Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].[N+:24]([O-])([OH:26])=[O:25]>S(=O)(=O)(O)O>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([N+:24]([O-:26])=[O:25])[CH:8]=2)[N:3]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)OC(=O)CCCCn1c(=O)c(=O)[nH]c2ccc(F)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)CCCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Temperature: 0 °C
Yield: 93 %

Procedure:
δ: 1.16 (6H, d, J=6.1 Hz), 1.60-1.62 (4H, m), 2.32 (2H, t, J=6.7 Hz), 4.01-4.08 (2H, m), 4.87 (1H, q, J=6.1 Hz), 7.01-7.05 (1H, m), 7.18 (1H, dd, J=5.5, 8.6 Hz), 7.32 (1H, dd, J=2.7, 11 Hz), 12.0 (1H, s). 4) In 10 ml of concentrated sulfuric acid cooled on an ice-methanol bath, 1.96 g (6.07 mmol) of isopropyl 5-[2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl]valerate was dissolved under stirring. To the resulting mixture, 300 μl of fuming nitric acid was added dropwise at -5° C. or lower, followed by stirring for 30 minutes. The reaction mixture was poured into ice water. The insoluble matter so precipitated was collected by filtration, washed with water and dried under reduced pressure to give 2.06 g (93%) of isopropyl 5-[2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]valerate.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([OH:23])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl>C(O)(C)C>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=1[Cl:30])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: ClCc1ccccc1Cl
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O)cc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4Cl)cc3c12
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
A solution is prepared from 500 mg (1.6 mmol) of 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester in 50 ml of isopropanol, combined with 500 mg (3.6 mmol) of anhydrous, pulverized potassium carbonate, and stirred under argon for 10 minutes. Then 0.25 ml (1.99 mmol) of 2-chlorobenzyl chloride is added and the mixture refluxed for 2 hours. After suctioning off from the potassium carbonate, the filtrate is concentrated and separated over silica gel with methylene chloride:acetone=3:1 as the eluent, thus producing 172 mg of 6-(2-chlorobenzyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 135°-141° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:12][NH:13][C:14]([NH2:16])=[S:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:28]([CH2:30][C:31](OCC)=[O:32])#[N:29].Cl>C(O)(C)C.CC(C)=O.O>[NH2:29][C:28]1[N:13]([CH2:12][C:11]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:14](=[S:15])[NH:16][C:31](=[O:32])[CH:30]=1
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(CNC(N)=S)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(Cn2c(N)cc(=O)[nH]c2=S)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1-(3-Benzyloxy-4-methoxy-benzyl)-2-thiourea (72.58 g, 240 mmole) was added to a solution of 97% t-BuOK (30.54 g, 264 mmole) in isopropanol (300 ml), the mixture heated under reflux until dissolution was complete, then ethyl cyanoacetate (26.1 .ml, 245 mmole) was added. After 5 hours at reflux, the mixture was cooled slightly, another batch of t-BuOK (2.78 g, 24 mmole) and ethyl cyanoacetate (5.12 ml, 48 mmole) was added, and the mixture heated under reflux for a further 15 hours. The reaction mixture was cooled to room temperature, poured onto water (1.21) and neutralized with cooling to pH 8 with 5M HCl (43 ml). After 1 hour stirring the solid was collected at 10° C. and washed first with water (180 ml), then saturated sodium bicarbonate solution (60 ml), isopropanol (60 ml) and finally cold water (500 ml). The crude material was suspended in 0.5M NaOH (1.4 l) and isopropanol (350 ml). The insoluble part was filtered off and washed with 0.1M NaOH and water to give recovered thiourea (10.45 g, 14.4%). The filtrate was neutralized to pH 8 with 2M phosphoric acid (175 ml ), crystallized over night, the solid collected and washed with the above three component liqours and water to give the crude thiouracil (73.33 g). This product was suspended in hot acetone (600 ml), concentrated to 500 ml and collected at 0-5° C. to give 6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-2-thiouracil (65.73 g, 74.1%), mp 239-240° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH:32]=[CH2:33]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:33][CH2:32][CH2:31][CH2:30][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]1
Reactant: C=CCCc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(CCCCc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and but-3-enyl-benzene analogous to Example 51: (M−1)−=359.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37]([N:14]2[CH2:13][C@@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:24])[CH3:11])[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15]2)=[O:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)C2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound 3-{(3R,4S)-3-(4-chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using rac-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light yellow oil. MS m/e: 546.2 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].[CH3:13]I>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:13])[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4]
Reactant: CI
Reactant: CCCC1CCC(C(=O)OC)C1
Solvent: C1CCOC1
Product: CCCC1CCC(C)(C(=O)OC)C1

