Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]1=[O:18].O.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]1=[O:18]
Reactant: COC(=O)C1CN(Cc2ccccn2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)N(Cc2ccccn2)CC1C(=O)O
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A suspension of sodium hydride (240 mg, 6 mmol, 60% dispersion in oil) in N-methyl-2-pyrrolidinone (6 ml) was stirred at 0° C. under argon. A solution of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (474 mg, 3 mmol) (prepared as described in step (ii) of Example 8) in N-methyl-2-pyrrolidinone (3 ml) was added dropwise over 10 minutes. The reaction was stirred at 0° C. for 15 minutes and 2-(bromomethyl)pyridine hydrobromide (835 mg, 3.3 mmol) was added portionwise over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 20 hours. The reaction was treated with ice water and extracted with dichloromethane. The mixture was applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg), LC/MS [M+H]+=250. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg, 0.76 mmol) in tetrahydrofuran (1.5 ml)/water (1 ml) at 0° C. was treated with lithium hydroxide (55 mg, 2.28 mmol) and the reaction mixture was stirred at 0-5° C. for 3 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue was dried to give 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylic acid which was used crude in the next step.
Reaction SMILES: C(=O)(OCC1C2(O)ON(CC3C2N3)C2C1=C(O)C=C(C=O)C=2)N.NC1C=CC=CC=1.[C:31](=[O:59])([O:33][CH2:34][CH:35]1[C:47]2([OH:49])[O:48][N:42]([CH2:43][CH:44]3[CH:46]2[NH:45]3)[C:41]2[C:36]1=[C:37]([OH:58])[CH:38]=[C:39]([CH:50]=[N:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH:40]=2)[NH2:32]>CO.[Pd]>[C:31](=[O:59])([O:33][CH2:34][CH:35]1[C:47]2([OH:49])[O:48][N:42]([CH2:43][CH:44]3[CH:46]2[NH:45]3)[C:41]2[C:36]1=[C:37]([OH:58])[CH:38]=[C:39]([CH2:50][NH:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH:40]=2)[NH2:32]
Reactant: NC(=O)OCC1c2c(O)cc(C=Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Agent: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: Nc1ccccc1
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(CNc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in methanol (5 ml). Aniline (0.05 ml) was added to this solution and the mixture was allowed to stand at room temperature for 3 hours to give a solution containing 6,9-dihydroxy-4-phenyliminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate. 10% Palladium on carbon (100 mg) was added to the solution, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere (4.5 atm). The mixture was filtered through cellulose powder and the filter cake was washed with methanol (20 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v/v) to afford 4-anilinomethyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg).
Reaction SMILES: Cl.[NH:2]([C:6]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1)C(C)=O>CO>[NH2:2][C:6]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Agent: Cl
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Reaction time: 8 h
Yield: 91.6 %

Procedure:
400 ml of 4N hydrochloric acid in methanol were added dropwise at reflux temperature to 22.4 g of 7-acetamino-8-nitro-3,4-dihydro-2H-1,5-benzodioxepine in 2000 ml of methanol, then the mixture was boiled overnight. After evaporation, the residue was taken up in methylene chloride, washed with 2N soda and twice with water, dried over sodium sulfate and again evaporated. The crude product was recrystallized from alcohol. 17.1 g (92.0% of theory) of 7-amino-8-nitro-3,4-dihydro-1H-1,5-benzodioxepine of melting point 125°-126° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[F:8][C:3]1[C:2]([NH:1][C:13]2[C:14](=[O:19])[C:15](=[O:16])[C:12]=2[O:11][CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccnc1F
Solvent: CCO
Product: CCOc1c(Nc2cccnc2F)c(=O)c1=O

Procedure:
A solution of Example 63A and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 62A to provide the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])[CH:11]=1
Reactant: CC(C)=O
Reactant: COc1ccc(Cl)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)cc1C=CC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In water (100 ml) was dissolved sodium hydroxide (3.0 g), and to the solution was added acetone (80 ml) and then was added dropwise a solution of 5-chloro-2-methoxybenzaldehyde (11.8 g) in acetone (30 ml). The reaction solution was stirred at room temperature for 2 hours, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(5-chloro-2-methoxyphenyl)-3-buten-2-one (6.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([N:17]=[C:18]=[S:19])=[O:16]>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:18](=[S:19])[NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][CH:22]=[C:12]([CH3:11])[CH:13]=1)=[O:5]
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Product: Cc1cccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)c1
Yield: 89.3 %

Procedure:
To a stirred mixture of 7.2 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 10 g of 3-methylbenzoyl isothiocyanate over 10 minutes. After 48 hours the solid was recovered, giving 14.8 g of N-[[[2-(aminocarbonyl)phenyl]amino]thioxomethyl]-3-methylbenzamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12]([NH2:14])[CH3:13]>O>[CH2:12]([NH:14][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])[CH3:13]
Reactant: NS(=O)(=O)c1cnccc1Cl
Reactant: CCN
Solvent: O
Product: CCNc1ccncc1S(N)(=O)=O

