Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:20]2[C@H:29]3[C:30]([O:32][CH2:33][C@@H:28]3[C@@H:27]([OH:34])[C:26]3[CH:25]=[C:24]4[O:35][CH2:36][O:37][C:23]4=[CH:22][C:21]2=3)=[O:31])[CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17]>N1C=CC=CC=1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C@H:20]2[C@H:29]3[C:30]([O:32][CH2:33][C@@H:28]3[C@@H:27]([O:34][C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])[C:26]3[CH:25]=[C:24]4[O:35][CH2:36][O:37][C:23]4=[CH:22][C:21]2=3)=[O:31])[CH:11]=[C:10]([O:9][CH3:8])[C:15]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)O1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)CCC(=O)O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
Succinic anhydride (0.9 g) was added to a solution of podophyllotoxin (207.2 mg, 0.5 mmol) in pyridine (12 mL). The resultant reaction mixture was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue. The crude residue was purified using a silica gel gravity column chromatography (35:7:1 CHCl3:MeOH:NH4OH) to give succinylpodophyllotoxin as white solid (198.5 mg, 80%) 1H NMR (500 MHz, DMSO-d6) δ 2.10 (d, J=5.4 Hz, 1H, H-4), 2.32 (dd, J=12.6, 4.8 Hz, 1H, H-2), 2.53 (m, 1H, H-3), 3.52 (s, 3H, OMe H-4′), 3.65 (dd, J=10.5, 7.5 Hz, 2H, H-11), 3.82 (s, 6H, two OMe groups, H-3′ and H-5′), 4.15 (t, J=7.9 Hz, 2H, CH2), 4.26 (t, J=7.9 Hz, 2H, CH2), 4.51 (d, J=5.4 Hz, 1H, H-1), 5.89 (s, 2H, OCH2), 6.00 (s, 2H, H-2′, H-6′), 6.67 (s, 1H, H-8), 6.94 (s, 1H, H-5), 12.15 (s, 1H, CO2H). Mass (ESI) (M−1) calcd for C26H26N2O11 513.15; found 512.93.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9]([S:28][CH2:29][CH2:30][C:31](Cl)=[O:32])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[C:9]([S:28][CH2:29][CH2:30][C:31]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:32])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 71.8 %

Procedure:
A solution of 1.51 g (0.01 mole) of L-proline in 20 mls of 2N NoOH is chilled in an icebath and treated with a total of 4.03 g (0.011 mol) of S-trityl-3-mercaptopropionyl chloride and 20 ml of 2N NaOH in 5 equal and alternate portions with vigorous intermittent shaking and cooling in an ice bath. The solution is kept at an alkaline pH by the addition of more alkali when necessary. Upon completion of the addition of the reagents, the reaction mixture is stirred for an additional 15 min. at room temperture and then acidified to Congo red with cooling by dropwise treatment with concentrated HCl. The reaction is placed in a refrigerator overnight. The resultant precipitate is recovered by filtration, washed several times with ice water and dried in a dessicator over phosphorus pentoxide. Recrystallization in EtOH/H2O gave 3.2 g (72%) of the desired product. The NMR and IR showed the required peaks.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:25]=1)=[C:8]([CH:22]=[CH:23][CH3:24])[CH:9]=[C:10]1[C:15]=2[O:14][CH2:13][C:12]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:11]1=2>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:25]=1)=[C:8]([CH2:22][CH2:23][CH3:24])[CH:9]=[C:10]1[C:15]=2[O:14][CH2:13][C:12]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:11]1=2
Reactant: CC=Cc1cc2c(c3ccc(OC)cc13)OCc1cc(OC)ccc1-2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc2c(c3ccc(OC)cc13)OCc1cc(OC)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A mixture of 2,8-dimethoxy-12-propenyl-6H-dibenzo[c,h]chromene (460 mg, 1.38 mmols) and palladium (92 mg, 10% on activated carbon) in 36 ml ethyl acetate was stirred under a hydrogen balloon at room temperature for 3 hours. The reaction mixture was filtered through Celite and concentrated to give 430 mg (94%) of the title compound as a light brown solid. The analytical sample was obtained by further purification with reverse-phase preparative HPLC: mp 88-90° C.; 1H NMR (DMSO-d6): δ 1.01 (3H, t, J=7.31 Hz), 1.68-1.80 (2H, m), 2.98 (2H, t, J=7.29 Hz), 3.81 (3H, s), 3.91 (3H, s), 5.25 (2H, s), 6.93 (1H, d, J=2.53 Hz), 6.98 (1H, dd, J=8.46 Hz, J=2.04 Hz), 7.17 (1H, dd, J=9.20 Hz, J=2.38 Hz), 7.28 (1H, d, J=2.36 Hz), 7.72 (1H, s), 7.77 (1H, d, 8.57 Hz), 8.08 (1H, d, J=9.14 Hz); MS (ESI) m/z335 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([OH:14])[CH3:13])(C)(C)C.[ClH:16].O1CCOCC1>ClCCl>[ClH:16].[NH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:13])[OH:14]
