Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>O>[Br:1][C:2]1[C:3]2[O:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1
Reactant: O=C(COc1ccc(-c2ccccc2)cc1Br)c1ccccc1
Solvent: O
Product: Brc1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12

Procedure:
A mixture of 156 g. of the product of step A and 1 kg. of polyphosphoric acid is heated at 100° C. for seven days. The reaction mixture is poured into 5 liters of water and stirred, then extracted with 2 liters of chloroform. The dried extracts are treated with decolorizing charcoal, then evaporated. The residue is chromatographed on silica gel, eluting with carbon tetrachloride. The residue is triturated with hexane to provide 7-bromo-3,5-diphenylbenzofuran as a pale yellow solid. The structural assignment is supported by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O>CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][N:9]([C:20]([NH2:19])=[O:21])[CH2:8]1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CC(C)=O
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 120 h

Procedure:
A mixture of 30.6 g (0.141 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine and 42 g (0.321 mole) of nitrourea (80%) in 500 ml of acetone was stirred for 5 days (5 days not required, but convenient) at room temperature. The mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between 150 ml of water and 100 ml of ethyl acetate and the layers separated. The aqueous layer was washed with 100 ml of ethyl acetate. The ethyl acetate layers were washed with 75 ml of 5% aqueous sodium hydroxide solution followed by 75 ml of water, dried over sodium sulfate and concentrated in vacuo. The residual oil was crystallized from ethyl alcohol-ethyl acetate to give 22 g (60%) substantially the title compound. Recrystallization twice from ethyl alcohol gave 9.9 g of white crystalline solid, m.p. 151°-152.5° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl[CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>O>[CH2:1]([NH:4][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C[Si](C)(C)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To 118 mL (1.57 mol) of allylamine warmed at 40° C. in an inert atmosphere was very slowly added 100 mL (0.72 mol) of chloromethyl trimethylsilane (approximate rate of 1 mL/min). The reaction mixture was slowly warmed to 70° C. and stirred for 24 h. The reaction mixture was cooled to 0° C. and to it was added water to break up the gel and then 300 mL of 2N NaOH solution. The reaction mixture was extracted with ether. The combined organic fractions were washed with 500 mL of sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by distillation (bp 80-84° C. @ 100 torr) to give 75 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:4][CH2:3]1.C(O)C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
0.46 g (0.95 mmol) of methyl 4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)benzoate is dissolved in 20 ml of tetrahydrofuran, 2 ml of ethanol and 1 ml of water, and 0.46 g (11 mmol) of lithium hydroxide monohydrate is then added. The reaction medium is refluxed for 15 hours, acidified with 2N hydrochloric acid solution and then extracted with ethyl acetate. The solid obtained is washed with a heptane/ethyl ether mixture (90/10) and then purified by chromatography (eluent: dichloromethane). An off-white powder is obtained (0.2 g; yield=45%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[C:8]([S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11])[CH:9]=1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)#[N:2]
Reactant: COc1ccc(CC#N)cc1S(=O)(=O)NC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC#N)cc1S(N)(=O)=O
Yield: 20.8 %

Procedure:
A suspension of 3.0 g of the compound from Example 2 and 0.1 g p-toluenesulfonic acid in 100 ml of dry toluene was refluxed in a flask equipped with a Dean-Stark apparatus. After being refluxed overnight the solution was concentrated and allowed to cool. The precipitate was filtered off to give 0.5 g light brown solid. The mother liquor was chromatographed over silica gel with 20:73:2:5, ethyl acetate:methylene chloride:methanol:THF to give additional product, m.p. 173°-177° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=2)[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: Fc1ccc(CBr)cc1
Product: O=C1C(Cc2ccc(F)cc2)CCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 67 %

