Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12](OC)=O>C(#N)C.O>[OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[CH:3]=1
Reactant: COC(=O)C1=C(O)CN(CC(N)=O)C1=O
Solvent: O
Solvent: CC#N
Product: NC(=O)CN1CC(C2=C(O)CN(CC(N)=O)C2=O)=CC1=O
Reaction time: 12 h

Procedure:
4.3 g of 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetamide are suspended in 50 ml of acetonitrile and 30 ml of water. Heating to 75° initiates the removal of carbon dioxide; the reaction mixture is stirred at this temperature for 12 hours. After cooling, the resulting product is filtered off, washed with water and acetone and dried under reduced pressure. 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide is obtained in the form of white crystals having a melting point of 300° (decomposition). The product is identical to that described in Example 1.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28]Br)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[SH:36].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:4]1[C:5]([CH2:28][S:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: Cn1ccnc1S
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(C)=O)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A mixture of 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.5 g), 1-methyl-2-mercaptoimidazole (0.417 g), potassium carbonate (0.495 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over magnesium sulfate. Evaporation of the solvent gave 3-acetyl-4-(3,4-dimethoxy-phenyl)-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]-quinoline (1.1 g, 71%). This compound was recrystallized from ethanol to give colorless prisms, mp. 175°-176° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:15]1([NH:14][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: CC#N
Product: CCOC(=S)c1cnc(C)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (15 g, 64.5 mmol) and aniline (12 mL, 132 mmol) in 200 mL of acetonitrile was stirred at room temperature for 24 hours. The mixture was then evaporated and ethyl acetate and 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with aqueous hydrochloric acid, dried over sodium sulfate, filtered and evaporated. The resulting solid was purified by trituation with 1:3 ether/hexanes to give 14.2 g (64%) of ethyl 4-phenylamino-2-methylthio-pyrimidine-5-carboxylate as a white solid, mp 88.2-88.7° C.
Reaction SMILES: [C:1](=[O:12])([O:9][CH2:10]Cl)[O:2][CH2:3][CH2:4][NH:5][C:6](=[O:8])[CH3:7].[I-:13].[Na+]>C(#N)C>[C:1](=[O:12])([O:9][CH2:10][I:13])[O:2][CH2:3][CH2:4][NH:5][C:6](=[O:8])[CH3:7]
Reactant: [I-]
Reactant: CC(=O)NCCOC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NCCOC(=O)OCI
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
[2-(acetylamino)ethyl] chloromethyl carbonate (5.0 g) was dissolved in acetonitrile (15 ml), and sodium iodide (15.0 g) was added. The mixture was stirred at 60° C. for 2 hours under an argon atmosphere. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (200 ml). The extract was washed with an aqueous 5% sodium thiosulfate solution (100 ml×2), water (100 ml×2) and a saturated sodium chloride aqueous solution (50 ml) successively. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [2-(acetylamino)ethyl] iodomethyl carbonate (3.5 g) as a yellow oil.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:40])[C@@H:6]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][N:7]1[C:18](=[O:39])[C@H:19]([CH:36]([CH3:38])[CH3:37])[NH:20][C:21](=[O:35])[C@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:23][C:24](=[O:26])[CH3:25].Cl>O1CCCC1.O>[C:24]([NH:23][C@H:22]([C:21]([NH:20][C@H:19]([C:18]([N:7]1[CH2:8][CH:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C@H:6]1[C:5]([OH:40])=[O:4])=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)[C@@H]1CC(Oc2ccccc2)CN1C(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(Oc2ccccc2)C[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Lithium hydroxide (57 mg, 1.37 mmol) was added to a solution of N-Acetyl-tyrosinyl-valinyl-(4-phenoxy)proline methyl ester (360 mg, 0.685 mmol) dissolved in 8 ml of tetrahydrofuran/water (1:1) and stirred at room temperature for 1 hour. The mixture was acidified with 10% hydrochloric acid giving a white precipitate that was collected to give 175 mg of the title compound.
Reaction SMILES: [CH:1]1([C:17]([O-:19])=[O:18])[CH:15]2[C:16]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:3][CH2:2]1.[C:20](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH3:20][O:18][C:17]([C:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)=[O:19]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C([O-])C1CCc2cccc3c2C1c1ccccc1-3
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cccc3c2c1-c1ccccc1-3
Yield: 97.6 %