Reactant: CC(C)(C)OC(=O)NC1CCCC1(C)O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(O)CCCC1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl-2-hydroxy-2-methyl-cyclopentylcarbamate (25 g, 104.5 mmol) in dichloromethane (210 mL) is added hydrogen chloride in dioxane (156 mL, 6 mol, 4 M) and the reaction is stirred at room temperature for 3 h. The solvent is evaporated and the resulting material is dried under vacuum to a constant weight to obtain the title compound (20.4 g) as a dark brown oil which is used in the next step without further purification. GC-MS 115.1 (M+); GC-MS analysis shows a cis/trans mixture in about a 3/2 ratio.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:13]=[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][N:7]3[N:6]=2)[CH2:4][CH2:3]1.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24]([N:10]1[CH2:11][CH2:12][N:7]2[N:6]=[C:5]([CH:2]3[CH2:4][CH2:3]3)[N:13]=[C:8]2[CH2:9]1)=[O:25])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: C1Cn2nc(C3CC3)nc2CN1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C3CC3)nc2C1)Cc1cc(F)c(F)cc1F

Procedure:
A 54 mg portion of 2-cyclopropyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D. Purification by two sequential preparative TLC columns (silica gel, 10% methanol/dichloromethane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:12][CH3:13])[CH:7]=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]([C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:24]
Reactant: COc1ccc(Br)c2c1ccn2C
Reactant: COC(=O)C(=O)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC)c2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of 1-methyl-4-methoxyl-7-bromoindole (1.17 g, 4.87 mmol) in THF (33 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 6.3 mL, 10.7 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (1.44 g, 12.2 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine and dried (Na2SO4), and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (0.7 g, 58.1%). 1H NMR (400 MHz, CDCl3) 3.95 (s, 3H), 4.0 (s, 3 H), 4.02 (s, 3H), 6.56 (d, J=8.61 Hz, 1H), 6.67 (d, J=3.13 Hz, 1H), 6.99 (d, J=3.13 Hz, 1H), 7.61 (d, j=8.6 Hz, 1H); MS (ES, m/z): C13H13NO4: 248.16 (M++1).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].C([O:12][C@@H:13]1[C@@H:34]([O:35]C(=O)C)[C@H:33]([O:39]C(=O)C)[C@@H:32]([C:43]([OH:45])=[O:44])[O:31][C@H:14]1[O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:26](OCC)=[O:27])[N:22]2[CH3:25])=[CH:18][CH:17]=1)(=O)C.[CH3:46][S:47]([OH:50])(=[O:49])=[O:48]>CN(C)C=O.O.C1(C)C=CC=CC=1>[CH3:46][S:47]([OH:50])(=[O:49])=[O:48].[O:15]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:26]([NH:4][C:3]([NH2:5])=[NH:2])=[O:27])[N:22]2[CH3:25])=[CH:18][CH:17]=1)[C@@H:14]1[O:31][C@H:32]([C:43]([OH:45])=[O:44])[C@@H:33]([OH:39])[C@H:34]([OH:35])[C@H:13]1[OH:12]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2n1C
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C(=O)NC(=N)N)cc2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
Guanidine hydrochloride (6.23 g, 65.2 mmol) was added to a mixture of sodium methoxide (3.52 g, 65.2 mmol) and N,N-dimethylformamide (25 ml), and the resulting mixture was stirred at room temperature for 1 hour. The solid precipitated was filtered off and a solution of (2-ethoxycarbonyl-1-methyl-1H-indol-6-yl) 2,3,4-tri-O-acetyl-β-D-glucopyranosideuronic acid (1.70 g, 3.26 mmol) in N,N-dimethylformamide (9 ml) was added to the filtrate obtained, followed by stirring at room temperature for 7 hours. After toluene was added to the reaction mixture, the resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by a reversed phase column chromatography (eluent; water:methanol=9:1) to obtain a free compound. The free compound was dissolved in water (50 ml) and methanesulfonic acid (1.15 g) was added thereto under ice-cooling. Subsequently, the solvent was distilled off under reduced pressure and the resulting residue was washed with tetrahydrofuran to obtain 0.78 g of [2-[[[amino(imino)methyl]amino]carbonyl]-1-methyl-1H-indol-6-yl] β-D-glucopyranosideuronic acid methanesulfonate.