Procedure:
By carrying out the reaction as in Preparation 13, but starting from 2 g of 4-chloropyridine-3- sulfonamide and 20 cm3 of 70% ethylamine in water, the compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:9][N+:10]([O-:12])=[O:11])[C:14]([CH3:16])([CH3:15])[CH:13]=[O:17])=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)(C=O)[C@@H](C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
The title compound was prepared from trans-1-bromo-4-(2-nitrovinyl)benzene and isobutyraldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=10:90), 1 mL/min; tmajor=11.5 min, tminor=9.3 min, [α]D20=−2.4 (c=2.9, CHCl3);
Reaction SMILES: [Si](O[C@H](C)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:24][CH2:25][CH2:26][CH2:27][C@:28]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:32]([C:33](=[O:38])[C@@H:34]([O:36][CH3:37])[CH3:35])[N:31]=[C:30]([C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[F:46])[S:29]1.NCCC[C@@]1(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=C(C2C=C(F)C=CC=2F)S1>>[NH2:24][CH2:25][CH2:26][CH2:27][C@:28]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:32]([C:33](=[O:38])[C@H:34]([O:36][CH3:37])[CH3:35])[N:31]=[C:30]([C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[F:46])[S:29]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1
Agent: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Product: CO[C@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 71 using (R)-2-(t-butyldiphenylsilyloxy)propanoic acid in place of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid. MS ESI (+) m/z 420 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.46 (d, 2H, J=7 Hz), 7.37 (t, 2H, J=8 Hz), 7.30 (t, 1H, J=7 Hz), 7.13 (m, 2H), 4.71 (q, 1H, J=6 Hz), 3.32 (s, 3H), 3.24 (m, 1H), 2.83 (m, 2H), 2.43 (m, 1H), 1.92 (m, 1H), 1.51 (d, 3H, J=6 Hz), 1.45 (m, 1H). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one and (S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].C(OC([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)=O)C1C=CC=CC=1>N1C=CC=CC=1>[NH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:20][CH2:19][N:15]2[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]3[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:38](=[O:39])[C:37]4[CH:36]=[CH:35][C:34]([NH2:33])=[CH:42][CH:41]=4)[C:4](=[O:22])[CH2:5]3)[CH2:17][C:16]2=[O:18])=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Nc1ccc(C(=O)Cl)cc1)OCc1ccccc1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Solvent: c1ccncc1
Product: Nc1ccc(C(=O)OCN2C(=O)CN(CCN3CC(=O)N(COC(=O)c4ccc(N)cc4)C(=O)C3)CC2=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 114.7 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.63 g, 2.0 m mol) and pyridine (10 ml), p-benzyloxycarbonylaminobenzoyl chloride (1.27 g, 4.4 m mol) dissolved in pyridine (12 ml) was added gradually at 0° C. and then the reaction mixture was stirred for 1 hour at 0° C. and successively for 16 hours at room temperature. The residue obtained by removing the solvent from the reaction mixture under reduced pressure was added to water (50 ml) and extracted with chloroform (150 ml×2). The extract solution was washed with 10% sulfuric acid solution and successively with water, further was washed with saturated sodium bicarbonate aqueous solution and successively with water and was dried. The residue obtained by removing the solvent from the extract solution was purified by silica gel column chromatography (ethyl acetate) to give benzyloxycarbonyl derivative of the titled compound (1.27 g; yield 77.4%). The derivative (1.27 g) was dissolved in a mixture of ethyl acetate (80 ml) and ethanol (80 ml), and 10% palladium-carbon (0.13 g) was added and the mixture was stirred overnight under hydrogen at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=95:5) and recrystallized from ether to give the titled compound (0.39 g; yield 45.7%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:4]>CC(O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][N:5]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:3](=[O:4])[C:2]([F:23])([F:1])[F:22])[CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)CCN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Product: CS(=O)(=O)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]-N-[(3-nitrophenyl)methyl]acetamide (0.88 g, 2.5 mmol) in 2-propanol (75 mL) was added 10% Pd/C (80 mg). The reaction was stirred at rt under a hydrogen atmosphere (1 atm) for 72 h. The reaction mixture was filtered through Celite, adsorbed to silica, and purified by column chromatography to generate the title compound in 93% yield (0.75 g, 2.3 mmol). 1H NMR (400 MHz, CDCl3): δ 7.17 (t, J=7.9 Hz, 1H), 6.66 (d, J=6.9 Hz, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.53 (s, 1H), 4.62 (s, 2H), 3.72-3.77 (m, 4H), 3.18 (t, J=6.8 Hz, 2H), 3.01 (s, 3H). MS (ESI) m/z=324 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]1[N:15]([CH2:16][CH2:17][CH3:18])[C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCCNC1Cc2ccccc2C1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)CC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
