Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C1(C)C=CC=CC=1>[CH3:36][O:37][CH2:38][CH2:39][NH:40][C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: COCCN
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCNC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
A suspension of 0.15 mg (0.35 mmol) of 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid in 4 ml of toluene was heated at 50° C. for 4 hours with 0.15 ml (2.1 mmol) of thionyl chloride. After removal of all volatile constituents by distillation the residue was suspended in 5 ml of dioxan, treated with 0.06 g (0.76 mmol) of 2-methoxy-ethylamine and stirred at room temperature for 4 hours. After concentration the residue was taken up in dichloromethane, extracted with water and dried with sodium sulphate. Concentration and washing of the residue with ether gave 0.14 g (74%) of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-amide as a yellow solid.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9](Cl)(=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>C(C(C)=O)C>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 70 °C
Yield: 78.9 %

Procedure:
Under a nitrogen atmosphere, p-aminophenol (109 g) was suspended in methyl ethyl ketone (2000 ml) and the suspension was heated to 70° C. Heptadecanoyl chloride (152 g) was added to the suspension with vigorous stirring, followed by refluxing with heating for 2 hours. A 5% aqueous hydrochloric acid solution (500 ml) was added to the resulting reaction mixture with vigorous stirring. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and recrystallized from methyl ethyl ketone to obtain 150 g of the desired product. Yield 80%; m.p. 137° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:10]=1/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C=CCCCCO[Si](C)(C)C(C)(C)C)cccc1OCCCC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCO[Si](C)(C)C(C)(C)C)c1CCC(=O)OCC
Yield: 85.8 %

Procedure:
To a solution of 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hex-1-enyl]-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (0.977 mmol, 507 mg) in ethyl acetate (10 mL) was added 10% palladium on carbon (350 mg) at room temperature. The resulting black mixture was stirred in the presence of atmospheric hydrogen gas in a balloon for 36 h at room temperature. Then, the catalyst was removed by filtration using a filter paper and the residue was washed with hot ethyl acetate (˜60 mL). The filtrate was concentrated in vacuo and the resulting residue was dried under high vacuum to obtain 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (438 mg, 86%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H50O6Si (M+Na)+ 545.3269. found 545.3267.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18].CCN=C=NCCCN(C)C.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(#N)C.C1COCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[O:16][C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)=[N:39][N:40]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: NNC(=O)c1ccccn1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 16.9 %

Procedure:
(4-Chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetic acid (0.017 g, 0.065 mmol) and EDCl (0.014 mg, 0.072 mmol) were combined in acetonitrile (3 mL) and stirred at rt for 3 min. 2-Pyridinecarbohydrazide (0.0094 g, 0.068 mmol) was added next and the resulting mixture was stirred for 60 min. To this solution was added THF (THF 3 mL) followed by tosyl chloride (0.015 g, 0.078 mmol) and P-BEMP (0.148 g, 0.325 mmol, 2.2 mmol/g resin load). The reaction vessel was sealed and heated to 100° C. in a microwave for 5 min. The resin was filtered away and washed with CH2Cl2 (×2). The concentrated filtrate was purified (SiO2, 25% EtOAc/hexanes) to afford the title compound (0.004 g): MS (APCI) m/z 365 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17](I)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]([C:27]1[CH:42]=[CH:41][C:30]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:29][CH:28]=1)#[CH:26].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Br:1][C:2]1[S:3][C:4]([C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:26]#[C:25][C:27]3[CH:42]=[CH:41][C:30]([C:31]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:28]=3)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=2)=[O:24])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c([N+](=O)[O-])c2)sc1Br

Procedure:
A solution of 2 (952 mg, 1.82 mmol), benzyl 4-ethynylbenzoate (472 mg, 2.00 mmol), Pd(PPh3)2Cl2 (128 mg, 0.18 mmol), K2CO3 (250 mg, 1.81 mmol), and Et3N (238 mg, 2.36 mmol) in DMF (4 mL) was stirred for 24 hours at room temperature. Water (5 mL) was added to the mixture and then extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 3 as a solid foam (600 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.11-8.06 (m, 3H), 7.87 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.52 (s, 1H), 7.47-7.34 (m, 5H), 5.38 (s, 3H), 4.19 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), and 1.28 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 183.86, 169.64, 165.88, 149.62, 142.04, 137.57, 136.41, 135.95, 135.92, 135.39, 133.02, 132.40, 131.08, 130.02, 129.93, 128.91, 128.66, 128.55, 126.69, 125.60, 124.44, 122.06, 99.57, 84.06, 67.32, 61.77, 35.25, and 14.42.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[O:16])=[CH:11][CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Na].CS.[Cl-].[NH4+]>CO>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)C(C)(SC)c1ccc(C(=O)c2cccs2)cc1
Agent: CS
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Methyl α-methylthio-α-[p-(2-thienylcarbonyl)phenyl]propionate (288 mg) was dissolved in 1 ml of anhydrous methanol, and 1.0 ml of a methanol solution (2.34 M) of sodium salt of methyl mercaptan was added. The mixture was stirred at room temperature for 1 hour and heated under reflux for 30 minutes. After cooling, an aqueous solution of ammonium chloride (1.5 g/20 ml) was added to the reaction mixture. The mixture was extracted with 20 ml of methylene chloride and twice with 10 ml of methylene chloride. The extract was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 117 mg of methyl α-[p-(2-thienylcarbonyl)phenyl]propionate in a yield of 47%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:25])[N:13]([CH3:24])[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][CH:16]=1.Br.[OH-].[Na+]>CC(O)=O.O>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:25])[N:13]([CH3:24])[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][CH:16]=1
Reactant: COc1cc(F)c(-c2cnc(Nc3ccccc3)n(C)c2=O)cc1F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(O)cc2F)c1=O
Temperature: 125 °C
Reaction time: 72 h