Reaction SMILES: Br[C:2]1[CH2:10][CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C([Li])(C)(C)C.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C(Cl)Cl.CO>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([B:20]([OH:21])[OH:19])[CH2:10][CH2:9][C:5]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrC1=Cc2ccsc2CC1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: OB(O)C1=Cc2ccsc2CC1

Procedure:
Following the general method described in example 19a, 5-bromo-6,7-dihydro-benzo[b]thiophene was reacted with tert.-butyllithium solution followed by triisopropylborate and 3N HCl. The title compound was obtained as a white crystalline material after chromatography (SiO2 with CH2Cl2-MeOH=98:2). MS: m/e=179 (M-H−).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[NH:7][CH2:8][C:2]1=2.[C:10](OC(NC1(C(O)=O)CC1)=O)(C)(C)[CH3:11]>>[NH:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[NH:7][C:8]3([CH2:11][CH2:10]3)[C:2]1=2
Reactant: O=C1NCc2[nH]ccc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Product: O=C1NC2(CC2)c2[nH]ccc21

Procedure:
This compound was prepared in a manner similar to that described for Intermediate 703, starting from 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (1H, br.), 7.53 (1H, s), 6.82 (1H, s), 6.11 (1H, d, J=2.2 Hz), 1.3 (2H, m), 1.27 (2H, m). m/z (ESI, +ve) 149.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.CN(C)C=O.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCOc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Temperature: 55 °C

Procedure:
2,4-Dichloro-5,6-dimethyl-3-nitropyridine (1.00 g), anhydrous N,N-dimethylformamide (5 ml), triethylamine (0.63 ml), and 2-phenoxyethylamine (0.59 ml) were combined and the resulting mixture was heated to 55° C. for 24 hours. Thin layer chromatography (TLC) monitoring of the reaction indicated that it was complete. The solvent was removed under reduced pressure and the remaining oil was dissolved in dichloromethane (DCM) and washed once with water. Following 2 additional extractions with DCM, the organic layers were combined, dried with magnesium sulfate, and the solvent was removed under reduced pressure. The product was passed through a column using 20/80 ethyl acetate/hexane as the eluant. NMR analysis of the resulting yellow solid indicated sufficient purity for use in the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[C:29]1([O:28][C:26](=[O:27])[NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
3,5-Bis-(trifluoromethyl)aniline (2.0 g, 8.7 mmol) was dissolved in dichloromethane (80 mL) and N,N-diisopropylethylamine (1.6 mL, 9.6 mmol) was added followed by slow addition of phenyl chloroformate (1.1 mL, 8.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was successively washed with 1N hydrochloric acid (3×100 mL), water (3×100 mL), a mixture of water and saturated aqueous sodium hydrogen carbonate (1:1, 2×100 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptane containing a little diethyl ether to afford 1.3 g (43%) of (3,5-bis-trifluoromethylphenyl)carbamic acid phenyl ester as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=1[OH:36].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=2[OH:36])=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc([N+](=O)[O-])c1O
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2O)cc1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