Procedure:
To a RB flask equipped with magnetic stirrer, condenser and N2 inlet line with bubbler was added methyl, 1,2,3,10b-tetrahydro-1-fluoranthenecarboxylate (Cambridge Chemical, Inc., 202 E. Smith Street, Milwaukee, Wis. 53207, 98.0 g, 0.372 mol), DDQ (Aldrich, 177.0 g, 0.781 mol) and dry PhCH3 (2 L). The reaction mixture was heated at 90° for 10 h, cooled, filtered and concentrated to a 500 mL volume. The crude material was purified on a plug of SiO2 (0.5 kg) using PhCH3 as the eluting solvent. The appropriate fractions were combined and concentrated by rotary evaporation to give a crude pale yellow solid which was recrystallized (CH2Cl2 /hexane), filtered and dried to give 94.5 g (96%) of methyl-1-fluoranthenecarboxylate mp 70°-71°, (C,H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1OC
Yield: 68.8 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (20.2 g, 0.077 mol) and o-anisidine (15 ml, 0.11 mol) were heated under reflux in 1,4-dioxan (150 ml) for 1 hour. The solvent was evaporated and the residue dissolved in dichloromethane and washed with dilute hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried, filtered and evaporated to a yellow solid, which was triturated with ether to give 3-butyryl-4-(2-methoxyphenylamino)-8-methoxyquinoline (18.55 g, 68.75%) m.p. 159°-161°.
Reaction SMILES: [Br:1]Br.[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[Br:1][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: O=Cc1cccc(Oc2ccc(Br)cc2)c1
Reaction time: 1 h

Procedure:
9.60 Grams (0.060 mole) of bromine were added dropwise to 9.90 g (0.050 mole) of m-phenoxybenzaldehyde at 0° C. taking a period of 1 hour with vigorous stirring. After the addition was finished, the reaction was continued for a further 3 hours at the same temperature. The unreacted bromine was distilled off under reduced pressure from the reaction system to obtain m-(p-bromophenoxy)benzaldehyde (No. 9 in Table 2).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]([CH2:16][C:17]#[N:18])[CH3:15])(=[O:13])=[O:12])(OC)=[O:2].C[O-].[Na+].CO>C1(C)C=CC=CC=1>[C:17]([C:16]1[N:14]([CH3:15])[S:11](=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]=1[OH:2])#[N:18]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N(C)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1C(C#N)=C(O)c2ccccc2S1(=O)=O
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of o-carbomethoxy-N-cyanomethyl-N-methylbenzenesulfonamide (108 g) in toluene (600 ml) was added 28% sodium methoxide-methanol solution (83 ml) with vigorous stirring. After 2 hours the solvent was evaporated to ca. 400 ml and water (800 ml) added to dissolve the viscous residue. The pH was adjusted to ca. 2 with 6N HCl. The resulting crystals were granulated for 1 hour, filtered off, washed with water and dried in vacuo to give the title product, 77.2 g (81.1%). Purified product was obtained in 75% yield by dissolving the compound (3.3 g) in isopropanol, followed by dropwise addition of water (35 ml).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)([CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C(N)CN>C1(C)C=CC=CC=1.[Cu]I>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]3[CH:25]=[CH:24][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[CH:22][CH:21]=3)([CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: NCCN
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCCC3=O)cc2)C1
Yield: 51.9 %

Procedure:
To a stifling suspension of potassium carbonate (1.23 g, 8.95 mmol) and CuI (42.5 mg, 0.22 mmol) in anhydrous toluene (10 mL) were added 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 1.6 g, 4.5 mmol) dissolved in toluene (10 mL) followed by addition of pyrrolidinone (0.5 mL, 6.2 mmol) and ethylene diamine (0.03 mL, 0.45 mmol). Reaction mixture was refluxed for 16 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 4:6 EtOAc:Pet. ether) to afford the title compound as white solid (800 mg, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene was added aniline (2 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N′-phenyl-urea as a light yellow solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13]1[O:18][CH2:17][N:16]([C:19]([CH3:29])([CH3:28])[CH:20]([CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[CH2:27])[OH:21])[C:15](=[O:30])[C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCOCC>ClCCl>[CH3:12][C:13]1[O:18][CH2:17][N:16]([C:19]([CH3:28])([CH3:29])[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[CH2:27])=[O:21])[C:15](=[O:30])[C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C1CCCC1C(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=C1CCCC1C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reaction time: 3 h
Yield: 50.3 %

