Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOCC1(COCc2ccccc2)CCC(=O)O1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.7 g (21.83 mmol) of the compund prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at b 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3N=C(N[C@H](C4C=CC(F)=CC=4)C)C(CNC(=O)C)=[CH:12][C:11]=3F)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:32][CH2:33][N:34](C(C)C)C(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C@@H:48]([NH2:50])[CH3:49])=[CH:44][CH:43]=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:11]=[CH:12][N:34]=[C:33]([NH:50][C@H:48]([C:45]4[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=4)[CH3:49])[CH:32]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Reactant: C[C@H](N)c1ccc(F)cc1
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)ccn1)c1ccc(F)cc1
Temperature: 160 °C

Procedure:
A mixture of (2-chloro-pyridin-4-yl)-(5-cyclopropyl-1H-pyrazole-3-yl)-amine (Method 4; 0.116 g, 0.49 mmol), DIEA (0.20 ml, 1.18 mmol), and (S)-1-(4-fluoro-phenyl)-ethylamine (1.0 ml, 7.4 mmol) was heated to 160° C. in a sealed tube for 2 days. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase prep HPLC (column: mC-PACK-ODS-AQ, 250×20 nm, 3.0×50 mm; 5-95% gradient MeCN (0.05% TFA) in water (0.1% TFA); flow rate: 10.0 ml/min). 1H NMR (400 MHz) δ 0.696 (m, 2H), 0.958 (m, 2H), 1.49 (m, 4H), 4.75 (q, 1H), 5.60 (s, 1H), 7.19 (t, 2H), 7.29 (t, 1H), 7.42 (t, 3H), 7.6 (s, 1H), 9.89 (s, 1H). MS: Calcd.: 337. Found: [M+H]+ 338.
Reaction SMILES: Cl.Cl.[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:5][NH:4]1.C(N(CC)CC)C.[O:29]=[C:30](Cl)OC(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>C(#N)C>[O:29]=[C:30]1[N:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH:6]2[CH2:5][N:4]1[NH:3][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)CONC1CNNc2ccccc21
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CON1C(=O)N2CC1c1ccccc1N2
Reaction time: 1 h
Yield: 80.8 %

Procedure:
5.63 g of the product obtained in stage D are dissolved in 2 l of acetonitrile. 8.45 g of triethylamine are slowly added, followed, at 0° C., by 1.658 g of diphosgene and 2.25 g of dimethylaminopyridine. The temperature is allowed to return to ambient temperature. After one hour, the acetonitrile is evaporated and the residue is treated with NaH2PO4 (1M aqueous solution). Extraction is carried out with AcOEt, and the organic phase is washed with water. It is dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica (eluent: heptane/AcOEt (4:1)). The compound obtained is crystallized from ether at 0° C. and 1.96 g of the expected product (41%) are isolated.
Reaction SMILES: N(C1C(C(OCC)=O)=CN=C2N(CC3OC=CC=3)N=CC=12)N.C(N1C2=NC=C(C(OCC)=O)C(NN)=C2C=N1)C.[CH2:41]([N:47]1[C:51]2[N:52]=[CH:53][C:54]3[C:55](=[O:63])[NH:56][C:57]4[N:58]([N:60]=[CH:61][N:62]=4)[C:59]=3[C:50]=2[CH:49]=[N:48]1)[C:42]1[O:46][CH:45]=[CH:44][CH:43]=1.[C:64]1(O)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(O)C>[CH2:41]([N:47]1[C:51]2[N:52]=[CH:53][C:54]3[C:55]([O:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[N:56][C:57]4[N:58]([N:60]=[CH:61][N:62]=4)[C:59]=3[C:50]=2[CH:49]=[N:48]1)[C:42]1[O:46][CH:45]=[CH:44][CH:43]=1
Reactant: Oc1ccccc1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1c2cnn1Cc1ccco1
Agent: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Agent: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Solvent: CCO
Product: c1ccc(Oc2nc3ncnn3c3c2cnc2c3cnn2Cc2ccco2)cc1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1 a, 8-furfuryl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1 b and then as in Example 4, substituting phenol for the ethanol to obtain 8-furfuryl-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo-[1,5-a]pyrimidine.
Reaction SMILES: CO.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[C:12]([C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]2[CH2:25][O:24]C(C)(C)[O:22]2)[CH:16]=1)=[O:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[C:12]([C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([OH:22])[CH2:25][OH:24])[CH:16]=1)=[O:14]
Reactant: CC1(C)OC[C@@H](c2cccc(C(=O)C(C(=O)c3cccc(F)c3)=C3Nc4ccccc4N3)c2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(C(C(=O)c1cccc([C@@H](O)CO)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A 20 ml portion of methanol solution containing 1.68 g of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]phenyl}-3-(3-fluorophenyl)propane-1,3-dione was mixed with 560 mg of p-toluenesulfonic acid monohydrate and stirred at room temperature for 18 hours. This was mixed with appropriate amounts of purified water and saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 640 mg (42%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-1,2-dihydroxyethyl]phenyl}-3-(3-fluorophenyl)propane-1,3-dione (Example 4-1) from a hexane-ethyl acetate (3:1-1:3) eluate.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]([CH2:13][C:14](OC)=[O:15])[C:10](=[O:18])[N:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pd]>[O:18]=[C:10]1[N:11]2[CH2:13][C:14](=[O:15])[NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([C:12]=32)[N:9]1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reaction time: 2 h

