>[OH:20][CH2:19][C:6]1[C:5]([CH2:4][O:3][CH3:2])=[CH:14][C:13]2[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=2[CH:7]=1
Reactant: COCOCc1cc2c(cc1COC)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: CO
Product: COCc1cc2c(cc1CO)C(C)(C)CCC2(C)C
Yield: 115.2 %

Procedure:
1.0 ml of 10% aqueous hydrogen chloride was added at room temperature to 5 ml solution of 294 mg 3-methoxymethyl-2-methoxymethoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in methanol. After the mixture was heated under reflux for 1 hour, methanol was distilled off. Ethyl acetate was added to the residue, and the resulting mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and then the residue obtained under reduced pressure was subjected to silica gel column chromatography to give 290 mg of the title compound as a yellow oil.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[C:27]([C:36]([OH:38])=[O:37])=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[C:27]([C:36]([OH:38])=[O:37])=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1cc2ccccc2cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2cc3ccccc3cc2C(=O)O)cc1OC
Yield: 67.6 %

Procedure:
Piperidine (0.23 mL, 2.3 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.38 g, 2.3 mmol) and 3-(2-carboxyacetamido)-2-naphthoic acid (0.56 g, 2.0 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-3-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]-2-naphthoic acid (0.51 g, 66%) was obtained as a yellow crystalline solid; mp 212-213° C.; δH (400 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.82 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, =8.2 Hz, 1H, H5′), 7.25 (dd, 4,6=8.2, J2′,6′=2.0 Hz, 1H, H6′), 7.38 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.49 (t, J6,7=J7,8=8.0 Hz, 1H, H7), 7.58 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J5,6=J6,7=8.0 Hz, 1H, H6), 7.89 (d, J7,8=8.0 Hz, 1H, H8), 8.03 (d, J5,6=8.0 Hz, H5), 8.71 (s, 1H, H1), 9.05 (s, 1H, H4), 11.30 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.6, 55.7, 110.4, 111.6, 117.1, 117.6, 120.1, 122.6, 125.6, 127.1, 127.3, 128.2, 129.1, 129.3, 133.1, 135.5, 136.3, 141.4, 149.0, 150.6, 164.2, 169.5; HRMS (ESI) Calculated for C22H19NO6 [M+H]+ 378.1336. found 378.1345; vmax 797, 1022, 1134, 1233, 1512, 1665, 1693, 3048 cm−1.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[S-2:12].[Na+].[Na+]>C(O)C.O>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[SH:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1S