Procedure:
Under an atmosphere of nitrogen, 3 ml. of a 1.4 M solution of n-butyllithium in n-hexane were added to a solution of 0.643 ml. of diisopropylamine in 3 ml. of dry tetrahydrofuran at -78° C. and the solution was stirred at that temperature for 15 minutes. To the lithium diisopropylamide solution thus obtained was added dropwise a solution of 300 mg. of 1-methoxycarbonyl-3-propylcyclopentane in 5 ml. of dry tetrahydrofuran and the mixture was stirred at -78° C. for 30 minutes. To the solution was added a solution of 0.216 ml. of methyl iodide in 5 ml. of dry tetrahydrofuran and the mixture was stirred at -78° C. for one hour. The reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed with 1 N hydrochloric acid, an aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 330 mg. of the title compound having the following physical characteristic:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](F)=[O:7].[OH-].[Na+].[F:16][C:17]1[CH:25]=[C:21]([C:22](O)=[O:23])[C:20]([NH2:26])=[CH:19][CH:18]=1.S(Cl)(Cl)=O>[Cl-].C[N+](C)(C)CC1C=CC=CC=1.ClCCCl>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[O:7][C:22](=[O:23])[C:21]=2[CH:25]=1
Reactant: O=C(F)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc12
Yield: 90 %

Procedure:
Under the reaction conditions described in Example 1, 14.4 g of m-trifluoromethylbenzoyl fluoride, 6 g of 50% strength aqueous sodium hydroxide solution, 11.6 g of 5-fluoroanthranilic acid and 0.15 g of trimethylbenzylammonium chloride in 185 g of 1,2-dichloroethane are reacted with one another, and the product is then subjected to a cyclization reaction with 11 parts of thionyl chloride. Working up the mixture gives 20.8 g (90%) of 6-fluoro-2-(m-trifluoromethylphenyl)-4H-3,1-benzoxazin-4one of melting point 118°-119° C.
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][C:5]1[N:6]=[CH:7][C:8]([C:20]#[N:21])=[N:9][C:10]=1[C:11]1[O:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][N:15]=1>CC(O)C>[NH2:4][C:5]1[N:6]=[CH:7][C:8](/[C:20](=[N:2]/[NH2:3])/[NH2:21])=[N:9][C:10]=1[C:11]1[O:12][C:13]([C:16]([CH3:18])([CH3:17])[CH3:19])=[N:14][N:15]=1
Reactant: CC(C)(C)c1nnc(-c2nc(C#N)cnc2N)o1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
Hydrazine hydrate (82 mL, 1.69 mol) was added to 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile (55 g, 225.18 mmol) in IPA (200 mL) and the mixture was heated at 50° C. under nitrogen for 16 hours. The mixture was cooled in an ice bath. The resulting precipitate was collected by filtration, washed with IPA and diethyl ether and dried to a constant weight to afford (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (49.2 g, 79%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.45 (9H, s), 5.26 (2H, s), 5.58 (2H, s), 7.56 (2H, s), 8.75 (1H, s); Mass Spectrum [M+H]+=277.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH3:73])[CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][NH:68]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[CH2:66][N:65]([CH2:63][CH3:64])[CH3:73])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(C)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(C)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-ethyl-N-methyl-N-(piperidin-2-ylmethyl)-amine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:36])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[Cl:43][C:41]1[CH:40]=[CH:39][C:38]([F:44])=[C:37]([C:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:19]3[N:18]=[C:17]4[CH2:16][NH:15][CH2:24][CH2:23][C:22]4=[N:21][C:20]=3[NH:25][CH:26]([CH3:27])[CH3:28])[CH2:30][CH2:31]2)=[O:36])[CH:42]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanone TFA salt (48.9 mg, 0.077 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 0.036 mmol) in THF (384 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon). After 3 h, the mixture was diluted with MeOH, filtered through a pad of Celite™, washing with MeOH, and concentrated to afford he title compound as its TFA salt (37.1 mg, 88%) as a yellow film, which was used without further purification. ESI-MS m/z [M+H]+ 432.3.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]2[C:9](=[O:22])[N:10]3[CH2:21][CH2:20][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([OH:19])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[F:24][C:2]([F:23])([F:1])[C:3]1[C:8]2[C:9](=[O:22])[N:10]3[CH2:21][CH2:20][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([NH2:27])=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.2 %

Procedure:
10 g (29.7 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 50 ml of N,N-dimethylformamide and treated portionwise at room temperature with 5.1 g (31.2 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the clear brown solution was stirred at 50° for 20 min., cooled and treated dropwise with 8 ml of conc. ammonia at a temperature below 150 within about 15'. After stirring for 40 minutes the suspension obtained was poured into 300 ml of ice-water, whereupon the mixture was stirred at room temperature for 20', filtered and rinsed with a small amount of water. After drying there were obtained 7.51 g (75%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. >300°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1>Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc(NC2CCNCC2)c1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(3-fluorophenyl)amino]-1-piperidinecarboxylate (D3) (2.30 g) in 2M HCl (5 ml) and 1,4-dioxane (40 ml) was heated at 70° C. with stirring overnight. On cooling, the solvent was removed in vacuo and the residue diluted with 2M NaOH solution and extracted with 9:1 EtOAc/tBuOH (×2). The organics were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (1.33 g). δH (CDCl3, 250 MHz) 7.07 (1H, q), 6.33 (3H, m), 3.83 (1H, br s), 3.33 (1H, br s), 3.12 (2H, m), 2.71 (2H, m), 2.04 (2H, m), 1.30 (2H, m).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[OH-].[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])([O-:8])=[O:7]>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccccc1[N+](=O)[O-]
Yield: 57.2 %

