Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].[C:11](=O)([O:37]C1C=CC=CC=1)[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[O:37])[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:31])([F:33])[F:32])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:19][CH:20]=1)(=[O:9])=[O:8]
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccn1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-pyridinesulfonamide (Naito, T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 Example 243).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])(C)C)(=[O:4])NN.C(N(CC)CC)C.Cl.C(O[NH:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)C.[NH2:39][NH:40][C:41]([CH2:43][CH2:44]C([O-])=O)=O>C(O)C.ClCCl>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:26]2[C:25]3[C:29](=[CH:30][CH:31]=[C:23]([C:22]4[NH:21][C:41]([CH2:43][CH2:44][C:1]([O:5][CH2:6][CH3:9])=[O:4])=[N:40][N:39]=4)[CH:24]=3)[NH:28][N:27]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: NNC(=O)CCC(=O)[O-]
Reactant: CCONCc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a round bottom flask under a nitrogen atmosphere containing tert-butyl carbazate (1.0 g, 0.008 mol) was added dichloromethane (16 mL) and triethylamine (1.06 mL, 0.008 mol). The flask was placed in an ice bath and to the reaction was added ethyl glytaryl chloride (1.38 mL, 0.0088 mol). The reaction was allowed to stir at room temperature overnight. Solvent was removed and the material was taken up in anhydrous ethanol. Gaseous hydrochloric acid was bubbled into the reaction and a solid crashed out of solution that was collected by filtration. This compound was determined to be ethyl 3-(N-aminocarbamoyl)propanoate. To a round bottom flask was added ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methylamine hydrochloride (200 mg, 0.62 mmol), triethylamine (0.25 mL, 1.86 mmol), and 3-(N-aminocarbamoyl)propanoate (243 mg, 1.25 mmol). This was taken up in anhydrous ethanol (10 mL) and molecular sieves were added to the reaction mixture. The reaction was allowed to stir at 75° C. overnight while under a nitrogen atmosphere. The solvent was removed and the material was purified by preparative HPLC (30–100% acetonitrile over 20 minutes) to yield the title compound (38 mg, 16% yield). Retention time 9.764 minutes 20–100% ODS 1 mL/min; ES-MS m/z 380 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+]>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.C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:7](=[O:8])[O:6][CH2:5][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyltin (1200 g, 3.6 mol), tetrakis(triphenylphosphine)palladium (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L). The mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100° C. for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated. The resulting solid was purified by silica gel column chromatography (heptane:ethyl acetate, 0→40%) to provide 5-allyl-2-benzofuran-1(3H)-one.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[O:12][C:13]1[C:14]([N:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[C:15]2[CH:21]=[N:20][N:19](CC3C=CC(OC)=CC=3)[C:16]2=[N:17][CH:18]=1.C(Cl)[Cl:48]>>[ClH:48].[ClH:48].[F:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[O:12][C:13]1[C:14]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Oc4cccc(F)c4)cnc32)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Fc1cccc(Oc2cnc3[nH]ncc3c2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
TFA (0.5 mL) was added to tert-butyl 4-(5-(3-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.020 g, 0.0375 mmol) in DCM (2 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in TFA (1 mL) and heated at 65° C. for 2 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The reaction was concentrated to dryness to give 5-(3-fluorophenoxy)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.014 g, 99%) as a solid. MS APCI (+) m/z 314.1 detected.
Reaction SMILES: [CH3:1][CH:2]1[S:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[OH:9]O>C(O)=O.C(OC(=O)C)(=O)C>[CH3:1][CH:2]1[S:7](=[O:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: CC1SCCNC1=O
Reactant: OO
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC1C(=O)NCCS1=O
Temperature: 0 °C

