Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[C:10]([CH2:12]C(O)=O)#[N:11]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([CH2:12][C:10]#[N:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=O)CC1
Reactant: N#CCC(=O)O
Solvent: Cc1ccccc1
Product: CCN1CC=C(CC#N)CC1
Yield: 122.6 %

Procedure:
2.9 g of 1-ethyl-4-piperidone, 3.3 g of cyanoacetic acid and 36 ml of toluene are placed in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. The mixture is refluxed for 4 hours, while removing the water using Markusson apparatus. The solvent is evaporated off under vacuum. 4.2 g of oil are obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=O)[N:18]=[C:17]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([CH2:21][CH2:22][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:18]=[C:17]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(-c2cc(Nc3cccnc3)nc(CC(=O)N3CCOCC3)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CCN3CCOCC3)n2)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A dry round bottom flask is charged with LiAlH4 (4 eq), and dry THF is added. The suspension is cooled down to 0° C. and a solution of compound 10 in THF is added dropwise. The reaction mixture is stirred 4 h at room temperature then cooled down to 0° C. and quenched with water, followed by 10% NaOH and then water again. The mixture is stirred overnight and the solid is filtered off. The aqueous phase is extracted with CH2Cl2, the organic extracts are collected and dried (Na2SO4). After evaporation of the solvent under reduced pressure and purification by reverse phase preparatory HPLC [6-(3-methoxyphenyl)-2-(2-morpholin-4-ylethyl)pyrimidin-4-yl]-3-pyridylamine 11 is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[NH2:19][CH:20]([CH3:24])[CH2:21][C:22]#[N:23]>C(#N)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH:20]([CH3:24])[CH2:21][C:22]#[N:23])=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(N)CC#N
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC#N
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)CC#N)cc1
Reaction time: 20 h

Procedure:
3.0 g (0.012 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxypropane are dissolved in 25 ml of acetonitrile and added dropwise to a boiling stirred solution of 0.96 g (0.011 mol) of β-aminobutyronitrile in 20 ml of acetonitrile. The mixture is stirred for 20 hours under reflux, the solvent is removed by distillation under reduced pressure and the oil which remains is partitioned between 150 ml of 0.1 N hydrochloric acid and 100 ml of ethyl acetate. The hydrochloric acid extract is separated off, rendered alkaline with sodium carbonate and extracted four times with 50 ml of ethyl acetate at a time. The organic phases are dried over sodium sulphate and evaporated under reduced pressure. The resulting oil solidifies on cooling to give crystals of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-(2-cyano-1-methylethyl-amino)-propane of melting point 122°-123° C.
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1>>[Cl:25][C:22]1[N:23]=[CH:24][C:19]([N:18]=[C:10]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Product: O=C1C(=Nc2ccc(Cl)nc2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 59 %

Procedure:
1-phenylisatin (23.0 mg, 0.10 mmol) and 5-amino-2-chloropyridine (12.8 mg, 0.10 mmol) were mixed and heated at 140° C. for 7 h. The resulting crude product was purified by preparative TLC using hexane/ethyl acetate (8:2) as the eluent, giving the desired product as a yellow-solid (19.7 mg, 59%). 1H NMR (400 MHz) δ 8.15 (d, J=8, 1H), 7.6-7.2 (m, 9H), 6.85-6.75 (m, 2H); ESI-MS m/z found 334 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>C(O)(=O)C.C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:19][N:20]=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:20][NH:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: NNc1ccccn1
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: C(=NNc1ccccn1)c1c2ccccc2c(C=NNc2ccccn2)c2ccccc12

Procedure:
A suspension of 4.68 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of ethanol containing 4.37 g. of 2-hydrazinopyridine and 2 drops of acetic acid is stirred and heated under reflux for two hours, then allowed to cool. Collection by filtration and washing with ethanol gives the desired product as an orange solid, which sinters from 267° C. to 272° C. (dec.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:1][C@@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@@H](OCc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a solution of cis-ethyl 3-hydroxycyclobutanecarboxylate (0.17 g, 1.2 mmol) in DMF (4 mL) was added K2CO3 (0.24 g, 1.8 mmol) followed by 4-(bromomethyl)benzonitrile (0.28 g, 1.4 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was partitioned between EtOAc (50 mL) and brine (50 mL). The layers were separated and the organic layer was washed with additional brine (50 mL). The organic layer was then dried over anhydrous Na2SO4, filtered, and concd in vacuo to give cis-ethyl 3-(4-cyanobenzyloxy)-cyclobutanecarboxylate (0.29 g, 95%) as an oil: 1H NMR (DMSO-d6) δ 7.82 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.93 (m, 1H), 2.58-2.45 (m, 1H), 2.41-2.28 (m, 2H), 1.98-1.85 (m, 2H), 1.20-1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][N:24]=[C:25]=[S:26])[CH3:20].C(N(C(C)C)CC)(C)C>>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][NH:24][C:25]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:14][CH2:15]1)=[S:26])[CH3:20]
Reactant: CCOC(=O)CN=C=S
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=S)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, isothiocyanato-acetic acid-ethy ester, and diisopropylethyl amine, are reacted to give the product as a white solid. LC-MS: 407 (M++1). 1H NMR (DMSO-d6): δ 1.16 (t, 3H), 3.05 (br.s, 4H), 4.01 (br.s, 4H), 4.06 (q, 2H), 4.20 (d, 2H), 6.24 (s, 1H), 6.47 (br.s, 2H), 7.08 (dd, 1H), 7.36 (d, 1H), 7.76 (d, 1H), 8.23 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][C:3]=1[F:13].[NH:14]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([N:14]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16][CH2:15]2)=[O:10])=[CH:4][C:3]=1[F:13]
Reactant: O=C1CCNCCN1
Reactant: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Product: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(F)c2)CCN1