Ref.: WO 96/11917. To a solution of 4-tert-butyl benzoic acid (0.81 g, 4.57 mmol) in CH2Cl2 (10 mL) cooled in an ice bath was added 1,1′-carbonyldiimidazole (0.94 g, 5.80 mmol). The solution was stirred for 5 min., then the bath was removed and the reaction was stirred at room temperature for 1.5 h. To a solution of 2-amino-6-nitro phenol (0.829 g, 5.38 mmol) in CH2Cl2 (40 mL) cooled in an ice bath was added the activated acid solution dropwise. The reaction was allowed to stir and gradually come to room temperature overnight. To the solution was added CH2Cl2 (50 mL) and H2O (25 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with H2O (25 mL), 1 N HCl (25 mL), and brine (25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel and purified by silica gel chromatography, eluting with 66% CH2Cl2/hexane to 75% CH2Cl2/hexane to afford the title compound (0.579 g) as a golden solid. MS (ESI-POS): [M+H]+=315; Anal. Calc'd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 64.98; H, 5.78; N, 8.89.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17])=[C:10]([NH:19][CH2:20][C:21]#[CH:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:15][CH2:16][CH3:17])[N:19]([CH2:20][C:21]#[CH:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C#CCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A solution of N-[2-chloro-4-(prop-2-ynylamino)quinolin-3-yl]-2-ethoxyacetamide (26.7 g, 84.0 mmol) and triethylamine (17.5 mL, 126 mmol) in ethanol (250 mL) was heated at 60° C. for 1.7 days. Additional triethylamine (17.5 mL) was added and the solution was heated at 60° C. for two more days. The volatiles were removed under reduced pressure and the resulting white solid was triturated with water, isolated by filtration, and dried to provide 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (24.2 g, 96%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]CC.[Na+].Cl>C(O)C>[CH2:12]([C:7]1[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1noc(C)c1C(=O)OCC
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCc1noc(/C=C/c2ccccc2)c1C(=O)O
Temperature: 25 °C
Yield: 41.5 %

Procedure:
To a solution of 3-butyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester (15.0 g, 71.0 mmol) and benzaldehyde (7.2 mL, 71.0 mmol) in ethanol (100 mL) was added sodium ethoxide solution (21% in ethanol, 29.1 mL, 78.0 mmol) and the reaction mixture was stirred at reflux for 2 h, cooled to room temperature and stirred for 17 h. Hydrochloric acid (1 N, 85 mL) was added and the resulting mixture was extracted twice with dichloromethane. The combined phases were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated to a bright yellow pasty solid and recrystallized from hot heptane/ethyl acetate to afford the title compound (8.0 g, 42%) as a yellow solid. MS: m/e=270.4 [M−H]−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([C:17]1([C:20](=[O:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36](OC4C=CC=CC=4)=[O:37])[CH:30]=3)=[CH:24][C:23]=2[F:45])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:47][N:48]1[CH2:53][CH2:52][N:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:50][CH2:49]1>CN(C)C=O>[CH2:7]([O:14][C:15]([C:17]1([C:20](=[O:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH:31]([NH:35][C:36]([N:57]4[CH2:58][CH2:59][CH:54]([N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)[CH2:55][CH2:56]4)=[O:37])[CH2:30]3)=[CH:24][C:23]=2[F:45])[CH2:18][CH2:19]1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)NC3CC(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)CCN3)CC2)CC1
Yield: 49.8 %

Procedure:
Potassium carbonate (772 mg) was added to a mixture of 1-[2-fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (2.75 g) and N,N-dimethylformamide (13.8 ml) was added, followed by stirring. 1-Methyl-4-(piperidin-4-yl)piperazine (1.02 g) was added, followed by stirring for 6 hours. The reaction mixture was partitioned after the addition of ethyl acetate (41 ml) and water (27.5 ml). The resultant organic layer was washed with water (13.8 ml, three times), dried over sodium sulfate, and filtered, and the filtrate was concentrated. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=30:1). The eluate was concentrated under reduced pressure, and the precipitate appeared by the addition of tert-butyl methyl ether (3 ml) and the application of a stimulus. tert-Butyl methyl ether (40 ml) was further added, followed by stirring overnight. The resultant precipitate was collected by filtration, washed with tert-butyl methyl ether (3 ml), and dried under aeration to give the target title compound (1.61 g).