Procedure:
To a solution of 9 g of 2-methyl-3-thiamorpholinone in a mixture of 50 cm3 of formic acid and 10 cm3 of acetic anhydride, cooled to 0° C., 7 cm3 of H2O2 at 110 vol. are slowly added. After an 18 hour reaction period, the solution is concentrated under reduced pressure. The resulting product is dissolved in chloroform and the chloroform solution is deposited on a silica gel column.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)[CH3:3].C([Li])CCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cl-].[Na+].O>[OH:31][C:28]1([C:8]2[S:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[C:4]=2[CH:2]([OH:1])[CH3:3])[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]1
Reactant: CC(O)c1csc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
Scheme IA, Step A: To a solution of 3-(1-hydroxyethyl)benzo[b]thiophene (2.036 g, 11.4 mmol) in tetrahydrofuran (75 mL) at −78° C. was added a solution of n-butyllithium (15.7 mL, 25.1 mmol, 1.6 M in hexanes). The solution was warmed to 0° C. for one hour then recooled to −78° C. A solution of 1-t-butyloxycarbonyl-4-piperidone (2.503 g, 12.6 mmol) in tetrahydrofuran was added dropwise and the mixture was warmed to 20° C. After stirring for 6 hours at 20° C. the mixture was diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 3.75 g (87%) of the intermediate title compound as a yellow amorphous solid. FDMS m/e=378 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:31](N1CCOCC1)=[O:32].Cl>C1COCC1>[F:1][C:2]1[C:11]([CH:31]=[O:32])=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: COc1ccc(F)c2c1OCCC2
Reactant: O=CN1CCOCC1
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCCC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a solution of 3.6 g of 5-fluoro-8-methoxychromane and 4.2 ml of N,N,N′,N′,N″-pentamethyldiethylenetriamine in 130 ml of THF there was added dropwise 8 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. After stirring at −74° C. for 1 hour, N-formylmorpholine was added. After further stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.50 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[Cl:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48][CH2:47]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][N:49]([C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]1=[O:17])[CH2:48][CH2:47]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2cc(Cl)ccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 6-chloro-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.11 (m, 4H), 7.03 (ddd, J=6.1, 10.3, 12.6, 3H), 4.65 (d, J=24.0, 2H), 4.33 (d, 1H), 4.21-4.04 (m, 1H), 3.89-3.44 (m, 5H), 2.87 (dt, J=5.9, 11.7, 2H), 2.66-2.44 (m, 1H), 2.23-2.04 (m, 1H); MS (DCI) m/z 387.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:8]4[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=4[N:2]([CH3:1])[C:10]=3[N:11]=2)[CH2:25][CH2:24]1
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: Cn1c2ccc(Cl)cc2c2c3ccccc3c(OCCN3CCOCC3)nc21

Procedure:
5-β-Morpholinoethyloxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 140°-142° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and β-morpholinoethyl chloride by the method described in Example 8.
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]([N:17]([CH3:27])[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][CH:25]=[N:26][C:19]=23)[CH2:11]1)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[CH3:27][N:17]([C@@H:12]1[C@H:13]([CH3:16])[CH2:14][CH2:15][NH:10][CH2:11]1)[C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:24][CH:25]=[N:26][C:19]=12
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2[nH]cnc12
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]cnc12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
In a microwave reaction vessel, to a solution of rel-N-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (130 mg) in ethanol (1.3 mL) were added 1,4-cyclohexadiene (1.5 mL) and palladium hydroxide on carbon (130 mg). The vessel was sealed and reacted in the microwave reactor at 110° C. for 0.5 hour. The reaction mixture was cooled to ambient temperature and filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was washed with diisopropyl ether to give N-methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-3H-imidazo[4,5-b]pyridin-7-aminedihydrochloride (48 mg) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=O.C(O[CH:15]([N:19]([CH3:21])C)[N:16](C)C)(C)(C)C.[O-]CC.[Na+].C(O)C.NC(N)=[S:31]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:9]=[CH:21][N:19]=[C:15]([SH:31])[N:16]=1
Reactant: NC(=O)c1ccccn1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Sc1ncnc(-c2ccccn2)n1
Yield: 39.8 %

Procedure:
To a stirred solution of picolamide (1.50 g, 12.3 mmol) in N,N-dimethylformamide (20 mL) was added tert-butoxybis(dimethylamino)methane (5.2 mL, 25 mmol). The mixture was refluxed for 2.5 hours and then concentrated. The resulting viscous brown oil was taken up in a 0.5 M solution of sodium ethoxide in ethanol (50 mL, 25 mmol). Thiourea (0.72 g, 9.5 mmol) was added and the solution was refluxed for 2.5 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and dilute aqueous sodium hydroxide solution. The aqueous layer was washed twice with ethyl acetate and neutralized with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered off and rinsed with water. Vacuum oven dying afforded 0.72 g (40%) of crude product as a fine brown solid. This material was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[CH2:10][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2cccc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCNCC1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(2-(3-chlorophenylamino)-2-oxoethyl)piperazine-1-carboxylate (0.061 g, 0.17 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h, then the solvents were removed under reduced pressure to afford N-(3-chlorophenyl)-2-(piperazin-1-yl)acetamide trifluoroacetate salt (an oily material) that was dried in vacuo. To a mixture of this material (supposedly 0.17 mmol) and isopropanol (3.5 ml) was added 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) followed by diisopropylethylamine (0.14 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 15% ethyl acetate in dichloromethane. The title compound was obtained as an orange solid (0.040 g, 56%). 1H-NMR (500 MHz, DMSO-d6) 2.65 (br s, 4H, piperazine N(CH2)2), 3.14 (br s, 4H, piperazine N(CH2)2), 3.21 (s, 2H, NCH2CO), 6.95 (s, 2H, NH2), 7.11 (dd, J=7.94, 1.23 Hz, 1H) and 7.54 (dd, J=8.29, 0.98 Hz, 1H) (4-ArH and 6-ArH), 7.34 (t, J=8.07 Hz, 1H, 5-ArH), 7.84 (t, J=1.80 Hz, 1H, 2-ArH), 8.07 (s, 1H, 6-H), 9.91 (s, 1H, CONH);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25]Cl)[CH3:22]>CN(C)C=O>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)[CH3:22]
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1c2ccccc2N(C)C(=O)c2ccc(C)nc21
Reaction time: 0.5 h

