Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=c1ccoc(CO)c1O
Reactant: CCOC(=O)CCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1c(CO)occc1=O
Yield: 54 %

Procedure:
To a solution of 2.75 g (0.042 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 5.93 g (0.042 mole) of 2-hydroxymethyl-3-hydroxy-4-pyrone, and the resulting mixture heated to 50°. A 12.4 g (0.046 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atomsphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 6.34 g (54%) of oily product, 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone: NMR (CDCl3): δ1.22 (3H, t, J = 7Hz), 2.30 (2H, t, J = 5.5 Hz), 4.63 (2H, s), 6.35 (1H, d, J = 6 Hz), 7.73 (1H, d, J = 6 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=O)[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=C1NS(=O)(=O)c2cccc(F)c21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2c(F)cccc21
Yield: 93.3 %

Procedure:
1.1 g of 4-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 2 g of thionyl chloride and a catalytic amount of DMF in 6 ml of dioxane are heated under reflux for 18 hours. Then additional 2 g of thionyl chloride are added and the mixture is heated for 8 hours. The mixture is concentrated and 1.12 g of a crude solid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:17][CH:16]([CH2:18][NH2:19])[CH2:15]1)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2.[O:22]=[C:23]1[NH:28][C:27]2[N:29]=[C:30]([CH:33]=O)[CH:31]=[CH:32][C:26]=2[S:25][CH2:24]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:15][CH:16]([CH2:18][NH:19][CH2:33][C:30]3[CH:31]=[CH:32][C:26]4[S:25][CH2:24][C:23](=[O:22])[NH:28][C:27]=4[N:29]=3)[CH2:17]1)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC(CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3CC(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 12 h
Yield: 109 %

Procedure:
To a stirred solution of [(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azetidinyl)methyl]amine (138 mg, 0.47 mmole) in dry CH2Cl2 (40 mL) and dry EtOH (5 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (91 mg, 0.47 mmole). After 12 h, NaBH4 was added to the reaction solution. After 4 hrs, silica gel was added to the reaction contents and the slurry was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.24 g, 50%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (1H, s), 8.17 (1H, d, J=9.0 Hz), 7.55 (1H, d, J=7.8 Hz), 7.04 (1H, d, J=9.0 Hz), 6.93 (1H, d, J=7.8 Hz), 4.08 (3H, s), 3.79 (2H, s), 3.51 (2H, t, J=7.4 Hz), 3.44 (2H, s), 3.22 (2H, app t), 2.95 (2H, t, J=6.7 Hz), 2.82 (4H, m), 2.65 (1H, m). LC-MS (ES) m/e 467 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([OH:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C(O)(=O)C.[N:23]1C=C[CH:26]=[CH:25][CH:24]=1>>[C:24]([C:25]1[C:26](=[C:15]([C:14]#[N:18])[C:16]#[N:17])[O:12][C:9]([CH3:11])([CH3:10])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)#[N:23]
Reactant: CC(C)(O)C(=O)c1ccc(Br)cc1
Reactant: c1ccncc1
Reactant: N#CCC#N
Solvent: CC(=O)O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the crude liquid 1-(4-bromophenyl)-2-hydroxy-2-methyl-propan-1-one (28.0 g, 65% 115 mmol, 74 mmol), malononitrile (35 g, 0.52 mol), acetic acid (0.4 g) and dry pyridine (100 mL) was stirred at room temperature for 24 hrs. The reaction mixture was then poured into 1 L of ice water with vigorous stirring and kept in the refrigerator overnight. The yellow precipitate was collected by vacuum filtration, washed with methanol and dried under vacuum. The product was recrystallized from 70% dichloromethane/methanol. Yield: 10.0 g (40%). mp: 235° C. 1H NMR (400 MHz, CDCl3) δ 1.77 (s, 6H),) 7.58 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H). 13C NMR (100 MHz, (100 MHz, CDCl3) δ 176.55, 174.76, 133.35 129.40, 129.18 125.89, 111.05, 110.19, 110.05, 99.21, 26.09.
Reaction SMILES: C1(CC(Cl)=O)CCCCC1.[CH:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:11]1([CH2:17][C:18]([NH:20][C:21]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([O:37][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][CH:29]=3)=[CH:39][CH:40]=2)=[S:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CC1CCCCC1)N=C=S
Agent: O=C(Cl)CC1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CC4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Cyclohexylethanoyl isothiocyanate was prepared using commercially available 2-cyclohexylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Cyclohexylethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[N:9]2[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=[O:4].[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:10]2[N:9]3[C:5]([C:3](=[O:4])[C:2]([F:26])([F:1])[F:27])=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:23]1=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2ncc(C(=O)C(F)(F)F)n12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3ncc(C(=O)C(F)(F)F)n23)C1=O