Procedure:
In a manner similar to the method described in Example 36-2, using 281 mg of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1, and using 4-fluorobenzyl bromide in place of iodoethane, 205 mg (yield: 67%) of the captioned compound was obtained as a diastereomer mixture.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]#[C:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1)(C)C.[H][H].O>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1
Reactant: [H][H]
Reactant: CCCCCCCC#CCC(OCOC)C1CCC(C2CCC(C(CC#CC=CCCCC(CC3=CC(C)OC3=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OCOC)O2)O1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCC(OCOC)C1CCC(C2CCC(C(CCCCCCCCC(O)CC3=CC(C)OC3=O)OCOC)O2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of {2R-[2α[2′R*, 5′R*(R*)],5β[1(S*), 2R*, 11R*]}-3-{2-[(1,1-dimethylethyl)diphenylsilyloxy]-11-methoxymethyloxy-11-[octahydro-5′-(1-(methoxymethyloxy)undec-3-ynyl) [2.2′-bifuran]-5-yl]-6-undecen-8-ynyl}-5-methyl-2-(5H)-furanone (64 mg, 70 mmole) in benzene (0.5 mL) is stirred at room temperature under a flow of nitrogen while tris(triphenylphosphine)rhodium chloride (14 mg, 15 mmole) is added. The mixture is charged with hydrogen gas and stirred at room temperature for two days. Water is added, and the layers are separated. The aqueous extracted with ethyl acetate (3×2 mL) and the combined organic fractions are washed (1×20 mL water) dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) affords the desired product.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[C:17]([C:28]([F:31])([F:30])[F:29])[CH:16]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl>O1CCOCC1>[OH:1][CH2:2][CH:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[C:17]([C:28]([F:29])([F:30])[F:31])[CH:16]=3)[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(CO)NCC(=O)OC(C)(C)C)cc3)no2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(CO)NCC(=O)O)cc3)no2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To tert-butyl N-[2-hydroxy-1-(4-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethyl]glycinate (0.200 g; 0.13 mmol) was added HCl solution in dioxane (4 M; 4 mL) and the reaction mixture stirred 80° C. for 1 hour. The reaction mixture was allowed to cool and the solvent evaporated in vacuo. The residue was purified by preparative HPLC to afford the title compound. 1H NMR: (CDCl3, 400 MHz) δ 8.57 (1H, d, J=1.2 Hz), 8.54-8.52 (1H, m), 8.14 (2H, d, J=8 Hz), 7.70 (1H, d, J=8 Hz), 7.63 (2H, d, J=8.4 Hz), 7.44-7.38 (2H, m), 7.34-7.30 (1H, m), 7.21-7.20 (1H, m), 3.94-3.91 (1H, m), 3.65-3.56 (1H, m), 3.52-3.47 (1H, m), 3.20 (1H, d, J=16.8 Hz), 3.06 (1H, d, J=16.8 Hz), 2.06 (3H, s). LC/MS (Method B): 496 (M+H)+. HPLC (Method D) Rt 3.04 min (Purity: 94.9%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>S(=O)(=O)(O)O>[C:19]([N:9]1[C:10]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Sc2cc(-c3ccccc3)n[nH]2)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)n1nc(-c2ccccc2)cc1Sc1ccccc1
Yield: 90 %

