Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[CH:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1([C:26]([NH:28][CH:29]([CH2:33][S:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:36])=[O:35])[C:30](O)=[O:31])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:30](=[O:31])[CH:29]([NH:28][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH2:33][S:34]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:35])=[O:36])[CH:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCN(C(=O)OCc2ccccc2)CC1O
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CCCN(C(=O)OCc2ccccc2)CC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester (150 mg, 0.57 mmol) prepared as in Reference 2, 2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (400 mg, 1.12 mmol), EDC (400 mg, 2.1 mmol), and HOBt (400 mg, 2.5 mmol) were combined. Dichloromethane (10 mL) was added followed by 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (100 mL) the solution was washed with 1N HCl, saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/methanol 9: 1) to yield 3-hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionyl-amino}-azepane-1-carboxylic acid benzyl ester (320 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[CH:10]=NO.S(=O)(=O)(O)[OH:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:13])[C:10]2=[O:15]
Reactant: O=C(C=NO)Nc1ccccc1F
Reactant: O=S(=O)(O)O
Product: O=C1Nc2c(F)cccc2C1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
31.3 g of the product of Step A were added at 75°-77° C. over 65 minutes to 155 ml of concentrated sulfuric acid and the mixture was heated over 10 minutes to 90° C. and held there for 10 minutes and then cooled to 20° C. The mixture was poured into 750 g of ice and the mixture was stirred until the ice melted and was filtered. The filtrate was saturated with sodium chloride and was extracted several times with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution until the wash water was neutral, dried, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 350 ml of xylene at reflux and the hot solution was filtered and the filter was washed with 20 ml of boiling xylene. The filtrate was iced and vacuum filtered. The product was washed with xylene and dried under reduced pressure at 80° C. to obtain 12.85 g of 7-fluoro- 1H-indole-2,3-dione melting at 198° C.
Reaction SMILES: C([Mg]Br)(C)C.CN(C)[CH:8]=[O:9].O.[Br:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16](I)=[N:17][CH:18]=1>O1CCCC1>[Br:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16]([CH:8]=[O:9])=[N:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(I)ncc1Br
Agent: CC(C)[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)ncc1Br
Temperature: -15 °C
Reaction time: 1 h

Procedure:
In an oven-dried flask the compound obtained in Step A (4.67 g) was dissolved in tetrahydrofuran (22 ml). The solution was cooled to −15° C., then isopropyl magnesium bromide (17.2 ml, 15% solution in THF) was added dropwise at a rate to keep the internal temperature between −15° C. to −10° C. The reaction was stirred at this temperature for 1 hour, then anhydrous dimethylformamide (1.8 ml) was added at a rate to keep the internal temperature below 0° C. The reaction was stirred at this temperature for 1 hour, then poured into water and extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude title aldehyde product (2.4 g, brown solid) was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C1COCCN1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C/C(=C\c1ccc(C(=O)N2CCOCC2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and morpholine there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid morpholide of melting point 143°-144° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][N:13]2[C:31]([O:32][CH3:33])=[O:34])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(S(C)(=O)=O)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 107.5 %

Procedure:
Methyl 2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylate hydrochloride (5.2 g, 15.58 mmol) and DIPEA (6.78 mL, 38.94 mmol) were dissolved in DCM (40 mL) and methyl carbonochloridate (1.472 mL, 18.69 mmol) added. The reaction was stirred at room temperature for 50 min. DCM (160 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding crude dimethyl 2-(4-(methylsulfonyl)phenyl)piperidine-1,4-dicarboxylate (5.95 g, 108%). MS m/z 356 (M+H)+
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=[O:5])#[C-:2].Cl.[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[N+:1]([CH2:3][CH:4]=[O:5])#[C-:2].[F:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: F[C@H]1CCNC1
Reactant: [C-]#[N+]CC(=O)OC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: [C-]#[N+]CC(=O)N1CC[C@H](F)C1
Product: [C-]#[N+]CC=O
Yield: 158.2 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 1.18 g, 11.9 mmol) was slowly added (S)-(+)-3-fluoropyrrolidine hydrochloride (97%, 1.5 g, 11.9 mmol), triethylamine (1.67 mL, 11.9 mmol) and MeOH (3 mL). The mixture was stirred for 15 h at RT and concentrated. The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-1(5)-3-fluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01166 (1.47 g, 79% yield) as a brown oil which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17](CCCN(C)C)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC3C=CC=CC=3)[CH:22]=2)=[O:19])=[CH:12][CH:11]=1.[C:42](OCC)(=O)[CH3:43].CO.[CH3:50][N:51]([CH:53]=O)[CH3:52]>[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[C:10]1[CH:11]=[CH:12][C:13]([CH:16]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[O:19])[CH2:42][CH2:43][CH2:53][N:51]([CH3:52])[CH3:50])=[CH:14][CH:15]=1
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2N)cc1)C(=O)Nc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCC(NC(=O)Nc1cccc(O)c1)c1ccc(C(=O)Nc2ccccc2N)cc1
Yield: 88 %

