Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(NC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-indanone (5 g, 37.83 mmol) in DCM (135 mL) were successively added aniline (3.4 mL, 37.83 mmol), AcOH (2.16 mL, 37.83 mmol) and Na(OAc)3BH (11.22 g, 52.96 mmol) portion-wise at ice cold conditions. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was then diluted with EtOAc (450 mL) and washed with water (150 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography and eluted with 1.7% EtOAc in hexane to obtain compound 7.
Reaction SMILES: CC(C)=[O:3].C[N+]1([O-])CCOCC1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]=[C:27](/[CH:29]=C/C3C=CC=CC=3)[O:28][C:22]=2[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O.C(OCC)(=O)C.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]=[C:27]([CH:29]=[O:3])[O:28][C:22]=2[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2nc(/C=C/c3ccccc3)oc2C1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(C=O)oc2C1
Reaction time: 8 h

Procedure:
Acetone (8.0 ml), water (4.0 ml), N-methyl-morpholine oxide (577 mg) and osmium tetroxide (0.039 M, 3.20 ml) were added to a solution of 5-(tert-butoxy-carbonyl)-2-(trans-styryl)-4,5,6,7-tetrahydrooxazolo-[5,4-c]pyridine (803 mg) in tetrahydrofuran (16 ml) at room temperature, and the mixture was stirred overnight. Ethyl acetate (50 ml) and a 10% aqueous solution (50 ml) of sodium thiosulfate were added to the reaction mixture to separate an organic layer. The water layer was then extracted with ethyl acetate (30 ml). After the resultant organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Methanol (8.0 ml), water (8.0 ml) and sodium metaperiodate (790 mg) were added to a solution of the residue in tetrahydrofuran (16 ml). After stirring for 3 hours, ethyl acetate (30 ml) and water (50 ml) were added to the reaction mixture to separate an organic layer. The water layer was extracted with ethyl acetate (20 ml). After the resultant organic layers were combined, washed with a saturated solution (50 ml) of sodium hydrogencarbonate and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→2:1) to obtain the title compound (234 mg) as a colorless amorphous substance. Since this aldehyde was unstable, it was immediately used in the next reaction.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[OH:38][CH:39]1[CH2:42][NH:41][CH2:40]1.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.C(Cl)Cl.CO.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:41]1[CH2:42][CH:39]([OH:38])[CH2:40]1)=[O:12]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(c1nc2ccccc2[nH]1)N1CC(O)C1
Reaction time: 6 h
Yield: 23.8 %

Procedure:
1H-benzo[d]imidazole-2-carboxylic acid (1.788 g, 11.03 mmol) was dissolved in 50 ml DMF and HATU (4.19 g, 11.03 mmol) was added. This mixture (A) was stirred for 30 min. 3-hydroxyazetidine hydrochloride (1.2083 g, 11.03 mmol) was added to 50 ml DMF, diisopropylethyl amine (5.76 mL, 33.1 mmol) was added and the mixture (B) was stirred for 5 min. Mixture (B) was added to mixture (A) and the resulting reaction mixture was stirred for 6 hours. The reaction was hydrolyzed with 30 ml water and 30 ml 1M HCl and the resulting mixture was extracted with EtOAc (3×200 ml). The combined organic layers were dried with magnesium sulfate and evaporated. Silica gel chromatography (0-10% MeOH in DCM) provided (1H-benzo[d]imidazol-2-yl)(3-hydroxyazetidin-1-yl)methanone (0.570 g, 2.62 mmol, 23.79% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][NH:11][C:12]=1[C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[ClH:25]>O1CCCC1>[ClH:25].[CH2:1]([C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]cnc1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1[nH]cnc1Cc1ccccc1

Procedure:
Reaction of this aminoketone (160 g.) with formamide (480 ml.) by heating at 120°-140° over five hours gave 4-benzyl-5-carbethoxyimidazole (75 g.) m.p. 168.5°-169.5°. Reduction of this ester (30 g.) with lithium aluminum hydride (6.4 g.) in tetrahydrofuran (600 ml.), followed by addition of water, filtration and acidification of the filtrate with ethanolic hydrogen chloride, gave 4-benzyl-5-hydroxymethylimidazole hydrochloride (22.9 g.), m.p. 149°-151°, after concentration and addition of ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:12][C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=O)=O.[CH2:22]([CH2:24][NH2:25])[OH:23]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:25]([CH2:24][CH2:22][OH:23])[C:15](=[O:17])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1
Reactant: NCCO
Reactant: COc1ccccc1CC(=O)Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1C
Product: COc1ccccc1Cc1nc2ccccc2c(=O)n1CCO
Temperature: 180 °C
Yield: 22 %