Procedure:
To a solution of 250 mg (0.6 mmol) of 3-[4-(3-trifluoroacetylimidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 54 μl (0.6 mmol) of n-butyraldehyde in 5 ml of ethanol, 6 μl (0.06 mmol) of piperidine was added, followed by refluxing for 1 hour. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 200 mg (70.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].S(OC)(O[CH3:24])(=O)=O>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH3:24])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccncc1)c1csc2cc(Cl)ccc12
Product: Cl
Temperature: 0 °C
Yield: 167.6 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (3 g, 11.5 mmol) was added portionwise as a powder to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.7 g, 17.5 mmol, washed with heptane) in 25 mL of dimethylformamide. After anion formation was completed dimethyl sulfate (1.6 g, 12.7 mmol) was added. After one hour the reaction mixture was poured into ice-water and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to give 3 g of a brown oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography yielded 1.7 g of an amber oil. Conversion to the hydrochloride salt in 10% methanol in ether afforded 1.4 g of yellow crystals, mp 280°-281° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([CH2:13]C(O)=O)[CH2:10][C@H:9]1[C:17]([N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)=[O:18])=O)(C)(C)C.F[C@H]1CCNC1.C(N1CCN([C:38](=[O:52])[CH2:39][CH:40]2[CH2:44][C@@H:43]([C:45](N3CCSC3)=O)NC2)CC1)C.C(N(CCC)C(C)C(NC[CH:62]1[CH2:66][CH:65]([C:67]([N:69]2CCSC2)=[O:68])NC1)=O)CC>>[O:52]([CH2:62][CH2:66][CH2:65][C:67]([NH:69][CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:17]([N:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[O:18])[NH:8][CH2:12]1)=[O:68])[C:38]1[CH:39]=[CH:40][CH:44]=[CH:43][CH:45]=1
Reactant: CCN1CCN(C(=O)CC2CN[C@H](C(=O)N3CCSC3)C2)CC1
Reactant: CCCN(CCC)C(C)C(=O)NCC1CNC(C(=O)N2CCSC2)C1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C[C@H]1C(=O)N1CCSC1
Agent: F[C@H]1CCNC1
Product: O=C(CCCOc1ccccc1)NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1

Procedure:
(2S′, 3S, 5S)-2-Dipropylamino-N-[5-(thiazolidine-3-carbonyl)-pyrrolidin-3-ylmethyl]-propionamide;
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].S(Cl)(Cl)=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/C(O)=O)=[CH:14][C:13]=1[O:23][CH3:24].[OH2:25]>>[CH3:24][O:23][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[O:11][CH3:10])[CH:18]=[CH:19][C:3]([NH:2][C:1]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:12]([OH:11])=[O:25])=[O:4]
Reactant: CN(C)C=O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: O
Solvent: O=S(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Into 15 ml of dimethylformamide was dissolved with heating 4.65 g (0.02 mol) of anthranilic acid-magnesium chloride complex. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g (0.01 mol) of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. After being stirred for additional 15 minutes, the resulting mixture was added dropwise to the solution of anthranilic acid-magnesium chloride complex. After the completion of the dropping, the reaction mixture was stirred for 30 minutes at the same temperature and then for 1 hour at room temperature. After the completion of the reaction, 80 ml of ice-water mixture was added thereto. Then, air was introduced thereinto for 30 minutes, and crystals deposited were collected by filtration and recystallized from ethanol-water (1:3) to give 2.58 g (78.9%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. Molting point: 209°-211° C.
Reaction SMILES: ClCC(O)CO.CN.CO.Cl.[CH3:12][NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17].[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>CO.C(N(CC)CC)C>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:13]([CH3:12])[CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:24]
Reactant: CNCC(O)CO
Reactant: O=C=NCCCl
Agent: CN
Agent: Cl
Agent: OCC(O)CCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CC(O)CO)C(=O)NCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A mixture of 3.3 g of 3-chloro-1,2-dihydroxy-n-propane and 20 ml of 30% methylamine-methanol solution is allowed to stand at room temperature for 3 days. The reaction mixture is condensed to dryness under reduced pressure, whereby 4.2 g of N-methyl-2,3-dihydroxy-n-propylamine hydrochloride are obtained as a crude product. 4.2 g of said crude product and 3 g of triethylamine are dissolved in 30 ml of methanol. To the solution, 3.2 g of 2-chloroethyl isocyanate are added dropwise to the solution at 0° to 5° C. The solution is stirred at room temperature for 2 hours. Then, the reaction solution is condensed under reduced pressure and the residue thus obtained is purified by silica gel chromatography (Solvent: chloroform-ethyl acetate-methanol(3:1:1)). 3.5 g of 1-(2-chloroethyl)-3-methyl-3-(2,3-dihydroxy-n-propyl)urea are obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][NH:24][CH3:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Reactant: CNC
Product: Cc1ccccc1N1CCc2c(N(C)C)nc3c(C)cccc3c21
Yield: 63 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.5 g. 4.9 mmol) and dimethylamine (33% in ethanol. 150 ml) were heated to 180° C. in a pressure vessel for 18 hours, then evaporated, taken up in dichloromethane, washed with sodium bicarbonate, dried and evaporated. Crystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4-dimethylamino- 6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.97 g, 63%), m.p. 120°-121°.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[C:12]3[C:13](=[O:21])[NH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:11]=3[N:10]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:9]=2)[CH:4]=1)#[N:2].[C:27](=[O:30])([O-])[OH:28].[Na+].Cl.[NH2:33]O.O>CS(C)=O>[CH:22]1([N:10]2[C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][NH:14][C:13](=[O:21])[C:12]=3[C:8]([C:5]3[CH:4]=[C:3]([C:1]4[NH:33][C:27](=[O:30])[O:28][N:2]=4)[S:7][CH:6]=3)=[CH:9]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1c[nH]c(=O)c2c(-c3csc(C#N)c3)cn(C3CCCC3)c12
Reactant: NO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1c[nH]c(=O)c2c(-c3csc(-c4noc(=O)[nH]4)c3)cn(C3CCCC3)c12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of methyl 3-(5-cyano-3-thienyl)-1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (111 mg) obtained in Example 73 in DMSO (2 mL) were added sodium hydrogencarbonate (127 mg) and hydroxylamine hydrochloride (84 mg) at room temperature, and the mixture was stirred at 90° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in THF (2 mL) were added 1,1′-carbonyldiimidazole (73.5 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.068 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:23]>CO>[NH2:23][C:15]([C:13]1[NH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=3)[C:7]=2[CH:14]=1)=[O:16]
Reactant: N
Reactant: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Solvent: CO
Product: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1

