Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[Br:9][C:10]1[C:11]([Br:23])=[C:12]([Br:22])[C:13]([Br:21])=[C:14]2[C:19](=[O:20])O[C:16](=[O:17])[C:15]=12>CN1C(=O)CCC1>[C:3]1([N:8]2[C:16](=[O:17])[C:15]3=[C:10]([Br:9])[C:11]([Br:23])=[C:12]([Br:22])[C:13]([Br:21])=[C:14]3[C:19]2=[O:20])[CH:4]=[CH:5][C:6]([N:7]2[C:19](=[O:20])[C:14]3=[C:13]([Br:21])[C:12]([Br:22])=[C:11]([Br:23])[C:10]([Br:9])=[C:15]3[C:16]2=[O:17])=[CH:1][CH:2]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Solvent: CN1CCCC1=O
Product: O=C1c2c(Br)c(Br)c(Br)c(Br)c2C(=O)N1c1ccc(N2C(=O)c3c(Br)c(Br)c(Br)c(Br)c3C2=O)cc1
Temperature: 200 °C

Procedure:
108 gms (1.0 mole) of p-phenylenediamine was dissolved in 1 liter of warm NMP under a nitrogen atmosphere and the solution filtered to remove suspended particles. This filtered solution was then added to a similarly prepared filtered solution of 928 gms (2.0 moles) of tetrabromophthalic anhydride in 2 liters of warm NMP in the apparatus described in Example 2. A mildly exothermic reaction took place and the mixture was further heated while stirring. At about 145° C., precipitation began. The quantity of brown precipitate increased with continued heating and a further 2 liters of NMP was added to facilitate stirring, the temperature being raised to 200° C. and maintained for 2 hours, before the mixture was allowed to cool. The precipitate was collected, washed with NMP, roughly dried and washed with acetone. The material was then stirred well with acetone, filtered and again washed before being dried overnight at 150° C. under vacuum. The product was a fine, rusty-gold precipitate with a melting point above 500° C. The yield was 486 gms (49%), the infrared spectrum having the characteristic imide structure, absorption bands at 1712s and 1765w cm-1. The compound was insoluble in water, methanol, ether, xylene, dimethyl sulphoxide and dimethyl acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:9]#[N:10].C(=O)([O-])[O-:21].[K+].[K+].CS(C)=O.OO.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:9]([NH2:10])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 35 °C

Procedure:
(±)-2-(2-Chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile (713 g; 2.46 mol) was added to methanol (3.505 l) at 23-28° C. with stirring. To this slurry, potassium carbonate (170 g; 1.23 mol) was added followed by dimethyl sulfoxide (263 ml; 3.7 mol). The contents were heated between 30-40° C. and 30.0% aqueous hydrogen peroxide solution (382 ml; 3.70 mol) was added between 40-50° C. slowly over a period of 3 hours. After the addition was over, the reaction mixture was maintained at this temperature for a further 2 hours, after which the reaction was brought to 20-30° C. 35% Hydrochloric acid (213.0 ml) in water (10.7 l) was added slowly to the reaction mixture over a period of 1 hour 15 minutes. After stirring for 1 hour, the solid formed was filtered and washed with a 1:1 methanol: water mixture (3.565 l). The isolated solid was dried in a vacuum oven at 75-80° C. for a period of 12 hours. Yield: 716 g (94.72%). mp: 124-126° C. The product was identified by IR spectrum, 1H and 13C NMR investigation.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:22])[CH2:13][O:14]CC2C=CC=CC=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:22])[CH2:13][OH:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(OC(=O)CO)cc1
Reaction time: 20 h
Yield: 57.4 %

Procedure:
Benzyloxyacetic acid 4-acetylamino-phenyl ester 24 (15 g, 50 mmol) was dissolved in methanol (150 ml) in a pressure vessel, palladium on carbon (5%, 8 grams) added and the mixture stirred under an atmosphere of hydrogen (3 Kg) for 20 hours. The catalyst was removed by filtration and the methanol was then distilled off. The crude 25 was recrystallized from mixture of chloroform:methanol (1:4) to get pure 25 (6 g, 57.2%) as a white powder. M.p: 144-146° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cu]C#N.C(N)CN>CN(C)C=O.O>[C:12]([C:10]1[C:4]2[CH:3]=[CH:2][S:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)#[N:11].[C:16]([C:15]1[CH:14]=[CH:13][C:12]2[CH:3]=[CH:2][S:6][C:5]=2[CH:4]=1)#[N:11]
Reactant: Brc1cc2ccccc2s1
Reactant: c1ccncc1
Agent: N#C[Cu]
Solvent: NCCN
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2ccsc2c1
Product: N#Cc1cccc2sccc12
Temperature: 60 °C
Yield: 39 %
Yield: 41 %

