Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:11]([OH:13])=O)=[C:7]([CH3:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:11]([C:6]5[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:9][S:8][C:7]=5[CH3:10])=[O:13])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: CC(=O)Nc1csc(C)c1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1csc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
A mixture of 4-acetylamino-2-methyl-thiophene-3-carboxylic acid (45 mg, 0.17 mmol) in dichloromethane (3 mL) at 25° C. was treated with triphenylphosphine (71 mg, 0.22 mmol). This mixture was cooled to 0° C. and then was treated with N-chlorosuccinimide (36 mg, 0.22 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (75 mg, 0.17 mmol). This solution was then cooled to 0° C. and was treated with triethylamine (38 μL, 0.22 mmol). The reaction was warmed to 25° C. and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-acetylamino-2-methyl-thiophene-3-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (27.8 mg, 26.1%): EI-HRMS m/e calcd for C32H31N6O4SF (M+Na)+ 637.2004, found 637.2018.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])=[N:3][CH:4]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Br)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(Br)cn1
Reaction time: 12 h

Procedure:
To a solution of 2-amino-5-bromo-pyridine (1.05 eq.) in TBF (0.2M) was added DBU (1.0 eq.) followed by iso-propyl-isocyanate (1.0 eq.). The mixture was stirred for 12 h, diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated. Crystallization from acetone afforded the title compound as a white solid.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[Cl:9].[CH2:10]=O.Cl>O>[Cl:3][C:4]1[N:5]=[C:6]([CH2:10][OH:1])[NH:7][C:8]=1[Cl:9]
Reactant: [OH-]
Reactant: Clc1nc[nH]c1Cl
Reactant: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: OCc1nc(Cl)c(Cl)[nH]1
Reaction time: 0.58 h

Procedure:
Potassium hydroxide (0.12 g, 2.14 mmol) in water (4 ml) was added to 4,5-dichloroimidazole, and the suspension was stirred for 35 min. Paraformaldehyde (0.11 g, 3.66 mmol) was added portionwise and the reaction mixture was stirred over night, then acidified with dilute HCl to pH 1 and then concentrated in vacuo to give a white solid, 0.6 g (98%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26](=[O:27])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (17.0 mg, 31%) having the following characteristics.
Reaction SMILES: [C:1]([CH:20]=[CH2:21])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:22][OH:23]>>[C:1]([CH2:20][CH2:21][CH2:22][OH:23])([C:4]([C:7]([C:10]([C:13]([C:16]([F:17])([F:18])[F:19])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CO
Product: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
After confirming disappearance of C6F13CH═CH2 by gas chromatography, the reaction was terminated by cooling to obtain a reaction liquid. From the obtained reaction liquid, majority of methanol was distilled off under reduced pressure, and then, the reaction liquid was washed with water to remove the remaining methanol thereby to obtain 430 g of C6F13CH2CH2CH2OH having a purity of 92.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:31]([C:33]([CH3:36])([CH3:35])[CH3:34])#[C-:32]>CO>[C:33]([NH:31][C:32]1[N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:8][C:9]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])([CH3:36])([CH3:35])[CH3:34]
Reactant: Nc1ccc(Cl)cn1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: N#Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1c(-c2cccc(C#N)c2)nc2ccc(Cl)cn12
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
5-chloropyridin-2-amine (200 mg, 1.56 mmol, Eq: 1.00), 3-formylbenzonitrile (214 mg, 1.63 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (88.8 mg, 467 μmol, Eq: 0.3) were dissolved in MeOH (2.00 mL) and the intensive yellow solution was stirred for 10 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (129 mg, 177 μL, 1.56 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 80 min whereupon a white precipitate was formed. The precipitate was filtered off, washed with MeOH (4 mL) and dried under vacuum to give the product as a white solid (351 mg, 69.5%). MS: 325.2 [M+H]+; 1H-NMR (D6-DMSO): δ 8.59 (m, 2H), 8.49 (d, 1H), 7.78 (d, 1H), 7.65 (t, 1H), 7.58 (d, 1H), 7.29 (dd, 1H), 4.88 (s, 1H), 1.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:18])[C:13]3[S:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:11])[NH:8]2)=[N:4][CH:3]=1.[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:18])[C:13]3[S:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:11])[N:8]2[C:19]([NH2:20])=[O:25])=[N:4][CH:3]=1
Reactant: O=C1Nc2cc(F)cnc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CC#N
Solvent: O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ncc(F)cc21

