Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:26]CC1C=CC=CC=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Pd]>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]=1[OH:26])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCc1cc(Cc2ccc(CC)cc2)ccc1OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CCc1cc(Cc2ccc(CC)cc2)ccc1O)OCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90.8 %

Procedure:
To a solution of 2-[2-benzyloxy-5-(4-ethylbenzyl)phenyl]ethylphosphonic acid diethylester (0.71 g) in methanol (7.0 mL) was added 5% Pd—C (0.07 g), and the reaction mixture was stirred for 4.5 hr at room temperature under a hydrogen gas atmosphere. After filtration and evaporation, the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=2/3) to give the title compound (0.52 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(Cl)=[S:14]>C1COCC1>[SH:14][C:13]1[O:12][C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(S)oc2c1
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 4-amino-3-hydroxybenzoate (4.45 g, 26.6 mmol) in THF (250 ml) at room temperature, thiophosgene (2.4 mL, 32 mmol) was added slowly via a syringe pump over a period of 1 hr. After stirring for 4 hr, excess thiophosgene was quenched by addition of a saturated aqueous solution of NH4Cl (100 mL), and the THF was removed by evaporation under reduced pressure. More water was added, and the aqueous mixture was extracted with EtOAc (3×). The Combined organic phase was washed with brine, dried (MgSO4), concentrated in vacuo to give Compound 4 as a tan solid. LC-MS, M+1=210
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17]([CH:20]([OH:23])[CH2:21][CH3:22])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=1[CH2:27][O:28][Si:29]([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:30])[CH3:31])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(O)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Product: CCC(=O)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner similar to that of Example 9(b), by reaction of 28 g (52 mmol) of 1{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-1-propanol with 45 g (520 mmol) of manganese dioxide, the desired product is obtained in the form of an orange-coloured oil (m=26 g; Y=93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:39]([O:41][CH2:42][C:43]1[N:44]([CH2:56][C:57]([NH2:60])([CH3:59])[CH3:58])[C:45]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[CH:47][C:46]=2[N:55]=1)[CH3:40]>CN(C=O)C>[CH2:39]([O:41][CH2:42][C:43]1[N:44]([CH2:56][C:57]([NH:60][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:59])[CH3:58])[C:45]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[CH:47][C:46]=2[N:55]=1)[CH3:40]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)N
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
6-[(tert-Butoxycarbonyl)amino]hexanoic acid (6.81 g, 29.5 mmol), 1-hydroxybenzotriazole (3.98 g, 29.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (5.66 g, 29.5 mmol) were added to a 0° C. solution of 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylamine (which was prepared by acid-mediated deprotection of tert-butyl 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate, which is described in U.S. Patent Publication No. 2004/0091491, 8.00 g, 26.8 mmol) in DMF (80 mL). The solution was stirred at room temperature overnight. More 6-[(tert-butoxycarbonyl)amino]hexanoic acid and EDC were added and the solution was stirred for an additional hour. The solution was partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to provide 3.99 g of tert-butyl 6-({2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-6-oxohexylcarbamate as a foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[C:4]([CH3:20])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:22](OC)(OC)(OC)[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:22][C:23]1[O:21][C:3]2[C:2]([N:1]=1)=[CH:19][C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:10][CH2:11][C:5]=1[C:4]=2[CH3:20]
Reactant: COC(C)(OC)OC
Reactant: Cc1c(O)c(N)cc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1nc2cc3c(c(C)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Yield: 94 %

Procedure:
1,1-Dimethylethyl 8-amino-7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.1 g) was treated with trimethyl orthoacetate (0.718 ml) and pyridinium p-toluenesulfonate (94 mg) in dry DMF (19 ml) at 60° C. for 1.5 hours. Volatiles were evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 1/4) providing the title compound as white solid (1.127 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg, 42%). mp 169–171° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 436 (M+H)+, 453 (M+NH4)+. Anal. calc for C20H19F2N3O4S.0.25 H2O: C, 55.17; H, 4.40; N, 9.65. Found: C, 54.19; H, 4.25; N, 9.35
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCOCC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC2(CCOCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.078 g, 0.36 mmol), tetrahydro-4H-pyran-4-one (0.200 g, 2.00 mmol), p-toluenesulfonic acid monohydrate (0.076 g, 0.40 mmol) and toluene (3.0 mL) was stirred for 2 h at 90° C. The mixture was poured into aqueous sodium hydrogen carbonate (50 mL). Extraction with ethyl acetate/tetrahydrofuran (2:1, 2×30 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (12 g, silica, Combiflash, dichloromethane to 80:20 dichloromethane/methanol) to afford the title compound (0.050 g, 46%) as a yellow solid:
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17][CH2:18][C:19]1[C@H:24]([C:25]([OH:27])=[O:26])[N:23]2[C:28](=[O:40])[C@@H:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:22]2[S:21][CH:20]=1>O1CCOCC1.C(O)(=O)C>[C:1]1([CH:7]([O:27][C:25]([C@@H:24]2[N:23]3[C:28](=[O:40])[C@@H:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@H:22]3[S:21][CH:20]=[C:19]2[CH2:18][S:17][CH3:16])=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CSCC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CSCC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 0.39 g of diphenyldiazomethane in 5 ml of petroleum ether is added dropwise over the course of half an hour to a solution of 0.5 g of 3-methylthiomethyl-7β -phenylacetylamino-2-cephem-4α-carboxylic acid in 20 ml of dioxane, while stirring. The solution is stirred for a further 15 hours at room temperature, treated with a few drops of glacial acetic acid and concentrated under reduced pressure. The residue is recrystallised from methyl acetate and gives pure 3-methylthiomethyl-7β-phenylacetylamino-2-cephem-4α-carboxylic acid diphenylmethyl ester which is dried for 16 hours at room temperature in a high vacuum. Melting point 175-177° C; thin layer chromatogram (silica gel): Rf = 0.77 (system: chloroform/methanol, 1:1); Rf = 0.17 (system: toluene/acetone, 2:1); [α]D20 + 342° ± 1° (c = 1.011 in dioxane); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): λmax = 255 mμ (ε = 7,800) and λmin = 244 mμ (ε = 7,200), infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.92μ, 5.61μ, 5.73μ, 5.92μ, 6.25μ and 6.67μ.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:34])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:25][CH:26](Cl)[CH3:27]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCOC(=O)OC(C)Cl
Product: CCCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl butyl carbonate (5.30 g, 29.3 mmol) were converted to title product, 600 mg yellow solid (1.3 mmol, 13.9%) which was recrystallized from isopropyl alcohol to give 325 mg white crystals: mp 132°-133° C.; IR (KBr) 1758, 1681 cm-1 ; 1H NMR (CDCl3) delta 0.87 (t, J=7 Hz, 3H), 1.18-1.35 (m, 2H), 1.42-1.58 (m, 2H), 1.76 (d, J=6 Hz, 3H), 3.11 (s, 3H), 4.01 (t, J=7 Hz, 2H), 6.35 (q, J=6 Hz, 1H), 7.05-7.15 (m, 1H), 7.65-7.82 (m, 3H), 7.82-7.95 (m, 2H), 8.30-8.40 (m, 2H), 9.39 (br s, 1H): precise mass calcd for C22H25N3O7S m/e 475.1413, found 475,1425.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][NH:5][C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[H][H]>C(O)C.[Pd]>[NH2:16][C:15]1[C:6]([NH:5][CH2:4][CH:3]([O:19][CH3:20])[O:2][CH3:1])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCC(OC)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To an argon purged solution of methyl 2-(2,2-dimethoxyethylamino)-3-nitrobenzoate (1.4 g, 4.7 mmol) from Step B above in ethanol (50 mL) at room temperature was added 10% palladium on carbon. A hydrogen balloon was then attached and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through celite and concentrated under reduced pressure to give methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.2 g, quantitative yield) as a dark red oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06 (d, J=5.0 Hz, 1H), 6.85 (dd, J=7.8, 1.2 Hz, 1H), 6.74 (t, J=7.8 Hz, 1H), 6.06 (t, J=7.5 Hz, 1H), 4.84 (s, 2H), 4.38 (t, J=5.4 Hz, 1H), 3.80 (s, 3H), 3.23 (s, 6H), 3.04 (dd, J=7.2, 5.7 Hz, 2H); MS (ESI+) m/z 254 (M+H).