Procedure:
A mixture of dimethyl 2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate from Step B (270 mg, 0.84 mmol) and 10% Pd/C (50 mg) in MeOH (10 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 2 h, the reaction was filtered through a Celite pad and concentrated in vacuo. The crude solid was dissolved in toluene (3 mL) and p-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) was added. The mixture was heated at reflux for 30 min and then concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH3:15][N:7]1[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH:6]12
Reactant: CN1c2ccc(O)cc2C2CCC(N)C21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1c2ccc(O)cc2C2CCC(NC(=O)OCc3ccccc3)C21
Reaction time: 2 h

Procedure:
To a solution of 3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent[b]indol-7-ol (10.7 grams) in methylene chloride (125 ml) was added triethylamine (5.6 grams) followed by the dropwise addition of benzyl chloroformate (10.0 grams) in methylene chloride (25 ml). The mixture was stirred for 2 hours, extracted with water, dried (Na2SO4) and concentrated. The product was purified by chromatography on silica gel, eluting with 2:1 hexane/acetone to provide 1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethoxycarbonylaminocyclopent[b]indol-7-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.[Li]CCCC>C1COCC1>[CH3:8][C:6]1[CH:7]=[C:2]([B:10]([OH:15])[OH:11])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc(C)n1
Reaction time: 3 h

Procedure:
4-Bromo-2,6-dimethyl-pyridine (910 mg, 4.9 mmol) and triisopropyl borate (2.3 mL, 10 mmol) in THF (10 mL) were cooled in a −78° C. bath. BuLi (2.7 M, 7 mL) was added in drop wise. After 3 hrs, the bath was removed. The reaction was acidified with 1N HCl till pH=1. The separated aqueous layer was neutralized with NaOH and subsequently extracted with ethyl acetate. A crude white solid was obtained (800 mg) as the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH2:17][P:18]([O:24]C(C)C)([O:20]C(C)C)=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C[Si](C)(C)Br.C(O)C.C1OC1C>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:28])[CH:6]=[C:7]([CH2:17][P:18]([OH:20])([OH:24])=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(C=C(COCc1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(COCc1ccccc1)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is dissolved in 10 ml of dichloromethane, and 0.8 ml (6 mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 6 hours, 10 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation, the residue is dissolved in 5 ml of ethanol, and a mixture of ml of propylene oxide and 5 ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 218°-220° (decomp.).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:24])[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([C:14]([F:17])([F:16])[F:15])[C:11]([C:18]([O:20]CC)=[O:19])=[CH:10][C:9]=2[CH:23]=1>C1COCC1.CCO.O>[F:24][CH:4]([F:3])[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([C:14]([F:17])([F:15])[F:16])[C:11]([C:18]([OH:20])=[O:19])=[CH:10][C:9]=2[CH:23]=1
Reactant: CCOC(=O)C1=Cc2cc(C(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(C(F)F)ccc2OC1C(F)(F)F
Reaction time: 60 h
Yield: 60.1 %

