Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:38]=[CH:37][C:6]2[O:7][C:8](C)(C)[CH:9]=[C:10](N3C=CC(C(OC(OC4C=CC=CC=4)=S)CC(OCC)=O)=CC3=O)[C:5]=2[CH:4]=1)#N.N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH:9]=[CH:10][C:5]2[CH:4]=[CH:3][CH:38]=[CH:37][C:6]1=2
Reactant: CCOC(=O)CC(OC(=S)Oc1ccccc1)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2OC1

Procedure:
In 3 ml of anhydrous toluene, is dissolved 73 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-2-ethoxycarbonylethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 32. Then, 45 mg of 2,2'-azobisisobutyronitrile and 80 mg of tri-n-butyltin hydride are added to the solution at room temperature, and the resulting mixture is reacted at 100° C. for 30 minutes. After the reaction, the reaction mixture is directly purified by silica gel column chromatography to obtain 42 mg of 6-cyano-2,2-dimethyl-4-}-1,2-dihydro-2-oxo-4-(2-ethoxycarbonylethyl)-1pyridinyl}-2H-benzo[b]pyran.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]([N:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH:22]1[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=1[C:19]([N:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[O:20]
Reactant: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1N)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1NCc1ccco1)C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.9 %

Procedure:
2-Furaldehyde (0.20 g) and tert-butyl 3-[{[2-amino-4-(trifluoromethyl)phenyl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (0.33 g) were dissolved in acetic acid (5.0 ml), sodium triacetoxyborohydride (0.31 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10→10:0) was concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred for 30 min. The reaction mixture was concentrated and purified by HPLC to give the object compound (12.2 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:40])[C:5]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=1)([CH3:39])[CH2:6][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1cccc(C(F)(F)F)c1)C(OC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C(F)(F)F)c1
Reaction time: 20 h

Procedure:
3-(4-Benzyloxyphenyl)-2-methyl-3-(2,2,2-trifluoroacetoxy)-2-(3-trifluoromethylphenoxy)-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[O:17])[CH:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[NH2:15][C:14]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C#N)C(Cc1ccc(Cl)cc1)C(=O)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(N)oc(-c2cccc(Cl)c2)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A solution of ethyl 3-(4-chlorobenzyl)-4-(3-chlorophenyl)-2-cyano-4-oxobutanoate (1.945 g, 5 mmol) in TFA (20 mL) was stirred at 100° C. for 3 h. The reaction was cooled to RT and concentrated to a residue which was diluted with EA (40 mL) and water (8 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give ethyl 2-amino-4-(4-chlorobenzyl)-5-(3-chlorophenyl)furan-3-carboxylate (1.4 g, 72% yield) as a white solid. LCMS: MH+ 390 and TR=2.503 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:11][C:12](=[O:28])[C@@H:13]([NH:17][C:18]([O:20]CC1C=CC=CC=1)=O)[CH:14]([CH3:16])[CH3:15])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.COC([C@@H:34]1[CH2:38][C@H:37]([O:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[N:43]=[C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH:41]=2)[CH2:36][C@H:35]1[C:58](=[O:71])[NH:59][C@H:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:61][CH2:62][CH3:63])=O.[Li+].[OH-].Cl>C(O)C.O1CCOCC1.O.[Pd]>[C:67]([O:66][C:64](=[O:65])[C@@H:60]([NH:59][C:58]([C@@H:35]1[CH2:36][C@@H:37]([O:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[N:43]=[C:42]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH:41]=2)[CH2:38][C@H:34]1[C:18](=[O:20])[NH:17][C@H:13]([C:12](=[O:28])[NH:11][C@@H:4]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[C:3]([O:2][CH3:1])=[O:29])[CH:14]([CH3:15])[CH3:16])=[O:71])[CH2:61][CH2:62][CH3:63])([CH3:68])([CH3:69])[CH3:70]
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCC1
Agent: [Pd]
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C1CCCCC1)C(C)C)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of 55 (40 mg, 0.099 mmol) in ethanol (95%) (7.5 mL) was added palladium on active carbon (10%, 40 mg) and the mixture was hydrogenated under pressure at room temperature for 2 h. The mixture was filtered through celite and evaporated. Compound 43 (38 mg, 0.083 mmol) was dissolved in dioxane/H2O 1:1 (3 mL) and the mixture was cooled to 0° C. before 1 M LiOH (140 μL, 0.140 mmol) was added to the stirred solution. After 1 h the mixture was neutralized with 1 M hydrochloric acid and the solvent was evaporated and co-evaporated with toluene. The residue was coupled to deprotected 55 using the same HATU coupling conditions as in the synthesis of compound 48. Purification by HPLC (MeOH/H2O 90:10 with 0.2% triethylamine) gave 56 (56 mg, 88%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:28]=[C:25]([CH3:26])[N:27]=[CH:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.6 g (0.005 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol was stirred at room temperature, under argon, and treated with 0.8 g (0.015 mol) of sodium methylate in one portion. After stirring for 10 min, 30 ml of methylene chloride was added and stirring was continued. Another 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.015 mol of sodium methylate and 0.0075 mol of acetamidine hydrochloride was repeated after another 2 hr and stirring at room temperature was continued overnight. After diluting with 50 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization occurred when the residue was dissolved in 20 ml of warm hexane and cooled. Evaporation of the solvent gave a second crop of product. Recrystallization from hexane (charcoal) gave off-white crystals: mp 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12](=[O:25])[C:11]([C:26]([O:28]CC)=O)=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1Cl)[NH2:35].FC1C=CC(N)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12](=[O:25])[C:11]([C:26]([NH2:35])=[O:28])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Nc1ccc(F)cc1
Product: NC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)c2cc(-c3ccncc3)ccc2c1=O

