Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:27])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:15]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:27])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:36])[CH:15]=1
Reactant: COC(=O)CSCc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CS(=O)Cc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Yield: 31.1 %

Procedure:
To a solution of 0.17 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethylthio)methyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 4 ml of methylene chloride was added 0.076 g of m-chloroperbenzoic acid in portions under ice-cooling. After stirred under ice-cooling, the solvent was distilled off under reduced pressure, water was added to the residue, this was extracted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, and further washed with an aqueous saturated sodium chloride solution. After dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.055 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethylsulfinyl)methyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (77a)] as a yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([CH3:44])=[CH:39][N:38]=1>O>[CH3:43][C:42]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=2)=[N:38][CH:39]=[C:40]([CH3:44])[CH:41]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: Cc1cnc(CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ncc(C)cc4C)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.0 g, 9.6 mmol) was added to a mixture of cesium carbonate (12.6 g, 38.6 mmol) and DMF (1000 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (2.25 g, 14.5 mmol) was added. The reaction mixture was heated for 4 h at 80° C. (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.2 g, 65.3%,) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.2 (s, 1H), 7.65 (d, 2H), 7.45 (s, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=430.4. HPLC (96.3%, Condition-A).
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([OH:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O.CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=2)[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a single necked round bottomed flask (500 mL) fitted with N2(g) balloon, Methyl 3-benzyloxy-5-hydroxybenzoate (Intermediate 5) (24 g, 93 mmol, 1 equiv.) followed by DMF (130 mL, 5 v/w) were added. To this stirring solution, potassium carbonate (38 g, 279 mmol, 3 equiv.) was added at room temperature. The mixture was stirred at the same temperature for 10 minutes. 4-Fluorobenzaldehyde (13.84 g, 111.62 mmol, 1.2 equiv.) was added. The reaction mixture was heated at 90° C. for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction was diluted with water and extracted with ethyl acetate. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate to furnish title compound as thick yellow liquid (32.5 g). The product can be purified by column chromatography by eluting with 10% ethyl acetate:pet ether as mobile phase.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][C:43]1=[O:55]>C(Cl)Cl>[Cl:8][C:9]1[C:10]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][C:43]2=[O:55])=[CH:11][C:12]([C:40]#[N:41])=[CH:13][C:14]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:33][CH2:34]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)CC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate (85 mg, 0.127 mmol) in DCM (4 mL) and the reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated and the crude was dried under vacuum for 10 min. The crude was dissolved in MeOH and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated and purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) as a light yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>ClCCl>[CH3:34][O:33][C:31]1[CH:30]=[C:27]([CH:28]2[O:4][CH2:1][CH2:2][O:3]2)[CH:26]=[C:25]([O:24][CH3:23])[CH:32]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Product: COc1cc(OC)cc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
4.2 ml of ethylene glycol, 4.1 ml of trimethyl orthoformate and 5 mg of p-toluenesulfonic acid are added to a solution of 5 g of 3,5 dimethoxy benzaldehyde in 100 ml of dichloromethane. It is allowed to stir for 20 more hours at 25° C. Then, it is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography. 5.67 g of product is obtained.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[N:8][CH:9]=1>O1CCCC1.O.[Na]>[Br:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:8][CH:9]=1
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)Nc1cnc(Br)cn1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Lithium hydroxide (0.058 g, 1.0 eq.) was added at room temperature to a solution of methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (Example II, 0.400 g, 1.0 eq.) in a mixture of tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at room temperature. The residue was diluted with a saturated solution of sodium hydrogenocarbonate and washed with ethyl acetate. The aqueous phase was acidified by addition of aqueous hydrochloric acid (concentrated) and extracted twice with ethyl acetate. The combined organic layer was dried on magnesium sulfate and concentrated under vacuum to give the desired compound 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoic acid A3 (0.343 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (bs, 1H), 11.02 (s, 1H), 9.12 (s, 1H), 8.60 (s, 1H), 2.67 (t, 2H), 2.55 (m, 2H) ppm. LC-MS (Method A): RT 1.08, 274 (M−H+)
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH:14]=[C:13](F)[CH:12]=1.O>CN(C=O)C>[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])[CH:14]=[C:13]([S:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[CH:12]=1
Reactant: OC(c1cc(F)cc(F)c1)(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
2-Trimethylsilylethane thiol (2.9 g, 21.9 mmol) was added dropwise to a suspension of NaH (1.8 g, 43.8 mmol) in dry DMF (60 mL) and stirred for 20 min. Then 1,3-difluoro-5-(hexafluoro-2-hydroxyprop-2-yl)benzene (Step 1 ) was added in dry DMF and the resulting reaction mixture was heated at 70° C. for 16 h. The reaction mixture was then added carefully to H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a residue which was chromatographed on silica gel, eluting with 95:5 mixture of hexane:EtOAc to afford the title compound (3.2 g, 55%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[NH:7].[Cl:9][C:10]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15]>>[NH2:17][CH2:16][C:13]1[C:14]([NH2:15])=[N:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][C:12]=1[C:11]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:10]=1[Cl:9]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cccs1
Product: NCc1c(N)nc(-c2cccs2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=351.2 (M+H+), was prepared from thiophene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 183.7 %

