Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J12) (173 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol) according to the general procedure M. Obtained as a yellow solid (140 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:15])=[C:7]([C:10]([CH3:14])=[CH:11][C:12]=1[CH3:13])[CH:8]=O.[CH3:16][C:17]([CH3:19])=[O:18]>O>[CH3:3][O:4][C:5]1[C:6]([CH3:15])=[C:7]([CH:8]=[CH:16][C:17](=[O:18])[CH3:19])[C:10]([CH3:14])=[CH:11][C:12]=1[CH3:13]
Reactant: CC(C)=O
Reactant: COc1c(C)cc(C)c(C=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cc(C)c(C=CC(C)=O)c1C
Temperature: 65 °C
Reaction time: 4 h

Procedure:
An aqueous solution of 2% sodium hydroxide (16.5 ml) was added dropwise over a period of 5 minutes to a suspension of 3-methoxy-2,4,6-trimethylbenzaldehyde (23.5 g) in acetone (21.3 g) and water (13 ml). The mixture was stirred at a temperature of 65° C. for a period of 4 hours and then extracted with dichloromethane. The organic extract was washed several times with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The product, 1-(3-methoxy-2,4,6-trimethylphenyl)but-1-en-3-one, was obtained as a viscous oil (28.0 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.25 (6H, s); 2.36 (3H, s); 3.67 (3H, s); 6.27 (1H, d); 7.16 (1H, s); 7.61 (1H, d).
Reaction SMILES: [N+](C1C=CC(C[C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:38])[C:13]3([CH:17](OC(=O)C)[C:18]3[S:26][C:25]4[CH2:24][CH2:23][N:22]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:21][C:20]=4[CH:19]=3)Br)[C:10]=2[C:39]([O-:41])=[O:40])=CC=1)([O-])=O.P([O-])([O-])([O-])=O>C1COCC1.C(#N)C.[Zn]>[CH2:27]([N:22]1[CH2:23][CH2:24][C:25]2[S:26][C:18](/[CH:17]=[C:13]3\[C@@H:14]4[N:11]([C:12]\3=[O:38])[C:10]([C:39]([OH:41])=[O:40])=[CH:9][S:15]4)=[CH:19][C:20]=2[CH2:21]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)OC(c1cc2c(s1)CCN(Cc1ccccc1)C2)C1(Br)C(=O)N2C(C(=O)[O-])=C(Cc3ccc([N+](=O)[O-])cc3)SC21
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3cc4c(s3)CCN(Cc3ccccc3)C4)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzy-6-[(acetyloxy)(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (450 mg, 0.65 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 hours at room temperature. The reaction mixture was filtered, cooled to 3° C., and 0.1 M NaOH was added to adjust pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 lits) and latter with 10% CAN:Water. The fractions containing the product were collected and concentrated at reduced pressure at room temperature. The yellow solid was washed with acetone and filtered. Dried. Yield: 50 mg, 18%; as yellow crystals; mp. 198° C.; (M+H) 411.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](I)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/B(O)O)=[CH:33][CH:32]=1.O>COC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:38]=[CH:37]/[C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cncc(/C=C/c3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (100 mg, 0.23 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added Na2CO3 (49 mg, 0.46 mmol, 2.0 equiv), trans-2-(4-fluorophenyl)vinyl boronic acid (95 mg, 0.57 mmol, 2.5 equiv), PdCl2(dppf) (17 mg, 0.02 mmol, 0.1 equiv) and water (0.1 mL) in a sealed tube. The reaction vessel was immersed in an oil bath preheated to 100° C. After stirring for 1 hr, the reaction mixture was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 5:95, v/v] and recrystallization (methanol/pentane) to give 2-{6-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (59 mg, 60%). 1H NMR (400 MHz, CD2Cl2) δ 9.17 (s, 1H), 8.63 (s, 1H), 7.81 (d, J=16.0 Hz, 1H), 7.61-7.64 (m, 2H), 7.27-7.37 (m, 5H), 7.09-7.13 (m, 3H), 6.23 (bs, 1H), 4.61 (d, J=8.0 Hz, 2H), 2.74 (s, 3H); HRMS (M+H)+=431.13.
Reaction SMILES: BrCCBr.C[Si](C)(C)Cl.[C:10]([O:18][CH2:19]I)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>C1COCC1.[Zn].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>[C:10]([O:18][CH2:19][C:26]1[CH:27]=[C:22]([Cl:21])[N:23]=[CH:24][N:25]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCI)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C(OCc1cc(Cl)ncn1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Zinc (4.81 g, 73.6 mmol) was suspended in THF (6 mL), treated with 1,2-dibromoethane (0.313 mL, 3.63 mmol) and the resulting mixture was heated at 60° C. under argon for 30 minutes. The reaction mixture was allowed to cool to room temperature, treated with trimethylchlorosilane (0.120 mL, 0.938 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of iodomethyl benzoate (Intermediate 23, 3.15 g, 12.02 mmol) in THF (6 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. This reaction mixture was added to a solution of 4,6-dichloropyrimidine (1.075 g, 7.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.695 g, 0.601 mmol) in THF (11 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was filtered through celite, diluted with saturated ammonium chloride solution and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and isohexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow solid (394 mg);
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18]([OH:20])=[O:19].CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[C:8]([NH:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)(C)CC(=O)O

