Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].Br[CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>O1CCCC1>[CH:12]1[C:11]2[CH:10]([S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: BrC1c2ccccc2-c2ccccc21
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a suspension of sodium hydride (840 mg of 60% NaH in oil, 21.0 mmol) in 40 mL of tetrahydrofuran is added methyl thioglycolate (1.68 mL, 18.8 mmol). The mixture is stirred at room temperature for 20 minutes. 9-Bromofluorene (Aldrich) (5.23 g, 21.3 mmol) in 30 mL of tetrahydrofuran is added and the reaction mixture is stirred at room temperature overnight then concentrated to dryness. The residue is taken up in ethyl acetate and washed with brine, saturated aqueous sodium bicarbonate, and again with brine. The organic layer is dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel, eluting with 10% ethyl acetate in hexane to provide 908 mg (18%) of methyl (9-fluorenylthio)acetate as a colorless oil.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:31]=[CH:30][C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:13][CH:12]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][N:1]2[CH2:8][N:7]([NH:10][C:11]3[CH:31]=[CH:30][C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:13][CH:12]=3)[CH2:5][N:4]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:30][CH:31]=3)[CH2:2]2)=[CH:31][CH:30]=1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCOC(=O)c1ccc(NN2CN(Nc3ccc(C(=O)OCCCCCCCCCCCC)cc3)CN(Nc3ccc(C(=O)OCCCCCCCCCCCC)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
18.5 g of cyanuric chloride and 92 g of dodecyl p-aminobenzoate in 1,000 ml of xylene were heated at 140° C. until HCl gas was no longer evolved. After 8 hours, the reaction solution was cooled to 80° C., washed twice with saturated sodium bicarbonate solution and once with water, and then cooled to room temperature. The precipitated crystals were filtered off under suction and dried.
Reaction SMILES: C(OC1C(=O)C=COC=1[CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)C1C=CC=CC=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(O)C>[CH2:16]([O:32][C:31]1[C:18](=[O:17])[CH:23]=[CH:22][N:34]([CH2:21][CH2:20][OH:19])[C:33]=1[CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1ccoc(C(OC2CCCCO2)c2ccccc2F)c1OCc1ccccc1
Reactant: NCCO
Solvent: CCO
Product: O=c1ccn(CCO)c(C(OC2CCCCO2)c2ccccc2F)c1OCc1ccccc1

Procedure:
3-Benzyoxy-1-(2-hydroxy-ethyl)-2-[-2-fluorophenyl)-(tetrahydro-pyran-2-yloxo)-methyl]-1H-pyridin-4oone: 5.66 g of 3-benzyloxy-2-[(2-fluorophenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-pyran-4-one are boiled under reflux for 24 hours in 50 ml of ethanol and 10 ml of ethanolamine. Working-up analogously to Example 1c yields 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[(2-fluorophenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-1H-pyridin-4-one in the form of a semi-crystalline yellow mass. Rf value: 0.2 (silica gel 60, ethyl acetate/ethanol 9/1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=[CH:8][C:5]=1[NH:6][CH3:7])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=[CH:8][C:5]=1[NH:6][CH3:7]
Reactant: CCCCCCCCCCCCc1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(NC)c(N)c1
Yield: 100 %

Procedure:
A solution of 2-nitro-4-dodecyl-N-methylaniline (32 g) in ethanol (250 ml) was hydrogenated using 5% palladium on charcoal (3 g) as catalyst. The mixture was filtered and the filtrate evaporated to dryness to give 29 g of 2-amino-4-dodecyl-N-methylaniline as a dark grey waxy solid.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14](=[O:26])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16].Cl>CN(C=O)C>[Cl:12][C:9]1[CH:8]=[C:7]2[C:6]([C:5](=[O:4])[C:15]([CH3:16])([C:17]3[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[C:14](=[O:26])[NH:13]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)ccc2C1=O
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of a sodium hydride (1.5 g, 37.5 mmol, 60% in mineral oil) in dry DMF (50 mL) was added a solution of 4-chloro-2-[2-(4-nitro-phenyl)-propionyl amino]-benzoic acid methyl ester (6.4 g, 17.5 mmol) in dry DMF (20 mL) at 0° C. The reaction mixture was stirred for 30 minutes, and the reaction was qeunched by the addition of 0.5M HCl solution (100 mL). The resulting mixture was extracted with ethyl acetate (200 mL×3). The organic layer was washed with water (200 ml×2) and brine (200 ml×2), and dried over anhydrous MgSO4. After evaporation fo the solvent, the residue was purified by a flash column chromatography (n-hexane:EtOAc=5:1) to provide the objective compound (5.50 g, 95%) as pale yellow solid: 1H NMR (200 MHz, CDCl3) δ 1.93 (s, 3H, CH3), 7.00 (d, J=1.8 Hz, 1H, ArH), 7.14 (dd, J=8.4, 2.0 Hz, 1H, ArH), 7.49 (d, J=9.2 Hz, 2H, ArH), 8.18 (d, J=9.2 Hz, 2H, ArH), 11.25 (br, 1H, NH); m.p. 209-210° C.; MS(EI) m/e 330 [M+].