Procedure:
To a solution of 7-(5-chloro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) and aminoguanidine hydrochloride (0.44 g) in ethanol (30 ml) were added a concentrated hydrochloric acid (0.83 ml) and water (0.83 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated. And precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-methoxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 166) (1.2 g) as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:24]2[C@@H:28]3[O:29][C:30]([CH3:33])([CH3:32])[O:31][C@@H:27]3[C@@H:26]([C:34](O)=[O:35])[O:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:45]1[CH:49]=[CH:48]N=C1)=O.C(N)C.O>O1CCCC1>[CH2:49]([NH:45][C:34]([C@@H:26]1[C@H:27]2[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@H:28]2[C@H:24]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:25]1)=[O:35])[CH3:48]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](C(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OCC)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 15 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (3aS,4S,6R,6aR)-6-[6-[(2,2-diphenylethyl)amino]-2-(ethoxycarbonyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (Preparations 67 and 68) (20.0 g, 0.0349 moles) in anhydrous tetrahydrofuran (100 ml) under an atmosphere of nitrogen was added 1,1′-carbonyldiimidazole (6.80 g, 0.0418 moles) and the resultant mixture was stirred at ambient temperature for 1.5 hours. To this solution was then added a solution of ethylamine in tetrahydrofuran (24.4 ml of a 2M solution, 0.0488 moles) with cooling at 15° C., and the resultant mixture was then stirred at ambient temperature for 2 hours. To the mixture was added more of a solution of ethylamine in tetrahydrofuran (3.5 ml of a 2M solution, 0.0007 moles) and stirring was continued for an additional 2 hours after which time deionised water (10 ml) was added. The resultant mixture was concentrated in vacuo and the residue was then partitioned between ethyl acetate (200 ml) and aqueous citric acid (200 ml of a 0.5M solution). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The organic phases were combined and were washed successively with deionised water (200 ml), saturated aqueous sodium bicarbonate solution (200 ml) and saturated brine (200 ml), and were subsequently dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude product as a cream coloured foam (20.22 g). The crude product was purified by flash chromatography on silica gel (700 g) eluting with a gradient system of 65% v/v ethyl acetate in heptane changing to 80% v/v ethyl acetate in heptane changing to ethyl acetate, to give the title compound (16.55 g) as a colourless foam.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][CH2:25][OH:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:26][CH2:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCCc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-phenylethanol, there is obtained 2-phenylethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 342 (18), 237 (71), 194 (100), 105 (18);
Reaction SMILES: C([NH:8][OH:9])(OC(C)(C)C)=O.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.Cl>C1COCC1.C(OCC)C>[NH2:8][O:9][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CON)cc1
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry THF (60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7 mmol) was then added and the suspension stirred. A catalytic amount of KI was then added to the reaction prior to the cautious addition of 4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was then allowed to stir overnight before removal of solvent in vacuo. The residue was taken up with diethyl ether (100 ml) and HCl gas bubbled in for 20 minutes, causing the start of precipitation of the product. The flask was stoppered and left to stand overnight. The product was then filtered off as a off-white wax (39–52% yield according to varying batches).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.37 min.; [M+H]+: 437.10 g/mol.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][CH:4]([CH3:9])[S:3]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:6]1[CH2:7][CH:2]([CH3:1])[S:3][CH:4]([CH3:9])[CH2:5]1
Reactant: CC1CC(=O)CC(C)S1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CC(C)SC(C)C3)c[nH]c12
Temperature: 0 °C
Yield: 26.3 %

