Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH2:10][CH2:9]3)=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH2:10][CH2:9]3)#[N:1]
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(C(N)=O)C2
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(C#N)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
The compound obtained in Example 259 (0.47 g, 1.9 mmol) was dissolved in methylene chloride (40 ml) and pyridine (0.64 ml, 8 mmol). To the obtained solution, trifluoroacetic anhydride (0.56 ml, 4 mmol) was added dropwise while cooling in an ice--water bath, and the mixture was stirred at 0° C. for 1.5 hours. Pyridine (0.64 ml, 8 mmol) and trifluoroacetic anhydride (0.56 ml, 4 mmol) were further added, and stirring was continued at 0° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. To the resultant residue, saturated ammonia--methanol (30 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure. The residue was combined with chloroform, and extracted. The organic phase was washed with water, aqueous 5% potassium hydrogensulfate, saturated aqueous sodium bicarbonate solution, and saturated aqueous NaCl solution in this order, and dries over magnesium sulfate. The solvent was reduced under reduced pressure, and the residue was subjected to silica gel column chromatography for separation and purification. As a result, 0.41 g of the title compound was obtained as pale yellow powder (94%).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH:15][C:16]1[C:25]2[C:24]3[CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29][C:23]=3[C:22](=[O:31])[O:21][C:20]=2[CH:19]=[C:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=1.Cl>C1C=CC=CC=1>[OH:31][CH2:22][C:23]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][C:24]=1[C:25]1[C:16]([OH:15])=[CH:17][C:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:19][C:20]=1[OH:21]
Reactant: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)CCC(C)C3
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: c1ccccc1
Product: CCCCCc1cc(O)c(C2=C(CO)CCC(C)C2)c(O)c1
Temperature: 25 °C

Procedure:
A solution of 90 ml. of a seventy percent solution of sodium bis(2-methoxyethoxy)aluminum hydride in 80 ml. of benzene was cooled in an ice-water bath and stirred while a suspension of 13.0 g. of 1-hydroxy-3-n-pentyl-6-oxo-9-methyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran in 220 ml. of benzene was added portion-wise over 15 minutes. The reaction mixture was warmed to about 25° C. and stirred for 2 hours. The reaction mixture was again cooled in an ice-water bath and stirred while 800 ml. of 10 percent aqueous hydrochloric acid solution was added. The aqueous acidic reaction mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent under reduced pressure provided 2-(2-hydroxymethyl-5-methyl-1-cyclohexenyl)-5-n-pentyl-resorcinol as a white crystalline solid. M.P. 109°-11° C.
Reaction SMILES: [OH:1][CH:2]([C:30]1[O:31][C:32]([CH2:35][O:36][CH3:37])=[N:33][N:34]=1)[CH:3]([NH:6][C:7](=[O:29])[CH:8]([CH2:18][S:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:20])[CH2:9][C:10](=[O:17])[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[CH3:37][O:36][CH2:35][C:32]1[O:31][C:30]([C:2]([CH:3]([NH:6][C:7](=[O:29])[CH:8]([CH2:18][S:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH2:9][C:10](=[O:17])[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:4][CH3:5])=[O:1])=[N:34][N:33]=1
Reactant: CCC(NC(=O)C(CC(=O)N1CCCCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(COC)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCCCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nnc(COC)o1
Reaction time: 1 h

Procedure:
The amide then was treated with Dess-Martin periodinane (180 mg, 0.364 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 26 mgs of N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide; H1 NMR(CDCl3): 8, 7.7(1H, d,d, NH, diastereomeric), 7.4–7.2(5H, m), 5.3–5.1(1H, m), 4.6(2H, s, OCH2), 4.3–4.1(3H, m), 3.8–3.2(9H, m), 3–2.4(2H, m), 2.2–1.4(8H, m), 0.95(3H, t); MS: 535.7(M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:41])=O>ClCCl>[CH3:1][C:2]1[C:3]([S:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:41])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1Sc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: Cc1cc2c(cc1Sc1ccc(C(=O)Cl)cc1)C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
A solution of 1.4 g (4 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid in 100 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 900 μl (4.4 mmol) of dicyclohexylamine were added and the mixture was stirred for one hour. Next, 320 μl (4.4 mmol) of thionyl chloride were added and the mixture was stirred for one hour. The reaction medium was evaporated to dryness, taken up in anhydrous ethyl ether, the dicyclohexylamine salt filtered off and the filtrate evaporated. 1.5 g (100%) of the crude acid chloride was recovered which was used as such in the continuation of the synthesis to follow.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=O)[CH2:7][O:6][C@@H:5]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH2:12][CH2:13][CH2:14][C@@H:4]12)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>O1CCCC1.CCOCC.C(O)(C)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[CH2:1]([N:3]1[CH2:8][CH2:7][O:6][C@@H:5]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH2:12][CH2:13][CH2:14][C@@H:4]12)[CH3:2]
Reactant: CCN1C(=O)CO[C@@H]2c3ccccc3CCC[C@H]21
Agent: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1CCO[C@@H]2c3ccccc3CCC[C@H]21