Procedure:
Powdered molecular sieve (4 A, 17 g) and pyridinium chlorochromate (4.3 g) were added to a stirred solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-ol (3.1 g) in dichloromethane at 20° C. After 3 hours, ether was added and the mixture filtered, evaporated and the residue purified by silica gel column chromatography eluting with n-hexane/ethyl acetate (3:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-one (Compound 1072, 1.55 g), NMR: 1.49(s,3H), 1.55(s,3H), 1.93(s,3H), 1.85-2.00(3H) 2.25-2.52(2H), 3.89(1H), 4.87(s,1H), 5.28(2H), 7.2-7.4(5H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2cccnc2n1
Product: Clc1ccc2cccnc2n1

Procedure:
1,8-Naphthyridin-2-ol (2.80 g, 19.16 mmol) was suspended in phosphorus oxychloride (100 ml, 1092 mmol) and heated at gentle reflux. The chlorination was followed by LC/MS and once the conversion was complete the reaction was evaporated to dryness and the residue partitioned between water (400 mL) and ethyl acetate (2×400 mL). The aqueous was extracted with additional ethyl acetate (2×400 mL). The combined organic layers were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude compound was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[N:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: Cc1cc(C(=O)O)cc(C)n1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)nc(C)c1
Reaction time: 20 h

Procedure:
To 2,6-dimethylisonicotinic acid (1.00 g, 6.61 mmol) in DCM (8.3 mL), CDI (1.18 g, 7.27 mmol) was added and the mixture was stirred for 45 minutes after which N,O-dimethylhydroxylamine hydrochloride (0.71 g, 7.3 mmol) was added and the mixture was stirred for 20 hours. The reaction mixture was quenched with 0.3 M aqueous solution of NaOH and partitioned between water and DCM. The aqueous layer was extracted with DCM, washed with aqueous saturated solution of NaCl, dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(Cl)c1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 216 h
Yield: 63.4 %

Procedure:
4-BROMO-3-CHLOROBENZENESULFONYL CHLORIDE (10.0 g, 0.0345 mol) and 2-AMINOTHIAZOLE (3.80 g, 0.0379 mol) were mixed in Pyridine (40 mL, 0.5 mol). The reaction was allowed to stir at room temperature for 9 days. The reaction was concentrated in vacuo to a total volume of approximately 40 mL. The residue was triturated with acetonitrile and the solid collected by filtration. The filtrate was concentrated in vacuo and the residue triturated with 1N HCl. The solid was collected by filtration and rinsed with acetonitrile then ethyl ether. The combined solid from steps 4 and 5 was dissolved in boiling acetonitrile and treated with activated carbon then filtered through a celite pad. The filtrate was reduced to ⅓ its original volume by distillation. The mixture was cooled to room temperature. The crystals were collected by filtration and rinsed with ethyl ether. Vacuum drying gave 7.73 g of yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]([CH2:31][CH3:32])[C:8](=[O:30])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:31][CH3:32])[C:8](=[O:30])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:13][CH:12]=2)=[CH:33][CH:34]=1
Reactant: CCN(Cc1ccc(Cl)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCN(Cc1ccc(Cl)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 88.7 %