Procedure:
Aqueous NaOH (1.31 mL, 3.277 mmol, 2.5 M solution) was added in one portion to the ester (Step 1) (0.880 g, 2.731 mmol) in THF:EtOH:H2O (7:2:1, 10 mL). The resulting solution was stirred for 60 hours. The reaction mixture was partially concentrated in vacuo to remove the organic solvents and was diluted with H2O. The resulting aqueous solution was washed with diethyl ether, sparged with nitrogen to remove trace ether, and acidified with concentrated HCl. The resulting oily suspension was extracted with diethyl ether. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo yielding the title compound (0.483 g, 60%) as an oil which solidified as a white crystalline mass: mp 134.7–136.2° C. 1H NMR (acetone-d6/300 MHz) 7.97 (s, 1H), 7.73 (s, 1H), 7.67 (dd, 1H, J=8.5, 1.0 Hz), 7.17 (d, 1H, J=8.5 Hz), 6.89 (t, 1H, J=56.2 Hz), 5.90 (q, 1H, J=7.1 Hz). FAB-ESLRMS m/z 293 (M−H). EIHRMS m/z 293.0235 (M−H, Calc'd 293.0237). Anal. Calc'd for C12H7F5O3: C, 49.0; H, 2.40. Found: C, 48.78; H, 2.21.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:7][CH2:6]2.S(Br)([Br:21])=O>C1(C)C=CC=CC=1>[Br:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:7][CH2:6]2
Reactant: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: O=S(Br)Br
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCc3cc(CBr)ccc32)cc1
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A suspension of 5-hydroxymethyl-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran (2 g, 8.2 mmol) in toluene (20 mL) was heated until the solid dissolved. Heating was then stopped. Thionyl bromide (2.2 g, 10.6 mmol) was added, and the mixture was stirred for 1 h. Silica (25 g) was added, and the mixture was filtered, and the residue was washed with a 1:1 v/v solution of ethyl acetate and heptane. The filtrate was evaporated to give the title compound as a red-orange oil (2.6 g, 90%). 1H NMR (d6-DMSO): δ 4.72 (s, 2H), 5.11 (d, 1H), 5.28 (d, 1H), 6.17 (s, 1H), 7.04 (d, 1H), 7.17 (t, 2H), 7.33 (d, 1H), 7.38 (dd, 2H), 7.45 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]2[CH:12]3[CH2:14][CH:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17][CH:11]3[CH2:10][O:9][C:8]=2[CH:7]=[C:6]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH3:27])[CH:5]=1.[C:28](Br)(=[O:31])[CH2:29][CH3:30]>>[C:28]([O:3][C:4]1[C:13]2[CH:12]3[CH2:14][CH:15]([N:18]([C:4](=[O:3])[CH2:5][CH3:6])[C:19](=[O:21])[CH3:20])[CH2:16][CH2:17][CH:11]3[CH2:10][O:9][C:8]=2[CH:7]=[C:6]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH3:27])[CH:5]=1)(=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)Br
Reactant: CCC/C=C\Cc1cc(O)c2c(c1)OCC1CCC(NC(C)=O)CC21
Agent: [H-]
Agent: [Na+]
Product: CCC/C=C\Cc1cc2c(c(OC(=O)CC)c1)C1CC(N(C(C)=O)C(=O)CC)CCC1CO2

Procedure:
Exhaustive acylation of 9-amino and 9-acylaminodibenzo[b,d]pyrans effects peracylation to afford 1-acyloxy-9-diacylamino-hexahydro-dibenzo[b,d]pyrans. Such peracylation can be effected by reacting either a 9-amino or a 9-acylamino-hexahydro-dibenzo[b,d]pyran with an excess of an acylating agent, for example from about 2 to 10 molar excess, as well as carrying out the reaction at an elevated temperature of about 60° to about 150° C. The peracylation is carried out in the presence of a strong base such as sodium hydride. As an illustration of peracylation, a compound such as dl-cis-1-hydroxy-3-(2-hexenyl)-9-acetamido-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran can be reacted with about a 5 molar excess of propionyl bromide in the presence of sodium hydride at about 100° C. for about seventy-two hours to afford dl-cis-1-propionoxy-3-(2-hexenyl)-9-(N-propionyl)acetamido-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15][C@@H:16]([CH2:19][CH3:20])[CH2:17]O.S(=O)(=O)(O)O.OC1C=CC(C(O)=O)=CC=1>C(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:15][C@@H:16]([CH3:17])[CH2:19][CH3:20])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC[C@H](C)CO
Agent: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC[C@H](C)COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 93 %

Procedure:
In a flask equipped with a Dean-Stark trap 6.78 g (0.036 mole) 6-hydroxyl-2-naphthaleneformic acid, 4.76 g (0.054 mole) (S)-2-methyl-1-butanol, 0.2 ml sulfuric acid and 15 ml anhydrous benzene were charged and refluxed for about 15 hours until all the 4-hydroxybenzoic acid was dissolved. The esterification reaction mixture was cooled to room temperature, extracted with ethyl ether, and washed with 5% (w/w) sodium hydrogen carbonate aqueous solution. The ethyl ether layer was collected, concentrated, and purified with column chromatography (ethyl acetate/n-hexane) to obtained light yellow solid. Yield: 93%. The optical rotation: [α]25D =+2.97 (c=1.0 g/dl, chloroform).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:29]5[C:30]([CH3:43])=[N:31][N:32]([CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=6)[C:33]=5[CH3:34])=[C:27]([CH:44]5[CH2:46][CH2:45]5)[N:26](C(OC(C)(C)C)=O)[C:23]4=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl.C(=O)(O)[O-].[Na+]>CO.C(Cl)(Cl)Cl>[CH:44]1([C:27]2[NH:26][C:23]3=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[CH:21]=[C:22]3[C:28]=2[C:29]2[C:30]([CH3:43])=[N:31][N:32]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[C:33]=2[CH3:34])[CH2:46][CH2:45]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c(C2CC2)n(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c(C2CC2)[nH]c2ncc(-c3ccc(N4CCNCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-cyclopropyl-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg) dissolved in 2 ml of methanol and added methanol/HCl (3 ml) at 0° C. and stirred at room temperature for 30 min. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was concentrated under reduced pressure to afford crude product. The residue was basified with saturated sodium bicarbonate solution and extracted with DCM (2×25 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 7 mg (9.72% yield) of the pure required product. 1H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 8.34 (s, 1H), 7.64-7.39 (m, 5H), 7.15-7.11 (t, 1H), 7.01-6.95 (m, 4H), 5.34 (s, 2H), 4.20-4.00 (m, 4H), 3.10-3.00 (m, 4H), 2.09 (s, 3H), 2.08 (s, 3H), 1.82-1.79 (m, 1H), 0.96-0.95 (m, 4H). MS: m/z=521.4 (M+1), HPLC Purity: 80.32% Method: A.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[C:13](=O)[C:12]([CH3:28])([CH3:27])[CH2:11]2)=[CH:6][CH:5]=1.O>CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[C:13](=[CH2:1])[C:12]([CH3:28])([CH3:27])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: C=C1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C

