Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(OC(=O)C)(=O)C.CC1OC(C)(C)OC(=O)C=1.C=C1OC(=O)C1>>[CH2:4]1[CH:5]2[N:6]([C:9](=[O:11])[CH2:8][CH2:7]2)[C:2](=[O:1])[CH2:3]1
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C=C1CC(=O)O1
Agent: CC1=CC(=O)OC(C)(C)O1
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC2CCC(=O)N12

Procedure:
In a process for preparing dihydro-1H-pyrrolizine-3,5(2H, 6H)-dione comprising the steps of catalytically hydrogenating an ester of 4-(hydroxyimino)heptanedioic acid and subsequently cyclizing the resulting product to dihydro-1H-pyrrolizine-3,5(2H,6H)-dione, the improvement comprises reacting an alcoholic solution of a mono(lower alkyl) ester of 4-(hydroxyimino)heptanedioic acid, wherein lower alkyl comprises from one to three carbon atoms, with hydrogen gas at a temperature of about 60° C. in the presence of rhodium/alumina catalyst and a tertiary lower alkyl amine, wherein said lower alkyl amine comprises from three to nine carbon atoms, to produce 5-oxo-2-pyrrolidinepropanoic acid; and thereafter heating said 5-oxo-2-pyrrolidinepropanoic acid in the presence of a cyclizing agent selected from acetic anhydride, 2,2,6-trimethyl-1,3-dioxen-4-one, and diketene at a temperature of about 90° C. to produce dihydro-1H-pyrrolizine-3,5(2H,6H)-dione.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>S(=O)(=O)(O)O>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 35 °C

Procedure:
To 758 g (7.7 moles) of cyclohexanone were added 260 g (1.44 moles) of anhydrous dextrose, followed by 20 ml of concentrated sulfuric acid. The mixture was heated to 35° C. and monitored by TLC. The flow rate of the desired product using Solvent A was Rf =0.95.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[C:8]([NH:15][C@@H:16]([CH2:18][OH:19])[CH3:17])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl>C1COCC1.O.CCOC(C)=O>[C:11]([O:10][C:8]([NH:15][C@H:16]([CH3:17])[CH2:18][O:19][CH2:4][C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](COCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 4.58 g, 114 mmol) was added portionwise to a solution of 2-bromoacetic acid (5.3 g, 38.1 mmol) and N-Boc-D-alaninol (10.0 g, 57.2 mmol) in THF (100 ml) at 0° C. The reaction mixture was stirred for 48 h at room temperature, diluted with water, washed 2× with EtOAc, hydrochloric acid (1M, 84 ml, 84 mmol) was added to the aqueous layer (pH 2-3) and the aqueous layer extracted 2× with DCM. The DCM layers were dried over Na2SO4 and evaporated to give the title compound as a yellow oil which crystallised on standing. (MS) ESI-MS 256.2 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[Cl:19])[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccccc1Cl
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccccc2Cl)nc(N)n1
Yield: 31 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 2-chloroaniline provided the title compound (31% yield). 1H NMR (DMSO-d6) δ 1.19-1.22 (t, 3H, CH3), 4.0-4.1 (q, 2H, CH2), 6.0-6.30 (s, 2H, NH2), 6.65 (s, 1H, Ar), 7.05-7.29 (m, 4H, Ar), 7.316 (d, 1H, Ar) 7.354 (d, 1H, Ar) 7.90 (d, 1H, Ar) 8.8 (br s, 1H, NH).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[F:18].[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][C:29]([C:32]#[N:33])([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[F:18])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1cnccc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Potassium hexamethyldisilazane (1.2 ml, 0.5 M solution in toluene) was slowly added to a solution of 4-chloro-3-fluoro-pyridin (0.5 g) and N-Boc-4-Cyano-Piperidine (0.312 g) in 1.5 ml toluene at room temperature, under nitrogen. The mixture was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was quenched in 1N HCl. The aqueous phase was extracted twice with toluene and the combined organic were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography [SiO2; ethyl acetate-hexane (1:1)] to give 104 mg (90%) of 4-cyano-3′-fluoro-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acid tert-butyl ester; MS (ES+) 306 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=O)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CCC(=O)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[6-(t-Butyldimethylsilanyloxymethyl)pyridin-2-yl]-propionic acid (1.65 g) was dissolved in 20 mL of methylene chloride, and 584 μL of morpholine, 1.6 g of WSC and 1.56 mL of triethylamine were added to the solution, and then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform, transferred into a separating funnel, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (chloroform-methanol=30:1) to give 1.91 g of 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]-1-morpholin-4-yl-propan-1-one as a yellow oil.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
4.7 g of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in 60 ml of methanol in the presence of 2.35 g of 10% Pd/C at room temperature and under normal pressure for 1 hour. Filtration of the reaction mixture and concentration of the filtrate by evaporation under a high vacuum yield the title compound: Rf (hexane/ethyl acetate=1:1)=0.15; FAB-MS (M+H)+ =509.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(OC[C@@H]2CCN2)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The compound of step 109b was dissolved in CH2Cl2 (10 mL) and TFA (10 mL) was added at 0° C. After 30 minutes of stirring the reaction was warmed to room temperature and stirred for an additional 45 minutes. Solvent was removed, and the residue was partitioned between sat'd K2CO3 solution and CH2Cl2. The aqueous layer was further extracted with CH2Cl2 (4×), and the combined organic extracts were dried over MgSO4 and concentrated. The crude material was chromatographed eltuing with 10% methanol/CHCl3 followed by 10% methanol/CHCl3 /0.5% NH4OH to give 475 mgs of a pale solid, 64% yield. m.p.=59-60° C. MS (CI) m/e 233 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.01 (d, J=2.8 Hz, 1H), 7.37 (d, J=2.8 Hz, 1H), 4.33-4.24 (m, 1H), 4.08-3.98 (m, 2H), 3.73 (dd, J=15.8, 8.4 Hz, 1H), 3.49-3.41 (m, 1H), 2.44-2.21 (m, 2H).
