Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:10]([C:12](Cl)=[O:13])=[O:11])=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[N:15]1(C(OC(C)(C)C)=O)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]([C:10](=[O:11])[C:12]([NH2:15])=[O:13])=[CH:8]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C1CNCCN1
Product: NC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To indole-3-glyoxylyl chloride I (3 gram, 14.45 mmol) in CH2Cl2 at room temperature was added tert-butyl 1-piperazinecarboxylate (2.7 gram, 14.45 mmol) and diisopropylethylamine (2.76 ml, 15.9 mmol). The light-brown color solution was stirred for 2 hr at room temperature after which time LC/MS analysis indicated the completion of the reaction. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate (250 ml) and diethylether (250 ml). The organic solution was then washed with water (100 ml×3) and brine (50 ml), dried over MgSO4, filtered and concentrated. To the light-yellow solid was then added 30 ml of 20% trifluoroacetic acid in CH2Cl2. The solution was concentrated and the light-brown solid was dried in vacuo to give 3.5 g (95%) of product II. LC/MS analysis indicated this product was 100% pure and it was used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][C:17]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:24]([C:23]1[N:19]([C:17]2[S:18][C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:31])=[CH:15][CH:16]=2)[N:20]=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:22]=1)=[O:25]
Reactant: COc1ccccc1CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1ccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
To a stirred solution of 25 (0.059 g, 0.128 mmol) in pyridine (0.851 mL) at 0° C. was added 2-methoxybenzylamine (0.020 mL, 0.153 mmol) and followed by dropwise addition of POCl3 (0.013 mL, 0.140 mmol). The mixture was stirred for 30 min at 0° C., then for 1 h from 0° C. to 21° C., then for 16 h at room temperature. The mixture was quenched with water and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 26e (18 mg, 24%) as a white solid. LRMS (ESI): calc. 581.2; found 604.3 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]1=[O:15].C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:4]1[C:3](=[O:15])[C:2]([CH3:16])([CH3:1])[O:6][C:5]=1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(Br)C1=O
Reaction time: 3 h
Yield: 30.6 %

Procedure:
To a stirred solution of 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g, 5.60 mmol) in CHCl3 (12 mL), NBS (1.1 g, 6.00 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.50 g, 31%) as an off white solid.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([S:41]([CH3:44])(=[O:42])=[O:43])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)S(C)(=O)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CS(=O)(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To Dowtherm at 250° C. was added ethyl 3-(4-bromophenylamino)-2-(methylsulfonyl)acrylate (1.08 g, 3.10 mmol) portionwise and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (573 mg, 61%) as a tan solid: ESI MS m/z 302 [C10H8BrNO3S+H]+.
Reaction SMILES: Cl.O.[C:3]([O:10][C:11]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[C:20]1([NH:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N+:30]([O-])=O)[C:21]1=[O:33])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)C.[Fe]>[C:3]([O:10][C:11]1[CH:16]=[C:15]([CH:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][C:12]=1[C:20]1([NH:34][C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH2:30])[C:21]1=[O:33])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCC)C(=O)c2cccc(N)c2C1=O
Yield: 59.2 %

Procedure:
Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-hexanamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate (40 mg, 0.07 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (21 mg, 57%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[OH:18][CH:6]1[CH:5]2[CH:4]3[CH:3]([CH2:8][CH:7]1[CH2:9]3)[CH2:2][O:1]2
Reactant: OCC1CC2C=CC1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OC1C2CC3COC1C3C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
12.4 g of 5-hydroxy methyl-2-norbornene and 300 ml of methylene chloride were put in a flask, and 28.7 g (75% content) of m-chloro perbenzoic acid was dropped therein at 30° C. After completion of dropping, it was agitated at the temperature for 1 hour, then it was cooled to 0° C., and the precipitated benzoic acid was removed by filtration. The filtrate was washed with an aqueous solution of sodium sulfite, an aqueous solution of sodium bicarbonate, and then the organic layer was concentrated under a reduced pressure. The resultant crude 2,3-epoxy-5-hydroxy methyl norbornane, 100 ml of toluene and a catalytic amount of a concentrated sulfuric acid were put in a flask, and agitated at 50° C. for 2 hours. Then, usual after-treatment was carried out to yield 10.1 g of 2-hydroxy-4-oxatricyclo[4.2.1.03,7]nonane.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][CH:9]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CS(C)=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: Fc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Brc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an amount of 400 mg of imidazole was dissolved in 7.5 ml of dimethyl sulfoxide under argon atmosphere, added with 255 mg of 60% sodium hydride, and stirred at room temperature. After 1 hour, the reaction mixture was added with 0.8 ml of 3-bromofluorobenzene, and stirred at 140° C. for 21 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, and washed with 20 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (3:1 to 1:1)) to obtain 1.1 g of the title compound.
Reaction SMILES: BrC1C=CC([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=CC=1.[CH3:24][O-:25].[Na+]>CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:11]2[N:12]=[C:13]([O:25][CH3:24])[N:14]=[C:9]([NH2:8])[N:10]=2)[CH:21]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(-c2cc(Cl)ccc2C)n1
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of the title compound of Example 20 (100 mg, 0.25 mmol) in methanol (5 ml) was added a solution of sodium methoxide in methanol (25-30%, 0.5 ml). After stirring for 72 hours, the mixture was concentrated under reduced pressure. The residue was stirred with water (20 ml). The solid was collected by filtration, washed with hexane (5 ml), and dried under reduced pressure to provide the title compound (60 mg, 59% yield). 1H NMR (DMSO-d6) 10.40 (s, 1H), 7.90 (s, 1H), 7.75 (m, 2H), 7.48-7.55 (m, 3H), 7.38 (m, 1H), 3.98 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:36])(=[O:35])[N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[CH3:26])=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C#CC2C=CC(C#CCN3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)=CC=2)COC(C)(C)OC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([S:24](=[O:35])(=[O:36])[N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[CH3:26])=[CH:22][CH:23]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2)c1
Agent: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2)c1