Procedure:
The starting acid was prepared by hydrolysis of ethyl 1-(3,4-dichlorophenyl)-1,4-dihydro-4-oxo-7-(4- pyridinyl)-3-quinolinecarboxylate (tan solid, m.p. 238°-240 ° C. when recrystallized from toluene), in turn prepared according to the procedures of Example 1, parts (e) and (f), substituting 3,4-dichloroaniline for the 4-fluoroaniline of part (e).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].Cl.O>C(O)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:12]=[C:11]([CH:22]([C:23]([F:25])([F:26])[F:24])[OH:27])[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nc(C(=O)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(C(O)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3.8 g (10 mmoles) of the compound of Example 9 in 50 ml ethanol chilled to 0°-5°, was added 1.0 g (25 mmoles) sodium borohydride all at once. After 0.5 hour at that temperature, the cooling was discontinued, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was then chilled to 0°-10° C., and 40 ml of 2 N HCl was cautiously added, followed by another 40 ml of water. Most of the ethanol was removed under vacuo. The crystalline product was collected by filtration, washed with water, and air dried. Recrystallization from acetonitrile yielded 3.9 of the title compound, m.p. 242°-245°. The infrared and NMR spectra were consistent with the assigned structure.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2(O)[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CO.[OH-].[Pd+2].[OH-]>[CH:18]1([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]=3[OH:8])=[CH:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OC1(c2ccc(Cc3ccccc3OCc3ccccc3)cc2)CCCC1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: Oc1ccccc1Cc1ccc(C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of 1-[4-(2-benzyloxybenzyl)phenyl]-cyclopentanol (1.14 g, 3.19 mmol) in methanol (21 mL), a 20% palladium hydroxide catalyst (114 mg) was added, and furthermore 36% HCl (0.255 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere overnight, and then cooled to 0° C., potassium carbonate (425 mg) was added thereto and the mixture was stirred for 20 minutes, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (744 mg, 92%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6].[BrH:14].C(O)(=O)C>>[BrH:14].[CH3:7][N:5]([CH2:4][C:3]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=1[F:1])[CH3:6]
Reactant: COc1ccc(F)c(CN(C)C)c1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)Cc1cc(O)ccc1F
Yield: 69 %

Procedure:
(2-Fluoro-5-methoxybenzyl)-dimethylamine (1.51 g, 8.24 mmol) was heated to reflux in 30% hydrogen bromide/acetic acid (10 mL) for 17 h. The cooled reaction mixture was triturated and decanted with successive portions of diethyl ether (4×), then triturated with diethyl ether overnight. The solid was collected by filtration, washed with ether and dried to give 3-dimethylaminomethyl-4-fluorophenol hydrobromide (1.43 g, 69%) as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:34])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:33][C:29]1[CH:28]=[C:27]([C:25]2[CH2:24][C:23](=[O:34])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(I)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Yield: 78.2 %

Procedure:
Prepared from {2-[3-(3-iodo-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K7) (871 mg, 1.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (542 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:18][CH2:17][CH2:16]2)[C:8]1=O.O>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:18][CH2:17][CH2:16]2)[CH2:8]1
Reactant: O=C1Nc2ccccc2C12CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCC21CCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 0.60 mL (0.60 mmol) of a 1M solution of lithium aluminium hydride in THF was added dropwise to 100 mg (0.58 mmol) spiro[cyclobutan-1,3′-indolin]-2′-one in 20 mL THF. Then the reaction mixture was stirred for 1 h at 65° C. After cooling 1 mL water was added and the mixture was stirred for 10 min. The organic phase was dried on sodium sulphate and evaporated down. The product was reacted without further purification.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)[CH:6]=[N:7][CH:8]=1.[C:21]1([O:27]C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:21][O:27][N:9]1[C:5]2[C:6](=[N:7][CH:8]=[CH:3][CH:4]=2)[C:16](=[O:17])[CH:11]=[CH:10]1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: COc1cncc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Solvent: CCCCCC
Product: COn1ccc(=O)c2ncccc21
Temperature: 245 °C