Reaction SMILES: COP([CH2:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)(=O)OC.[CH:24]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[N:30][CH:31]=1)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([CH:24]=[CH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)=[CH:27][N:28]=1
Reactant: Cc1ncc(C=O)cn1
Reactant: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C=CC(=O)CCCCc2ccc3c(n2)NCCC3)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-6 (5.5 g, 16.2 mmol), 5-formyl-2-methylpyrimidine (1-6a, 1.8 g, 14.7 mmol; for preparation, see J. Heterocyclic Chem., 28, 1281 (1991)) in 40 mL DMF was added K2CO3(4.07 g, 32 mmol). The mixture was stirred at ambient temperature for 15 hr, and concentrated to a paste. The residue was diluted with water, extracted with ethyl acetate, and dried over magnesium sulfate. Following concentration, the residue was chromatographed on silica gel (70 chloroform/25 ethyl acetate/5 methanol) to give 1-7 as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Brc1ccccn1
Product: Cc1cc(-c2ccccn2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.91 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@H:11]2[C@@H:16]([CH2:17][OH:18])[C@H:15]3[CH2:19][C@@H:12]2[CH2:13][CH2:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl[Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32]>C1COCC1>[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@H:11]2[C@@H:16]([CH2:17][O:18][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[C@H:15]3[CH2:19][C@@H:12]2[CH2:13][CH2:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: N#Cc1cnc(N)cc1N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1Nc1cc(N)ncc1C#N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Racemic 6-amino-4-(((1S*,2R*,3S*,4R*)-3-(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl)amino)nicotinonitrile (intermediate 57, 420 mg, 1.63 mmol) was dissolved in THF (8 ml), treated with DIPEA (1.99 ml, 11.4 mmol) and chlorotriethylsilane (1.36 ml, 8.13 mmol). The reaction mixture was then stirred at 70° C. for 2 h. The reaction mixture was quenched with water and diluted in EtOAc. The org layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.41 (s, 2H), 6.08 (d, 1H), 5.64 (s, 1H), 3.72 (d, 2H), 3.43 (t, 1H), 2.10-2.20 (m, 2H), 1.85-1.92 (m, 1H), 1.73 (d, 1H), 1.43-1.58 (m, 2H), 1.21 (t, 2H), 1.06 (d, 1H), 0.91 (t, 9H), 0.55-0.64 (m, 6H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH2:23])=[CH:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH:23][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])=[CH:20]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Yield: 74.9 %

Procedure:
A solution of 5.00 g 7-(2-quinolinylmethoxy)-2-naphthalenamine (17 mmol), prepared according to the procedure of Example 7, 1.7 g triethylamine (17 mmol) and 2.18 g ethanesulfonyl chloride (17 mmol) in 50 mL tetrahydrofuran is refluxed overnight. The solvent is removed and the residue is partitioned between methylene chloride and saturated sodium bicarbonate. After drying over potassium carbonate, the organic layer is freed of solvent to afford 5.00 g of a brown gum. Chromatography on alumina and elution with 9:1 methylene chloride/ethyl acetate affords 1.4 g of a white solid which is recrystallized from ethyl acetate. Rechromatography on HPLC and final recrystallization from ethyl acetate affords 0.6 g (9%) of white crystals, m.p. 166°-167.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]4=[O:21])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:22][C:23](N(C)C)=O>>[C:22]([C@:12]1([OH:21])[CH2:11][CH2:10][C@H:9]2[C:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:18]=4[C:17]=3[CH2:16][CH2:15][C@:13]12[CH3:14])#[CH:23]
Reactant: CC(=O)N(C)C
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C#C[C@]1(O)CC[C@H]2C3=C(CC[C@@]21C)c1ccc(OC)cc1CC3
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Add solid lithium acetylide-ethylenediamine complex (9.5 g) to 3-methoxyestra-1,3,5(10),8-tetraen-17-one (10 g) in dimethylacetamide (100 ml), stir the mixture for 15 hours and then pour into ice water. Extract with ether-benzene (1:1), and wash, dry and evaporate the organic extract. Recrystallize the residue from methanol to obtain dl-17α-ethynyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (2.8 g), m.p. 133°-137°; infrared absorption peaks at 3.1 μ, 6.25 μ.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:19])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Product: Cc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.0 g, 15 mmol) and morpholine (10 mL, 100 mmol) was heated for three days in a high-pressure vessel at 100° C., allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4.8 g of 2-methyl-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.