Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH+]1C=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH3:17])[CH:12]=CC(S([O-])(=O)=O)=C[CH:8]=1.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH:20]([O:21][C:7]([CH3:8])([CH3:12])[CH3:17])=[CH2:19].[CH2:22]([OH:21])[CH2:18][C:19]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:20]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: c1cc[nH+]cc1
Product: C=COC(C)(C)C
Product: OCCc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 100 ml of tetrahydrofiran (THF) and 30 g of powdered polyhydroxystyrene (PHS) was added to a 250 ml three-necked flask equipped with a temperature probe, an overhead mechanical stirrer and a nitrogen inlet. The mixture stirred for 30 minutes to form a homogeneous solution before 5.0 g of tertiary butyl vinyl ether, 4.8 g of phenethyl alcohol and 140 mg of solid pyridinium-para-toluene sulfonate was added. A brief exotherm was observed followed by a temperature rise of 23° to 27° C. The solution was allowed to stir at 23° C. for 20 hours before 4 g of triethylamine solution (prepared by dissolving 2.31 g of triethylamine in 200 g of THF) was added to the reaction mixture to quench the acid. The reaction mite was stirred for additional 30 minutes. The polymer solution was drop-wise added to 1000 ml of de-ionized water under vigorous stirring. The precipitated solid polymer was isolated by filtration. The polymer was washed two times with 250 ml of de-ionized water. The polymer was dried under vacuum at 60° C. for 18 hours.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:9]=1
Reactant: CCCn1cc(-c2ccncc2)cc([N+](=O)[O-])c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCCn1cc(-c2ccncc2)cc(N)c1=O
Reaction time: 6 h

Procedure:
A solution containing 15.1 g. of 3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone in 400 ml. of dry dimethylformamide was charged into an 800 ml. Parr bottle with 1.5 teaspoons of Raney nickel and the mixture was shaken under 650 p.s.i. of hydrogen at room temperature for four hours, during which time the reaction temperature was no more than 50° C. The catalyst was filtered off; the filtrate was treated with decolorizing charcoal and filtered; and, the solvent was distilled off under reduced pressure to leave 12.7 g. of crystalline solid. The solid was recrystallized from methanol to yield 7.2 g. of crystalline 3-amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 171°-173° C. after drying at 70° C. and 0.001 mm. for six hours.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:24](=[O:26])C>O1CCCC1.CCCCCC>[CH:13]1([CH:19]([CH2:24][OH:26])[C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC=O
Reactant: COC(=O)CC1CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (0.85 ml, 6.10 mmol) in 30 ml tetrahydrofuran at -78° under argon was added n-butyllithium (2.5 ml of a 2.5M solution in hexane). After 0.5 hour, methyl cyclohexylacetate (1 ml, 6.10 mmol) was added dropwise in 10 ml tetrahydrofuran. The solution was stirred for 45 minutes, after which was added acetaldehyde (1 ml) in 10 ml tetrahydrofuran. This solution was stirred for two hours at -78°, warmed to room temperature and stirred an additional 12 hours, quenched with water and acidified with 10% hydrochloric acid. The mixture was extracted twice with ethyl ether, and the combined organic portions were then washed once with 10% hydrochloric acid, twice with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the alcohol as an orange oil (b.p. 85°-92°, 0.5 mm).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:9]([CH:44]=1)=[CH:10][C:11]1[C:12]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])=[C:13]3[S:29][C:28]([C:30]([O:32]CC)=[O:31])=[CH:27][C:14]3=[CH:15][C:16]=1[C:17]=2[O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO>[CH2:25]([CH:20]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][O:18][C:17]1[C:16]2[CH:15]=[C:14]3[CH:27]=[C:28]([C:30]([OH:32])=[O:31])[S:29][C:13]3=[C:12]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])[C:11]=2[CH:10]=[C:9]2[CH:44]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=12)[CH3:26]
Reactant: CCCCC(CC)COc1c2cc3cc(C(=O)OCC)sc3c(OCC(CC)CCCC)c2cc2cc(C(=O)OCC)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC(CC)COc1c2cc3cc(C(=O)O)sc3c(OCC(CC)CCCC)c2cc2cc(C(=O)O)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 760 %