Procedure:
A suspension of 3.0 g (10 mmol) of methyl ester of N-(2-methoxyphenylacetyl)anthranilic acid and 1.2g (20 mmol) of monoethanolamine in xylene was heated at 180° C. for 16 hours in a sealed tube. After cooling, the precipitated crystals were collected by filtration to obtain 0.7 g (22%) of 2-(2-methoxyphenylmethyl)-3-(2-hydroxyethyl)- 4(3H)-quinazolinone (m.p.: 154°-155° C.). Subsequently, to 0.7 g (2.2 mmol) of this 3-(2-hydroxyethyl) derivative was added thionyl chloride (5 ml) and the resulting reaction mixture was stirred at room temperature for 1 hour. An excess of the thionyl chloride was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent:dichloromethane) to obtain 0.14 g (20%) of 2-(2-methoxyphenylmethyl)-3-(2-chloroethyl)-4(3H)-quinazolinone. (m.p.: 109°-111° C.).
Reaction SMILES: C([O:8][CH2:9][CH3:10])(OCC)OCC.[CH3:11][C:12]1[NH:13][CH:14]=[C:15](C)[C:16]=1[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1>C(O)(C(F)(F)F)=O>[CH3:14][C:15]1[C:16]([C:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH:18]=2)=[C:12]([CH3:11])[NH:13][C:10]=1[CH:9]=[O:8]
Reactant: CCOC(OCC)OCC
Reactant: Cc1c[nH]c(C)c1C1=CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(C=O)c(C)c1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethyl orthoformate (6 mL) was added to a solution of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine (360 mg) in TFA (6 mL) at 0° C. The mixture was stirred at 0° C. for 10 mins and then at rt for 40 mins. The solvent was removed and to the residue was added NaHCO3, extracted with ethyl acetate, dried and concentrated to give 356 mg of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[OH:5]>CCCCCC.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(C(O)CC(C)(C)C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Product: Cc1ccc(C(=O)CC(C)(C)C)cc1
Temperature: 65 °C
Yield: 102.3 %

Procedure:
To a stirred solution of (±)-3,3-dimethyl-1-p-tolyl-butan-1-ol (2.15 g, 11.3 mmol) in hexane (30 mL) add manganese dioxide (2.94 g, 33.8 mmol) and heat the mixture overnight at 65° C. Cool to ambient temperature, filter the manganese salts, and concentrate in vacuo to give the desired intermediate as a colorless oil (2.2 g, 100%).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:79]=[CH:78][C:77]2[C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:70](=[O:80])[C:69]=2[CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:67]2[CH:79]=[CH:78][C:77]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[C:70](=[O:80])[C:69]=3[CH:68]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(=O)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
(3,4,5-Tris(octadecyloxy)-cyclohexyl)-methanol (82.5 mg, 89.7 μmol), 2-hydroxy-9-fluorenone (26.4 mg, 135 μmol) and triphenylphosphine (35.3 mg, 135 μmol) were dissolved in dehydrated THF (1.6 mL), DIED (27 μL, 137 μmol) was added, and the mixture was stirred for 1.5 hours. THF was evaporated, and 90% aqueous acetonitrile (10 mL) was added to the residue to allow crystallization. The crystals were filtered, and the obtained crystals were washed well with acetonitrile (10 mL) to give 2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenone (91.2 mg, 83.1 μmol, 93%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[C:24](O)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].ClC1C=CC=C[NH+]=1.C(N(CC)CC)C.[NH2:42][CH2:43][CH:44]([OH:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48]>C(Cl)Cl>[CH2:47]([N:46]([CH2:45][CH:44]([OH:51])[CH2:43][NH:42][C:24]([C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10]([C:9]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:25])[CH2:49][CH3:50])[CH3:48]
Reactant: CCN(CC)CC(O)CN
Reactant: O=C(O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1
Agent: Clc1cccc[nH+]1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC(O)CNC(=O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1