Procedure:
10% Palladium on carbon (100 mg) was added to a solution of N-(2-aminophenyl)-4-[3-(3-benzyloxyphenyl)-1-(3-dimethylaminopropyl)ureidomethyl]benzamide (Compound No. 1-76, 640 mg, 1.2 mmol) in a mixed solvent (ethyl acetate (10 mL), methanol (10 mL), and DMF (10 mL)), and then the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 32 hours. After the insoluble was filtered off, water (100 mL) was added to the filtrate, the whole was extracted with ethyl acetate (100 mL) twice, and then the organic layer was washed with brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 480 mg of the title compound as a white amorphous product. (Yield 88%)
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].C(O)C.Cl>[OH-].[Na+]>[C:9]([CH2:8][CH2:7][C:6]1[CH:12]=[CH:13][C:3]([CH:1]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:4][CH:5]=1)([OH:11])=[O:10]
Reactant: O=Cc1ccc(CCC(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 5.34 g of 4-formyldihydrocinnamic acid in 50 ml of 1N sodium hydroxide was added a solution of 3.6 g of acetophenone and 20 ml of ethanol. The reaction mixture was stirred at room temperature for 4 hrs. and then poured onto 300 g of crushed ice. 1N Hydrochloric acid was added and, after stirring at 0°C for 15 min., the precipitate was collected and washed with water. The precipitate was dissolved in 500 ml of ethyl acetate, dried over anhydrous sodium sulfate and the drying agent was collected on a filter. The filtrate was concentrated to about 100 ml and seeded with crystalline product. The solid was collected, washed with 1:4-ethyl acetate-ether followed by ether and dried at 70°-75°C under vacuum to give 8.4 g (72%) of 4-(2-carboxyethyl)benzalacetophenone, as yellow needles, m.p. 159°-160°C.
Reaction SMILES: C([O:4][C@H:5]([C@H:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][N:31]([CH3:36])[C:30]3=[O:37])[C:22]1=[O:38])[C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17](=[O:19])[O:16][N:15]=2)=[CH:10][CH:9]=1)(=O)C.[NH3:39].CO>CO>[OH:4][C@H:5]([C@H:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][N:31]([CH3:36])[C:30]3=[O:37])[C:22]1=[O:38])[C:6]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([O-:19])[O:16][N:15]=2)=[CH:12][CH:13]=1)=[O:20].[NH4+:39]
Reactant: CC(=O)O[C@@H](C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Reactant: N
Solvent: CO
Product: CN1Cc2ccc(N3CCO[C@H]([C@@H](O)C(=O)Nc4ccc(-c5noc([O-])n5)cc4)C3=O)cc2C1=O
Product: [NH4+]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound 70-5 (30 mg) in MeOH (2 mL) at 0° C. was added 7M NH3/MeOH (0.3 mL) dropwise. The mixture was stirred for 1 h at 0° C. and an additional hour at rt. The mixture was concentrated under reduced pressure and placed under high vacuum to afford compound 70-6 (27 mg) as a clear glass. LC-MS: M+H=480 (free base).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)Cl
Reactant: OC(CNCc1ccccc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)N(Cc1ccccc1)CC(O)C(F)(F)F
Reaction time: 0.08 h

