Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:26][O:27][CH3:28])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C:16]([CH2:26][O:27][CH3:28])=[CH:17]2
Reactant: COCc1cc2cc(OC)ccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
1-(4-Benzyloxyphenyl)-5-methoxy-2-methoxymethyl-1H-indole (0.16 g, 0.43 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (1 mL). Palladium on carbon (0.32 g, 10% wet) and ammonium formate (0.14 g, 2.14 mmol) were added, and the reaction was stirred at reflux for 2 hours. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the crude material taken on without purification. LC-MS (C17H17NO3 calc'd 283) m/z 284 (M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.CO[C:15](=O)[CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)[S:17][C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:31][C:27]1[CH:26]=[C:25]([CH:16]([S:17][C:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH:19]=2)[C:15]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)C(SC1=CCN(C)CC1)c1cccc(Br)c1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC=C(SC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 1,2-phenylenediamine (213 mg) in toluene (2 mL) is added dropwise a solution of 2M trimethylaluminium in toluene (1 ml). The reaction mixture is heated at 75° C. for 2 hours then a solution of (3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)acetic acid methyl ester (example 530B, 358 mg) in toluene (2 mL) is added, and the heating is continued at 75° C. for 3 hours. Water is added and the reaction mixture is made alkaline by adding 1N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residue is the dissolved in acetic acid (5 mL) and the reaction mixture is refluxed for 3 hours. The solvent is removed under reduced pressure. Water is added and the reaction mixture is made alkaline by adding 2N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residual solid is triturated with acetonitrile, filtered and the solid is washed with diethyl ether to give 2-[(3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)methyl]-1H-benzimidazole melting at 189° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(=S)=S>[CH3:23][O:22][C:20]([C:17]1([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[C:12]([C:5](=[O:7])[CH3:6])[CH:13]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(O)c(C(C)=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
To a stirred suspension of AlCl3 (58 g, 440 mmol) in CS2 (500 mL) was added acetyl chloride (7.4 g, 95 mmol) at room temperature. After stirring for 5 min, methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (15 g, 73 mmol) was added. The reaction mixture was heated at reflux for 2 h before ice water was added carefully to the mixture at room temperature. The resulting mixture was extracted with EtOAc (150 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 1-(3-acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (15 g, 81%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 12.28 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.47 (dd, J=2.0, 8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.64 (s, 3H), 2.64 (s, 3H), 1.65-1.62 (m, 2H), 1.18-1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:7]1)=[O:5])[CH3:2].[ClH:25].O>C(OCC)(=O)C>[ClH:25].[ClH:25].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C2CCNCC2)C1
Temperature: -78 °C

Procedure:
[1,4′]Bipiperidinyl-3,1′-dicarboxylic acid 1′-tert-butyl ester 3-ethyl ester (21.14 g, containing some isopropyl ester) was dissolved in ethyl acetate (80 mL) under nitrogen, cooled to −78° C. and hydrogen chloride passed in for several minutes until the solution became saturated. The solution was allowed to warm to ambient temperature with provision for the evolved gases to be trapped by water in a scrubber. After 3 hr the solution was evaporated to dryness in a stream of dry nitrogen to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[CH2:17]1[NH:22][CH2:21][CH2:20][N:19]2[CH2:23][C@H:24]([CH2:27][OH:28])[CH2:25][CH2:26][C@@H:18]12.[F-].[Cs+]>CS(C)=O>[NH2:8][C:6]1[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]3[CH2:23][CH:24]([CH2:27][OH:28])[CH2:25][CH2:26][CH:18]3[CH2:17]2)[N:7]=1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1nc(N2CCN3CC(CO)CCC3C2)cc2nc(-c3ccco3)nn12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
7-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (1 eq, see U.S. Pat. No. 6,222,035 B1), cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq.), and CsF (1-2 eq.) were dissolved in DMSO. The mixture was stirred at around 120° C. for 18 hours. The solution was then cooled to room temperature, filtered and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to give the desired, compound as a white solid. Alternatively, for scale up synthesis, the DMSO solvent was removed and the crude product was chromatographed on silica gel column using 5-10% MeOH/CH2Cl2 as eluant to afford the desired product: 1H NMR (400 Hz, CD3OD) δ 7.71 (d, J=2.0 Hz, 1H), 7.14 (d, J=3.5 Hz, 1H), 6.63 (dd, J=3.5, 2.0 Hz, 1H), 5.99 (s, 1H), 4.26 (d, J=13.5 Hz, 1H), 4.19 (d, J=13.5 Hz, 1H), 3.83 (dd, J=10.5, 7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.04 (dt, J=12.5, 3.0 Hz, 1H), 2.95 (d, J=12.0 Hz, 1H), 2.80 (d, J=11.0 Hz, 1H), 2.62 (dd, J=12.5, 10.5 Hz, 1H), 2.22 (m, 2H), 1.98 (m, 1H), 1.86 (brd, 12.0 Hz, 2H), 1.62 (m, 1H), 1.50-1.42 (m, 2H). MS m/z: 370 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:20])[O:17][C@@H:16]([CH2:18][OH:19])[CH2:15][O:14]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
p-Toluenesulfonyl chloride (6.5 g, 34.1 mmol) was added portionwise over a period of 10 min to a solution of (S)-(+)-1,2-isopropylideneglycerol (3.0 g, 22.7 mmol) and DMAP (30 mg, 0.25 mmol) in anhydrous pyridine (30 mL) in a water bath. The resulting solution was stirred overnight. The pyridine was removed under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed subsequently with water (2×40 mL), cold aqueous 1 M HCl (40 mL), saturated NaHCO3 (40 mL) and water (40 mL). The organic layer was dried over Mg2SO4, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography (eluent: 10% ethyl acetate in hexane to 30% ethyl acetate in hexane) to afford (R)-2,2-Dimethyl-1,3-dioxolane-4-methanol p-toluenesulfonate i (5.91 g, 90.9% yield) as a colorless viscous oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][CH:7]=1)=[O:5])C.[ClH:13]>[OH-].[Na+].C(O)C>[Cl:13][C:7]1[S:8][C:9]([CH2:11][CH3:12])=[CH:10][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1csc(CC)c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)O)c(Cl)s1
Temperature: 140 °C