Procedure:
The 1,4-oxazin-3-one from Step B was dissolved in 50 ml of tetrahydrofuran and added dropwise to 0.3 g (0.008 m) of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture was heated at reflux temperature for one hour, cooled and treated with sufficient saturated aqueous sodium sulfate solution to quench excess lithium aluminum hydride. The mixture was filtered and concentrated to dryness in vacuo. The residue was dissolved in methylene chloride, dried (Na2SO4), and concentrated to dryness in vacuo to a residue of crude product (2.1 g, 81%). The maleate salt was prepared by treating with a stoichiometric amount of maleic acid in a minimum of warm isopropanol and adding ether to the cooled solution to incipient cloudiness. After precipitation was complete the salt was collected and recrystallized from benzene to give trans-4-ethyl-2,3,4,4a,5,6,7,11b-octahydrobenzo[6,7]cyclohept[1,2-b]-1,4-oxazine hydrogen maleate, m.p. 132°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:13]([NH2:16])[CH2:14][CH3:15]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](=[O:11])(=[O:10])[NH:16][CH2:13][CH2:14][CH3:15]
Reactant: CCCN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CCCCO
Product: CCCNS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorobenzenesulphonyl chloride (500 mg 2.1 mmol) and 1-propylamine (0.2 ml, 2.4 mmol) in n-butanol (10 ml) was heated at reflux for 48 hours. The volatiles were removed by evaporation and the residue triturated with diethylene ether and the product collected by filtration to give the title compound. NMR: 0.78 (t, 3H), 1.35 (q, 2H), 2.79 (t, 2H), 7.60 (dd, 1H), 7.84 (d, 1H), 7.92 (d, 2H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]Cl>CC(C)=O>[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][S:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Sc1nccs1
Reactant: FC(F)(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(Cl)CCCSc1nccs1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Solid anhydrous potassium carbonate (9.33 g) was added in two portions to a stirred mixture of 2-mercaptothiazole (7.90 g), 1,4-dichloro- 1,1-difluorobutane (9.70 g) and acetone (150 ml) under a nitrogen atmosphere, and the resultant mixture heated at the reflux temperature for 4 hours. After cooling to the ambient temperature the solid component was removed by filtration and washed with acetone (2×50 ml) and the combined washings and filtrate concentrated by evaporation of the solvent under reduced pressure. Diethyl ether (150 ml) was added to the residue and the resultant solution washed with aqueous potassium carbonate solution (2×100 ml) and with water (100 ml). After drying over anhydrous magnesium sulfate the solution was concentrated by removal of the solvent by evaporation under reduced pressure to yield 2-(4-chloro-4,4-difluorobutylthio)thiazole (13.98 g, 94%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[F:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: FC1CCNC1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(F)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3-fluoropyrrolidine (27 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 25-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (31 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 2.02-2.45 (m, 2 H) 3.86-4.02 (m, 1 H) 4.05-4.47 (m, 3 H) 5.35-5.64 (m, 1 H) 6.26 (s, 1 H) 7.01 (br. s., 1 H) 7.60 (d, J=8.34 Hz, 2 H) 7.88-8.10 (m, 3 H) 10.80 (br. s., 1 H). ESI-MS: m/z 384.2 (M+H)+.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CC(O)=O.[Si]([O:30][CH2:31][C@@H:32]1[O:38][C@@H:37]2[N:34]([C:35](=[O:39])[CH2:36]2)[CH2:33]1)(C(C)(C)C)(C)C.CCCCCC.C(OCC)(=O)C>C1COCC1>[OH:30][CH2:31][C@@H:32]1[O:38][C@@H:37]2[N:34]([C:35](=[O:39])[CH2:36]2)[CH2:33]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN2C(=O)C[C@@H]2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1C[C@@H]2O[C@@H](CO)CN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A THF solution of 1N Bu4NF (2.71 ml, 2.71 mmole) containing AcOH (90 mg, 1.5 mmole) was added to a solution of ref. compound 1A (465 mg, 1.81 mmole) in THF (5 ml) at 0-5° C. The mixture was stirred at room temperature for 2 hrs, then poured into a silica gel column. The column was eluented with hexane-ethyl acetate (1:2) and 250 mg of title compound was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][NH2:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][NH:12][C:21](=[O:22])[O:23][CH3:24]
Reactant: COC(=O)Cl
Reactant: COc1cc(Cl)c(Cl)c(CN)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(OC)cc(Cl)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A stirred solution of 54.0 grams (0.262 mole) of 2,3-dichloro-5-methoxy-phenylmethylamine and 27.0 grams (0.267 mole) of triethylamine in 1000 mL of THF was cooled below 5° C., and 24.8 grams (0.262 mole) of methyl chloroformate was added dropwise at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of addition, the reaction mixture was stirred at about 5° C. for one hour, then it was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time thin layer chromatographic (TLC) analysis of the reaction mixture indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to a residue, which was then shaken with ethyl acetate and water. The aqueous layer was washed with ethyl acetate, and the wash was combined with the original organic layer. The combination was then washed with one portion of water and one portion of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 66.0 grams (95.3% yield) of the subject compound, mp 90°-91° C. (99% pure by gas chromatographic (GC) analysis). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:19])[C:7]=1[CH2:20]Br)=[O:5])[CH3:2].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:19])[C:7]=1[CH2:20][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:5])[CH3:2]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
A mixture of 1-benzyl-3-bromomethyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid ethyl ester (270 mg, 0.77 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (210 mg, 0.85 mmol), sodium iodide (219 mg, 1.54 mmol) and potassium carbonate (213 mg, 1.54 mmol) in DMF (7 mL) was stirred at r.t. for 16 h. EtOAc (40 mL) and brine (10 mL) were added, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-70% EtOAc/hexanes) to give 232 mg of the title compound as a yellow oil. MS: (+) m/z 513.19 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH3:39][N:40](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:39]#[N:40])=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:29])[F:31])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Yield: 82 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1 (2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (209.5 mg, 0.352 mmol), zinc cyanide (62.0 mg, 0.528 mmol), tetrakis(triphenylphosphine)palladium (0) (40.7 mg, 0.0352 mmol) and N,N-dimethylformamide (1.5 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (136.1 mg, 0.288 mmol, 82%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:44][N:45]([CH2:47][CH2:48][NH2:49])[CH3:46].[Cl-].[NH4+]>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:18]=[C:17]([NH:49][CH2:48][CH2:47][N:45]([CH3:46])[CH3:44])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCOC1CCCCO1
Reactant: CN(C)CCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NCCN(C)C)nc1OCCOC1CCCCO1