Procedure:
At 20° to 25° C, a few drops of concentrated sulfuric acid are added to a solution of 10 parts of 3-phenyl-5-phenylthiopyrazole in 100 parts of acetic anhydride. After 15 hours the solution is concentrated in vacuo and 50 parts of water is added to the residue. There is obtained 10.5 parts (90% of theory) of 1-acetyl-3-phenyl-5-phenylthiopyrazole; m.p.: 83° to 84.5° C (recrystallized from methanol).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[H-].[Na+].[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22])([CH3:19])[CH3:18]>O1CCCC1.C(OCC)(=O)C>[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:22])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: C#CCN1CCCc2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCN1CCCc2ccc(OC(=O)N(C(C)C)C(C)C)cc21
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) in dry tetrahydrofuran (THF; 5 mL) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment at room temperature (25° C.). The reaction, mixture was stirred for 30 minutes. Then, N,N-diisopropyl carbamoyl chloride (510 mg) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 10h as semisolid. Yield: 72.6%.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)CC)C.[O:29]1[C:34]2[CH:35]=[CH:36][C:37]([C:39](Cl)=[O:40])=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>ClCCl>[S:19]1[CH2:20][CH2:21][N:17]([C:15]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:39]([C:37]3[CH:36]=[CH:35][C:34]4[O:29][CH2:30][CH2:31][O:32][C:33]=4[CH:38]=3)=[O:40])[CH2:10]2)=[O:16])[CH2:18]1
Reactant: O=C(Cl)c1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (31.6 mg, 0.1 mmol) in anhydrous dichloromethane (1 mL) was added triethylamine (0.021 mL, 0.15 mmol) followed by 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (23.8 mg, 0.12 mmol). The mixture was shaken overnight at room temperature and concentrated under reduced pressure, MS (APCI) m/e 472 (M+H)+. The residue was dissolved in anhydrous dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was allowed to stir for 5 hours at room temperature, concentrated under reduced pressure, and the residue purified by reverse-phase HPLC to provide the titled compound. MS (ESI) m/e 372 (M+H)+; 1H NMR (500 MHz, CD3OD): δ ppm 1.75-2.4 (m, 1 H), 2.74 (m, 2 H), 3.15 (m, 3 H), 3.33 (m, 1 H), 3.47 (m, 3 H), 3.75 (m, 1 H), 3.87 (m, 1 H), 4.28 (m, 4 H), 4.51 (m, 1H), 4.66 (m, 2 H), 6.90 (dd, 1 H), 7.33 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>O1CCOCC1.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>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][N:6]=[C:5]3[OH:12])=[CH:16][CH:15]=1
Reactant: Oc1ncnc2ccc(Br)cc12
Reactant: OB(O)c1ccc(F)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of 6-bromo-4-hydroxy-quinazoline (2.4 g, 10 mmol), 4-fluoro-phenylboronic acid (1.54 g, 11 mmol), K2CO3 (4.15 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmol) in dioxane (150 ml) and water (50 ml) was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was neutralized with acetic acid to pH 6-7. The precipitate was collected by filtration, washed with water and diethyl ether to yield the crude product. The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:40), yielding the pure title compound as a white solid (2.15 g, yield: 95%) which was characterized by its mass spectrum as follows: MS (m/z): 241 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([N:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:19]3=[O:34])[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([N:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:19]3=[O:34])[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 37 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate (12.6 mg, 0.020 mmol) in THF (1.2 mL) and methanol (0.5 mL) was added 1 M NaOH solution (0.3 mL, excess). The reaction mixture was stirred at 37° C. for 6 h. The reaction mixture was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30ClN4O4S: 613.17; Found: 613.2; 1H-NMR: 400 MHz, (CD3OD) δ 8.89 (dd, J=7.6, 2 Hz, 1H), 8.02 (s, 2H), 7.75 (s, 1H), 7.70-7.63 (m, 3H), 7.53-7.49 (m, 4H), 6.61 (t, J=7.2 Hz, 1H), 5.27 (s, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][C:15](=O)[NH:14][CH2:13]1)C.O.[OH-].[Na+]>O1CCCC1.CO.ClCCl>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:12]2([CH2:11][CH2:10][OH:9])[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:19]=1
Reactant: CCOC(=O)CC1(c2cccnc2)CNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: OCCC1(c2cccnc2)CCNC1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
Combine lithium aluminum hydride (4.0 g, 105 mmol) and anhydrous tetrahydrofuran (200 mL). Slowly, add a solution of (3-(pyrid-3-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester (13.0 g, 52.4 mmol) in anhydrous tetrahydrofuran (100 mL). After the addition is complete, heat to reflux. After 4 hours, cool in an ice-bath. Add water (4 mL) dropwise at such a rate that the temperature of the reaction mixture does not rise above 20° C. Cool to 10° C., add 2 M aqueous sodium hydroxide solution (4.0 mL). Add water (16 mL) and stir. After 16 hours, filter the reaction mixture and concentrate the filtrate in vacuo to give an aqueous layer. Extract with dichloromethane and lyophilize the aqueous layer to give a residue. Combine the residue and dichloromethane and methanol. Filter and evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][C:7]=1[Cl:8].Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH3:45][C:46]([NH2:49])([CH3:48])[CH3:47]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([C:12]([NH:49][C:46]([CH3:48])([CH3:47])[CH3:45])=[O:14])=[CH:10][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)c(Cl)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2nc(Cl)c(Br)nc12
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-bromo-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (600 mg, 1.48 mmol) in DMF (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (650 mg, 3.39 mmol) and HOBT (520 mg, 3.39 mmol) and the mixture stirred for 10 min. 2-methylpropan-2-amine (432 mg, 5.9 mmol) was added and the mixture stirred at room temperature for 16 h, then diluted with 10% citric acid and ethyl acetate. The organic layer was separated and washed with 10% citric acid, saturated aqueous NaHCO3 and brine, then concentrated in vacuo and purified by chromatography (silica, 5-20% ethyl acetate in hexanes) to give 2-bromo-N-tert-butyl-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (530 mg, 1.15 mmol, 78%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.30 (s, 1H), 7.72 (s, 1H), 5.64 (s, 2H), 3.57 (t, J=8.3 Hz, 2H), 1.56 (s, 9H), 0.96 (t, J=8.3 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1.[CH3:10][NH2:11]>>[CH3:10][NH:11][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1
Reactant: Cn1cc(CCCl)cn1
Reactant: CN
Product: CNCCc1cnn(C)c1
Reaction time: 15 h