Procedure:
To a stirred solution of 172.6 g (1 mole) of 2-chloro-5-nitroaniline in boiling ethanol/water (5:2) is added a solution of sodium sulfide (generated from sodium sulfide nonahydrate and sodium bicarbonate), and the reaction is heated at reflux for one hour. The mixture then is cooled in ice, and the resulting crystalline product is collected by filtration and recrystallized from water.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([Br:9])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3].C([N-]C(C)C)(C)C.[Li+].[F:20][C:21]([F:41])([F:40])[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:28]=[CH:27]2)=[O:23]>C1COCC1>[CH2:1]([N:4]1[C:8]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:28]=[CH:27]3)([OH:23])[C:21]([F:40])([F:20])[F:41])=[C:7]([Br:9])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C=CCn1cc(Br)c(C#N)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCn1nc(C#N)c(Br)c1C(O)(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a chilled (−78° C.) solution of 1-allyl-4-bromo-1H-pyrazole-3-carbonitrile (116 mg, 0.550 mmol) in dry THF (2 mL) was added lithium diisopropylamide (367 μL, 1.5 M solution in hexanes, 0.55 mmol). After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.500 mmol) in 2 mL of THF was added. After 15 minutes, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on SiO2 (0-50% ethyl acetate in hexanes, gradient) to afford 213 mg (82%) of the title product. MS m/z 520.19/522.20 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N+:10]([O-:14])=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC(N)=O
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(Cl)[n+]([O-])c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
2,6-Dichloro-4-methyl-nicotinic acid (0.234 g, 1.14 mmol) and hydrogen peroxide-urea adduct (0.537 g, 5.70 mmol) were suspended in CH2Cl2 to give a white slurry. Trifluoroacetic anhydride (0.65 ml, 4.67 mmol) was added dropwise over 5 minutes and the resulting pale yellow solution was stirred overnight at rt. The reaction mixture was quenched with water (10 ml) and then dry loaded onto silica gel and purified using column chromatography (MeCN/MeOH/NH4OH, 8:1:1, v/v/v) to give 2,6-dichloro-4-methyl-nicotinic acid-N-oxide as a pale yellow crystalline solid (0.103 g, 41%). 1H NMR (CD3OD) δ 2.37 (s, 3H), 7.60 (s, 1H).
Reaction SMILES: C1(NC(C2C3C=C(C4C(C)=CN=C(NCCCC5CCCNC5)N=4)SC=3C=CC=2)=O)CC1.[CH:33]1([NH:36][C:37]([C:39]2[C:47]3[CH:46]=[C:45]([C:48]4[C:53]([Cl:54])=[CH:52][N:51]=[C:50](Cl)[N:49]=4)[S:44][C:43]=3[CH:42]=[CH:41][CH:40]=2)=[O:38])[CH2:35][CH2:34]1.C(OC([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][CH2:70][CH2:71][NH2:72])[CH:65]([CH:73]([CH3:75])[CH3:74])[CH2:64]1)=O)(C)(C)C>>[CH:33]1([NH:36][C:37]([C:39]2[C:47]3[CH:46]=[C:45]([C:48]4[C:53]([Cl:54])=[CH:52][N:51]=[C:50]([NH:72][CH2:71][CH2:70][CH2:69][N:66]5[CH2:67][CH2:68][NH:63][CH2:64][CH:65]5[CH:73]([CH3:75])[CH3:74])[N:49]=4)[S:44][C:43]=3[CH:42]=[CH:41][CH:40]=2)=[O:38])[CH2:35][CH2:34]1
Reactant: CC(C)C1CN(C(=O)OC(C)(C)C)CCN1CCCN
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: Cc1cnc(NCCCC2CCCNC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Product: CC(C)C1CNCCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of racemic 2-[5-methyl-2-(3-piperidin-3-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and racemic 4-(3-aminopropyl)-3-isopropylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a solid. ES+(m/z) 513 (35Cl) and 515 (37Cl) [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:16][O:17][C:18]([C:20]1[S:24][C:23](Br)=[N:22][C:21]=1[Br:26])=[O:19].O>CN1CCCC1=O>[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]([N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=3[N:7]=[CH:8]2)=[N:22][C:21]=1[Br:26])=[O:19]
Reactant: COC(=O)c1sc(Br)nc1Br
Reactant: COc1cc2nc[nH]c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 5,6-Dimethoxy-1H-benzimidazole (1.0 g, 5.65 mmol) in 1-methyl-2-pyrrolidinone (10 ml) at 0° C. was added NaH (60% dispersion; 339 mg, 8.475 mmol). After gas evolution had stopped, 2,4-Dibromo-thiazole-5-carboxylic acid methyl ester (1.7 g, 5.65 mmol) was added. The resulting solution was stirred at ambient temperature for 1 hr. 50 ml water was added. The suspension was stirred for 10 min and filtered to afford 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (1.6 g, 73%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 3H), 3.98 (s, 3H), 4.03 (s, 3H), 7.32 (s, 1H), 7.58 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=[CH:3]1.[CH2:11]=[O:12]>CO>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: C=O
Reactant: COC(=O)c1cncn1C
Solvent: CO
Product: COC(=O)c1cnc(CO)n1C
Yield: 65.9 %

Procedure:
A solution of 5 g of methyl 1-methyl-1H-imidazole-5-carboxylate and 22.5 g of paraformaldehyde in 50 ml of methanol was heated at 140° C. for 60 hours under a sealed tube condition. The precipitate was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 4 g of methyl 2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:6](=[O:11])[C:7]=1[C:8]([OH:10])=[O:9].CC1N=CN(C2C=CC(C)=CC=2)C(=O)C=1C(OCC)=O.[H-].[Na+:40]>C(COC)OC.CCOCC>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:6](=[O:11])[C:7]=1[C:8]([O-:10])=[O:9].[Na+:40]
Reactant: Cc1ccc(-n2cnc(C)c(C(=O)O)c2=O)cc1
Agent: CCOC(=O)c1c(C)ncn(-c2ccc(C)cc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1ccc(-n2cnc(C)c(C(=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
A mixture of 8.0 g (0.033 mole) of 1,6-dihydro-4-methyl-6-oxo-1-(4-tolyl)pyrimidine-5-carboxylic acid, prepared from ethyl 1,6-dihydro-4-methyl-6-oxo-1-(4-tolyl)pyrimidine-5-carboxylate by the hydrolysis method of Example 2, and one equivalent of sodium hydride (added as mineral oil dispersion), slurried in 300 ml of glyme is stirred at ambient temperature for 3 days. The solid product is isolated by filtration, slurried in ether and reisolated to give after drying 5.0 g (57% yield) of sodium 1,6-dihydro-4-methyl-6-oxo-1-(4-tolyl)pyrimidine-5-carboxylate, m.p. 208°-10° C. dec.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:43]([Si:46](Cl)([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])([CH3:45])[CH3:44].O>O1CCCC1>[CH2:34]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[N:20]([Si:46]([CH:50]([CH3:52])[CH3:51])([CH:47]([CH3:49])[CH3:48])[CH:43]([CH3:45])[CH3:44])[CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Reaction time: 0.08 h

Procedure:
To (3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (55, 0.84 g, 1.6 mmol) in tetrahydrofuran (150 mL) was added sodium hydride (210.0 mg, 60% in mineral oil, 5.3 mmol) under an atmosphere of nitrogen. The reaction was stirred for 5 minutes. Triisopropylsilyl chloride (0.80 mL, 3.8 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to provide the compound (56, 420 mg, 39%). MS (ESI) [M+H+]+=687.4.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.CCCCCC>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH:13]=[CH2:12])=[CH:7][CH:6]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCCBr)cc1