Procedure:
To a solution of the isomeric bromobenzo[b]thiophene (14.2 g, 66.5 mmol) from Step B above in N,N-dimethylformamide (130 mL) were added pyridine (7.5 mL) and copper(I) cyanide (7.75 g). The reaction mixture was heated under reflux for 20 hours. The reaction solution was then cooled to 60° C. and poured into a solution of ethylene diamine in water. The resultant mixture was stirred for 30 minutes and extracted with diethyl ether and ethyl acetate. The combined organic extract was washed with 1:1 brine/water, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (95:5 to 91:9 hexanes/ethyl acetate) to give 4-cyanobenzo[b]thiophene (4.15 g, 39%) as a light yellow solid, and 6-cyanobenzo[b]thiophene (4.34 g, 41%) as a reddish oil: 1H NMR for 4-cyanobenzo[b]thiophene (CDCl3, 500 MHz) δ8.10 (d, J=8.2 Hz, 1H), 7.74-7.70 (m, 2H), 7.62 (dd, J=5.5, 0.6 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H); 1H NMR for 6-cyanobenzo[b]thiophene (CDCl3, 500 MHz) δ 8.22 (app s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.72 (d, J=5.4 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.42 (dd, J=5.4, 0.5 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][NH2:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][NH:26][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1ccc2ccccc2c1
Yield: 58.4 %

Procedure:
Experimental conditions were analogous to Example 1. 0.27 g (1.76 mmol) of naphthalene-2-carbaldehyde, 0.35 g (1.76 mmol) of (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, were dissolved in 10 mL dichloromethane, and 0.55 g (2.64 mmol) of sodium triacetoxyborohydride was added. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using flash chromatography (ethyl acetate in hexane), yielded to 350 mg of the free base as colorless oil. LC-MSD, m/z for C21H28N2O2 [M+H]+: 341.2
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a mixture of methyl 4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoate (279 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (220 mg, 82%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.C1COCC1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[Cl:22])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NNc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NNc1ccc(Br)cn1)c1ccccc1Cl
Reaction time: 16 h
Yield: 85.5 %

Procedure:
To (5-bromo-pyridin-2-yl)-hydrazine (2.0 g, 10.6 mmol) and triethylamine (1.5 mL, 11.0 mmol) in 1:1 THF:CH2Cl2 (15 mL) was added 2-chlorobenzoyl chloride (1.34 mL, 10.6 mmol) and the resulting reaction stirred for 16 hours. The reaction was quenched with water (100 mL), the resulting solids filtered, and dried to give the title compound (2.96 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][NH:32][C:33](=[O:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:44])[CH3:16])=[CH:11][CH:10]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][CH2:34][C:33]([NH:32][CH2:31][CH2:30][C@@:20]1([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[O:19][C:18](=[O:44])[N:17]([C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][CH:13]=2)[CH3:16])[CH2:22][CH2:21]1)=[O:43]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CNC(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CN)(c2ccc(F)cc2)OC1=O
Yield: 61.1 %

Procedure:
A solution of tert-butyl 2-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylamino)-2-oxoethylcarbamate (98 mg, 0.16 mmol) in TFA/CH2Cl2 (20%, 5 mL) was stirred at 0° C. for 2 h. The solvent was evaporated to give the crude product, which was purified by preparative HPLC to afford 2-amino-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (50 mg, 60%). 1H NMR (CDCl3): 1.41-1.49 (d, 3H), 2.15-2.29 (m, 5H), 2.80-2.94 (m, 2H), 3.25-3.36 (m, 1H), 3.70-3.85 (m, 2H), 5.50 (m, 1H), 6.75-6.97 (m, 7H), 7.00-7.14 (m, 3H), 7.26-7.29 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][C@@H:20]([C:22]3[CH:33]=[CH:32][C:25]4[O:26][C:27]([CH3:31])([CH3:30])[O:28][CH2:29][C:24]=4[CH:23]=3)[O:19][C:18]2=[O:34])=[CH:4][CH:3]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[CH3:31][C:27]1([CH3:30])[O:26][C:25]2[CH:32]=[CH:33][C:22]([C@H:20]3[O:19][C:18](=[O:34])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:44]([NH:43][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:45])=[CH:36][CH:35]=4)[CH2:21]3)=[CH:23][C:24]=2[CH2:29][O:28]1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(N)cc4)C(=O)O3)ccc2O1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(NC(=O)Nc5ccccc5)cc4)C(=O)O3)ccc2O1
Reaction time: 5 h