Procedure:
A mixture consisting of 7.2 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 70 ml of dimethyl formamide and 1.9 gm of 50% sodium hydride in mineral oil was stirred at 30° to 50° C. in a nitrogen atmosphere for 30 minutes. Thereafter, a solution of 6.8 gm of 2-diethylaminoethyl chloride in 30 ml of dimethyl formamide was added dropwise, and the mixture was stirred at 100° C. for 2 hours and then evaporated in vacuo. The residue was admixed with an aqueous potassium carbonate solution, and the mixture was extracted with ether. The evaporation residue of the combined ether extracts, which were dried with sodium sulfate, was purified in a silica gel column and recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 62% of theory of the compound of the formula ##STR13## which had a melting point of 91°-93° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:61]([O:63]CCCC)=[CH2:62]>C(O)CO.C(Cl)Cl.Cl.[Pd](Cl)Cl>[C:61]([C:14]1[C:15]([O:22][CH3:23])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:63])[CH3:62]
Reactant: C=COCCCC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C(C)=O)c1OC
Temperature: 140 °C

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.82 g), triethylamine (0.7 ml), 1,3-bis(diphenylphosphino)propane (0.04 g) and palladium chloride (0.01 g) in ethylene glycol (4 ml) was sealed in a vial under nitrogen and the mixture was stirred and heated to 140° C. Butyl vinyl ether (0.8 ml) was then added and the resultant mixture was stirred and heated at 140° C. for 2 hours. After cooling, the mixture was diluted with DCM and 1M hydrochloric acid was added. The mixture was stirred at room temperature for 30 minutes then the two layers were separated and the aqueous layer was extracted with further DCM. The combined organic layers were dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-80%) to give crude ethyl 3-acetyl-6-(benzenesulphonylmethyl)-2-methoxybenzoate (0.33 g) as an oil.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.COS(OC)(=O)=O.[C-:16]#[N:17].[K+]>C(O)C.O>[C:16]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[CH3:7])#[N:17]
Reactant: [C-]#N
Reactant: Cc1ccc[n+]([O-])c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCO
Product: Cc1cnccc1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
To a cooled (0° C.) round bottom flask charged with 3-picoline-N-oxide (4.53 g, 42 mmol) was added dimethylsulfate (5.8 g, 47 mmol). The mixture was stirred for 18 hours and allowed to warm to room temperature. To this mixture was added potassium cyanide (3.25 g, 50 mmol) dissolved in ethyl alcohol/water (75 mL, 1:1). The reaction was stirred at room temperature for 18 hours, concentrated to half the volume and diluted with chloroform (100 mL). The organic layer was separated and washed with sodium chloride (sat. 25 mL) and dried over Na2SO4. The solvent was removed and the residual material was chromatographed (SiO2, hexanes/ethyl acetate) to give the title compound as off-white crystals (2.01 g, 41%). 1H NMR (300 MHz, DMSO-d6): δ 2.55 (s, 3H); 7.47 (d, 1H); J=5.1 Hz); 8.60 (d, 1H, J=5.1 Hz); 8.68 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:21][C:20]([CH3:22])([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([OH:24])=[O:23]
Reactant: ClCc1ccccc1
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of diisopropylamine (48.91 g, 483 mmol) in THF (100 mL) under nitrogen at 0° C. was added a solution of 2.5M n-butyllithium in hexane (179 mL, 447.5 mmol.) followed by the dropwise addition of isobutyric acid (15.77 grams, 179 mmols). The reaction mixture was stirred at room temperature for 1.5 hours, then cooled to −15° C. Benzyl chloride (22.66 g, 179 mmol) was added dropwise while maintaining the temperature below −5° C., and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between Et2O and water. The aqueous layer was acidified by the addition of concentrated HCl (36%, 50 mL), and extracted with Et2O (4×150 mL), The organic layer was dried over MgSO4 and concentrated to afford the title compound (21.36 g) as a colorless liquid. LC-MS (ES) m/z=177 [M−H]−.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[CH3:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=O)[CH2:20]Br)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:20]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(C)cc3)cs2)cc1
Yield: 61 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 4-methylphenacyl bromide to obtain methyl 4-[4-(4-methylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 61%. Pale yellow prisms. Melting point: 185 to 187° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[O:38]=[C:26]1[CH2:27][C:28]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1cc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)ccn1
Temperature: 100 °C
Yield: 35.8 %

Procedure:
A mixture of (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J2) (0.14 g) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K3) (0.14 g) in toluene (1.5 mL) was heated to 100° C. for 4 h, a fine precipitate being formed. The mixture was cooled and the precipitae was isolated by filtration. A solution of this solid in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was stirred for 0.5 h at 20° C. and then evaporated in vacuum. The residual oil was dissolved in AcOEt and the solution was washed with saturated Na2CO3 solution and with brine, dried over Na2SO4 and evaporated in vacuum. The solid residue was triturated with CH2Cl2 to give the title compound (0.06 g) as light-yellow crystals.