[NH:13]1[C:21]2[C:16](=[C:17]([C:22]3[CH:23]=[C:24]([NH2:37])[C:25]4[C:29]([CH:30]=3)=[N:28][N:27](C3CCCCO3)[CH:26]=4)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[NH:13]1[C:21]2[C:16](=[C:17]([C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][NH:28]4)=[C:24]([NH:37][C:10]([C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[O:12])[CH:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1H-Benzimidazole-2-carboxylic acid (available from Apollo Scientific, 25 mg, 0.151 mmol), O-(7-Azabenzatriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.17 mmol) and 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg, 0.15 mmol) were dissolved in anhydrous DMF (3 ml) and then treated with DIPEA (0.05 ml, 0.30 mmol). The reactions were then stirred at room temperature for 15 hours. The mixture was treated with methanol (3 ml) and then Macroporous-Tosic Acid (170 mg, 0.75 mmol) then stirred for 15 hours. The mixture was then treated with 0.88 ammonia solution (0.60 ml), stirred for 10 minutes, then filtered and solvent blown off under a stream of nitrogen. The crude residue was purified by Mass Directed Automated Preparative HPLC (Method B) to give after evaporation of solvents the title compound as a yellow solid (27 mg). LCMS (Method B) m/z 393 [MH+], Rt=1.04 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:22]=[CH:23][CH:24]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cccc(F)c1
Product: O=c1[nH]c2nccc(Nc3cccc(F)c3)c2c2ccccc12
Yield: 65.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-fluoroaniline (96 mg, 0.87 mmol) to provide 190 (86 mg, 65% yield) as a white solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)\[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>CO>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12](/[C:7](/[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:20])=[O:2])=[CH:17][CH:16]=1
Reactant: CCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4nonadienoic acid methyl ester (8 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the reaction was worked up in the normal manner and the crude product crystallized from 2-propanol-hexane to give 6.2 g of (E,E)-5-(4-methoxyphenyl)-2,4-nonadienoic acid, mp 138°-139.5° C.
Reaction SMILES: CC([O:10][C:11]([C:13]12[C:24]3([CH:26]=[O:27])[CH2:25][CH:16]([C:17]1([CH2:29][O:30][C:31]14[CH:43]([OH:44])[CH:37]5[CH:38]([O:39][CH2:40][CH2:41][CH3:42])[CH:33]([CH:34]([O:36]5)[O:35]1)[O:32]4)[CH2:18][CH:19]1[CH:23]3[CH2:22][CH2:21][CH:20]1[CH3:28])[CH:15]=[C:14]2[CH:45]([CH3:47])[CH3:46])=[O:12])(C)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:40]([O:39][CH:38]1[CH:33]2[CH:34]3[O:35][C:31]([O:30][CH2:29][C:17]45[CH:16]6[CH2:25][C:24]([CH:26]=[O:27])([C:13]4([C:11]([OH:12])=[O:10])[C:14]([CH:45]([CH3:47])[CH3:46])=[CH:15]6)[CH:23]4[CH:19]([CH:20]([CH3:28])[CH2:21][CH2:22]4)[CH2:18]5)([CH:43]([OH:44])[CH:37]1[O:36]3)[O:32]2)[CH2:41][CH3:42]
Reactant: CCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(C)(C)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
13 mg of compound (31) was dissolved in 2 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with chloroform-methanol (20:1). The fraction containing the desired product was concentrated to dryness to give 9.0 mg of compound (32).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH2:32][OH:33])[C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24])[CH3:29]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CCNCCO
Product: CCN(CCO)C(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Yield: 74 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-(ethylamino)ethanol. And then, the product was recrystallized with isopropanol and hexane to give a desired compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:24][CH3:25])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([CH2:24][CH3:25])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1[NH:37][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]2)=[CH:39][CH:38]=1)(=[O:3])[NH2:2]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Reaction time: 22 h
Yield: 31.7 %

Procedure:
A mixture of tert-butyl 3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (790 mg), 4-(4-methylpiperazin-1-yl)aniline (448 mg), diisopropylethylamine (729 μL), and N,N-dimethylformamide (5.53 mL) was stirred at 120° C. for 22 hours. The reaction mixture was left to be cooled and then diluted with ethyl acetate, and the organic phase was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-30:1:0.1), and then washed with diisopropyl ether to obtain tert-butyl 3-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (355 mg) as a pale yellow solid.