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.C(N(CC)CC)C.C(Br)C=C>C(OCC)(=O)C.O>[CH2:4]([NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1)[CH:3]=[CH2:2]
Reactant: COc1cccc(N)c1
Reactant: C1CCOC1
Solvent: C=CCBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCNc1cccc(OC)c1
Reaction time: 0.5 h

Procedure:
To 10 mL of a tetrahydrofuran solution containing 1.0 g of m-anisidine, 1.2 mL of triethylamine and 0.70 mL of allyl bromide were added under cooling with ice. The reaction mixture was stirred for 30 minutes. Water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was separated with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 0.36 g of a yellow oily substance, N-allyl-3-methoxyaniline.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O)C.[NH3:14]>>[C:12]([C:6]1([C:4]([NH2:14])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:13]
Reactant: N
Reactant: CCOC(=O)C1(C#N)CCCCC1
Product: N#CC1(C(N)=O)CCCCC1
Temperature: -78 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
1-Cyano-cyclohexanecarboxylic acid ethyl ester (11.4 g, 63.0 mmol) was placed into a glass pressure vessel and cooled to −78° C. It was charged with ammonia via needle until the total volume had doubled. The vessel was sealed and allowed to stir at room temperature for 20 hours. The solvent was evaporated and the resulting slurry triturated with ethyl acetate. The solids were collected by filtration and then filtered through a silica funnel (50 g silica), washing with ethyl acetate. The filtrate was concentrated to give the product (2.51 g, 26%) as a white solid. [M+H]+ 153.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH2:24]I)[CH:21]=[CH:20][C:19]=1[N:26]1[S:30](=[O:32])(=[O:31])[N:29]([CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28](=[O:39])[CH2:27]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:62]1[CH:67]=[C:66]([CH2:68][CH3:69])[CH:65]=[CH:64][N:63]=1>CN(C)C(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([CH2:24][C:62]2[CH:67]=[C:66]([CH2:68][CH3:69])[CH:65]=[CH:64][N:63]=2)[CH:21]=[CH:20][C:19]=1[N:26]1[S:30](=[O:32])(=[O:31])[N:29]([CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28](=[O:39])[CH2:27]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCc1ccnc(Br)c1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CI)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CCc1ccnc(Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In pressure vessels, zinc powder (2.145 g, 33 mmol) is dried by heating under vacuum, then cooled, placed under N2, and slurried in N,N-dimethylacetamide (4 mL). To the slurry is added 1,2-dibromoethane (220 μL, 2.55 mmol) and the mixture is heated until boiling. The mixture is allowed to cool, and TMSCl (325 mL, 2.55 mmol) is added, followed by stirring for 30 min. to produce a green solution. To the slurry of activated zinc is added 5-(2-benzyloxy-4-iodomethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (3.0 g, 5.37 mmol) in N,N-dimethylacetamide (5 mL) over 30 min. The organozinc solution is filtered and degassed with N2, then to it is added Pd2(dba)3 (250 mg, 0.275 mmol) and 2-(di-t-butylphosphino)biphenyl (330 mg, 1.1 mmol), followed by degassed 2-bromo-4-ethylpyridine (1.20 g, 6.44 mmol) in N,N-dimethylacetamide. The vessels are sealed and the reaction heated in the microwave in 4 batches, 120° C. for 20 min. The reaction is allowed to cool to ambient temperature, then filtered through Celite. The resulting solutions are combined and diluted with EtOAc (150 mL) and washed with water and brine, then dried over MgSO4. The solvent is removed under reduced pressure and the crude residue is purified via silica gel chromatography using a gradient of 0-75% EtOAc/hexanes to afford the title compound as a colorless oil: MS (M+H)+=616.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.O.[CH2:20](O)C>>[C:1]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:20])=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Agent: Cl