Procedure:
2,6-Dimethyltetrahydro-4H-thiopyran-4-one (0.293 g, 2.03 mmol) was dissolved in dichloromethane (35 mL) in an oven dried flask containing 3 Å molecular sieves and stirred under argon at 0° C. TMS-OTf (0.451 g, 2.03 mmol, 0.36 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (0.293 g, 2.031 mmol) was dissolved in DCM (10 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 3 hours between 0 and 10° C. The reaction was cooled to 0° C. and triethylsilane (0.353 g, 0.485 mL, 3.04 mmol) was then added all at once and the reaction was stirred at room temperature overnight. The reaction was then quenched with a saturated sodium bicarbonate solution, filtered, then extracted with DCM. The combined organics were washed with water. The combined aqueous layers were back-extracted with DCM. The combined organics were washed with brine, dried with MgSO4, and concentrated. The crude compound was purified on Combiflash silica column with 0-30% EA/DCM to give 0.212 g (26%) of the title compound.
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:14])[CH2:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH:1](=[C:8]1/[C:9]([O:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: O=C1CC(=O)/C(=C/c2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)OC1=CC(=O)N/C1=C\c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 67.0 g of (Z)-5-benzylidene pyrrolidin-2,4-dione cooled to 0° C. in 670 ml of dichloromethane, 40.0 g of butyryl chloride and then 47.1 g of triethyl amine were added and the mixture was stirred another 5 minutes at 0° C. Then the mixture washed twice with 200 ml of 5 percent NaHCO3 solution each and then twice with 200 ml of 0.5M hydrochloric acid each. The aqueous phases were extracted separately with dichloromethane. The combined organic phases were dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue was recrystallized from 230 ml of toluene. The yield of the title compound was 67.25 g (73 percent of theory). The title compound had a melting point of 139.8° to 141.5° C. Other data concerning the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[CH2:12]O.O=S(Cl)[Cl:16]>>[Cl:1][C:2]1[C:3]([CH2:12][Cl:16])=[CH:4][N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: OCc1cnc(C(F)(F)F)cc1Cl
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1cc(Cl)c(CCl)cn1
Yield: 87 %

Procedure:
[4-Chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (Int-12) (90 g, 0.426 mol) was added to SOCl2 (700 mL) slowly with ice bath, the mixture was refluxed for 1 hour. The mixture was concentrated and the residue was poured into water (1 L). The mixture was adjusted to pH=7-8 with solid NaHCO3. The mixture was extracted with ethyl acetate (500 mL*3). The combined organic layer was concentrated to yield 4-chloro-5-(chloromethyl)-2-(trifluoromethyl)pyridine (Int-13) (80 g, 87%) as brown syrup which was used for the next step without further purification.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:11]([C@@H:12]3[O:18][C@H:15]([CH2:16][OH:17])[C@@H:14]([N:19]=[N+:20]=[N-:21])[CH2:13]3)[C:10]2=[O:27])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:11]([C@@H:12]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:14]([N:19]=[N+:20]=[N-:21])[CH2:13]2)[C:10]1=[O:27]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN)c1=O

Procedure:
A solution of approximately 0.5 mmole 3-PHT-P AZT (Example 26) in methanol was treated with 50 ul hydrazine hydrate and incubated overnight at room temperature. The resulting suspension was filtered through a 0.45 um PTFE membrane and the filtrate chromatographed by preparative TLC on silica gel-F 2000 um using the solvent system CHCl3 /MeOH/15M NH4OH (85+15+1). The major band (Rf =0.27; UV positive; ninhydrin positive)was well separated from 3-PHT-P-AZT (Rf =0.78; UV positive; ninhydrin negative) and from hydrazine (Rf =0.0; UV negative; ninhydrin postive). The product was eluted with MeOH. It was found to be immunologically active in an AZT assay by FPIA, was homogeneous on analytical TLC and its UV spectrum resembled that of a 3-alkylated AZT derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH3:19][O:20][CH2:21][CH2:22][C:23](Cl)=O>>[Br:18][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[C:23]([CH2:22][CH2:21][O:20][CH3:19])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Product: COCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Yield: 37.6 %

Procedure:
The method described in Part A of Example 9 was used to react 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (29.0 g, 93.5 mmol) with 3-methoxypropionyl chloride (11.5 g, 93.5 mmol). The crude product was recrystallized from 2:1 ethyl acetate:hexane and then purified by flash column chromatography on silica gel (eluting sequentially with 60:40 acetone:toluene and acetone). The resulting solid was recystallized from 3:1 ethyl acetate hexane to provide 13.3 g of 1-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as translucent crystals.