Procedure:
A two-necked round bottomed flask equipped with an air condenser was charged with 5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (18 g) and diphenyl ether (180 mL). The reaction mixture was heated at 240-250° C. for 5 min under N2 atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtain product as a brown solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([CH3:16])[CH:9]=1)=[O:7]>>[CH:6]([C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:2])=[C:10]([CH3:16])[CH:9]=1)=[O:7]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C=O)ccc1C#N
Product: Cc1cc(C=O)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 108 h

Procedure:
In 0.40 g of 4-formyl-2-methylbenzonitrile, 7 mL of concentrated sulfuric acid was added, and stirred at room temperature for 4.5 days. After the completion of the reaction, the reaction mixture was poured in 20 mL of ice water, extracted with ethyl acetate (15 mL×2). The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with 5 mL of diisopropyl ether to obtain 0.26 g of the aimed product as white crystal.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[NH:2][NH2:3].C(OCC)(=O)NN.[C:19](Cl)([Cl:21])=[O:20]>ClCCl>[O:5]([C:1]([NH:2][NH:3][C:19]([Cl:21])=[O:20])=[O:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)Oc1ccccc1
Agent: CCOC(=O)NN
Solvent: ClCCl
Product: O=C(Cl)NNC(=O)Oc1ccccc1

Procedure:
Example 1 was repeated but substituting phenyl carbazate (77.3, 0.57 mole) for the ethyl carbazate and using phosgene (50 ml, 0.7 mole) in dry dichloromethane. 2-Phenoxycarbonylhydrazinecarbonyl chloride was isolated as impure solid (42 g, 54%) mp 76°-80° C. decomp., whose ir spectrum was consistent with the named compound being the major component.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19](OC)=[O:20])=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([C:13]2[N:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Lithium aluminium hydride (2.43 g) was added to a solution of methyl 6-phenyl-3-pyridinecarboxylate (14.00 g) in tetrahydrofuran (200 ml) at 0° C., which was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (22.50 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated to obtain 6-phenyl-3-pyridylmethanol (11.63 g, yield 96%) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:21])=[C:17]([CH:20]=1)[CH:18]=O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C.C=C(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:17]1[CH:20]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[CH3:21])[CH2:3][C:4]2([CH3:9])[CH3:5])=[O:11]
Reactant: Cc1ccc(Br)cc1C=O
Reactant: COC(=O)c1ccc(N)cc1
Agent: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1C)N2
Temperature: 85 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and 5-bromo-2-methyl-benzaldehyde (12 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (7.1 g, 35%) as a light yellow solid: MS (ESI) M+1=402.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[N:8][C:6]=2[N:7]=1.O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Reactant: COc1ccncc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccncc1-c1nc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
5-Chloro-2-iodo-7-morpholinothiazolo[4,5-d]pyrimidine, 4-methoxypyridine-3-boronic acid hydrate, and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 100° C. for 10 minutes. Water was added and the solution was filtered to give the product 5-chloro-2-(4-methoxypyridin-3-yl)-7-morpholinothiazolo[4,5-d]pyrimidine.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCC.O1CCCC1>[C:19]([N:17]1[CH:13]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][C:16]1=[O:18])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16 cm3 of a 1.6M solution of butyllithium in hexane is added at -70° C. to 4.5 g of 5-n-hexyloxy pyrrolidin-2-one in solution in 130 cm3 of anhydrous tetrahydrofuran. Agitation is carried out for 20 minutes at -70° C. and under the same conditions a solution of 3.4 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. After allowing to return to ambient temperature and concentration under reduced pressure, the residue is chromatographed on silica (eluent: toluene-ethyl acetate 8-2). 3.3 g of the product sought is obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]([C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[O:8]1)=O.B.CSC>C1COCC1>[I:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:5][NH:4][CH2:3][C@H:2]([OH:1])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:15]2
Reactant: O=C(NC[C@H](O)COc1ccccc1)[C@H]1CCc2cc(I)ccc2O1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O[C@@H](CNC[C@H]1CCc2cc(I)ccc2O1)COc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution containing (2R)-N-[(2S)-2-hydroxy-3-phenoxypropyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 79, 9.204 mmol, 1 eq.) in THF (140 mL) at room temperature was slowly added borane-methyl sulfide complex (2 M in THF, 46.07 mmol, 5.0 eq.). After completion of addition, reaction solution was heated to reflux, maintained at that temperature for 2 hours, and then cooled to room temperature. The resulting solution was quenched with EtOH (5 mL) dropwise, then with 2 M HCl (20 mL) slowly. The resulting mixture was heated at reflux for 1 hour and was then allowed to cool to room temperature. This solution was basified with 1 N NaOH and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was dissolved in MeOH and EtOAc and filtered. The filtrate was concentrated and dried in vacuo to afford the product as a white solid in 99% yield. MH+=440.2, retention time (LC-MS)=2.24 min.