Procedure:
5-Ethyl-thiophene-3-carboxylic acid ethyl ester (0.83 g, 3.8 mmol) was dissolved in a solution of aqueous sodium hydroxide (1 M, 6 mL) and ethanol (4 mL). The mixture was then heated to 140° C. for 10 minutes using microwave irradiation. The reaction mixture was acidified with 1 N hydrochloric acid and the resulting precipitate was isolated by filtration, washed with water and then dried under vacuum to give the title compound (0.53 g). 1H NMR (400 MHz, DMSO-d6): δ 7.05 (s, 1H), 2.75 (q, 2H), 1.4 (t, 3H), 1.2 (t, 3H).
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:12]([CH3:13])[CH2:11][CH2:1][C:2]2[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cc(CCC(C)=O)ccc1O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCC(C)NCc2ccc(Cl)cc2)ccc1O
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-chlorobenzylamine (3.82 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0° C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.16 g, 75%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 1, A (made by the Conditioned Extraction method).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:25][CH3:26])[C@@H:22]([O:24][CH3:37])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]([C@H](C)OC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 50 mg (0.102 mmol) of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 153, Step A) in 0.3 mL of DMF was added 60% sodium hydride (20.31 mg, 0.508 mmol) at 25° C. After being stirred at 25° C. for 20 min, iodomethane (25.4 uL, 0.406 mmol) was added. The reaction was stirred for an additional 30 min and was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 60% EtOAc/hexanes) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH2:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:24][CH2:22][CH3:23])=[O:15])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Agent: Cl
Product: CCNC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and ethylamine hydrochloride in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:17]([O:26][CH3:27])[CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:17]([O:26][CH3:27])[CH:16]=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1OC

Procedure:
3.41 g of methyl 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxyphenylacetate was dissolved in 50 ml of toluene. After adding 3.5 g of p-toluenesulfonic acid monohydrate, the mixture was heated under reflux for 1 hour and 45 minutes. After adding water and triethylamine, the reaction mixture was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 3.6 g of a pale yellow oily substance was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]([CH3:12])[N:5]=2)[CH2:3][CH2:2]1.C1(C2N(C)N=CC=2C(O)=O)CC1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:33]=[C:34]([CH:51]=[CH:52][CH:53]=1)[O:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([N:42]=[C:43]([NH:45][C:46]([CH:48]3[CH2:50][CH2:49]3)=[O:47])[N:44]=2)[CH:41]=1>O1CCCC1.CN(C)C=O.O>[CH:1]1([C:4]2[C:8]([C:9]([NH:31][C:32]3[CH:53]=[CH:52][CH:51]=[C:34]([O:35][C:36]4[CH:37]=[CH:38][C:39]5[N:40]([N:42]=[C:43]([NH:45][C:46]([CH:48]6[CH2:49][CH2:50]6)=[O:47])[N:44]=5)[CH:41]=4)[CH:33]=3)=[O:11])=[CH:7][N:6]([CH3:12])[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(C(=O)O)c(C2CC2)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: Cn1ncc(C(=O)O)c1C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a mixture of 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid and 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid (430 mg, 2.59 mmol) in tetrahydrofuran (7 mL) were added oxalyl chloride (338 μL, 3.87 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (400 mg, 1.29 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=70/30→0/100), and then by column chromatography (silica gel, ethyl acetate/methanol=95/5) and recrystallized from ethyl acetate to give the title compound (120 mg, 20%) as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([S:26][CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([S:26]([CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)=[O:9])[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(SCc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)Cc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
m-Chloroperbenzoic acid (80%, 1,4 g) was added under ice-cooling to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1-methylimidazol-2-ylmethylthio)quinoline-3-carboxylate (3.0 g) in dichloromethane (90 ml), and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was washed successively with an aqueous saturated NaHSO3 solution, aqueous saturated sodium bicarbonate solution and water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/dichloromethane (4:1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1-methylimidazol-2-ylmethylsulfinyl)quinoline-3-carboxylate (2.17 g, 70%). mp. 151°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].C([O-])(=O)C.[K+].N[C:26](N)=[S:27]>>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:26]([SH:27])=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: NC(N)=S
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(S)=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (13 g), anhydrous potassium acetate (0.34 g) and thiourea (0.96 g) was heated at 170°-180° C. for 2 hours. After digestion with water the mixture was filtered and the solid was dissolved in I Normal sodium hydroxide solution then re-precipitated by the addition of acetic acid. The dried solid was digested with chloroform and with ethanol to leave l.12 g of a crude product. Repeated recrystallisations from dimethylformamide, 2-methoxyethanol, and acetic acid yielded the title compound, 0.32 g, m.p. 305°-307° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]3SC)=[O:7])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH2:13]3)=[O:7])=[CH:20][CH:21]=1
Reactant: CSC1C(=O)Nc2c(C(=O)c3ccc(Cl)cc3)cccc21
Solvent: C1CCOC1
Product: O=C1Cc2cccc(C(=O)c3ccc(Cl)cc3)c2N1
Yield: 93 %