Propionic acid chloride (2 mL, 2.1 g, 23 mmol) was added dropwise to a solution of indan-2-yl-propylamine (4.0 g, 23 mmol) and triethyl amine in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours. Aqueous (10%) sodium carbonate was added and the mixture was shaken. The organic phase was dried (magnesium sulfate), filtered and evaporated to yield 4.5 g (85%) of the title compound as an oil.:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](=[O:29])[N:23]([CH2:25][C:26]([OH:28])=O)[CH:24]=2)=[CH:15][CH:14]=1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:9]([CH3:10])[C:26](=[O:28])[CH2:25][N:23]1[CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH:20]=[CH:21][C:22]1=[O:29]
Reactant: CNCc1cccc(Cl)c1
Reactant: COc1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(=O)n(CC(=O)N(C)Cc3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
According to Scheme 9 Step 3: To a solution of (3-chlorophenyl)-N-methylmethanamine (1 eq, 0.19 mmol, 0.03 g), 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetic acid (1 eq, 0.19 mmol, 0.05 g) and hydroxybenzotriazole (1.1 eq, 0.21 mmol, 0.03 g) in CH2Cl2 (2 mL) at room temperature was added EDCI.HCl (1.5 eq, 0.29 mmol, 55 mg). The reaction was stirred at room temperature for 12 hours then diluted with AcOEt. The reaction washed with brine and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt (50/50) as eluent to afford the N-(3-chlorobenzyl)-2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-N-methylacetamide (0.11 mmol, 44 mg, 57%) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([CH:18]=[O:19])[NH:8][C:7]=1[CH2:20][CH2:21][NH2:22])=O)C.O.[OH-].[Li+].O>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:6]3[C:4](=[O:3])[NH:22][CH2:21][CH2:20][C:7]=3[NH:8][C:9]=2[CH:18]=[O:19])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(CCN)[nH]c(C=O)c1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
A stirred solution of 2-(2-amino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester (257.5 mg, 2.5 mmol), lithium hydroxide monohydrate (840 mg, 20 mmol) in ethanol (95%, 20 ml) was heated to reflux under an argon atmosphere for 3 hours. The mixture was added with cold water (150 ml), stirred for 10 minutes, extracted with a 5 to 1 solvent mixture of dichloromethane and methanol (50 ml×7), washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from dichloromethane and methanol to give 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (170 mg, 26.3%) as a red solid.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:23])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6](=[O:23])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(CCCCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CCCCc1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
A solution of 17.8 g of potassium hydroxide in 200 ml of ethanol is added dropwise to 91 g of 4-phenylbutylmalonic acid diethyl ester in 200 ml of ethanol at room temperature (20° C.). The mixture is stirred for 24 hours and substantially concentrated in vacuo; the residue is taken up in 500 ml of water, and the aqueous mixture is extracted twice with 100 ml of diethyl ether each time. The aqueous phase is acidified with concentrated hydrochloric acid (while cooling with ice) and extracted 3 times with 200 ml of diethyl ether each time; after drying over sodium sulfate, the organic phase is concentrated. 72.8 g of a viscous oil remain.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1.O>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
Aniline (3.4 g, 37 mmol) was dissolved in pyridine (50 mL), then ethyl chloroxoacetate (5.0 g, 37 mmol) was added to the resulting solution dropwise. The resulting mixture was stirred at room temperature for 48 hours, then diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with 1N HCl, water, brine, then dried (Na2SO4) and concentrated to provide 5.8 g (81%) of an oil that crystallized on standing. 1H-NMR (DMSO-d6) δ: 1.3 (t, J=7 Hz, 3H), 4.3 (q, J=7 Hz, 2H), 7.1–7.8 (m, 5H), 10.7 (s, 1H); MS ES+m/e 194.2 (p+1), ES−m/e 192.3 (p−1).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10]CC)=O)=[CH:5][CH:4]=1)#[N:2].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:8]([C:6]1[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:10])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1ccc(C#N)s1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(C#N)s1

Procedure:
Prepared from ethyl 5-cyano-2-thiophenecarboxylate [CAS-No. 67808-35-9] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow solid (6.66 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:39]=[C:27]1[CH2:28][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:9]=2[NH:22]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccn2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccn4)cc3NC(=O)C2)c1
Yield: 85.5 %

Procedure:
Prepared from (2-amino-4-pyridin-2-ylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G19) (124 mg, 0.4 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (147 mg, 0.48 mmol) according to the general procedure K. The obtained material (199 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (124 mg).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A dry 100 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.9339 g, 5.49 mmol) and thionyl chloride (6 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (80 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 5-Acetyl-thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.16 g, 3.94 mmol, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[N:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccncc21
Product: CC1c2cnccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.