Procedure:
An ethereal solution of methyllithium (50 ml, 1.9 M) was added over 45 min. to a stirred solution of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone (18.5 g) in dry ether (150 ml) and the mixture heated under reflux for 30 min. After cooling, excess methyllithium was decomposed with water, the ether layer was separated, dried (MgSO4) and treated with a solution of hydrogen chloride in ether. The hydrochloride salt of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-methylidene tetralin precipitated as a white solid (15.6 g, 77%). A portion was recrystallized from ethanol-ether, m.p. 233°-235°.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[C:22]=1[Cl:32].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[C:22]=2[Cl:32])[C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A suspension of 26.7 g (0.096 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde (prepared in Example 96 (i) and (ii)) and 28.01 g (0.203 mol) of dry potassium carbonate in 350 mL of dimethylformamide was stirred under argon for 20 minutes. Then 30 g (0.10 mol) of methyl 4-bromomethyl-2,3-dichlorobenzoate was added and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was poured into water and extracted several times with ether. Filtration of the solid formed at the ether-water interface gave 19.35 g of product. The ether layer was washed 4 times with water, once with brine, and then concentrated under vacuum to give a solid. Recrystallization of the combined solids from methanol gave 32.55 g (68%) of product; mp 135°-173° C.
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[CH:10]=[CH:11][CH:12]=1.O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH3:6])[CH:8]=2)[N:17]=1
Reactant: Cc1cccc(C(=O)CSC#N)c1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (20 ml) solution was added to a solution of 2-(3-methylphenyl)-2-oxoethyl thiocyanate (2.29 g, 12.0 mmol) in acetic acid (20 ml), and the mixture was stirred at 130° C. for 2 hours. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.03 g (66.8%) of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([CH2:20][C:21]([OH:23])=O)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH:29]1[CH:30]=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.Cl.C[C@@H]1CCCN1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([CH2:20][C:21]([N:35]3[CH2:30][CH2:29][CH2:34][C@H:33]3[CH3:32])=[O:23])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CC(=O)O
Agent: C[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CC(=O)N1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a mixture of [2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-acetic acid [CAS 403611-89-2] (2.2 g, 6.8 mmol) in CH2Cl2 (40 mL) is added EDC (1.57 g, 8.2 mmol) and HOBT (1.11 g, 8.2 mmol). After a few minutes, (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3] (1.0 g, 8.2 mmol) and DIPEA (2.5 mL, 13.6 mmol) are added. The mixture is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2×), and the combined organic phase is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography [120 g SiO2, elute gradient 30% EtOAc/hexane to 80% EtOAc/hexane) to yield 1.25 g of the title compound as a yellow oil. MS (m/e): 391.2 (M+1)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])C1C=C(C2CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)C=CC=1.C(N)C#C.C([C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:45][N:44]([C:46]([NH:48][CH2:49][CH:50]=[CH2:51])=[O:47])[CH2:43]2)=[CH:38][CH:37]=1)(C)(C)C>>[F:1][C:2]([F:27])([F:26])[C:41]1[CH:40]=[C:39]([CH:42]2[CH2:43][N:44]([C:46]([NH:48][CH2:49][C:50]#[CH:51])=[O:47])[CH2:45]2)[CH:38]=[CH:37][CH:36]=1
Reactant: FC(F)(F)c1cccc(C2CN(C(c3ccccc3)c3ccccc3)C2)c1
Reactant: C=CCNC(=O)N1CC(c2ccc(C(C)(C)C)cc2)C1
Agent: C#CCN
Product: C#CCNC(=O)N1CC(c2cccc(C(F)(F)F)c2)C1

Procedure:
This product was prepared from compound (38) and propargylamine using the procedure described for compound (12). m.p. 121° C.