Solvent: O
Product: CCOC(=O)C1CCC(C(C)=O)CC1

Procedure:
Dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (see Process K) (26.5 g.) was added to a solution of concentrated hydrochloric acid (290 ml.) in ethanol (140 ml.). After refluxing for 7.5 hours, the reaction mixture was poured into water and then extracted with dichloromethane. The organic phase was then washed with saturated sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to give ethyl 4-acetylcyclohexanecarboxylate as a colourless oil. This was purified by distillation (b.p 144°-148° C./14 mm Hg.).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:28][C:29]1[C:34](O)=[C:33]([Cl:36])[C:32]([Cl:37])=[C:31]([Cl:38])[C:30]=1[Cl:39]>ClCCl>[Cl:28][C:29]1[C:34]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:33]([Cl:36])[C:32]([Cl:37])=[C:31]([Cl:38])[C:30]=1[Cl:39]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#CC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in 80 ml. of dichloromethane. 10.3 g. (0.05 moles) of dicyclohexylcarbodiimide and 13 g. (0.05 moles) of pentachlorophenol are added dropwise dissolved in 50 ml. of dichloromethane. The mixture is stirred for 4 hours, cooled to 0° C. and the precipitated dicyclohexylurea is filtered. The filtered substance is washed twice on the filter with 15 ml. of dichloromethane. The combined organic layers are distilled off and the precipitated ester is taken up with 20 ml. of diisopropyl ether and the crystals are filtered, washed twice with diisopropyl ether and dried.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[F:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Fc1ccc2c(c1F)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c1ccc(F)c2F
Yield: 55.8 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, 383 mg of 4,5-difluoro-2,3-dihydro-1H-indole hydrochloride, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.32 ml of pyridine and 4 ml of N,N-dimethylformamide. 210 mg of 2-[2-(4,5-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink, powdery solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2snc(Cl)c2c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of 3-chloro-5-nitrobenzo[d]isothiazole (4.53 g, 21.1 mmol), iron (7.2 g, 129 mmol) and ammonium chloride (2.4 g, 45 mmol) in ethanol/water (2:1, 270 mL) is allowed to stir at 80° C. for 1.5 h. The resulting dark reaction mixture was filtered through Celite while still hot and concentrated under reduced pressure to give a brown solid, which was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a brown solid which was triturated with hexanes to provide 3-chlorobenzo[d]isothiazol-5-amine (3.7 g) as a yellow solid. 1H NMR (300 MHz, CDCl3): 7.57 (dd, 1H), 6.99 (dd, 1H), 6.66 ppm (dd, 1H). MW=184 confirmed by LC-MS, tr=10.41 min (Method Y) MH+=185.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([CH:20]([OH:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH-].[K+]>CC(C)=O>[C:20]([C:18]1[O:19][C:15]2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=[C:11]([C:9](=[O:10])[CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:30])[C:16]=2[CH:17]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(O)c3ccccc3)oc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
Compound 164a (1.0 g) obtained in Step A was dissolved in acetone (200 ml) and 2.67M Jones' reagent (1.0 ml) was added thereto, followed by stirring at room temperature for 10 minutes. A 1N aqueous solution of potassium hydroxide was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was triturated with diethyl ether to give Compound 164 (0.66 g, 66.5%) as a colorless solid.