Procedure:
The title compound was prepared from 6-fluoro-3-(2-thenoyl)-4-azaoxindole (Example 5) according to the procedure of Example 2C, using 6-fluoro-3-(2-thenoyl)-4-azaoxindole (419 mg, 1.60 mmol), N-chlorosulfonyl isocyanate (0.2 mL, 2.3 mmol), and acetonitrile (8 mL). Reaction time: 3 days. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO in a flask open to the air, diluting with water, and collecting the product by filtration. The product was recrystallized from acetic acid. Yield: 210 mg (43%).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[O-:11][C:12]#[N:13].[K+]>O>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:12]([NH2:13])=[O:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)CNC(N)=O
Temperature: 0 °C

Procedure:
To a solution of glycine tert-butyl ester hydrochloride (15.13 g, 89.5 mmol) in water (12 ml), a warm solution of potassium cyanate (8.89 g, 107.4 mmol) in water (12 ml) is added in one portion. The clear solution is heated to 65° C. to 70° C. for 15 minutes before removing from heat and cooling to 0° C. in an ice bath. MeOH (approximately 5 ml) is added to dissolve the oil formed and the mixture allowed to sit at 0° C. The crystals formed are filtered, washed with ice water (3×2 ml) and dried to give the title compound; [M+H]+ 174
Reaction SMILES: [Br:1]Br.Cl.O=[C:5]1[NH:14][C:13]2[N:12]=CC(/C=C/C(O)=O)=CC=2[CH2:7][CH2:6]1.[C:20]([OH:23])(=O)[CH3:21]>>[NH2:12][C:13]1[C:21]([CH2:20][OH:23])=[CH:7][C:6]([Br:1])=[CH:5][N:14]=1
Reactant: BrBr
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CC(=O)O
Agent: Cl
Product: Nc1ncc(Br)cc1CO
Reaction time: 8 h

Procedure:
Bromine (8.4 mL, 189.4 mmol) was added dropwise over 1 hour to a solution of 2-amino-3-(hydroxymethyl)pyridine (19.6 g, 157.8 mmol; which may be prepared as described in D1, Step 1) in acetic acid (350 mL) at room temperature. The reaction mixture was then stirred overnight. After concentration to dryness, the residue was partitioned between a saturated solution of potassium carbonate (300 mL) and ethyl acetate (200 mL). The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with a saturated solution of sodium chloride (200 mL), dried over sodium sulfate, filtered and concentrated to dryness. After trituration of the residue in pentane, the title product was obtained as a yellow solid (27.0 g, 84%).
Reaction SMILES: S1C=CC=[C:2]1S(O)(=O)=O.[C:10]([OH:27])(=[O:26])[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]>CO>[CH3:2][O:26][C:10](=[O:27])[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]
Reactant: O=S(=O)(O)c1cccs1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OC

Procedure:
The thienylsulfonic acid-functionalized SBA-15 (15ThioSO3H-SBA-15-p) was used as the solid acid catalyst in the liquid phase esterification of palmitic acid (PA) with methanol (MeOH) to form methylpalmitate. The reaction was carried out at the reflux temperature of MeOH.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])[N:6]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:34]>>[ClH:34].[ClH:34].[NH2:1][C:2]1[S:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8])[N:6]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1nc(N)sc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1nc(N)sc1-c1ccccc1
Yield: 90 %

Procedure:
2.0 g (5.5 mmol) of t-butyl [2-(2-amino-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate were dissolved in 15 ml of methylene chloride and heated to reflux for 3 hours with 2.1 ml (27.6 mmol) of trifluoroacetic acid. Thereafter, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in methanol, treated with ~2 M methanolic hydrochloric acid and evaporated. Recrystallization of the residue from methanol/ether with the addition of a small amount of hexane yielded 1.65 g (90%) of 2-amino-N-(2-aminoethyl)-5-phenyl-4-thiazolecarboxamide dihydrochloride as white crystals, melting point 203°14 205°.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.BrC1C=CC(F)=CC=1.[Mg].Cl>C1(C)C=CC=CC=1.CCOCC>[C:1]([CH:3]([CH:9]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(C)cc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(C)cc1)c1ccc(F)cc1