Procedure:
Triethylamine (1.8 mL, 12.8 mmol), acetic anhydride (1.2 mL, 12.8 mL) and DMAP (10 mg, 0.09 mmol) are subsequentially added to a suspension of 3-amino-3-methyl-butyric acid (1.00 g, 8.5 mmol) in THF (100 mL). After heating at 60° C. for 3 h AcOEt is added and the organic phase is washed with 1N HCl. Drying (Na2SO4), filtration and evaporation of the solvent yields the desired product. MS (LC-MS): [M+H]+=160.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.40 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=S)=[CH:4][CH:3]=1.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[N:41][C:40]#[N:39])=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4ccc(F)cc4)cc3)c2cc1OC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
N-(4-Fluorophenyl)-N'-(4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl)thiourea (33 mg) obtained in Example 165, dicyclohexylcarbodiimide (31 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (10 ml). To this solution, a solution of cyanamide (16 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 34 mg of the title compound (yield: 99%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]=[CH:10][C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Cl.C([SiH](CC)CC)C.[N+:32]([CH3:35])([O-:34])=[O:33]>C(O)(C(F)(F)F)=O.O>[N+:32]([CH2:35][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1)([O-:34])=[O:33]
Reactant: O=C1C=CCCc2ccccc21
Reactant: C[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])CC1CCc2ccccc2CC1
Temperature: 55 °C
Yield: 42 %

Procedure:
A solution of 8,9-dihydro-5H-benzo[α][7]annulen-5-one (323 g, 2 mol) in nitromethane (620 ml) was treated with DBU (327 g, 2.1 mol) dropwise at such a rate that the temperature was maintained between 40 and 50° C. After GC analysis showed reaction completion, 3M HCl (600 ml) was added and the resulting mixture was extracted with tert-butyl methyl ether (2×500 ml). The combined organic phases were treated with brine (500 ml), dried over MgSO4, filtered and evaporated to an oil (496 g, 90%). To 347.5 g (1.58 mol) of this material dissolved in TFA (1045 ml) was added triethylsilane (583 ml, 3.65 mol) at such a rate that the temperature of the reaction mixture was maintained between 50 and 55° C. After the addition was complete, the mixture was maintained at 55° C. until GC analysis indicated reaction complete. The mixture was poured onto ice (1500 g) and water (500 ml). The resulting slurry was filtered and washed with cold hexanes (2×150 ml) then dried to give the title compound (139 g, 42%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[Na+]>O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(-c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccc(-c2cncc(O)c2)cc1
Temperature: 160 °C
Yield: 76 %

Procedure:
A mixture of 1.9 g (9.02 mM) of 4-(5-methoxy-3-pyridinyl)benzonitrile and 6.39 g (54.2 mM) of pyridinium hydrochloride is heated at 160° C. for 5 hours. After cooling and the addition of water, the pH is adjusted to 5 with concentrated sodium hydroxide solution. The mixture is extracted with ethyl acetate and the extract is dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 92/8; v/v, then dichloromethane/methanol 9/1; v/v) to give the expected product in the form of a beige solid with a yield of 76%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[CH:26]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][CH2:27]2.[I-].[K+].O>CC(=O)CC>[CH:26]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:28]5[CH2:29][CH:30]6[CH2:33][CH2:34][CH:26]([CH2:32][CH2:31]6)[CH2:27]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=1)=[O:6])[CH2:27]2
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Reactant: C1CC2CCC1CNC2
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C(CCCN1CC2CCC(CC2)C1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CC4CCC(CC4)C3)ccc1-2
Reaction time: 72 h

Procedure:
A mixture of 11.25g (0.03 mole) of 2,7-bis(4-chlorobutyryl)fluorene, 30.1g (0.24 mole) of 3-azabicyclo[3.2.2]nonane and 10.0g (0.06 mole) of potassium iodide in 200 ml butanone is heated at reflux with stirring for 3 days. The reaction mixture was poured into 1000 ml of water, and the resulting solid precipitate filtered and recrystallized from chloroform-acetone to yield the desired product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]=[C:11]1[NH:23][NH:24][C:25](OCC)=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1([CH2:30][O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]2[C:25](=[O:26])[NH:24][N:23]=[C:11]12)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)NNC1=Nc2cc([N+](=O)[O-])ccc2OC1(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2-n2c1n[nH]c2=O