Procedure:
A mixture of dimethylamine (30 g, 270 mmol) and sodium hydroxide (7.2 g, 180 mmol) in 60 mL of dioxane was stirred and 2-nitrobenzoyl chloride (23.8 mL, 180 mmol) in 100 mL of dioxane was added dropwise. The mixture was stirred at room temperature for approximately 12 hours and then partitioned between 100 mL of saturated sodium bicarbonate solution and 150 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined ethyl acetate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 4% methanol/methylene chloride to give N,N-dimethyl-2-nitrobenzamide (20 g, 103 mmol), m.p. 74°-76° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.CNCCNC.[CH:17]1([S:20]([O-:22])=[O:21])[CH2:19][CH2:18]1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:17]1([S:20]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)(=[O:22])=[O:21])[CH2:19][CH2:18]1
Reactant: O=S([O-])C1CC1
Reactant: Ic1ccnc2[nH]ncc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=S(=O)(c1ccnc2[nH]ncc12)C1CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
To a solution of 4-iodo-1H-pyrazolo[3,4-b]pyridine (5.2 g) in dimethyl sulfoxide (70 mL) were added N,N′-dimethylethylenediamine (114 μL), copper (I) iodide (202 mg), sodium cyclopropanesulfinate (8.16 g) and potassium carbonate (5.06 g) at room temperature under argon atmosphere, and the mixture was stirred at 100° C. for 16 hr. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.42 g, yield 9%) as yellow crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 224 (MH+).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][N:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:14])=[O:13])[CH3:10]>>[CH3:10][N:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])(=[O:14])=[O:13])[CH3:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CN(C)NS(=O)(=O)c1ccccc1O
Product: CN(C)NS(=O)(=O)c1ccccc1OS(=O)(=O)N=C=O

Procedure:
To 5.2 ml (0.06 mole) chlorosulfonyl isocyanate in 75 ml dry xylenes was added 10.1 g (0.05 mole) of 2-(dimethylaminosulfamoyl)phenol in 15 ml xylenes, keeping the reaction temperature <5° C. This mixture was then heated to reflux temperature for 1 hour. The reaction solution was then cooled and the solvent evaporated to give an oil. The infrared spectrum showed NCO absorption at 2270 cm-1.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32](=[O:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.S(O)(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:32](=[O:34])[CH3:33])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Yield: 70.2 %

Procedure:
A solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (Example 271; 332 mg, 0.54 mmol) in TFA (3 mL) was treated with TfOH (0.1 mL). The solution was heated at 80° C. in an oil bath for 4 h, allowed to cool to room temperature, and concentrated. The dark residue was treated with a few ice cubes followed by sat. NaHCO3 while rapidly stirring. The precipitated yellow solid was collected by filtration and rinsed with water (5 mL). The yellow solid was purified by flash chromatography eluting with 1-15% MeOH in DCM to give 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (140 mg, 69%) as a bright yellow crystalline solid. m/z (ESI, +ve ion) 460 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.38 (br., 1H); 9.26 (d, J=2.2 Hz, 1H); 8.96 (d, J=2.2 Hz, 1H); 8.42 (s, 1H); 8.35 (dd, J=12.3, 1.6 Hz, 1H); 8.00 (s, 1H); 7.83 (s, 1H); 3.96 (s, 3H); 2.57 (s, 3H); 2.46 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCCN(Cc3ccc(Cl)cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCCN(Cc3ccc(Cl)cc3)C2)cc1

Procedure:
3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-1-3-piperidinecarboxylic acid as prepared starting from ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-3-piperidinecarboxylate (1.64 g, 3.3 mmol) dissolved in THF:Methanol (15:50 ml) and NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 1 (step 7); Yield 1.11 g (75%), white solid: mp 115.2° C.; MS (ES): m/z 462.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(F)cc2)cc1
Yield: 27.8 %

Procedure:
In a manner similar to that described in Example 3, 4-fluorobenzoyl chloride (0.053 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.0219 g of 4-[4-(4-fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 253-255.° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[C:35]([CH3:41])[C:34]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:34]4[C:35]([CH3:41])=[C:36]([CH3:40])[CH:37]=[C:38]([CH3:39])[C:33]=4[CH3:32])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(C)c(C)c(S(=O)(=O)Cl)c1C
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)c(C)cc(C)c4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,3,5,6-tetramethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=617.7)=80%.