Procedure:
90 mg (0.285 mmol) of 4-(3-chloroanilino)-6-ethoxycarbonyl-7H-pyrrolo-[2,3-d]pyrimidine (stage 1.4) in 30 ml of methanol and≈5 g of ammonia are heated at 120° C. for 48 h in an autoclave. The reaction mixture is treated with silica gel, evaporated, applied to a silica gel column as a powder and finally eluted with methylene chloride/methanol/THF (210:35:10). Filtration with methanol through an alumina column (basic) and stirring in ethyl acetate yields 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=8.1; TLC-Rf=0.18 (CH2Cl2/methanol [10:1]); high resolution MS: (M+H)+=288.0669 (calc. 288.0652).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:4]([OH:5])=[O:3])=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Nc2c(C(=O)O)[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.1 %

Procedure:
To a solution of 3-(4-methoxybenzoyl)amino-2-indolecarboxylic acid ethyl ester (720 mg, 2.13 mmol) in tetrahydrofuran (7 mL) was added 5 N aqueous sodium hydroxide (2 mL). The resulting mixture was stirred for 10 h at room temperature. An additional portion of 5 N aqueous sodium hydroxide (5 mL) was added and the mixture heated at 60° C. for 5 h. The mixture was cooled to room temperature, stirred for 10 h, diluted with water, and extracted with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with three fresh portions of ethyl acetate. The combined ethyl acetate fractions were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 450 mg (68%) of the title compound as a yellow solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[CH:34]1[C:46]2[CH:45](O)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:45]1[C:46]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]3[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:11])[CH2:3]2
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(OC1c2ccccc2-c2ccccc21)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (95 mg, 0.50 mmol), EDC (143 mg, 0.74 mmol), triethylamine (242 μl, 1.73 mmol), and HOBT (114 mg, 0.74 mmol) were dissolved in dry THF (5 ml). 9H-fluoren-9-ol (99 mg, 0.54 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. The resulting suspension was stirred at room temperature overnight. The mixture was evaporated, and the crude taken up with EtOAc and washed sequentially with water and sat. NaHCO3. The organic phase was dried over sodium sulfate, filtered. and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/1) to afford 9H-fluoren-9-yl quinuclidine-3-carboxylate (102 mg, racemic mixture).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cn1
Product: Cl
Temperature: 60 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To solution of 5-hydroxypicolinic acid (820 mg, 5.89 mmol) in methanol (20 mL) was dropwise added thionyl chloride (0.430 mL, 5.89 mmol) at rt. The mixture was stirred at 60° C. for 20 h. The mixture was concentrated in vacuo to give a crude methyl 5-hydroxypicolinate hydrochloride (1.12 g, 5.89 mmol, 100% yield), which was used for the next step without purification. LCMS (M+H)+=154.01. 1H NMR (500 HMz, methanol-d4) δ 8.45 (d, J=6.0 Hz, 2H), 8.08 (dd, J=9.0, 2.3 Hz, 1H), 4.09 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.[NH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzaldehyde (400 mg) in dichloromethane (4.00 mL) were added anhydrous magnesium sulfate (615 mg) and tert-butyl glycinate hydrochloride (679 mg), followed by stirring at room temperature overnight. The reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (12.0 mL), and sodium borohydride (193 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain tert-butyl N-(2-chloro-4-hydroxybenzyl)glycinate (613 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:14][CH2:13]1)[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14]1)[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2C1CC1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2C1CC1

Procedure:
5-Amino-1-cyclopropyl-7-fluoro-1,3-dihydro-indol-2-one (0.560 g, 2.72 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.472 g, 2.72 mmol) and lithium trifluoromethanesulfonate (0.415 g, 2.72 mmol) in acetonitrile (5 ml) are heated at 85° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow solid. HPLC r.t. 3.98 min; MS for C19H26FN3O4 m/z 380.1 (M+H)+.