Procedure:
A solution of 3-(Benzylamino)-1,1,1-trifluoropropan-2-ol (2.68 g, 12.3 mmol) and triethylamine (1.7 mL, 12.2 mmol) in CH2Cl2 is cooled to 0° C. The solution is treated drop wise with 2-bromopropanoyl chloride (1.2 mL, 12 mmol, Aldrich) and stirred for 5 minutes. The solution is diluted to 100 mL with CH2Cl2 and washed sequentially with 1.0M HCl, saturated NaHCO3, and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation yielding (N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide as a golden oil. Dry NaH is suspended in dry, inhibitor free THF (25 ml) in a flame dried flask and the mixture is cooled to 0° C. with stirring on an ice bath. The N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide (4.25 g, 12 mmol) is added as a solution in dry, inhibitor free THF (25 ml) and the resultant suspension is warmed to RT. After stirring for one hour the reaction is quenched with MeOH over an ice bath until no more gas evolved and the mixture is poured into 1.0M HCl (200 mL). The aqueous mixture is extracted into MTBE (200 mL) and the organic layer is washed with saturated NaHCO3 and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered, and the solvent is removed by rotary evaporation yielding an amber oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:3]=[CH:2]1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>CN(C=O)C>[C:13]1([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
A solution of the product from Step 4.a. (3.2 g, 17.5 mmol) in DMF (50 ml) was treated with chlorotriphenylmethane (4.88 g, 17.5 mmol) and Et3N (5.4 ml, 38.5 mmol) and the reaction was stirred at room temperature for about 6 hours. The DMF was evaporated under reduced pressure and the residue was distributed between EtOAc and saturated NaCl solution. The EtOAc layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield product as a viscous oil (6.96 g, 104%) which crystallized on standing. Mass spec. 383.3 MH+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[C:6]([Br:28])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:18])=[CH:11][C:10]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1>O=S(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[C:6]([Br:28])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:2][CH2:3][C:4]([CH3:29])=[CH2:5])=[CH:11][C:10]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: Cc1cccc(C(=O)c2cc(O)c(C(C)C)cc2Oc2c(Br)cc(CC(=O)O)cc2Br)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 109.8 %

Procedure:
Five drops of SOCl2 was added to a solution of 3,5-dibromo-4-[4-hydroxy-5-isopropyl-2 -(3-methylbenzoyl)phenoxy]phenylacetic acid (0.30 g, 0.52 mmol), in 20 mL MeOH. The mixture was stirred at room temperature for 12 h and concentrated leaving the title compound (0.18 g, 60%). 1H NMR (CDCl3): δ 7.9–7.7 (m, 2H), 7.5–7.1 (m, 4H), 6.9 (s, 1H), 6.2 (s, 1H), 4.7 (s, 3H), 4.5 (s, 2H), 3.1 (m, 1H), 2.4 (s, 3H), 1.1 (d, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[C:9]([O:12][C:13](=O)[CH3:14])(=O)C.[C:16](O)(=O)C>[Cl-].[Zn+2].[Cl-]>[C:5]([C:4](=[CH:16][CH:14]=[CH:13][O:12][CH3:9])[C:3]([N:2]([CH3:8])[CH3:1])=[O:7])#[N:6]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C(=O)CC#N
Agent: [Cl-]
Agent: [Zn+2]
Product: COC=CC=C(C#N)C(=O)N(C)C
Yield: 44.3 %

Procedure:
To a 250 ml 3-necked R.B. flask was charged 50 g malonodialdehyde bis(dimethylacetal), 22.5 g N,N-dimethyl-2-cyanoacetamide, 60 g acetic anhydride, 0.5 g zinc chloride and 100 ml acetic acid. It was heated to reflux to distill off low boilers until the pot temperature reached 125° C. and head reached 110° C. and a total of 60 ml distillate was collected. GC analysis of the pot content showed disappearance of N,N-dimethyl-2-cyanoacetamide. The reaction mixture was filtered to remove zinc catalyst and then rotovapped. The pot residue was crystallized from a methanol in dry ice-acetone bath to afford 16 g (44.3%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH2:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[S:14].[CH3:16][O:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[O:20][CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>>[CH3:16][O:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[O:20][CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][NH:1][CH:2]([CH3:15])[CH2:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[S:14]
Reactant: COc1ccccc1OCCn1cccc1C=O
Reactant: CC(N)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Product: COc1ccccc1OCCn1cccc1CNC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Yield: 12.9 %

Procedure:
The title compound was prepared in accordance with the general method described above using 3-(2-aminopropyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (0.18 g, 0.54 mmol, obtained from Example 29(c)) and 1-[2-(2-methoxyphenoxy)ethyl]-1H-pyrrole-2-carbaldehyde (125.8 mg; 0.513 mmol), which after preparative HPLC generated 0.17 g of the product. Further purification was accomplished with a portion of this material (0.76 g) by trituration with water, which after drying in vacuo, generated 30.0 mg (29% yield) of the title compound.
Reaction SMILES: I[C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[N+:8]([C:6]1[CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([OH:11])=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(-c2ccccc2)c1