Procedure:
5-(2,5-difluoro-4-methoxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.066 g, 0.192 mmol) was dissolved in AcOH (2 mL) and HBr (1.087 ml, 9.612 mmol; 48 wt % in H2O) was added. The mixture was stirred at 125° C. for 3 days. The reaction mixture was cooled to room temperature and then diluted with H2O. The pH of the reaction mixture was adjusted to a pH of about 5 with 6M aqueous NaOH, which resulted in the formation of an off-white precipitate that was filtered and washed with H2O. The solid was dried directly in the fritted funnel under vacuum overnight and then dissolved through with MeOH/THF and concentrated. The product was obtained (58 mg; 92%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (br s, 1H), 8.91 (br s, 1H), 7.70 (s, 1H), 7.55-7.48 (m, 2H), 7.36 (t, 2H), 7.23 (m, 1H), 7.14 (m, 1H), 6.77 (m, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 330 (M+1).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[N:9]1[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=12>CN(C)C=O>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:25]/[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:10]2[N:9]=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[CH:11]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(=O)c1ccc(-c2cn3ccccc3n2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 120 °C

Procedure:
Subsequently, N,N-dimethylformamide dimethyl acetal (3.0 mL) was added to a solution of 1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-ethanone (2.13 g) in N,N-dimethylformamide (50 mL), followed by heating at 120° C. for 8 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was recovered through filtration, followed by washing with ethanol. The filtrate was concentrated under reduced pressure. The thus-obtained solid and the residue were subjected to flash chromatography. Fractions eluted by dichloromethane-methanol (30:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of ethyl acetate. Through the above procedure, (E)-3-dimethylamino-1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-2-propen-1-one (2.38 g) was yielded.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:12])=[C:6](N)[C:7]([F:10])([F:9])[F:8])C.[CH3:14][NH:15][NH2:16]>C(=O)([O-])O.[Na+]>[CH3:14][N:15]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([CH3:12])[C:4]([OH:3])=[N:16]1
Reactant: CNN
Reactant: CCOC(=O)C(C)=C(N)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(O)nn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
3-Amino-4,4,4-trifluoro-2-methyl-but-2-enoic acid ethyl ester (25.5 g, 124 mmol) was cooled to 0° C. and methyl hydrazine (7 ml, 132 mmol) was added dropwise. The mixture was allowed to warm to room temperature and heated to 50° C. for 20 hours. The mixture was allowed to cool to room temperature and was stirred for 16 hours. The mixture was cooled to 0° C. and saturated aqueous sodium hydrogencarbonate solution (50 ml) was added. The solid was removed by filtration and washed with cold water (0° C.) to give the product as a white solid (8.46 g, 38% yield over two steps).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(N(CC)CC)C.[C:17]1([CH3:29])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>O1CCCC1.O>[CH3:29][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:26])=[O:27]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
L-Asparagine (20.0 g, 0.15M) was suspended in a mixture of tetrahydrofuran (l30 mL) and water (250 mL). Triethylamine (49 g, 0.48M) was added followed by mesitylenesulfonyl chloride (49.7 g, 0.227M), The reaction mixture became slightly exothermic and the solids dissolved over a period of 0.5 h. to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed with ether, and methylene chloride. The aqueous layer was separated, and acidified to ca. pH=1.5 with conc. HCl, during which time a thick precipitate formed. After 0.5 h. the product was filtered,washed with water and dried to yield a white solid (34 g, 72%). m.p.=193.5 - 1950C 1H NMR (DMSO) δ 2.24 (s, 3H), 2.28 (dd, 1H), 2.45 (dd, 1H), 2.55 (s, 6H, 3.98 (m, 1H), 6.88 (br s, 1H), 6.99 (s, 2H), 7.32 (br s, 1H), 7.82 (d, 2H), 12.58 (br s, 1H). Mass spectrum ESI m/z 315.2, (M+H base peak).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCCCO)cc2)cc1
Yield: 59.2 %