Procedure:
A solution of (5R)-3-(6-{2-[(4-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (150 mg) in dichloromethane (5 ml) under nitrogen was treated with phenyl isocyanate (0.07 ml) and the mixture stirred at 20° for 5 h. Isopropyl alcohol (5 ml) was added and the solution was stirred for a further 18 h. The solvent was evaporated in vacuo and the residue purified by SPE (silica, 10 g). Elution with EtOAc-cyclohexane (3:7) then EtOAc gave the title compound (159 mg). LCMS RT=3.68 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[NH2:19]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:15]2[S:14][CH:18]=[CH:17][N:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with Thiazol-2-ylamine to produce 4-Chloro-3-nitro-N-thiazol-2-yl-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7](O)O[C:9](=[O:10])[C:4]2=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.CO.B.[K]>C(O)(=O)C.O>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C1OC(O)c2ccccc21
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: B
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 94.3 %

Procedure:
1.5 g of o-phthalaldehydic acid and 1.5 g of p-aminophenylacetic acid were added to 30 ml of methanol to form a mixture which was agitated at room temperature for one hour and incorporated with 0.54 g of potassium boron hydride in several portions. Then, the whole was reacted at room temperature of 5 hours and then freed from the solvent under a reduced pressure. The resulting residue was incorporated with 50 ml of water and then with a small amount of acetic acid to obtain an acidic solution, after which crystals precipitated from the thus obtained solution were filtered off, dried and recrystallized from ethanol to obtain 2.5 g of 1-oxo-2 -{p-(carboxymethyl)-phenyl}-isoindoline.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[OH:32].[Na+]>Cl>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:32])[NH2:30])[CH:24]=2)[CH2:21][CH2:22]1
Reactant: O=C([O-])O
Reactant: Cc1c(/C=C/CN2CCN(c3cccc(C#N)c3)CC2)cnn1-c1ncccn1
Agent: Cl
Agent: [Na+]
Product: Cc1c(/C=C/CN2CCN(c3cccc(C(N)=O)c3)CC2)cnn1-c1ncccn1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
88 mg of the compound obtained in Example 32 (3) was dissolved in 0.5 ml of conc. hydrochloric acid and stirred at room temperature for 62 hours. Then the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:3). Then the product was converted into hydrochloride with a 1N hydrochloric acid/ethanol solution and recrystallized from ethanol. Thus 50 mg of the title compound was obtained in the form of colorless crystals.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=C=O)(=[O:9])=[O:8].[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[S:19][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[O:24])=[CH:21][N:22]=1.C(N(CC)CC)C>CCCCCC.ClCCl>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([C:20]1[S:19][C:18]([NH:17][CH2:16][CH2:15][CH2:14][NH:13][S:7]([NH:10][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:9])=[O:8])=[N:22][CH:21]=1)=[O:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(NCCCNS(=O)(=O)NC(C)(C)C)s1
Yield: 24 %