Procedure:
In a schlenck tube, a mixture of 3-iodo-5-nitropyridin-2-ol (7.52 mmol, 2 g), phenylboronic acid (8.28 mmol, 1.01 g), PdCl2dppf.DCM (0.75 mmol, 0.6 g), Cs2CO3 (22.56 mmol, 7.4 g) in a dioxane/water 4:1 mixture (26 ml) was heated at 100° C. for 4 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The organic phase was evaporated and the crude was suspended in methanol affording a solid that was filtered off and dried under vacuum overnight affording 1.2 g (74% of yield) of the expected product.
Reaction SMILES: [O-]CC.[K+].C(O)C.[C:8]([C:11]1[C:15]([NH:16][C:17](=O)[C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[N:20][C:19]=2[O:35][CH2:36][CH3:37])=[C:14]([CH2:39][CH3:40])[N:13]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[N:12]=1)(=[O:10])[NH2:9]>C(OCC)(=O)C>[CH2:36]([O:35][C:19]1[N:20]=[CH:21][C:22]([S:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH2:32]2)(=[O:25])=[O:26])=[CH:23][C:18]=1[C:17]1[NH:9][C:8](=[O:10])[C:11]2[C:15](=[C:14]([CH2:39][CH3:40])[N:13]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[N:12]=2)[N:16]=1)[CH3:37]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CC
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 120 °C
Yield: 83 %

Procedure:
Potassium ethoxide solution (86 g, 0.25 mol, 24% w/w in ethanol) was charge to the vessel. To this was added ethanol (235 mL). Ethyl acetate (10.8 g) was added to reaction mixture at ambient. N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl) nicotinamide (70 g, 0.122 mol) was added in one portion to the solvent mixture and the reaction was stirred at ambient. The reaction mixture was warmed in a pressurised vessel to a temperature of 120° C., producing an internal pressure of approximately 50-60 p.s.i., the pressure was then made up to 80 p.s.i. by applying a nitrogen pressure and the reaction was stirred for 8 hours. The reaction was cooled after 8 hours and ethanol is then reduced under atmospheric distillation to a volume of about 720 ml (3 ml/g). Ethyl Acetate (840 ml) was added to the ethanol solution and then reduced under atmospheric distillation to a volume of 1920 ml (8 ml/g). Dilute aqueous hydrochloric acid was added to adjust the pH of the reaction mixture from about pH=13 to pH=8. This was a slow addition over 30 min showing no exotherm. The mixture was stirred for 5 minutes, warmed to 50° C. and the phases were separated. The aqueous was run off to the effluent. Water (140 mL) was added to ethyl acetate layer (remaining in the vessel), stirred, warmed to 50° C. and the phases were separated. The aqueous was run off to the effluent. The ethyl acetate phase was slowly cooled from 50° C. to 0-5° C. over two hours, and stirred for a further hour, filtered of the solid, wash with ethyl acetate (3) 0-5° C. and dried under vacuum at 60° C. to afford the title compound (83%) as a white solid. Mpt 178-180° C. (CDCl3): 1.02 (3H, t), 1.30, 3H, t), 1.58 (3H, t), 2.21 (2H, q), 2.55 (4H, m), 3.04 (2H, q), 3.10 (4m), 4.75 (2H, q), 5.69 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.57 (1H, d), 8.63 (1H, d), 9.02 (1H, d). m/z (Found:553 [M+H]+, 100%. C26H32N8O4S requires 553.66).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:10]=[C:9]([NH2:18])[CH:8]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:29][C:28]([C:38]([OH:40])=O)=[N:27]1.[I-].Cl[C:43]1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:29][C:28]([C:38]([NH:18][C:9]2[CH:8]=[C:7]([C:2]3[CH:1]=[CH:6][C:5]([CH3:43])=[CH:4][CH:3]=3)[N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:10]=2)=[O:40])=[N:27]1
Reactant: Cc1ccc(-c2cc(C(=O)O)nn2C2CCCCO2)cc1
Reactant: C[n+]1ccccc1Cl
Reactant: Cc1ccccc1-c1cc(N)nn1C1CCCCO1
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(NC(=O)c3cc(-c4ccc(C)cc4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
5-Tolyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (compound A, 81 mg, 0.31 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.34 mmol), 2-chloro-1-methylpyridinium iodide (122 mg, 0.47 mmol) and N,N′-diisopropylethylamine (163 μL, 0.94 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE-EtOAc, 9:1) and gave 1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (70 mg, 43%).