Procedure:
A solution of 5.0 g of 4'-hydroxybiphenyl-4-carbonitrile and 5.1 g of 8-chloro-1-octanol in 100 ml of ethyl methyl ketone was treated with 14.1 g of finely powdered potassium carbonate and the mixture was heated under slight reflux overnight. The suspension was suction filtered and the filtrate was concentrated in a vacuum. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) gave 4.9 g of 4'-(8-hydroxyoctyloxy)biphenyl-4-carbonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[CH:40]=[O:41].O1CCCC1>C(O)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][C:35]=4[CH:40]=[O:41])[CH2:24][CH2:25]3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: O=Cc1cnccc1Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCN(c4ccncc4C=O)CC3)cc2C1
Yield: 89.9 %

Procedure:
To a solution of 7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (442 mg) in ethanol (3 ml) were added triethylamine (0.3 ml) and 4-chloro-3-formylpyridine (Journal of Heterocyclic Chemistry, vol. 25, p. 81 (1988)) (150 mg), and the mixture was stirred under reflux for 27 hours. After completion of the reaction, tetrahydrofuran and diethyl ether were added and insoluble material was removed. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1) and dried under reduced pressure to give the title compound (430 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:15])[CH:14]=1>O1CCCC1.Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:28][CH2:27][CH2:26][N:25]1[C:18]2[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:10]=[N:11][CH:12]=[C:13]([Cl:15])[CH:14]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:23]=[CH:24]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cncc(Cl)c4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Product: NCCn1ccc2ncnc(Nc3ccc(Oc4cncc(Cl)c4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 16 h
Yield: 372.2 %

Procedure:
tert-Butyl {2-[4-({3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (700 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (50 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (663 mg) as a solid powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.[CH3:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OCC)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:13](=[O:15])[C:12]([NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:10]4)=[O:16])[CH2:28][CH2:29]2)=[CH:30][CH:31]=1
Reactant: O=C1Cc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: COc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: COc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4c(c3)CC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-oxalamic acid (Example 101b) and 4-(4-methoxy-benzyl)-piperidine [U.S. Pat. No. 3,632,767 (1972)] according to the method described in Example 1c. Melting Point: 215-217° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([CH:21]2[CH2:22][CH2:23][N:24]([CH:31]3[CH2:32][CH2:33][CH2:34][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH2:25][CH2:26]2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCNCC1
Reactant: CN1CCCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCCC(N2CCC(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)CC1

Procedure:
The title compound is prepared from 5-chloro-2-(piperidin-4-ylcarbonylamino)-N-(5-chloropyridin-2-yl)-benzamide and 1-methyl-hexahydro-4H-azepin-4-one by reductive alkylation using NaCNBH3 and 5%-acetic acid in methanol, for example using a procedure similar to that of Example 25-F.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:30]3[N:26]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][O:20]4)[N:27]=[CH:28][CH:29]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1cccc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (1.3 g, 3.3 mmol, from Step 2), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 3.9 mmol, Aldrich), and Na2CO3 (1.7 g, 16 mmol) in 1,2-dimethoxyethane (40 mL) and water (6 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol, Strem) was added, and the reaction was heated to reflux for 35 minutes. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc three times. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a light yellow oil (0.87 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[CH2:4][N:5]([CH3:29])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24](OC)[O:25]C)[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[I-].[Na+].ClC([SiH3])(Cl)Cl>>[F:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]([CH3:29])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([CH:24]=[O:25])[CH2:22][CH2:23]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(NC(=O)N(C)Cc3c(F)cccc3F)cc2)CC1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)(Cl)Cl
Product: CN(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1

Procedure:
The title compound was prepared from 1-(2,6-difluoro-benzyl)-3-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenyl]-1-methyl-urea (0.250 g, 0.5 mmol), sodium iodide (0.188 g, 1.26 mmol), and trichloromethylsilane (0.118 mL, 1.0 mmol) according to the procedure used for example 84 (Step D) and used directly in the next step.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1.[C:13]([O:18]C(=O)C(C)C)(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[O:1]=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5]([O:6][CH2:7][CH3:8])[CH:4]=1
Reactant: CC(C)C(=O)OC(=O)C(C)C
Agent: CCOc1cc(C=O)ccc1O
Product: CC(C)C(=O)O
Temperature: 90 °C

Procedure:
166 g of ethylvanillin are introduced into a 500 ml three-neck flask fitted with a 30 cm packed column and melted, and 189.6 g of isobutyric anhydride are added at a maximum temperature of 100° C. The reaction is only slightly exothermic. When addition is complete, the isobutyric acid can firstly be distilled off at a still temperature of 120° C. and 150 mbar, and iso-butyric acid and excess anhydride can finally be distilled at up to 130° C. and 20 mbar. The system is allowed to cool to 90° C., 500 ml of isopropanol are added and crystallization takes place upon further stirring and cooling to 7° C. The crystals are filtered off with suction, washed twice with 60 ml of cold isopropanol and dried, giving 182 g of ethylvanillin isobutyrate. Repeated crystallization from the mother liquor produces another 22.8 g of ethylvanillin isobutyrate.