Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]CC)(=O)[CH2:2][CH2:3][C:4]([CH3:6])=O.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>[Pd]>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][N:15]1[CH:4]([CH3:6])[CH2:3][CH2:2][C:1]1=[O:8]
Reactant: CN(C)CCN
Reactant: CCOC(=O)CCC(C)=O
Agent: [Pd]
Product: CC1CCC(=O)N1CCN(C)C
Temperature: 150 °C
Reaction time: 6 h

Procedure:
To a 600-mL Hastelloy® C-276 autoclave reactor (Parr Model 2302 HC) equipped with a gas entrainment turbine impellor and electrical heating mantle was added 150.0 g (1.04 mol) ethyl levulinate, 192.6 g (2.18 mol) N,N-dimethylethylenediamine, and 7.5 g ESCAT® 142 5% Pd/C catalyst. The reactor was purged first with nitrogen and then hydrogen, and then pressurized with 50 psig (0.4 MPa) hydrogen and stirred at 600 rpm while heating the reaction mixture to 150° C. On reaching this reaction temperature, the reactor was further pressurized to 1000 psig (7.0 MPa) with hydrogen and maintained at this pressure by adding additional hydrogen as required for the duration of the reaction. After 6 hours at these conditions, the reactor was cooled and vented, and the liquid reaction mixture was recovered for product isolation. The crude mixture was filtered through a glass frit via aspirator vacuum to remove the catalyst followed by removal of byproduct ethanol and unreacted N,N-dimethylethylenediamine in vacuo. The remaining contents were fractionally distilled with a 20-cm Vigreaux column under high vacuum (˜0.05 mmHg) to give 136.5 g water-white product at 85° C. in 77% isolated yield. Product purity was >99% as determined by GC/MS (HP-6890 equipped with MSD).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][C:25]#[CH:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:22])[CH2:24][C:25]#[CH:26])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C#CCNC
Product: C#CCN(C)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Methyl-prop-2-ynyl-amine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-prop-2-ynyl-amine as colorless oil, MS: 415 (MH+, 1Br).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:38])[CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[CH3:15][O:16][C:17](=[O:38])[CH:18]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(-c2ccccc2)cc1
Yield: 98.4 %

Procedure:
To a stirred solution of 4-biphenylcarboxaldehyde (7.289 g, 40 mmol) in MeCN (80 ml) under nitrogen at room temperature was added methyl(triphenylphosphoranylidene)acetate (16.049 g, 48 mmol). After 18 h the reaction mixture was concentrated and the residue purified by flash chromatography, eluting with 10% EtOAc/hexane. The appropriate fractions were collected, filtered, concentrated and dried to give 3-biphenyl-4-yl-acrylic acid methyl ester (9.384 g, 39.38 mmol, 98%) as a pale yellow solid, mp 144-147° C. 1H NMR (DMSO-d6) δ 3.75 (s, 3H), 6.70 (d, 1H), 7.35-7.53 (m, 3H), 7.65-7.78 (m, 5H), 7.82 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([Cl:23])=[O:14])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(CCC(=O)O)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(CCC(=O)Cl)ccc1F
Reaction time: 2 h
Yield: 100 %

Procedure:
3-(3-Cyano-4-fluorophenyl)-propionic acid (Int. A7) was dissolved in dichloromethane (30 ml) containing 0.1 ml DMF and oxalyl chloride (0.79 g, 6.2 mmol) added dropwise over 5 min. The reaction mixture was stirred for 2 h then concentrated in vacuo to yield the title compound as an oil (1.3 g, 100%). 1H-NMR (CDCl3) δ 3.02 (2H, t), 3.21 (2H, t), 7.13 (1H, t), 7.45 (2H, m).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:18]([CH2:20][NH2:21])[OH:19]>>[OH:19][CH2:18][CH2:20][NH:21][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: NCCO
Product: O=C(O)c1ccc2cc(C(=O)NCCO)ccc2c1