Reaction SMILES: Cl.[C:2](=[NH:8])([O:6][CH3:7])[CH2:3][CH2:4][CH3:5].[N:9]#[C:10]N.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>>[C:10]([N:8]=[C:2]([O:6][CH3:7])[CH2:3][CH2:4][CH3:5])#[N:9]
Reactant: N#CN
Reactant: CCCC(=N)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCCC(=NC#N)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The methyl butyrimidate salt from Example 1 (322 g, 2.34 mol) was dissolved in a 50% aqueous solution of cyanamide (236 g, 2.81 mol) and cooled in an ice-bath. Dibasic sodium phosphate (164 g, 1.15 mol) was added to the reaction mixture in portions over a period of 1 hour. The resulting suspension was stirred at room temperature for 2 hours and the liquid decanted from the reaction mixture. The remaining solid was diluted with water (2 L) and extracted with ether (3×600 mL). The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue distilled under high vacuum to afford 258 g of methyl N-cyanobutyrimidate. MS (DEI) 127 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18].Br[CH2:23][C:24]1[C:36]([F:37])=[CH:35][C:27]([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])=[C:26]([F:38])[CH:25]=1>CS(C)=O.Cl>[Cl:7][C:8]1[CH:9]=[C:10]([O:21][CH2:23][C:24]2[C:36]([F:37])=[CH:35][C:27]([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])=[C:26]([F:38])[CH:25]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: Oc1cnc(OCCC(F)(F)F)c(Cl)c1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(COc2cnc(OCCC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Potassium carbonate (61 mg, 0.229 mmol) was added to a solution of 5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-ol (Preparation 67, 45 mg, 0.19 mmol) in DMSO (2 mL) and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 5 minutes. 4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 10, 63 mg, 0.19 mmol) was then added and the resulting mixture stirred under nitrogen at room temperature for 120 hours. The reaction mixture was diluted with aqueous hydrochloric acid solution (2 M, 15 mL), extracted with EtOAc (20 mL). The organic layer was washed with aqueous hydrochloric acid solution (2 M, 2×10 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude solid was triturated with TBME/heptane (2:1), washed with heptane and dried in vacuo to yield the title compound as an off-white solid (73 mg, 74%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.2 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D52) (100 mg), ethyl 4-piperidinecarboxylate (78 mg) and acetic acid (1.428 μL) in dichloromethane (DCM) (8 mL) and N,N-dimethylformamide (DMF) (0.400 mL) stirred under nitrogen at room temperature for 20 min was added sodium triacetoxyborohydride (106 mg). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, separated between water and EA, the water phase was extracted by EA. The organic phases were concentrated in vacuo. The residue was dissolved in Isopropanol (8.00 mL) and water (0.800 mL), 20% sodium hydroxide (0.5 mL) was added, then the reaction mixture stirred at room temperature for overnight. The mixture was neutralized with acetic acid, the resulting solution was concentrated and the residue was purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E24) (40 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.14 (3H, t), 1.35 (6H, d), 1.85 (2H, m), 2.14 (2H, m), 3.01 (6H, m), 3.27 (3H, m), 3.68 (2H, m), 4.86 (1H, m), 7.36 (3H, m), 7.73 (1H, d), 8.02 (1H, dd), 8.14 (1H, d), 9.56 (1H, br s), 12.66 (1H, br s). δF (DMSO-d6, 376 MHz): −73.8. MS (ES): C27H32ClN3O3S requires 513. found 514.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH2:13]([NH:17][OH:18])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([N+:17]([O-:18])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNO
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: CCCC[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 6.7 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-n-butylhydroxylamine, the title compound was prepared in 6.7% yield as the sodium salt, m.p. 212.8° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH3:24][C:25]1([CH3:39])[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][P:28]([OH:38])(=[O:29])[O:27][CH2:26]1>C(Cl)Cl.CC(O)C.C(O)C>[OH:38][P:28]1(=[O:29])[O:30][C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]([CH3:24])([CH3:39])[CH2:26][O:27]1.[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC1(C)COP(=O)(O)O[C@@H]1c1ccccc1
Agent: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCO
Product: CC1(C)COP(=O)(O)O[C@H]1c1ccccc1
Temperature: 40 °C

Procedure:
To a solution of (±)-(cis)-7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (12.06 g, 31.65 mmol) in 120 mL of CH2Cl2, 25 mL of 2-propanol and 25 mL of ethanol at 40° C. was added a warm solution of (+)-phencyphos (3.84 g, 15.82 mmol) in 50 mL of CH2Cl2, 25 mL of 2-propanol and 25 mL of ethanol. The mixture was heated at 40° C., CH2Cl2 was carefully evaporated until a small amount of crystals was formed, and then the mixture was gradually cooled down to ambient temperature. The precipitate was filtered off and recrystallized to yield the title compound (3.94 g, 20%).
Reaction SMILES: O=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([O:19][CH3:20])=[O:18].Cl.[CH3:22][O:23][NH2:24]>N1C=CC=CC=1>[CH3:22][O:23][N:24]=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CON
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CN(C(=O)OCc2ccccc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A solution of 1-benzyl 3-methyl 4-oxopyrrolidine-1,3-dicarboxylate (12 g, 43.2 mmol) in pyridine (50 mL) at 0° C. was added O-methylhydroxylamine hydrochloride (5.51 g, 66.0 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 16 hrs. The reaction mixture was concentrated to yield a crude product which was partitioned in 300 mL of 1N HCl and 300 mL of EtOAc. The organic layer was washed with 100 mL of brine. The combined aqueous phases were extracted with 200 mL of EtOAc. The combined organic phases were dried over Na2SO4. Filtration and concentration to yield the product (12.6 g, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([N:24]2[CH2:25][CH2:26][N:21]([CH:19]([CH3:20])[CH3:18])[CH2:22][CH2:23]2)=[O:17])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3 g (12 mmol) 4-tert-butoxycarbonylamino-trans-cyclohexane carboxylic acid (commercially available), 1.74 g (14 mmol) 1-(2-propyl)-piperazine (commercially available), 4.75 g (15 mmol) TBTU and 3.64 g (36 mmol) NEt3 in 10 ml DMF was stirred for 3 h at room temperature. After evaporation the residue was washed with 1N NaHCO3 solution, extracted with DCM and the combined organic layers dried with MgSO4 and evaporated to dryness to yield 4.56 g (94%) of the title compound. MS (m/e): 354.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[NH:8][CH:7]=[N:6][C:5]=2[C:4](=S)[NH:3]1.O.[NH2:13][NH2:14]>>[NH:13]([C:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[NH:10][C:2](=[O:1])[N:3]=1)[NH2:14]
Reactant: NN
Reactant: O=c1[nH]c(=S)c2nc[nH]c2[nH]1
Solvent: O
Product: NNc1nc(=O)[nH]c2[nH]cnc12
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
2-Oxo-6-thioxo-1,2,3,6-tetrahydro-9H-purine (J. Am. Chem. Soc., 76, 5633 (1954)) (0.5 g, 2.97 mmol) was added to 80% hydrazine hydrate (5 ml), and the mixture was stirred for 10 minutes at 120° C. After completion of reaction, crystals that precipitated were collected by filtration, and washed with water. The crystals were recrystallized from water to obtain 0.31 g (yield 63%) of colorless powdery crystals (m.p.=278° C. (decomposed)).