Procedure:
When the product of Step C was substituted for tert-butyl-5-((4-(3-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-yl)prop-1-ynyl)phenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 14, Step D, the similar process afforded the title compound in 59%, as creamy paste. 1H-NMR (CDCl3) 1.45 (s, 3H); 1.46 (s, 9H); 1.49 (s, 3H); 1.58 (s, 2H); 2.63 (5, 2H); 3.13 (s, 3H); 3.75 (s, 3H), 3.96 (d, 2H, J=17.23 Hz); 4.07 (d, 2H, J=17.23 Hz); 6.54 (dd, 1H, J=1.66, 7.92 Hz); 6.69 (tr, 1H, J=2.18 Hz); 6.79 (dd, 1H, J=2.39, 10.68 Hz); 7.16 (tr, 1H, J=8.15 Hz); 7.47 (s, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.[C:37](O)(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].S(=O)(=O)(O)O>>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([CH2:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:2]=1[F:1]
Reactant: CCCCCC(=O)O
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Product: CCCCCC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Yield: 55 %

Procedure:
Substantially the same manner as that in Example 123 was repeated except that 1.06 g (2.10 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4), 24 mL of hexanoic acid and 6 mL of concentrated sulfuric acid were used, and the resulting compound was purified by silica gel column chromatography (chloroform:acetonitrile=30:1-20:1) and recrystallized from ethyl acetate/n-hexane, to give 489 mg of Compound 125 (yield: 55%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:33])[CH2:22][C:23]34[CH2:32][CH:27]5[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]5)[CH2:24]3)[CH2:30]4)=[C:16]([CH3:34])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>CO.O1CCOCC1>[ClH:35].[ClH:35].[CH3:34][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]12[CH2:30][CH:29]3[CH2:31][CH:25]([CH2:26][CH:27]([CH2:28]3)[CH2:32]1)[CH2:24]2
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(N2CCNCC2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-[4-(2-(tricyclo[3.3.1.13,7]dec-1-yl)acetylamino)-3-methylphenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.05 g, Example 36c) was dissolved in methanol (2 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to 2/3 original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a solid (0.043 g)
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[NH2:47][CH:48]1[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49]1>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:47][CH:48]4[CH2:52][CH2:51][NH:50][CH2:49]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCNC5)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl) imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, step A) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (14 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. tert-Butyl 3-aminopyrrolidine-1-carboxylate (32 mg, 0.17 mmol) was added to the reaction mixture. The mixture was sealed and heated at 70° C. for 2 hours and cooled to ambient temperature. DMF was removed under reduced pressure. The residue was triturated with Et2O. The resulting tan solid was dissolved in DCM (1 mL). TFA (1 mL) was added to the DCM solution. The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (10 mg). MS (ES+APCI) m/z=523 (M+H).
Reaction SMILES: COC(C1SC([N:22]=[N+:23]=[N-:24])=C(C#N)C=1C1C=CC=CC=1C(C)(C)C)=O.[CH2:25]([O:27][C:28]([C:30]1[S:31][C:32](S(C)(=O)=O)=[C:33]([C:42]#[N:43])[C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([I:41])=[CH:37][CH:36]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1[S:31][C:32]([N:22]=[N+:23]=[N-:24])=[C:33]([C:42]#[N:43])[C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([I:41])=[CH:37][CH:36]=1)=[O:29])[CH3:26]
Reactant: COC(=O)c1sc(N=[N+]=[N-])c(C#N)c1-c1ccccc1C(C)(C)C
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(I)cc1
Product: CCOC(=O)c1sc(N=[N+]=[N-])c(C#N)c1-c1ccc(I)cc1

Procedure:
Using a method substantially in accordance with the method of example 5-azido-3-(tert-butyl-phenyl)-4-cyano-thiophene-2-carboxylic acid methyl ester starting with the compound 3-(4-iodophenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Yield: 80.7 %