Procedure:
Methyl 2-{[2-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-ethyl]thio}benzoate (0.085 g, 0.170 mmol) was dissolved in a mixture of acetonitrile/water (1/1, 4 ml) and lithium hydroxide (0.008 g, 0.341 mmol) was added. The reaction was performed in an single node microwave oven (5 min. 150 deg). The solvent was removed by evaporation and then HCl (2 ml, 1 M) was added. The water phase was extracted with two portions of EtOAc (20 ml). The combined organic phase was dried (MgSO4) and the solvent was removed by evaporation and gave 0.073 g of 2-{[2-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoic acid (yield 88.4%) as an oil which solidified on cooling and standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1.[C:14]([N:18]=[C:19]=[S:20])([CH3:17])([CH3:16])[CH3:15].C([Li])CCC>C1COCC1.CCCCCC>[C:14]([NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCCCSc1cccc(N)n1
Reactant: CC(C)(C)N=C=S
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=S)Nc1cccc(SCCCC#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
A solution of 4-(2-aminopyrid-6-ylthio)butyronitrile (0.39 g.) and t-butylisothiocyanate (0.25 g.) in THF (10 ml.) was stirred under an argon atmosphere while adding a solution of n-butyl lithium in hexane (1.55M; 2 ml.). The mixture was stirred at room temperature for three hours and then evaporated to dryness. The residue was partitioned between EtOAc and water and the EtOAc phase was dried and evaporated to dryness. The residue was recrystallised from EtOH to give 4-[2-(3-t-butylthioureido)pyrid-6-ylthio]butyronitrile (0.32 g.), m.p. 156°-157°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([F:20])=[N:11][C:12]2[C:17]([C:18]=1F)=[CH:16][N:15]=[CH:14][CH:13]=2.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)C>[CH:21]([NH:25][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[N:11]=[C:10]([F:20])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH2:23][CH3:24])[CH3:22]
Reactant: Fc1cccc(Cl)c1-c1c(F)nc2ccncc2c1F
Reactant: CCC(C)N
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)Nc1c(-c2c(F)cccc2Cl)c(F)nc2ccncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Step 1 (0.10 g) was dissolved in DMF (2 ml). Sec-butylamine (0.1 ml) and DMAP (0.001 g) were added and the mixture was stirred in a sealed tube at ambient temperature for 18 hours. The brown reaction mixture was diluted with diethyl ether, washed with brine and dried over sodium sulphate. After evaporation of the solvent the resulting yellow gum was purified by flash column chromatography on silica gel (40-60) in ethyl acetate:hexane 1:3 to give N-sec-butyl-3-(2-chloro-6-fluorophenyl)-2-fluoro-1,6-naphthyridin-4-amine as a dark yellow solid (0.06 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[H-].[Na+].Br[C:10]1[C:11]2[N:12]([C:17]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])=[O:21])=[CH:18][N:19]=2)[N:13]=[C:14]([Cl:16])[CH:15]=1.CN(C=O)C>C1COCC1>[Cl:16][C:14]1[CH:15]=[C:10]([NH:6][C:3]2[CH:4]=[CH:5][O:1][N:2]=2)[C:11]2[N:12]([C:17]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])=[O:21])=[CH:18][N:19]=2)[N:13]=1
Reactant: Nc1ccon1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(Cl)nn12
Reaction time: 0.17 h

Procedure:
To a solution of isoxazol-3-amine (25.8 mg, 0.307 mmol) in THF (0.5 mL) was added 60% NaH (12.26 mg, 0.307 mmol). The mixture was stirred for 10 min and 5A (40 mg, 0.123 mmol) was added followed by DMF (0.5 mL). The mixture was stirred overnight. The solvent was removed under a stream of nitrogen and water was added. The resulting solid was collected by filtration, rinsed with water, and dried on vacuum to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4cc(C(F)(F)F)ccn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
5-Chloro-3-(4-(4-(trifluoromethyl)pyridin-2-yloxy)phenyl)pyridin-2-amine (470 mg) was added to a mixture of NaH (60%, 257 mg) and 2-chloroethanesulfonyl chloride (628 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with IPE to give the title compound (502 mg) as a yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid (1st crop impure, 2nd crop (254 mg)). The 1st crop was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (263 mg) as a white solid.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH2:34][CH3:35])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
107.35 mg (0.31 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A are added to 5 ml of pyridine, and the mixture is cooled to 0° C. 33.25 mg (0.31 mmol) of ethyl chloroformate are added, and the reaction is left to stir at RT overnight. The pyridine is evaporated in vacuo in a rotary evaporator, and the residue is purified by preparative RP-HPLC.