Procedure:
A stirred solution of 9 g. (0.028 mole) of 7-(4-chlorobenzoyl)-3-methylthioindolin-2-one in 180 ml. of tetrahydrofuran was treated over a two-hour period with 45 g. of a commercial Raney nickel water suspension. After the addition was complete the mixture was filtered. A drop of concentrated hydrochloric acid was added to the filtrate which removed some color and the resulting solution was then stripped under water pump vacuum to yield a cream color material. Recrystallization from toluene gave needles, (93% yield); the material sintered at 177° C. and melted at 186° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([C:18]#[N:19])=[CH:4][N:3]=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][NH:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].Cl>CC(O)CC>[C:18]([C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([S:27](=[O:29])(=[O:28])[NH:26][CH2:25][CH:21]3[CH2:22][CH2:23][CH2:24][O:20]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1)#[N:19]
Reactant: Nc1ccc(S(=O)(=O)NCC2CCCO2)cc1
Reactant: N#Cc1cnc(Cl)nc1NCCCN1CCOCC1
Agent: Cl
Solvent: CCC(C)O
Product: N#Cc1cnc(Nc2ccc(S(=O)(=O)NCC3CCCO3)cc2)nc1NCCCN1CCOCC1
Yield: 13.2 %

Procedure:
2Chloro-5-cyano-4-(3-morpholinopropylamino)pyrimidine (Method 66; 525 mg, 1.87 mmol), 4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]aniline (Method 2; 430 mg, 1.68 mmol) and 1M ethereal hydrogen chloride (1.87 ml, 1.87 mmol) in 2-butanol (3 ml) was heated at 90° C. for 3 hours. The mixture was allowed to cool, the resulting precipitate was collected by filtration and was washed with ethyl acetate. The crude solid was purified by chromatography eluting with DCM/methanolic ammonia/(100:0) increasing in polarity to (97:3). The product was recrystallized from methanol to give the title compound (111 mg).
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([CH2:4][CH2:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:2][CH2:3]1
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1/C=C/C1CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1CCC1CC1
Yield: 25 %

Procedure:
To a solution of 2-[2-((E)-2-cyclopropyl-vinyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid (138) (120 mg, 0.33 mmol) in absolute EtOH (10 mL) is added the catalyst, Pd—C (5 wt. % Pd, 28 mg, 1.3% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, room temperature, overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed by EtOH. The combined solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (139) as white solid (30 mg, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:14]1(C)C=CC(CC(OCC)=O)=CC=1.[Li+].CC([N-]C(C)C)C.CI>C1COCC1.CN1C(=O)N(C)CCC1>[C:10]1([CH3:14])[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(C)cc1
Yield: 86 %

Procedure:
According to the procedure given for the synthesis of 202, ethyl p-tolylacetate (2.72 g, 15.2 mmol) was reacted with LDA (7.6 mL, 15.25 mmol) and methyl iodide (3.03 g, 21.30 mmol) in anhydrous THF (70 mL) and DMPU (1 mL). After aqueous workup and extraction, the residue was distilled in high vacuo to give 203 (2.5 g, 86.0%) as an oil. Bp 59-63° C./0.2 mmHg. 1H NMR (CDCl3): δ (ppm) 7.18 (d, 2 H, J=8.1), 7.10 (d, 2 H, J=8.1), 4.09 (m, 2 H), 3.67 (q, 1 H, J=7.2), 2.29 (s, 3 H), 1.47 (d, J=7.2 Hz, 3 H), 1.20 (t, J=5.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 174.71, 137.80, 136.63, 129.33, 129.14, 127.36, 60.66, 45.18, 21.05, 18.70, 14.15.