Procedure:
2.1 g of naphthalene-2,6-dicarboxylic acid monomethyl ester and 25 ml of ethanolamine are heated at 150° C. for 3 h. The excess ethanolamine is distilled off in vacuo, and the residue is dissolved in water and the mixture is extracted with ethyl acetate. After acidifying the aqueous phase, the product which is deposited is filtered off with suction and recrystallized from ethanol. 1.2 g of 6-(2-hydroxyethyl-aminocarbonyl)-2-naphthoic acid are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].C(=O)([O-])[O-].[K+].[K+].[C:25]([O:28][CH2:29][CH3:30])(=O)[CH3:26]>CN(C)C=O>[O:28]1[C:25]2[CH2:26][CH2:9][N:8]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]34[CH2:17][CH2:16][CH2:15][C:13]5[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=5)[NH:8][C:7]4=[O:18])[CH2:7][C:6]=2[CH:30]=[CH:29]1
Reactant: CCOC(C)=O
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2occc2C1)CCC3

Procedure:
5-Benzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine (410 mg, 1.9 mmol) was dissolved in ethanol (4 ml), and the solution was mixed with 10% palladium on activated carbon (80 mg) and stirred at room temperature for 15 hours in an atmosphere of hydrogen. The reaction solution was filtered to remove 10% palladium on activated carbon, and the solvent was removed by evaporation under a reduced pressure to obtain crude 4,5,6,7-tetrahydro-furo[3,2-c]pyridine. This compound and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (590 mg, 1.9 mmol) and potassium carbonate (400 mg, 2.9 mmol) were stirred at room temperature for 18 hours in anhydrous N,N-dimethylformamide (4 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 94 mg (0.27 mmol, 14% in yield) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[N:19]([CH3:24])[C@@H:18]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16].[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][C@@H:38]([CH2:41]I)[CH2:39][CH3:40]>C1COCC1>[CH3:13][O:14][C:15]([N:17]1[CH2:22][CH:21]([CH2:41][CH:38]([CH2:37][C:31]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=2[F:29])[CH2:39][CH3:40])[C:20](=[O:23])[N:19]([CH3:24])[CH:18]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16]
Reactant: CC[C@H](CI)Cc1ccc(F)cc1F
Reactant: COC(=O)N1CCC(=O)N(C)[C@@H]1C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(Cc1ccc(F)cc1F)CC1CN(C(=O)OC)C(C(C)(C)C)N(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A flask was charged with 1.35 mL (9.64 mmol) of diisopropyl amine and 15 mL of dry THF. The solution was cooled to −78° C. and 6.0 mL (9.64 mmol) of 1.6 M n-butyl lithium solution in hexanes was added. The mixture was warmed to 0° C. and stirred for 30 minutes. The mixture was cooled again to −78° C. and 2.0 g (8.76 mmol) of (2S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester was added as a solution in 10 mL of THF. This mixture was warmed to 0° C. and stirred for 1 hour. The anion solution was cooled again to −78° C. and 2.99 g (9.64 mmol) of (S)-2,4-difluoro-1-(2-iodomethyl-butyl)-benzene was added as a solution in THF. The mixture was stirred at −78° C. for 4 hours. The reaction mixture was warmed to −21° C. and stirred at that temperature for 5 days. The reaction mixture was quenched with sat. aq. ammonium chloride solution. The crude reaction mixture was extracted with diethyl ether. The ether was removed under reduced pressure, and the crude residue was purified by column chromatography (9:1 hexanes/EtOAc eluent) which gave 1.67 g (46% yield) of the titled compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=2[CH3:9])[CH2:21][CH2:20]1
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Reactant: BrCC1CC1
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-Hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.445 g) and bromomethyl cyclopropane (0.275 g) as a light yellow oil (0.357g). MS (ESI): 277.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=2)[CH:20]=[CH:19]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:27]([C:24]4[CH:25]=[C:26]5[C:21]([CH:20]=[CH:19][NH:18]5)=[CH:22][CH:23]=4)=[O:28])=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc5cc[nH]c5c4)ccc32)cc1

Procedure:
Compound 557 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and indole-6-carboxylic acid. [M+H]+ calcd for C22H17N5O: 368.14; found: 367.90.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][S:22]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:24])=[O:23]
Reactant: COC(=O)CCCCCN
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 12 h
Yield: 54.9 %

Procedure:
Then, 5.43 g of 6-aminocaproic acid methyl ester hydrochloride, 6.78 g of 1-naphthalenesulfonyl chloride and 3.03 g of triethylamine were dissolved in 50 mL of dichloromethane and stirred for 12 hours. The reaction mixture was washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 5.50 g of 6(1-naphthalenesulfonyl)aminocaproic acid methyl ester. The resulting 6-(1-naphthalenesulfonyl)aminocaproic acid methyl ester (3.35 g) was dissolved in methanol, and the solution was added with 20 mL of 1 N sodium hydroxide, and stirred for 3 hours. Then, the methanol was evaporated under reduced pressure, and the residue was made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.02 g of 6-(1-naphthalenesulfonyl)aminocaproic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Reaction time: 6 h
Yield: 99.3 %