Procedure:
A solution of 860 grams of ethyl α-cyano-4-methylcinnamate in 1500 milliliters of hot toluene was added to a solution of 4-fluorophenyl magnesium bromide prepared from 860 grams of 4-bromofluorobenzene and 130 grams of magnesium turnings in 2500 milliliters of ether, under simultaneous distillation of the ether, until a final temperature of 80 degrees Centigrade was reached in the reaction mixture. The reaction mixture was then refluxed for 1 hour, whereupon it was hydrolysed with ice and 450 milliliters of concentrated hydrochloric acid. The mixture was then extracted with ether, washed with water, dried over anhydrous magnesium sulfate, treated with active carbon and evaporated in vacuo to give 1275 grams of crude ethyl α-cyano-3-(p-fluorophenyl)-3-(p-tolyl)-propionate.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@@H:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:24]([F:27])([F:26])[F:25])[C:6]=2[NH:5]1.Cl.F[C:30](F)(F)C1C2NC(=O)[C@@H]3CNC[C@@H]3C=2C=CC=1.IC>C1COCC1>[CH3:30][N:5]1[C:6]2[C:7]([C:24]([F:27])([F:25])[F:26])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH:13]2[C:4]1=[O:3]
Reactant: O=C1Nc2c(cccc2C(F)(F)F)[C@H]2CNC[C@@H]12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3NC(=O)[C@@H]2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C2CN(C(=O)OC(C)(C)C)CC2c2cccc(C(F)(F)F)c21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (40 mg of 60% dispersion in mineral oil, 1.0 mmol) in 5 mL of THF was added (±)-cis-tert-butyl 4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate, the intermediate from Example 3 (80 mg, 0.22 mmol) in 3 mL of THF. The mixture was stirred for 30 min and then there was added iodomethane (0.10 mL, 1.6 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was filtered through a pad of silica gel and concentrated. The residue was purified by chromatography (ISCO, elution with 1-10% EtOAc in hexane) to afford tert-butyl 5-methyl-4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate. To this material in 4 mL of hexane was added HCl (4 mL of a 4N solution in 1,4-dioxane, 16 mmol) and the resulting solution was allowed to stir at ambient temperature overnight. The solvents were removed in vacuo and the residue was purified by HPLC (C18 reverse phase, elution with gradient H2O/CH3CN+0.5% TFA). Pure fractions were combined and concentrated. The residue was partitioned between aq NH4OH and CHCl3, the organics were washed with brine, dried (K2CO3) and concentrated to afford 12 mg (60%) of the title compound of Example 4. 1H NMR (CDCl3): δ 7.60 (d, 1H), 7.42 (d, 1H), 7.18 (t, 1H), 3.81 (dd, 1H), 3.39 (s, 3H), 3.37-30 (m, 2H), 3.22-3.18 (m, 1H), 3.05-2.98 (m, 1H), 2.81 (t, 1H). LRMS (ESI): 271.16 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C@@H:8]([O:31][CH3:32])[C@@H:9]([N:13]([C:15](=[O:30])[C@H:16]([CH:27]([CH3:29])[CH3:28])[NH:17][C:18](=[O:26])[C@H:19]([CH:23]([CH3:25])[CH3:24])[N:20]([CH3:22])[CH3:21])[CH3:14])[CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:22][N:20]([CH3:21])[C@H:19]([C:18]([NH:17][C@H:16]([C:15]([N:13]([C@@H:9]([CH:10]([CH3:12])[CH3:11])[C@H:8]([O:31][CH3:32])[CH2:7][C:6]([OH:33])=[O:5])[CH3:14])=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H](CC(=O)O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Reaction time: 2 h
Yield: 148.9 %

Procedure:
To a solution of t-butyl-(3R,4S)-4-[N-(N,N-dimethyl-L-valyl-L-valyl)-N-methylamino]-3-methoxy-5-methylhexanoate (0.22 g, 0.433 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml). After stirring for 2 h, the reaction mixture was concentrated in vacuo. Reevaporation of the residue with toluene (5×10 ml) gave the deprotected product (0.268 g) which was used for the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[C:21](=[O:24])[NH:22][N:23]=[C:13]3[C:12]3[CH:25]=[CH:26][CH:27]=[N:28][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:22]1[C:21](=[O:24])[N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8](=[O:9])[CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]2=[N:23]1
Reactant: O=C(CN1CCCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CN(C)CCn1nc2n(c1=O)-c1ccccc1N(C(=O)CN1CCCCC1)c1ncccc1-2
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-(piperidinoacetyl)-3 H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (2-chloroethyl)dimethylamine in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-[2-(dimethylamino)ethyl]-9-(piperidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:24]([C:26]1[C:27](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[O:28][C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:32]([F:35])([F:34])[F:33])[C:30]=1[CH3:31])#[N:25]>C(O)C>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:31][C:30]2[C:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:32]([F:35])([F:33])[F:34])[O:28][C:27](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[C:26]=2[C:24]#[N:25])=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=CC=CC=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 88.2 %