Procedure:
0.06 g of 5,10-bis(2-ethylhexyloxy)-1,6-dithia-dicyclopenta[b,g]naphthalene-2,7-dicarboxylic acid diethyl ester (0.009 mmol) was dissolved in 0.5 mL of THF:Methanol (1:1), and 0.2 mL of water and 0.01 g of lithium hydroxide (0.04 mmol) were added thereto and stirred at room temperature for 8 hours. Again, the mixture was further stirred at 50° C. for 8 hours, the solvent was removed, and a temperature was lowered to 0° C., and the resultant was acidified by 2N HCl solution, thereby obtaining 0.04 g of the title compound (74.0%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C:6]([CH3:15])([S:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:7])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:2]([O:4][C:5](=[O:16])[C:6]([S:8][CH:9]1[CH2:10][CH2:11][N:12]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([CH3:15])[CH3:7])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(C)SC1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)SC1CCN(S(C)(=O)=O)CC1
Yield: 41.9 %

Procedure:
To a solution of 4.47 g (16.74 mmol) of 2-methyl-2-(piperidin-4-ylsulfanyl)-propionic acid ethyl ester hydrochloride salt in anhydrous THF (30 mL) are added 13.45 mL (77.36 mmol) of N,N-diisoproylethylamine, followed by 2.98 mL (38.58 mmol) of methanesulfonyl chloride. The reaction mixture is heated for 2 d to 60° C. The mixture is concentrated under reduced pressure and the residue is partitioned between saturated aqueous NaHCO3 solution (75 mL) and ethyl acetate (75 mL). The basic aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layer is separated and washed with brine (50 mL), dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography (silica, eluent: heptanes, 30% ethyl acetate) to give 2.17 g of 2-(1-methanesulfonyl-piperidin-4-ylsulfanyl)-2-methyl-propionic acid ethyl ester as a brown solid. Yield: 42%, ES-MS: m/z 310 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.22 (3 H, t, J=7.11 Hz), 1.47 (6 H, s), 1.59-1.69 (2 H, m), 1.92-2.00 (2 H, m), 2.70 (3 H, s), 2.90-2.99 (3 H, m), 3.39-3.47 (2 H, m), 4.10 (2 H, q, J=7.12 Hz)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[CH3:6][C:7]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:12][CH:13]1[C:25](=[O:26])[N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[C:25](=[O:26])[CH:13]([CH2:12][C:8]3[N:9]=[CH:10][NH:11][C:7]=3[CH3:6])[CH2:14][CH2:15][C:16]=12)[CH3:3]
Reactant: Cc1[nH]cnc1CC1CCc2cc3ccccc3n2C1=O
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(CN(C)C)c3ccccc3n2C1=O
Temperature: 60 °C

Procedure:
To a mixture of aqueous 50% dimethylamine solution (0.20 ml), aqueous 35% formaldehyde solution (0.20 ml), and acetic acid (4 ml) at 15° C. was added 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (418 mg). The mixture was heated at 60° C. for 24 hours. After evaporation of the solvent, the residue was dissolved in water, made basic with aqueous 3N sodium hydroxide solution, and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The oil was purified by silica gel column chromatography (20% methanol-chloroform) to give 8,9-dihydro-10-[(dimethylamino)methyl]-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (240 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1.CO.Cl.[N:47]([O-])=O.[Na+]>O.Cl[Cu]>[N+:1](=[C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH2:3]1)=[N-:47]
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reactant: O=N[O-]
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C(=O)C(C)C(O)C(C)CCC1=C(C(=O)O)C(O)=C(C)CC1=[N+]=[N-])C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Temperature: 25 °C

Procedure:
A solution of 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid (1.28 g.) in 10 ml. methanol and 2 ml. of aqueous N HCl was cooled to 0° and a chilled solution of 150 mg. of NaNO2 in 1 ml. water was slowly added. To the solution was added 320 mg. of CuCl in 1 ml. of concentrated HCl. The reaction mixture was allowed to slowly warm up to room temperature and then diluted with water and extracted with ether. The ether extract was concentrated to a small volume and the crystallized product was collected by filtration, m.p. 137°-138°. [α]D -13.5° (0.7%, CH3OH).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].[Cl:21][CH2:22][C:23](Cl)=[O:24].C(Cl)(Cl)Cl>O>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:24]
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(N)s1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(NC(=O)CCl)s1