Procedure:
To a solution of 1-(4-(4-nitrophenoxy)phenyl)ethanone (9.0 g, 35.02 mmol), in methanol (50 mL) under nitrogen atmosphere, was added a solution of 10% palladium on charcoal (1.80 g, 20% by weight) in methanol (20 mL). The reaction mixture was evacuated and purged with hydrogen balloon and stirred at r.t for 6 h. After the completion of reaction as confirmed by TLC, the reaction mixture was brought under nitrogen atmosphere. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to afford the title compound (7.90 g, 99%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>CCO>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: COC(=O)c1sccc1N
Reactant: NC=O
Solvent: CCO
Product: O=c1[nH]cnc2ccsc12
Temperature: 240 °C
Yield: 26 %

Procedure:
A mixture of methyl 3-aminothiophene-2-carboxylate (1 g, 6.3 mmol) and formamide (2 g) is heated at 240° C. for 10 min. Upon cooling a precipitate appeared. It is dissolved in EtOH and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel chromatography eluting with 10% MeOH in CH2Cl2 to yield 3H-thieno[3,2-d]pyrimid-4-one (249 mg, 26%) as a solid. 1H NMR (DMSO) δ 12.61 (1H, brs), 8.20 (1H, s), 8.17 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: Cc1ccccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Agent: Cl
Product: Cc1ccccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2nccn2)C1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 48, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): δ 9.98 (s, 1H), 7.80 (s, 1H), 7.54 (d, 2H), 7.24-7.08 (m, 6H), 7.04-6.92 (m, 4H), 5.49 (q, 2H), 4.53-4.48 (m, 1H), 3.90-3.83 (m, 1H), 2.80-2.62 (m, 3H), 2.29 (s, 3H), 2.05-1.88 (m, 2H). MS (EI) for C29H28FN5O3. found 514.2 (MH+).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[CH3:19][C:20]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:21]=1[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[CH3:15][C:11]([NH:10][C:9]1[C:8](=[O:16])[C:7](=[O:17])[C:6]=1[NH:23][CH2:22][C:21]1[C:20]([CH3:19])=[CH:27][C:26]([CH3:28])=[CH:25][C:24]=1[CH3:29])([CH3:14])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1cc(C)c(CN)c(C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2c(C)cc(C)cc2C)c(=O)c1=O
Yield: 42.2 %

Procedure:
Tetrahydrofuran (15 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol), 2,4,6-trimethylbenzylamine hydrochloride (0.928 g, 5 mmol, Example 9, Step 2) and triethylamine (0.506 g, 5 mmol) were stirred together at room temperature for 3 days. The mixture was then prepared as in Example 9, Step 3. Three recrystallization of the crude product from acetonitrile provided 0.664 g of the title compound as a white solid: mp 284°-5° C. (dec) (softens 282° C.). MS (m/z) 314 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([SH:11])[CH:8]=[N:7]1)[CH3:2].Cl[CH2:14][C:15](=[O:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][CH2:14][C:15](=[O:17])[CH3:16])[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)Cn1cc(S)cn1
Product: CCOC(=O)Cn1cc(SCC(C)=O)cn1

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: (4-mercapto-pyrazol-1-yl)-acetic acid ethyl ester and chloroacetone.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].O.CO.O>CO>[CH2:1]([C:4]([CH:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Solvent: CO
Solvent: O
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1ccccc1N)c1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of prepulverized stannous chloride dihydrate (23.82 g, 105.59 mmol) in methanol/concentrated sulfuric acid (318 ml/31.8 ml) at room temperature under a stream of nitrogen was added α-(2-propenyl)-[2-(2-nitrophenyl)--1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester as a solution in 151 ml of methanol. The reaction was run at 40°-58° C. (water bath temperature) for several hours, and then at room temperature overnight. The reaction was quenched by addition of the following reagents in the order specified: Celite, ethyl acetate (389 ml), saturated aqueous potassium carbonate solution (150 ml), and potassium carbonate (101 g), followed by agitation for about 15 minutes. Filtration through two Celite pads (once with a C porosity fritted glass funnel then a D porosity fritted glass funnel) followed by evaporation of the solvents in vacuo yielded a tan oil. Trituration from methanol/water (1 crop) yielded an off-white solid which was recrystallized from methanol (2 crops) to yield 6.87 g of an off-white crystalline solid, melting point 117°-118° C.
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([CH:37]=O)[CH:36]=1)[O:33][C:32]([CH3:40])([CH3:39])[CH2:31][C:30]2([CH3:42])[CH3:41]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([CH:37]=[CH2:1])[CH:36]=1)[O:33][C:32]([CH3:40])([CH3:39])[CH2:31][C:30]2([CH3:42])[CH3:41]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Yield: 72 %