Procedure:
To neat 4-(2-chloroethyl)-1-methyl-1H-pyrazole (50 g, 0.24 mol) was added a 25% aqueous solution of methylamine (1.15 L, 7.21 mol). The mixture was placed into an autoclave at 60° C. for 15 h. The resulting mixture was concentrated in vacuo, treated with aqueous solution of NaOH and extracted with DCM. The combined organic layers were concentrated in vacuo and purified by vacuum distillation to afford the title compound. b.p. 89-90° C./2 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].[C:12]1([C:18]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClCCl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([O:11][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19])=[O:10]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(O)CC1CCCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
To a mixture of (2-oxocyclohex-1-yl)acetic acid (5.6 g), benzoin (7.4 g), 4-dimethylaminopyridine (0.42 g) and dichloromethane (60 ml), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (8.7 g) was added in ice-water bath. After the reaction mixture was raised to room temperature, N,N-dimethylformamide (10 ml) was added to dissolve benzoin and stirred overnight. After usual workup, 1,2-diphenyl-2-oxoethyl (2-oxocyclohex-1-yl)acetate (15.5 g) was obtained as a crude solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([C:15]#[N:16])[C:5]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])(=[O:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:5]1[C:6]([C:15]#[N:16])=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:8][C:4]=1[C:1](=[O:3])[CH:2]=[CH:27][N:28]([CH3:30])[CH3:29]
Reactant: CC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl

Procedure:
A solution of 5-acetyl-4-(2,4-dichlorophenyl)-2-morpholin-4-ylthiophene-3-carbonitrile (52.3 mg, 0.000137 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.0 mL, 0.0075 mol) was flushed with argon and irradiated in microwave at 160° C. for 30 min. The reaction mixture was evaporated to dryness to give 4-(2, 4-dichlorophenyl)-5-(3-(dimethylamino)acryloyl)-2-morpholinothiophene-3-carbonitrile as an intermediate. The above intermediate and hydrazine hydrate (30 mg, 0.0006 mol) in AcOH (1.5 mL, 0.026 mol) was irradiated in microwave at 120° C. for 15 min. The reaction mixture was evaporated and the residue was purified by column chromatography to afford 4-(2,4-dichlorophenyl)-2-morpholino-5-(1H-pyrazol-5-yl)thiophene-3-carbonitrile (19.5 mg, 84%). LCMS: (FA) ES+ 405.06, ES− 403.23; 1H NMR (400 MHz, d4-methanol) δ: 7.65 (d, 1H), 7.45 (m, 2H), 7.33 (d, 1H), 5.48 (s, 1H), 5.45 (br, 1H), 3.85 (m, 4H), 3.54 (m, 4H).