Procedure:
To 5 ml of ethanol were added 100 mg (0.32 mmol) of 5-(4-dibutylamino-2-methoxyphenyl)-2,4-pentadienal and 110 mg (0.35 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile, and the mixture was stirred with heating at 50° C. for 2.5 hours. The precipitate was separated by filtration and purified by silica gel column chromatography to give 173 mg of a yellowish brown crystal (yield: 89.1%; mp: 208-210° C.)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[ClH:8].[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH2:10]>C(O)(C)C>[ClH:8].[Cl-:8].[N:14]1[CH:15]=[CH:16][C:11]([CH2:9][CH2:10][N+:1]2[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=2)=[CH:12][CH:13]=1
Reactant: C=Cc1ccncc1
Reactant: Cc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc[n+](CCc2ccncc2)cc1
Product: [Cl-]
Temperature: 60 °C

Procedure:
To 70 parts of 4-picoline, also called 4-methylpyridine, was added 270 parts of a 21.5% solution of hydrogen choride in isopropanol, then 118 parts 4-vinylpyridine was added and the resulting solution heated to 60° C. for 10 hours. The mixture was cooled to 30° C. and filtered to give 148 parts 1-[2-(4-pyridyl)ethyl]-4-picolinium chloride hydrochloride. The 1-[2-(4-pyridyl)ethyl]-4-picolinium chloride hydrochloride was then reacted with acrylontrile as in Example 13 to give 4-[tris(2-carboxyethyl)methyl]pyridine.
Reaction SMILES: [CH:1]([O:6]C)(OC)[O:2][CH3:3].C([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)(O)=O>C1(C)C(S(O)(=O)=O)=CC=CC=1.CO>[CH3:3][O:2][C:1]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[O:6]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Yield: 95.9 %

Procedure:
A glass reaction vessel fitted with a reflux condenser and magnetic stir bar was charged with trimethyl orthoformate (34.28 grams), 4-carboxybenzenesulfonamide (50.00 grams), toluenesulfonic acid (2.5 grams) and methanol (197 mL). The mixture was heated to 70° C. for 16 hours. The cooled mixture was concentrated on a rotary evaporater. Diethyl ether (200 mL) was added to the concentrate and stirred. The resulting solid was filtered to afford 51.3 grams of the desired 4-methoxycarbonyl benzenesulfonamide. In a glass reaction vessel fitted with a reflux condenser, a thermometer, a pressure-equalizing addition funnel, and a nitrogen inlet was placed a 60 weight percent dispersion of NaH in mineral oil (16.22 grams). The dispersion was washed three times with heptane by stirring the mixture for several minutes, allowing the mixture to stand, and using a pipette to decant the supernatant heptane. NMP (50 grams) was added to the flask and the mixture was stirred. To this stirred mixture was added a solution of camphoric anhydride (14 grams), 4-methoxycarbonyl benzenesulfonamide (15 grams), and NMP (61 grams) slowly via the addition funnel. The resulting mixture was stirred at room temperature for approximately 1 hour, poured into a beaker of deionized water that was vigorously stirred. The basic mixture was acidified with 10N HCl and subsequently extracted with EtOAc. The volatile components were removed using a rotary evaporator to afford a solid intermediate. This intermediate was combined with THF (111 grams), acetic anhydride (8.54 grams), and triethylamine (23.3 grams) and stirred for 1 hour at 60° C. The mixture was poured into aqueous 1N HCl and the resultant solid isolated by filtration. The solid was combined with methanol and this mixture was heated to boiling, cooled to room temperature, filtered, and washed sequentially with methanol and diethyl ether. The solid was dried overnight in a vacuum oven at room temperature and 67 Pa (0.5 mm Hg) to give the desired product.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH2:29][C:30](O)=[O:31]>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH2:29][C:30]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:31]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Product: COc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c(OC)c1

Procedure:
The product of Example 1B and 2-(2,4-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.92 (m, 1H), 7.22 (d, J=8.2 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.2, 2.4 Hz, 1H), 3.82-3.84 (m, 4H), 3.80 (s, 3H), 3.76 (s, 3H), 3.53 (s, 2H), 3.06-3.14 (m, 4H); MS (ESI+) M/Z 425 (M+H)+.