Procedure:
To a solution of 45.0 g of 4-(2-bromoethoxy)-phenol (0.207 mol) in 310 ml of acetone was added 54 ml of allyl bromide (0.619 mol) and 45.0 g of anhydrous potassium carbonate (0.326 mol). The reaction mixture was stirred under reflux for eleven hours and was cooled and poured into 2500 ml of water. The mixture was extracted twice with 3:1 ether:methylene-chloride, and the organic layers were washed twice with 1 N NaOH, once with H2O, dried (Na2SO4) and concentrated to dryness under reduced pressure to yield a colorless oil. The analytical sample was prepared by crystallization from hexane to give colorless crystals, mp 27°-28°.
Reaction SMILES: [C:1]([C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][P:18]([CH:21]([F:23])[F:22])(=[O:20])[OH:19])=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C:9]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][P:18]([CH:21]([F:22])[F:23])(=[O:19])[OH:20])=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C(C/C=C/c1ccccc1)(Cc1ccc(OP(=O)(O)C(F)F)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=P(O)(Oc1ccc(CC(CCCc2ccccc2)(Cc2ccccc2)c2ccccc2)cc1)C(F)F

Procedure:
The compound of Example 9 in EtOAc was treated with Pd/C and H2 (50 psi) for 2 days. After filtration and evaporation the title compound was obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([CH3:23])[NH:20]2)=[CH:16][CH:15]=1.ClCCN1CCOCC1>CS(C)=O>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[C:19]([CH3:23])[N:20]2[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:16][CH:15]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc2ccc(Cl)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc2ccc(Cl)cc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (134 mg, 0.72 mmol) in 0.3 mL DMSO was added pulverized KOH (102 mg, 1.81 mmol), then after 10 min, a solution of 6-chloro-2-methylindole (100 mg, 0.60 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. Additional 2-chloroethylmorpholine (22 mg, 0.12 mmol) and KOH (17 mg, 0.3 mmol) added and stirred overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 50% ethyl acetate in hexane to give a final yield of 149 mg (0.54 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.44 (s, 3H), 2.49 (t, J=4.4 Hz, 4H), 2.62 (t, J=7.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 4.11 (t, J=7.2 Hz, 2H), 6.23 (s, 1H), 7.06 (dd, J=8.4 Hz, 1.7 Hz, 1H), 7.28 (s, 1H), 7.42 (d, J=8.3 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.79, 41.18, 54.11, 57.83, 67.5, 100.30, 108.95, 119.90, 120.53, 126.40, 126.70, 137.06, 137.37. MS m/z 279.3 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13].[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22]>C1COCC1.CCOCC>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:22]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 17 h

Procedure:
A solution of n-butyllithium in hexane (12.8 mL of 2.5 M, 32 mmol) is added with stirring to t-butanol (46 mL) at 25° C. under an argon atmosphere. After 30 min the mixture is treated dropwise with a solution of 3-bromo-5-nitro-benzoyl chloride (J. Mindl, Collect. Czech. Chem. Commun. (1973), 38, 3496-505; 32 mmol) in dry THF (40 mL) and stirred for a further 17 h. The mixture is then treated with ether (250 mL) and washed with brine. The ether solution was dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 20% ethyl acetate in hexane) and recrystallised from ether-hexane to afford the title compound as colourless crystalline solid, m.p. 77-78° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[O:9])=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:24][C:23]([CH3:25])([CH3:26])[C:22]([C:12]1[C:11]([CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[C:3]([C:41]3[CH:40]=[N:39][C:38]([O:37][CH3:36])=[CH:43][CH:42]=3)[CH:4]=2)=[O:9])[N:18]2[C:13]=1[CH:14]=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:17]2)=[O:27]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cn1
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: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(-c2ccc(OC)nc2)c1
Temperature: 23 °C
Yield: 88.4 %

Procedure:
A solution of methyl 3-{3-[(4-bromophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.185 mmol), 2-(methoxy)pyridine-5-boronic acid (42.5 mg, 0.278 mmol), tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.019 mmol) in THF (2.0 mL) and aqueous 20% Na2CO3 (1.0 mL) is heated at 70° C. for 1 h. The mixture is cooled to 23° C. and partitioned between Et2O and water. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 30% EtOAc in hexanes) gives methyl 3-[1-(2,2-dimethylpropanoyl)-3-{[3-(6-methoxypyridin-3-yl)phenyl]carbonyl}-7-(propan-2-yl)indolizin-2-yl]-2,2-dimethylpropanoate (93 mg, 88%) which is dissolved in MeOH (1.5 mL), and 6M aqueous NaOH (1.5 mL) and heated at 70° C. for 1 h. The mixture is then cooled to 23° C., acidified to pH=1 with concentrated aqueous HCl, and partitioned between CH2Cl2 and brine. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give the title compound (68 mg, 75%).