Procedure:
10.5 g of N-phenyl-3-benzyloxyindole-2-carboxylic acid are reacted with 4.5 g of 2-chloro-N-pyridinium iodide, 4.2 ml of triethylamine and 2.5 g of 1-amino-2-hydroxy-3-diethylaminopropane in 45 ml of methylene chloride at room temperature, After 14 h, the reaction mixture is washed with a saturated solution of sodium chloride and with a 10% sodium carbonate solution, dried over sodium sulfate, filtered and evaporated. The residue is dissolved in dilute hydrochloric acid/ether and the ether phase separated. The aqueous phase is made alkaline and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and evporated. The raw 2-[3-N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-benzyloxy-1-phenylindole is recrystallized from isopropanol/ether. Melting point: 80°-81° C.
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:12]=[C:13]([N:17]2[C:21]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[S:28](=[O:31])(=[O:30])[CH2:29][C:20]=3[C:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:9])C1C=CC=CC=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN1CCCC1=O.O>[N:37]1([C:8]([NH:10][C:11]2[CH:12]=[C:13]([N:17]3[C:21]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[S:28](=[O:31])(=[O:30])[CH2:29][C:20]=4[C:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:18]3)[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)c1nn(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1nn(-c2cccc(NC(=O)N3CCOCC3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 55 °C
Yield: 81.4 %

Procedure:
A mixture of ethyl 1-{3-[(phenoxycarbonyl)amino]phenyl}-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (100 mg, 0.198 mmol), morpholine (0.03 mL, 0.3 mmol), triethylamine (0.03 mL, 0.3 mmol) in N-methyl-2-pyrrolidone is heated under microwave irradiation for 15 min at 55° C. The reaction mixture is diluted with water and is stirred for another hour. The precipitate is filtered and dried under vacuum to afford 80 mg (81%) of the title compound. MS (ESI+): 497.2.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:5]=[N:4][C:3]1=2.[OH-].[K+].Cl>O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
20.00 g (84.66 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, ethyl ester (AIT-0027) was placed into a 500 ml round bottom flask equipped with a magnetic stirring bar. 150 ml of water was added to the flask and the solution stirred. To the stirring heterogeneous solution was added 10.46 g (0.1854 mol) of KOH pellets. Within a few minutes the solution became a homogeneous light green color. The solution was stirred at room temperature for 3.5 hours. The solution was acidified (pH approximately 1.0) with concentrated HCl. The precipitated solution was placed at 4° C. overnight. The solid was collected by filtration, washed sequentially with water, methanol and ether, and dried. 17.63 g (84.7 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid (AIT-0080) was obtained as a free flowing white solid. Yield: 100%.
Reaction SMILES: FC(F)(F)C(O)=O.N1C(C)=CC=CC=1C.[C:16]([C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:20]([C:21]([OH:23])=[O:22])[C:19]=1[OH:28])#[N:17].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[Li+].Cl>O>[CH3:27][C:25]1[CH:24]=[C:20]([C:21]([OH:23])=[O:22])[C:19]([OH:28])=[C:18]([C:16]2[NH:31][N:30]=[N:29][N:17]=2)[CH:26]=1
Reactant: Cc1cc(C#N)c(O)c(C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)O)c(O)c(-c2nnn[nH]2)c1
Yield: 59.1 %

Procedure:
Trifluoroacetic acid (0.8 ml) was added to dry 2,6-lutidine (10 ml) and the mixture was then treated with 3-cyano-5-methylsalicylic acid (0.885 g), sodium azide (0.65 g) and lithium chloride (20 mg), and heated at reflux for 20 hours. The mixture was then diluted with water (20 ml) and acidified by treatment with concentrated hydrochloric acid. The resulting precipitate was collected and recrystallized from a large amount of acetic acid to give 5-methyl-3-(tetrazol-5-yl)salicylic acid (0.65 g), m.p. 290°-292° C. (with decomposition).
Reaction SMILES: [Na].[O-]CC.[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([OH:16])[C:12]([O:14]C)=O.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=1>C(O)C.O>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[C:12](=[O:14])[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:28])([F:17])[F:29])[CH:20]=2)=[C:26]([NH2:27])[O:16]1
Reactant: COC(=O)C(O)c1cccs1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2cccs2)O1
Yield: 12.3 %