Procedure:
In analogy to the procedure described for intermediate 1A, (E)-4-chloro-3-fluorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as white solid. MS: 297.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[C:8]([CH2:13][C:14]#[N:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH2:5][CH2:4][O:3]1>C(O)C.[Ni]>[CH3:1][C:2]1([C:7]2[C:8]([CH2:13][CH2:14][NH2:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2cccnc2CC#N)OCCO1
Agent: [Ni]
Solvent: CCO
Product: CC1(c2cccnc2CCN)OCCO1
Reaction time: 7 h

Procedure:
[3-(2-Methyl-1,3-dioxolan-2-yl)-2-pyridyl]methyl cyanide (540 mg, 2.64 mmol, 1.0 equiv) is dissolved in ethanol. A catalytic amount of Raney Nickel is added and the resulting mixture is placed under a hydrogen atmosphere. The mixture is stirred for 7 h using a hot water bath to warm the reaction mixture. After flushing with nitrogen, the mixture is filtered over kieselguhr and rinsed with ethyl acetate. The filtrate is concentrated in vacuo with replenishment of dichloromethane. This gave 490 mg of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH3:41])[CH:24]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 44.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-tolylboronic acid (25 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.024 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (23 mg, 44%). LC-MS m/e 421.31 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([OH:27])=O)[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].C[N:29]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([NH2:29])=[O:27])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(=O)O)c2c(Cl)nc(C)nc21
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(Cl)nc(C)nc21
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
In 4 ml of tetrahydrofuran, 0.47 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetic acid was dissolved. After the reaction mixture was cooled to −15° C., 0.14 g of N-methylmorpholine and 0.19 g of isobutyl chloroformate was added thereto. After the reaction solution was stirred for 5 minutes, 0.085 ml of 28% aqueous ammonia was added thereto. The reaction mixture was warmed up to room temperature and was subsequently stirred overnight. Water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=50:1) to yield 0.41 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide as an oil.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.[Cl-].[CH3:27][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:4]2[N:3]=[C:2]([CH3:27])[N:7]3[C:8](=[O:11])[NH:9][N:10]=[C:6]3[C:5]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:24][CH:23]=1
Reactant: C[Zn+]
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12

Procedure:
To a stirred solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 0.128 mmol) and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in THF (0.5 mL) at room temperature under argon was added 2.0 M methylzinc chloride solution in THF (0.25 mL, 0.5 mmol). The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was cooled in an ice bath and quenched with saturated aqueous NH4Cl. EtOAc (5 mL) and water (5 mL) were added and the layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with 40% EtOAc-hexanes to obtain 40 mg of the title compound as a white solid. HPLC/MS: retention time=3.883 min, [M+H]30 =371.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10].[C:31](Cl)(=[O:33])[CH3:32]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:31](=[O:33])[CH3:32])[C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10]
Reactant: CC(=O)Cl
Reactant: COC[C@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCC1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(c3)cc(C)n4C(C)=O)c2s1
Yield: 69 %

Procedure:
To a solution of (2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone and DMAP (120 mg, 0.28 mmol) in DMF (5 mL) was added acetyl chloride (44 mg, 0.56 mmol). After 3 h the reaction was quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), and concentrated onto silica gel (5 mL). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 97:3) afforded the title compound as a white solid (0.36 g, 69%). MS: 464 (MH+); HPLC Rf: 6.12 min; HPLC purity: 96%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH3:15]O>>[CH3:15][O:11][C:10]([C:8]1[S:7][C:6]2[CH:13]=[CH:14][C:3]([CH3:2])=[CH:4][C:5]=2[CH:9]=1)=[O:12]
Reactant: Cc1ccc2sc(C(=O)O)cc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2cc(C)ccc2s1