Procedure:
Ethyl 5-amino-4-(2-chlorobenzoyl)thiophene-2-carboxylate (280 g) and chloroacetyl chloride (218 ml) were added to chloroform (4 l), and the mixture was refluxed under heating for 2.5 hours. Water was added thereto. The organic layer was taken out, and dried over magnesium sulfate. The solvent was evaporated. Then, diisopropyl ether was added, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give 325 g of ethyl 5-(2-chloroacetylamino)-4-(2-chlorobenzoyl)thiophene-2-carboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22]([C:19]4[CH:20]=[CH:21][C:16]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:17][CH:18]=4)=[O:23])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 4-biphenylcarbonyl chloride (87 mg; 0.37 mmol; 1.5 eq.) as a white powder (53.7 mg, 56%). HPLC, Rt: 4.25 min. (purity 95.2%). LC/MS, M+(ESI): 381.4, M−(ESI): 379.4.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:23]2[CH2:24][NH:25][CH2:26][CH2:27][N:22]2[CH2:21][CH2:20][OH:19])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: OCCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-5-octylbarbituric acid (23.52 g) in 70 ml of dimethylsulfoxide, kept under nitrogen atmosphere and at a temperature of 5-10° C., is dropped N-(2-hydroxyethyl)piperazine (36.2 ml), then the mixture is stirred at room temperature for 2 hours 30 minutes. The reaction mixture is poured into water (1 l) under stirring and cooling with an ice bath. The white solid which separates is recovered by filtration washed with water and dried under vacuum at 40° C., to give, after crystallization from ethanol (140 ml) 10.91 g of the product as a white solid, m.p. 183-184° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36][C@H]1CCN(S(C2C3C(Cl)=CN=C(N)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl
Product: Nc1ncc(Br)c2c(S(=O)(=O)N3CC[C@H](N)C3)cccc12

Procedure:
Intermediate 29a was used in the method of Example 39-1, Step B instead of Intermediate 28a to obtain the title compound as hydrochloride.
Reaction SMILES: [O-:1]I(=O)(=O)=O.[Na+].[CH3:7][S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([Br:18])=[CH:11][C:10]=1[CH:19]([CH3:21])[CH3:20]>O.CO.CC(C)=O>[CH3:7][S:8]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12]([Br:18])=[CH:11][C:10]=1[CH:19]([CH3:21])[CH3:20])=[O:1]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cc(C(C)C)c(Br)cc1C(C)C
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cc(S(C)=O)c(C(C)C)cc1Br
Reaction time: 16 h

Procedure:
4-Bromo-2,5-diisopropylphenyl methyl sulfoxide was prepared as follows: A solution of 25.7 g of sodium m-periodate in 200 ml of water was added portionwise over 0.5 hour to 31.9 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide (prepared in Example 1C) in 200 ml of methanol and 350 ml of acetone at ambient temperature. After stirring for 16 hours, the reaction mixture was filtered and the solid portion was extracted with chloroform. The filtrate was diluted with 1 liter of water and the solid residue that formed was collected on a filter. The second residue was extracted with chloroform. The two chloroform extracts were combined, washed with half-saturated sodium chloride solution, and dried over sodium sulfate. Removal of the chloroform gave a pale-yellow product containing some sulfide which was removed by recrystallization from n-hexane to give pure 4-bromo-2,5-diisopropylphenyl methyl sulfoxide which softened at 110°C and melted at 114°-117°C [Ʊ(S=O) 9.6μ].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]3)=[C:20]3[CH2:26][CH2:25][CH:24]([OH:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:29]3)=[C:20]3[CH2:26][CH2:25][C:24](=[O:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3=O)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.5 %

Procedure:
To a solution of tert-butyl {(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (100 mg, 0.17 mmol) in DCM (0.8 mL), Dess-Martin periodinane (95 mg, 0.22 mmol) was slowly added. The reaction mixture was stirred at room temperature for 40 min. The reaction mixture was neutralized with 1 M NaOH, diluted with MeOH, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography using CombiFlash® (0 to 100% EtOAc in hexanes) to give light brown powder as the sub-title compound (41 mg, 41%). LCMS calc. for C30H31F3N5O4 (M+H)+: m/z=582.2. Found: 582.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:15])[S:9][C:10]=1[NH:11][C:12]([NH2:14])=[O:13])=O)C.[OH-].[Na+]>CC(O)C.O>[CH3:15][C:8]1[S:9][C:10]2[NH:11][C:12](=[O:13])[NH:14][C:4](=[O:3])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1nc(C)sc1NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2c(=O)[nH]c(=O)[nH]c2s1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a suspension of 2-methyl-5-ureido-thiazole-4-carboxylic acid ethyl ester (21.0 g, 0.079 mol) in iPrOH (300 mL) was added an aqueous solution of NaOH (3 M, 26 mL, 0.078 mol) at 80° C. The thick white suspension was heated at 80° C. for 45 min, then diluted with H2O and cooled to 0° C. The reaction mixture was acidified to pH 3 and the precipitate collected by filtration. The white solid was washed with H2O and dried in vacuo at 60° C. for 17 h to give the title compound as a white solid (12.3 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:16]=1[C:15]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=1[Cl:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nccs1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccc(Cl)cc2Cl)nc2sccn12