Reaction SMILES: [C:1]([S:4][C:5](=[CH:14][N:15]([CH3:17])C)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=O)C.C[O-].[Na+].Br.BrCCN>C(O)C>[C:8]1([C:6]([C:5]2[S:4][CH2:1][CH2:17][NH:15][CH:14]=2)=[O:7])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)SC(=CN(C)C)C(=O)c1ccccc1
Agent: Br
Agent: C[O-]
Agent: NCCBr
Solvent: CCO
Product: O=C(C1=CNCCS1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 39.56 g (0.16M)α-acetylthio-β-dimethylaminoacrylophenone in 300 ml absolute ethanol stirring under nitrogen at 0° a solution of 8.64 g (0.16M) sodium methoxide in 230 ml ethanol is added dropwise over a period of 15 minutes. After complete addition, the dark red solution is stirred at 0 to -3° for 0.5 hours. To the solution stirring at -3° a solution of 32.79 g (0.16M) 2-bromoethylamine hydrobromide in 270 ml absolute ethanol is added dropwise over a period of 25 minutes. After complete addition the dark solution is stirred at 0° for 0.5 hours, and a solution of 8.64 g (0.16M) sodium methoxide in 230 ml absolute ethanol is added dropwise over a period of 15 minutes. The dark solution is stirred at 0° for 1 hour. The reaction mixture is allowed to warm slowly to 20° . A suspension is formed within an hour of removing the cooling bath. The reaction mixture is stirred for 16 hours at ca 20° . The suspension is cooled to 5° and acidified to pH 2 with 30 ml of a 1:1 mixture of ethanol and concentrated hydrochloric acid. The suspension is concentrated in vacuo to remove all but ca. 100 ml of ethanol. The residue is suspended in 200 ml CHCl3 and the mixture is washed with water and a saturated NaCl solution. The organic layer is concentrated in vacuo to give a partially crystalline residue. This residue is triturated with a 1:1 mixture of ether and ethanol. Orange crystals are collected to give the title compound. M.P. 184°-186.5°.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)[C:3]1=[O:23].[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.N1C=CC=CC=1>O=S(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=2)=[O:18])[C:3]1=[O:23]
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C
Reactant: Nc1ccc(F)cn1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)Nc3ccc(F)cn3)ccc1C)c(=O)n2C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoic acid 29 (154 mg, 0.5 mmol) in SOCl2 (1 mL) is heated at reflux for 2 h. Excess SOCl2 is removed in vacuo and the resultant solid is added to a solution of 5-fluoropyridin-2-amine (112 mg, 1 mmol) and pyridine (0.4 mL, 5 mmol) at rt. The resulting mixture is stirred for 30 min and evaporated. The residue is purified by preparative LC/MS to give the desired product M32 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.28 (m, 1H), 8.04 (s, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.65 (dt, J=9.1, 2.9 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J=8 Hz, 1H), 3.8 (s, 3H), 2.73 (s, 3H), 2.32 (s, 3H); LC/MS (M+1, m/z): 403.1.