Procedure:
A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and (11.8 mL, 19 mmol) of a 1.6M solution of n-butyl lithium in hexanes] was added 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30, 0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted with hexane, washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil (0.37 g, 72%).
Reaction SMILES: [OH2:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10]([CH3:21])([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:9][CH2:8][CH2:7]2>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10]([CH3:21])([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:9][CH2:8][C:7]2=[O:1]
Reactant: COc1cc2c(cc1OC)C(C)(CCC(=O)O)OCC2
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(C)(CCC(=O)O)OCC2=O
Reaction time: 1.5 h

Procedure:
A solution of chromium trioxide (25.7 g) is a mixture of acetic acid (120 ml) and water (35 ml) is added dropwise to a solution of 6,7-dimethoxy-1-methylisochroman propionic acid (27.0 g), described in Example 16, in acetic acid (140 ml) keeping the temperature of the mixture below 20° C. The mixture is kept at room temperature for 1.5 hr. and then poured into water and extracted with chloroform. The extracts are thoroughly washed with water, dried and evaporated. The residue is crystallized from benzene to give the title compound, m.p. 172° - 173° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:15]O>C(O)(=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:14])[N+:13]=1[O-:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1cccc(C)n1
Reactant: OO
Solvent: CC(=O)O
Product: CCCCCCOc1cccc(C)[n+]1[O-]
Reaction time: 3 h

Procedure:
To a solution of 8.60 g (44 mmol) of 6-hexyloxy-α-picoline dissolved in 43 ml of acetic acid was added 6.4 ml of hydrogen peroxide, the mixture was stirred at 70° to 80° C. for 3 hours, further 4 ml of hydrogen peroxide was added, and the mixture was stirred at the same temperature for 3 hours. After concentration under a reduced pressure to a half amount, water was added and the mixture concentrated under a reduced pressure (repeated for three times). A crude in an amount of 5.50 g was obtained.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.[CH:20]1[N:24]([CH2:25][O:26][CH:27]([CH2:30]O)[CH2:28][OH:29])[C:23]2[N:32]=[C:33]([NH2:37])[N:34]=[C:35]([OH:36])[C:22]=2[N:21]=1.C(O)(C)C>[Pd].CO>[CH3:16][CH:14]([C@H:13]([NH2:12])[C:17]([O:19][CH2:30][CH:27]([O:26][CH2:25][N:24]1[C:23]2[NH:32][C:33]([NH2:37])=[N:34][C:35](=[O:36])[C:22]=2[N:21]=[CH:20]1)[CH2:28][OH:29])=[O:18])[CH3:15].[ClH:1]
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
Hydrochloric acid (2.6 g) and 10% palladium on carbon (1.1 g, 50% wet) were added to a solution of mono-benzyloxycarbonyl-L-valine ganciclovir (10 g) in aqueous methanol (Methanol:Water::50 mL:8 mL) at ambient temperature. The reaction mass was flushed with nitrogen twice and hydrogenated at about 35° C. to 40° C. at hydrogen pressure of about 0.5-1 kg/cm2 for about 1 hour. The reaction mass was filtered and washed with methanol (10 mL). Methanol was distilled out completely under reduced pressure at about 30° C. to 35° C. The residue was dissolved in water (8 mL) and stirred to obtain clear solution. Iso-propanol (56 mL) was added slowly over a period of about 1 hour. The reaction mass was cooled to about 0 to 5° C., maintained for about 1 hour, filtered, washed with 10% aqueous iso-propanol (10 mL) followed by washing with iso-propanol (10 mL) and dried to obtain valganciclovir hydrochloride (6 g).