Procedure:
Hydrogen chloride gas was passed into a solution of 5-methylbenzo[b]thiophene-2-carboxylic acid (7.50 g.) in methanol (250 ml.) until the solution was saturated. The solution was heated under reflux for 1 hour and then evaporated. The residue was washed with water and recrystallized from methanol to give 5-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (7.80 g.) m.p. 78°-79°.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:38])[CH:35]([CH3:37])[CH3:36])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:38][CH:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(CCCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)CCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.1 ml of concentrated sulphuric acid in 1 ml of methanol with 60 mg (0.13 mmol) of 7-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methylheptan-3-ol in 1 ml of methanol and 1 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a yellowish oil (m=7 mg; Y=16%) is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1N=CN[CH:5]=1.[OH:12][C:13]1[CH:18]=CC(NCC(O)=O)=[CH:15][CH:14]=1>>[NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:5]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The above procedure is repeated using the methyl and ethyl esters of histidine and 4-hydroxy phenylglycine, and the ethyl ester of L-tyrosine to produce the corresponding amino acid ester derivatives.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[C:4]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1)#[CH:3]
Reactant: CC(C)(O)C#Cc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[5-(3-methyl-3-hydroxy-butyn-1-yl)-3-pyridyl]-4-tert-butoxycarbonyl-homopiperazine (0.40 g, 1.1 mmol), sodium hydride 60% (4.5 mg, 0.11 mmol) and toluene (10 ml) was stirred at 110° C. for 3 h. The crude mixture was purified by chromatography on silica gel with ethyl acetate: toluene, (3:1) gave the title compound. Yield 0.13 g, 39%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][C:19]=2[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:35][N:36]1[C:45]2[NH:44][C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[NH:41][CH2:40][C:39]=2[CH:38]=[N:37]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:41]3[CH2:40][C:39]4[CH:38]=[N:37][N:36]([CH3:35])[C:45]=4[NH:44][C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]3=4)=[O:26])=[CH:20][C:19]=2[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (865 mg, 2.3 mmol) in dichloromethane (50 ml) was treated with triethylamine (to pH9), WSCD (865 mg, 4.5 mmol) and DMAP (276 mg, 2.3 mmol), and the mixture was stirred at room temperature for 10 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (541 mg, 2.7 mmol) was added. The mixture was heated at reflux for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (615 mg, 48%).
Reaction SMILES: [N:1]1([CH:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][C:7]2([CH3:18])[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[N:1]1([CH:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[N:8]([CH3:21])[C:7]2([CH3:18])[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)NC(=O)c2ccccc2C1n1ccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C(n2ccnc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-imidazol-1-yl-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one, which can be prepared as described in Example 36d (140 mg, 0.58 mmol) in DMF (8 mL) at −10° C. is added NaH [60% dispersion in oil (30 mg, 0.75 mmol)]. After 10 min, the reaction is warmed to room temperature for 5 min and then re-cooled to −10° C. The reaction is then charged with methyl iodide (0.075 mL, 1.2 mmol) and placed at room temperature. After 20 min, the reaction is cooled to −10° C., quenched with saturated aqueous NH4Cl, and diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic layers are dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:12) to afford 4-imidazol-1-yl-2,3,3-trimethyl-3,4-dihydro-2H-isoquinolin-1-one; HRMS (ESI) m/z 256.1448 [(M+H)+: Calcd for C15H18N3O: 256.1450]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 3 H), 1.33 (s, 3 H), 3.09 (s, 3 H), 5.01 (s, 1 H), 6.78 (s, 1 H), 7.02 (s, 1 H), 7.20 (d, J=3.8 Hz, 1 H), 7.47-7.57 (m, 3 H), 8.20-8.28 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:29])([F:28])[C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:28][C:17]([F:29])([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)[C:14]1[N:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]#[N:31])[CH:7]=3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: CN(C)C=O
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccnc(Cl)c3)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)ccn1

Procedure:
A mixture of 6-{[6-(2-Chloro-pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-difluoro-methyl}-quinoline (see Example 100b) (50 mg, 0.122 mmol) in DMF (4 mL) and Zn(CN)2 (43 mg, 0.367 mmol) was degassed with house vacuum for ˜5 min, and tetrakis(triphenylphosphine)palladium (13.4 mg, 0.012 mmol) were then added. The mixture was microwaved at 190° C. for 20 min. Following the aqueous work up, solvent was removed by vacuo. The target compound, 211 mg (41%), was obtained by column purification. 1H NMR (CDCl3) δ 9.04 (dd, J=4.2, 1.6 Hz, 1H), 8.95 (d, J=5.12 Hz, 1H), 8.41 (d, J=9.8 Hz, 1H), 8.22-8.35 (m, 4H), 8.00-8.05 (m, 2H), 7.70 (d, J=9.8 Hz, 1H), 7.54 (dd, J=8.2, 3.8 Hz, 1H); MS (ES) m/z 400.3 (M+H+).