Procedure:
900 mg {3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester was dissolved in diethyl ether and hydrogen chloride in ether added dropwise with stirring. The mixture was stirred overnight at room temperature and poured into saturated aqueous sodium bicarbonate solution. The organics were extracted with dichloromethane (3×25 ml), dried over magnesium sulfate and evaporated under reduced pressure to afford [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone as a yellow gum (579 mg, 88%). A solution of 0.22 ml tert-butanol in hexane (2 ml) was cautiously added to a stirred solution of 0.2 ml chlorosulfonyl isocyanate in hexane (5 ml). The resulting white precipitate was stirred until it had dissolved (1.5 h) and the mixture cooled to −78° C. before the slow addition of a solution of [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone and 0.4 ml triethylamine in dichloromethane. The cooling bath was removed and the yellow mixture allowed to reach room temperature and stirred 2 h at room temperature. The mixture was poured into water and the organics extracted with ethyl acetate (2×25 ml). The combined organics were washed with brine, dried over magnesium sulfate and evaporated. The resulting oil was purified by column chromatography on silica gel (150 g, 2:1 ethyl acetate/hexane) to afford the title compound (241 mg, 24%) as a pale yellow oil. MS (m/e): 409.3 (M−H, 100%)
Reaction SMILES: Cl.[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([OH:18])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1.Cl[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([O:18][CH2:34][CH2:33][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1
Reactant: CCC(Cl)C(=O)OC
Reactant: COc1c(O)ccc2c1N=C(C=C(O)c1cccnc1)N1CCN=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc2c(c1OC)N=C(C=C(O)c1cccnc1)N1CCN=C21
Temperature: 120 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A mixture of 5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol hydrochloride (Example 1-4) 50.4 mg (0.14 mmol), methyl chlorobutyrate 22.2 mg (0.16 mmol) and potassium carbonate 186.9 mg (1.35 mmol) in N,N-dimethylformamide 1 mL was stirred at 120° C. for 4 hours. The reaction mixture was poured into water and extracted into dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed by diethyl ether to give the title compound 35.0 mg as yellow solid. Yield 59.3%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)O)[S:8][C:6]=2[N:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[N:10]=[C:9]([CH:11]=[CH:12][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:8][C:6]=2[N:7]=1
Reactant: OC(Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCOCC2)c2nc(C=Cc3ccccc3)sc2n1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-phenyl-ethanol (1.1 g, 2.9 mmol) in toluene (25 mL) was added p-toluenesulfonic acid (0.11 g, 0.58 mmol) and the resulting solution stirred at 120° C. for 24 h. The reaction mixture was concentrated in vacuo to give 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine as a crude yellow solid which was used without purification. To a suspension of 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-c]pyrimidine (2.9 mmol) in THF (9 mL), acetonitrile (9 mL) and H2O (3 mL) were added ruthenium(III) chloride (18 mg, 0.081 mmol) and periodic acid (1.3 g, 5.80 mmol). The resulting solution was stirred at RT for 2 h, then partitioned between EtOAc and an aqueous solution of sodium thiosulfate. The aqueous layer was isolated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (0.34 g, 42%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=1)=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CO>[CH3:3][C:2]([C:4]1[C:12]2[C:7]([NH:8][CH:9]=[N:10][C:11]=2[N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[N:6][CH:5]=1)=[CH2:1]
Reactant: C=C(C)c1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCC(NC(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)c1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-{1-[5-(1-methylethenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D8 (100 mg) and cesium carbonate (195 mg, 0.598 mmol) in THF (1.4 mL) and MeOH (0.7 mL) was stirred at room temperature for 4 hours. LCMS showed complete loss of starting material, but a few products were present. The mixture was partitioned between EtOAc (15 mL) and water (15 mL) and then the organic layer was washed with water (15 mL) and brine (15 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by MDAP and the one clean fraction was concentrated in vacuo to give E19 (12 mg) as a white solid, 1H NMR (d6-DMSO) δ 11.88 (1H, s), 8.32 (1H, d), 8.27 (1H, s), 7.85 (2H, d), 7.51 (1H, t), 7.44 (2H, t), 7.31 (1H, s), 5.10 (2H, s), 4.10 (2H, d), 4.02 (1H, m), 2.97 (2H, t), 2.13 (3H, s), 1.83 (2H, d), 1.67 (2H, ddd), MS(ES+) 362 [M+H]+.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2C(=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2CCC)=O.CO[C:20]1[CH:21]=[CH:22][C:23](/[CH:32]=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=[CH:24][C:25]=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:32]\[C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:5][CH2:4][CH2:3][CH2:12][CH3:11])/[C:34](=[O:35])[N:36]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCCc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-propyl-quinoline-3-carbonitrile (example 72c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-pentyl-quinoline-3-carbonitrile. LC-MS m/e 351 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([NH:17][C:18]([N:20]1[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]1=[O:22])=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C>C(O)C.[OH-].[Na+]>[N:20]1([C:18]([NH:17][CH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([OH:29])=[O:3])=[O:19])[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]1=[O:22]
Reactant: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)n1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn(C(=O)NC(CCCNC(=O)OC(C)(C)C)C(=O)O)c(=O)[nH]c1=O
Reaction time: 12 h

Procedure:
The product from Example 11, 15, is dissolved in ethanol (500 mL) and to this added 2M sodium hydroxide (50 mL) and the reaction stirred for 12 hours. The reaction is neutralized with 2M HC1 solution (50 mL) and evaporated to a small volume. This residue is diluted with water (250 mL) and extracted with dichloromethane (4×100 mL), dried, filtered, and evaporated to give a solid.