Procedure:
A dry, 250-ml, three-neck, round-bottom flask equipped with a mechanical stirrer, addition funnel and a reflux condenser bearing a nitrogen inlet tube was charged with 4.2 g of sodium and 100 ml of absolute ethanol. To the resulting sodium ethoxide solution was added dropwise a mixture of 21.1 g of methyl thien-2-yl-hydroxyacetate and 22.7 g of m-trifluoromethylphenyl-acetonitrile in 20 ml of ethanol. The resulting mixture was heated at reflux for 4-5 hours after which time it was added to 300-400 ml of water and extracted with petroleum ether. The aqueous phase was acidified with aqueous 10 weight percent hydrochloric acid and extracted two times with diethyl ether. The ether extracts were washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield a thick dark oil. This oil was triturated with 20-30% ether/petroleum ether which afforded 4.9 g of the title compound as a tan powder.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:31]1[N:32]=[N:33][NH:34][N:35]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:9]1=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:52][CH2:53][OH:54]>CN(C=O)C>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=2)[C:31]2[N:32]=[N:33][N:34]([CH2:52][CH2:53][OH:54])[N:35]=2)[C:9]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]([F:28])([F:29])[F:30])=[CH:22][C:10]1=2)=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
Dissolve (S)-tert-Butyl 5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 16) (0.252 g, 0.395 mmole) in DMF (4 mL), add potassium carbonate (0.0929 g, 0.672 mmole) in one portion. Inject 2-bromoethanol (0.0420 mL, 0.593 mmole) dropwise. Stir at room temperature overnight. Partition the reaction mixture between ethyl acetate (50 mL) and water (50 mL). Extract aqueous back with more ethyl acetate (20 mL). Combine organic layers, Dry over sodium sulfate, filter and concentrate the solution. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-100%), to provide the title compound as a colorless oil (0.0700 g, 26%). MS (ES+): 705 (M+Na).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:20]([C:21](OCC)=[O:22])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([C:9]1[C:20]([CH2:21][OH:22])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: CCOC(=O)c1c(CC)nn2ccc3c(c12)CCO3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn2ccc3c(c2c1CO)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a suspension of 80% lithium aluminum hydride (548 mg, 11.8 mmol) in tetrahydrofuran (30 mL) was added a solution of ethyl 2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate (770 mg, 2.96 mmol) in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Sodium sulfate decahydrate (10 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (485 mg, yield 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]4[CH:26]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]4[CH:26]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(Cl)nc4)cc3)cn2c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)nc4)cc3)cn2c1
Temperature: 170 °C
Yield: 73.5 %

Procedure:
A stirred mixture of 6-chloro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pyridine-3-carboxamide (0.15 g, 0.414 mmol), dimethylamine hydrochloride (0.845 g, 10.36 mmol) and K2CO3 (1.43 g, 10.36 mmol) in dry DMSO (10 ml) was heated at 170° C. for 16 h under an atmosphere of argon. The cooled reaction mixture was added to water (200 ml) and the precipitate was collected by filtration and dried in the air. The solid was purified by flash chromatography (12:1 DCM/MeOH) to give the title compound (0.113 g, 73%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:11]=[CH:10][O:9][C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[CH:10][O:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:14])[CH:7]=1
Reactant: O=c1[nH]cc(Br)c2ccoc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccoc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of the title compound of step 1 (500 mg, 2.3 mmol) stirred at 0° C. in DMF (5 mL) was added NaH (68 mg, 2.81 mmol, 60% in mineral oil). After stirring at 0° C. for 30 min, methyl iodide (400 mg, 2.8 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 4 h. The reaction mixture was treated with saturated NH4Cl (aq. 30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc=10:1) to give the title compound (500 mg, 94%). 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J=2.0 Hz, 1H), 7.30 (s, 1H), 6.70 (d, J=2.0 Hz, 1H), 3.66 (s, 3H). LCMS (M+H)+=229.