Procedure:
##STR143## (1) A mixture of 4-tert-butyl-N-{5-(2-methoxyphenoxy)-2-methylsulfonyl-6-[2-(tetrahydropyran-2-yloxy)ethoxy]pyrimidin-4-yl}benzenesulfonamide obtained in Reference Example 10-(2) (200 mg), dimethylaminoethylamine (138.8 mg) and dimethylsulfoxide (1 ml) is reacted at 100° C. for 15 hours, and then reacted at 120° C. for five hours. The reaction mixture is treated with ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure. The residue is purified by preparative silica gel thin layer chromatography (solvent; chloroform:methanol=10:1) to give 4-tert-butyl-N-{2-(2-(N,N-dimethylamino)-ethylamino)-5-(2-methoxyphenoxy)-6-[2-(tetrahydropyran-2-yloxy)ethoxy]-pyrimidin-4-yl}benzenesulfonamide (99.7 mg) as a crystal.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([CH3:36])[NH:30][C:29]3=[O:37])[CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([O:1][CH2:2][CH:3]([NH:13][C:14](=[O:38])[C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH2:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([CH3:36])[NH:30][C:29]3=[O:37])[CH2:22][C:23]#[CH:24])=[CH:19][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)(=[O:41])[CH3:40]
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NC(CO)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(=O)OC(C)=O
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NC(COC(C)=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 4, N-[2-hydroxy-1-(3-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide was reacted with acetic anhydride to give N-[2-acetoxy-1-(3-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (containing 2 equivalents of water) in 56% yield, m.p. 133°-135° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)(=[O:4])[NH:2][NH2:3].[CH3:24][C:25]1([CH3:41])[CH2:30][CH:29]([NH:31][C:32](=[O:38])[C:33](OCC)=[O:34])[CH2:28][C:27]([CH3:40])([CH3:39])[NH:26]1>CO>[CH3:24][C:25]1([CH3:41])[CH2:30][CH:29]([NH:31][C:32](=[O:38])[C:33]([NH:3][NH:2][C:1]([O:5][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:23])[CH:10]=2)=[O:4])=[O:34])[CH2:28][C:27]([CH3:40])([CH3:39])[NH:26]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: NNC(=O)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)OCCOc2ccc(C(=O)c3ccccc3)c(O)c2)CC(C)(C)N1
Temperature: 70 °C

Procedure:
Into a 100 ml 3-neck flask was added 6.4 grams (0.027 mole) of 2-(3-hydroxy-4-benzoylphenoxy)ethyl carbazate from (A), 8.1 grams (0,027 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate and 25 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with a reflux condenser. The reaction was heated in an oil bath and the methanol was slowly distilled off through the Dean Stark trap. After the methanol stopped coming over, the reaction was heated one hour, a vacuum was applied to the system to remove any residual methanol and the reaction was heated for another 11/2 hours at 70° C. The reaction was dissolved in 50 ml of hot methanol. The solution was filtered to remove a small amount of insoluble material. The methanol was stripped from the filtrate on a rotating evaporator, leaving 9.4 grams of a yellow crystalline solid. Liquid chromatography indicated the product was about 85-90% pure.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:29][OH:30]>>[OH:30][CH2:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: OC[C@@H]1CCCCN1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCC[C@@H]1CO

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-2ylmethanol (1.2 equiv) to give 162 (12.1 mg, M+1 411.1)