Procedure:
Compound 30 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,4-dichlorobenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: COC([CH:5]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=O.[C:28]([OH:34])(C(F)(F)F)=[O:29].[CH2:35](Cl)Cl>C(Cl)Cl>[CH3:35][O:34][C:28]([C@H:6]1[CH2:5][N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][N:12]=2)[CH2:9][CH2:8][NH:7]1)=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cn1
Reactant: ClCCl
Product: COC(=O)[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (110 mg, 0.28 mmol) was combined with 2.0 mL of 25% TFA/CH2Cl2 and was stirred at room temperature for 30 min. After this period the reaction mixture was diluted with CH2Cl2 (25 mL) and was washed with sat'd NaHCO3 (2×10 mL) and brine. The resulting CH2Cl2 layer was dried over anhydrous Na2SO4 and was evaporated in vacuo to yield crude amine. The crude amine was purified using flash silica chromatography (0-10% MeOH/CH2Cl2) to yield 77 mg (94%) of (R)-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester as a yellow residue. This material was combined with 6-Chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester from Step 2 (102 mg, 0.27 mmoles) and triethylamine (46 μL, 0.33 mmol) in 2.0 mL of anhydrous THF, and was stirred at 60° C. for 5 hours. After this period the reaction mixture was evaporated in vacuo and the resulting residue was combined with 30 mL of benzene. The resulting heterogeneous mixture was filtered with benzene washings. The filtrate was then evaporated in vacuo and purified using flash silica chromatography (0-30% EtOAc/Hexane) to yield 4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](C=O)=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:37][C:38](=[O:40])[CH3:39])C=CC=CC=1.[CH:53]1C=CC=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([CH:53]=[CH:37][C:38](=[O:40])[CH3:39])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=1)([O:3][CH3:4])=[O:2]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: c1ccccc1
Product: CCCCc1nc(Cl)c(C=CC(C)=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
A mixture of 0.5 g of 1-(2'-carbomethoxybi-phenyl-4-yl)methyl-2butyl-4-chloroimidazole-5-carboxaldehyde and 0.04 g of 1-triphenylphosphoran-ylidene-2-propanone in 20 mL of benzene was refluxed for 16 hours. The reaction mixture was concentrated to give an oily residue which was purified by flash chromatography on silica gel (hexane:ethyl acetate=1:1 elution). The desired compound was obtained as a thick yellowish liquid, 0.46 g; NMR (200 MHz, CDCl3): δ 7.9-6.8 (m, 10H); 5.24 (s, 2H); 3.62 (s, 3H); 3.62 (s, 3H); 2.69 (t, 2H, J=7.4 Hz); 2.26 (s, 3H); 1.72 (m, 2H); 1.38 (m, 2H); 0.91 (t, 3H, J=7.4 Hz).
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH3:15])=[CH:9][C:8]=1[F:31])(C)(C)C.C(OCC)C>C(O)=O>[CH2:24]([O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([F:31])[CH:9]=1)[CH2:14][CH3:15])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)c(F)c1
Solvent: O=CO
Solvent: CCOCC
Product: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)c(F)c1

Procedure:
tert-Butyl-4-[N-(2-benzyloxybenzyl)-N-ethylamino]-2-fluorobenzoate (1.81 g) in formic acid (5 mL) was heated on a steam bath until a clear solution was obtained. The reaction mixture was evaporated to dryness and the oil obtained solidified on trituration with diethyl ether to give 4-[N-(2-benzyloxybenzyl)-N-ethylamino]-2-fluorobenzoic acid, yield 0.51 g, mp 154° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=3)[O:12][CH2:13][C:14]=2[CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: c1ccc(CNc2ccc3c(c2)COC(Nc2cccc(C4CC4)c2)=N3)cc1
Yield: 55 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (200 mg, 0.72 mmol) and benzaldehyde (68 mg, 0.66 mmol) according to the procedure described for example 88. Obtained the title compound as a white foam (134 mg, 67%), MS (ISP) m/e=370.1 [(M+H)+].