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(NC(C)C)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:26][CH2:27][CH2:28][C:29]4=[O:30])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1nnc2ccc(-c3cccc(N4CCCC4=O)c3)nn12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 2 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 400 ml of dichloromethane was added 1.7 ml of diisopropylamine and 1 ml of 4-chlorobutyryl chloride. This solution was stirred for 12 hours, then poured onto 200 ml of saturated aqueous sodium bicarbonate and extracted with 150 ml portions of dichloromethane. The combined extracts were dried and concentrated in vacuo. The residue was dissolved in 200 ml of dimethylformamide and 2.0 g of potassium carbonate was added. This solution was heated to 80° C. for 12 hours, then poured onto 200 ml of water and extracted with 150 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing the desired product were combined, concentrated in vacuo and the solid recrystalized from dichloromethane-hexane to give 1.67 g of white crystals, mp 235°-237° C.
Reaction SMILES: B(Br)(Br)Br.ClCCl.C([O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:28]([CH3:41])[C:29](=[O:40])[N:30]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=4[F:39])[C:19]=3[C:18]=2[CH:17]=1)C1C=CC=CC=1.O>FC(F)(F)C(O)=O>[F:39][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:31]=1[N:30]1[C:19]2[C:18]3[CH:17]=[C:16]([OH:15])[C:25]([O:26][CH3:27])=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:28]([CH3:41])[C:29]1=[O:40])[C:35]#[N:36]
Reactant: COc1cc2ncc3c(c2cc1OCc1ccccc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A boron tribromide solution in dichloromethane (1.0 M, 14.5 ml, 14.5 mmol) was slowly added dropwise with ice-bath cooling in a dry nitrogen atmosphere to a solution of 4-(8-benzyloxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile (1.45 g, 3.19 mmol) in trifluoroacetic acid (29 ml). When the addition was complete, the mixture were subsequently stirred for a further 30 min. When the reaction was complete (HPLC-MS check), the reaction mixture was carefully added to water (700 ml) and extracted twice with ethyl acetate (290 ml each time). The combined organic phases were washed with water (100 ml) and semi-saturated NaHCO3 solution (150 ml), subsequently dried using Na2SO4 and filtered with suction. The filtrate was evaporated in vacuo, and the residue was chromatographed over flash silica gel (solvent gradient ethyl acetate/0-33% by vol. of ethanol), giving 3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (1.10 g, 3.03 mmol), as solid. MS: 365.1 (M+H+), TLC (HPTLC): Rf=0.46 (ethyl acetate/ethanol 2:1, parts by volume).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21]([Cl:31])(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C)C=O>[ClH:31].[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 16 g. of sodium methoxide in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 17 g. of p-anisoyl chloride was added to produce 3-hydroxy-4-(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 35 g. of the acetic salt, m.p. 170°-175° C. (dec.)(uncorr.). By treating this salt in (dec.) (uncorr.), with concentrated hydrochloric acid there was obtained 28 g. of the hydrochloride salt, m.p. >235° C. (dec.) (uncorr.). When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [N:1]1([C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:29]1[C:37]2[C:32](=[CH:33][C:34]([C:8]3[C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=4)[N:9]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (290 mg, crude) in dioxane (5 mL) was added 1H-indol-5-ylboronic acid (337 mg, 2.1 mmol), K3PO4 (443 mg, 2.1 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) and water (0.5 mL). The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of CH2Cl2 (100 mL), washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 5% ethyl acetate in petroleum ether to afford methyl 2-(1H-indol-5-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (90.0 mg, 33%).