Procedure:
Ethyl 2-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazin-3-yl)hydrazine-1-carboxylate (4 g) was dissolved in DMF (34 ml). The reaction mixture was microwaved at 200° C. for 10 min. The reaction solution was evaporated to give 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.207 g, 1.03 mmol) in DCM (5 mL) was added oxalyl chloride (0.112 mL, 1.29 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h., the solvent was removed in vacuo and the 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[C:5]([OH:8])=[CH:6][CH:7]=1.Br[CH2:24][C:25]([O:27]CC)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][C:25]([OH:27])=[O:26])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)=[O:10])[C:3]=1[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(Cl)ccc(O)c1C(=O)c1cnn(-c2ccccc2)c1
Product: Cc1c(Cl)ccc(OCC(=O)O)c1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from (3-chloro-6-hydroxy-2-methyl-phenyl)-(1-phenyl-1H-pyrazol-4-yl)methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.34 min, m/z 370.6 [M+1]+; 1H NMR (CDCl3): δ 2.44 (s, 3H), 4.77 (s, 2H), 6.92 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.59 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 8.19 (s, 1H), 8.52 (s, 1H), 10.39 (br s, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26].C(OCC)(=O)C>C(#N)C.O>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOc1cc(C(=O)OC)c(C)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
To stirred solution of methyl 5-hydroxy-2-methyl-3-nitrobenzoate (1.50 g, 7.61 mmol) in ACN (15 mL) was added cesium carbonate (4.96 g, 15.2 mmol) and 1-bromo-2-methoxyethane (1.57 g, 11.4 mmol). The resulting reaction mixture was heated at 80° C. overnight. On completion, the reaction mixture was diluted with water and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (1.3 g, 68).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12]1
Reactant: CNNC(=O)c1ccc(Cl)cc1
Reactant: N#Cc1cccnc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)cc2)nc1-c1cccnc1
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
To 3-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-(p-chlorobenzoyl)hydrazine (3.6 g.) in methanol (40 ml.). The reaction mixture is heated at reflux for 5 hours and is then concentrated to an oil which solidifies. After recrystallization from isopropanol, yielding 0.2 g of 1-methyl-3-(p-chlorophenyl)-5-(3-pyridyl)-1,2,4-triazole, m.p. 157°-158°C. is obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[C:39]([C:33]1[CH:34]=[N:35][C:36]2[C:31]([C:32]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=1)=[CH:30][C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:38][CH:37]=2)#[N:40]
Reactant: O=C(O)C#CCN1CCCCC1
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CCN4CCCCC4)cc23)c1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Partially dissolved 1.46 g (8.75 mmol) 4-piperidino-2-butynoic acid in 100 ml THF and chilled to 0° C. under N2. Added 1.16 ml (10.5 mmol) N-methylmorpholine and 911 μl (7.00 mmol) isobutyl chloroformate and stirred for 30 minutes. Added a solution of 1.00 g (3.50 mmol) 6-amino-4-[(3-cyanophenyl)amino]-3-quinolinecarbonitrile in 8 ml pyridine. At 3.5 hours poured onto ice bath and made basic with saturated sodium bicarbonate. Extracted with ethyl acetate, dried organic layers with magnesium sulfate, filtered, and reduced solvent to a small volume. Loaded compound onto a column of silica gel and eluted with 7% methanol/ethyl acetate. Stripped solvent from desired fractions and dried in vacuo, giving 1.008 g of off-white solid: mass spectrum (electrospray m/e): 435.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8]1[O:19][C:18]2[CH:17]=[CH:16][C:12]([CH2:13][Mg]Cl)=[CH:11][C:10]=2[O:9]1.Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH2:8]1[O:19][C:18]2[CH:17]=[CH:16][C:12]([CH2:13][C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]=3)=[CH:11][C:10]=2[O:9]1
Reactant: Clc1cnccn1
Reactant: Cl[Mg]Cc1ccc2c(c1)OCO2
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cnc(Cc2ccc3c(c2)OCO3)cn1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of chloropyrazine (1.14 g) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (106 mg) in dry tetrahydrofuran (40 ml) was added a solution of 3,4-methylenedioxybenzylmagnesium chloride (0.6 M in tetrahydrofuran, 29 ml) at 5° C. under nitrogen atmosphere over 15 minutes. After 1 hour of stirring at 5° C., 3N hydrochloric acid was added slowly under nitrogen atmosphere and the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water and dried over magnesium sulfate. The usual work up followed by flash chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1-4:1) gave 2-(3,4-methylenedioxybenzyl)pyrazine (454 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH2:27][O:28][Si](C(C)(C)C)(C)C)=[CH:21][C:20]=2[Cl:36])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:1][C:2]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH2:27][OH:28])=[CH:21][C:20]=2[Cl:36])=[O:17])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-4-((3-(4-((tert-butyl(dimethyl)silyloxy)methyl)-2-chloro-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2-thienyl)-acetate (intermediate 41; 0.76 mg, 1.08 mmol) in tetrahydrofuran (19 mL) was added hydrochloric acid 1M (3.25 mL, 3.25 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized by a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The crude obtained was purified by column chromatography with silica gel, eluting with chloroform/methanol 50/1 to give the title compound as an oil (84%).