Procedure:
(3,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10 ml). The mixture was heated at 70° C. for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate). The desired fractions were concentrated to yield N-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7% yield) as a colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (m, 1 H), 7.40 (m, 1 H), 7.19 (dd, J=8.09, 1.98 Hz, 1 H), 4.94 (s, 1 H), 4.43 (s, 2 H), 3.47-3.77 (m, 4 H), 1.41-1.79 (m, 6 H). LC/MS RT=2.15; [M+H]+=305.1.
Reaction SMILES: C[O-].[Na+].Cl.[CH:5]1([C:8]2[N:12]([CH2:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[CH:16][C:15]=3[F:24])[N:11]=[C:10]([C:25](=[NH:27])[NH2:26])[C:9]=2[CH3:28])[CH2:7][CH2:6]1.C(O[CH:32]=[C:33]([C:36]#[N:37])[C:34]#[N:35])C>>[NH2:37][C:36]1[C:33]([C:34]#[N:35])=[CH:32][N:26]=[C:25]([C:10]2[C:9]([CH3:28])=[C:8]([CH:5]3[CH2:7][CH2:6]3)[N:12]([CH2:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[CH:16][C:15]=3[F:24])[N:11]=2)[N:27]=1
Reactant: CCOc1cc(F)c(Cn2nc(C(=N)N)c(C)c2C2CC2)c(F)c1
Reactant: CCOC=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(C#N)c(N)n3)c(C)c2C2CC2)c(F)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
146 mg of sodium methanolate (2.70 mmol, 1.0 eq) were diluted in 20 ml of methanole at room temperature under a nitrogen atmosphere. Then 1.0 g of 5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazole-3-carboximidamide hydrochloride 1:1 1-3-6 (2.70 mmol, 1.0 eq) and 329 mg of (ethoxymethylene)malononitrile (2.70 mmol, 1.0 eq) were added and the mixture was stirred at 65° C. bath temperature for 18 hours. After cooling to rt the reaction mixture was concentrated in vacuo and purified via HPLC (ACN/H2O/0.2% NH3) to give 284 mg (0.65 mmol, 24%) of analytically pure target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:24][O:25][CH2:26]Cl>CS(C)=O.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:24][O:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCOc1cc(C#N)ccc1OCc1ccccc1
Yield: 62.3 %

Procedure:
To a solution of the resulting 4-benzyloxy-3-hydroxy-benzonitrile (300 mg, 1.33 mmol) and potassium tert-butoxide (300 mg, 2.66 mmol) in dimethylsulfoxide (4 mL) was added chloromethyl methyl ether (0.204 mL, 2.66 mmol) portionwise under nitrogen atmosphere stirring on an ice bath, and the solution was stirred for 2 days. NH silica gel (25 mL) was added to the reaction solution, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=7:3) then silica gel column chromatography (hexane:ethyl acetate=7:3), and the title compound (306 mg, 0.829 mmol, 85.3%) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7](I)[CH:6]=1)[CH3:2].[CH:20]([C:23]1[N:24]=[N:25][S:26][CH:27]=1)([CH3:22])[CH3:21].C([O-])(=O)C.[K+]>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7]([C:27]2[S:26][N:25]=[N:24][C:23]=2[CH:20]([CH3:22])[CH3:21])[CH:6]=1)[CH3:2]
Reactant: CC(C)c1csnn1
Reactant: CCOC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(C)cn2)cc(-c2snnc2C(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester (367 mg, 1 mmol), 4-isopropyl-[1,2,3]thiadiazole (640 mg, 5 mmol), palladium II tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and potassium acetate (196 mg, 2 mmol) in 10 mL of DMF was warmed to 120° C. and stirred for 16 hours. The reaction mixture was cooled and transferred directly onto a silica column and purified by liquid chromatography (0% to 10% EtOAc/hexanes) to give 250 mg of 3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester, MS (M+H)=368.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:9][CH:10]=1)(=O)C.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:13]/[CH:12]=[CH:11]/[C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([O:14][CH3:15])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: C=CCc1ccc(OC(C)=O)c(OC)c1
Reactant: CC(=O)O
Product: COc1cc(/C=C/COC(C)=O)ccc1O

Procedure:
A mixture of eugenol acetate (16 g,0.0777 mol) and mercuric acetate (44.5 g, 1.4 mol) in 160 ml of acetic acid was refluxed for 20 hr. After filtration, the acetic acid solution was poured into water (150 ml) and extracted with ether (200 ml). The etheral solution was washed successively with water, aqueous NaHCO3, saturated NaCl solution and dried (Na2SO4). The solvent was evaporated to give 18 g of coniferyl acetate. Subsequent reduction of the coniferyl acetate with Red-Al gave coniferyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3N)cccn12
Reactant: CCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)CC)cccn12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 8-(2-methyl-6-aminobenzylamino)-3-(2-propynyl)-2-methlimidazo[1,2-a]pyridine (0.26 g) in chloroform (7.8 ml) was added dropwise propionyl chloride (0.074 ml) at 1°-5° C. and the mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure and the residue was dispersed into a mixture of an aqueous solution of sodium bicarbonate and chloroform. The chloroform layer was separated and washed with water and dried over magnesium sulfate. Following filtration, the solvent was removed under reduced pressure and the residue was triturated with diethyl ether and collected by filitration to give 8-(2-methyl-6-propionylaminobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.25 g).