Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[N:40][O:41][CH3:42])[C:36](OC)=[O:37])/[C:3](=[N:22]/[O:23][CH2:24][CH3:25])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:6][CH:5]=1.[CH3:43][NH2:44]>C(O)C>[CH3:43][NH:44][C:36](=[O:37])[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][O:27][N:26]=[C:2]([CH3:1])/[C:3](=[N:22]/[O:23][CH2:24][CH3:25])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)=[CH:6][CH:5]=1)=[N:40][O:41][CH3:42]
Reactant: CCO/N=C(/C(C)=NOCc1ccccc1C(=NOC)C(=O)OC)c1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Reactant: CN
Solvent: CCO
Product: CCO/N=C(/C(C)=NOCc1ccccc1C(=NOC)C(=O)NC)c1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Reaction time: 96 h

Procedure:
A mixture of 6.8 g of methyl 2-[[[(1-methyl-2-(4-(3-trifluoromethylphenylmethoxy)-phenyl)-2-E-[ethoxyimino]ethylidene)amino]oxy]methyl]-α-(methoxyimino)-phenylacetate and 4.3 ml of an 8 molar solution of methylamine in ethanol is left to stand at room temperature for 4 days. The mixture is then evaporated in vacuo. The residue is taken up in methyl acetate and the solution is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from methyl acetate/hexane 1:1. The title compound with a melting point of 130-132° C. is obtained.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 52 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (53 mg, 0.095 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.14 mL, 0.14 mmol). The mixture was heated in a microwave reactor at 120° C. for 500 seconds and 1 N hydrochloric acid (0.14 mL, 0.14 mmol) was added. The mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with brine and concentrated. The solid was washed with ether and dried overnight under a nitrogen stream at 45° C. to afford 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (27 mg, 52%). 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.97 (m, 1H), 2.44-2.33 (m, 4H), 2.14-2.04 (m, 1H), 1.99-1.90 (m, 1H). HRMS (ESI) C29H21Cl2N3O4: 546.0982 (M+H)+, found: 546.0982 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[CH:7][C:6]=2[C:5]([Cl:15])=[CH:4][C:3]=1[F:14]
Reactant: CC1(C)C=Cc2ccc(F)c(N)c2O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(Cl)cc(F)c(N)c2O1
Yield: 329.4 %

Procedure:
By a method analogous to that of Example 11, Step J, 1.5 grams (0.0008 mole) of 8-amino-2,2-dimethyl-7-fluoro-2H-1-benzopyran was reacted with 1.1 grams (0.008 mole) of N-chlorosuccinimide in 50 mL of N,N-dimethylformamide. The crude reaction product was purified with column chromatography on silica gel, with hexane and 1:1 methylene chloride:hexane hexane as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of 8-amino-5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:30][CH:31]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: COC(=O)C(C)Oc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 60.6 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.57 mmol) was reacted with methyl 2-(4-aminophenoxy)propanoate (0.133 g, 0.68 mmol) to afford the title compound (0.146 g, 97%) as an off-white solid. MW=422.90. 1H NMR (DMSO-d6, 500 MHz) δ 7.98 (s, 1H), 7.88-7.86 (m, 1H), 7.74-7.69 (m, 1H), 7.46-7.38 (m, 2H), 7.22-7.17 (m, 2H), 7.02 (s, 1H), 6.96-6.89 (m, 2H), 4.96 (q, J=6.8 Hz, 1H), 3.69 (s, 3H), 2.89 (t, J=7.6 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.13-2.03 (m, 2H), 1.51 (d, J=6.7 Hz, 3H); APCI MS m/z 423 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)[CH:22]=1>>[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[CH:22]=1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1cccc(OCCCCCOS(C)(=O)=O)c1
Product: CCCc1c(OCCCCCOc2cccc(CCC(=O)OC)c2)ccc2c1OCCC2=O
Yield: 57 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.48 g (1.4 mmol) of 3-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 67), 3-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentoxy]benzenepropanoic acid methyl ester was obtained in 57% yield (0.36 g) as a yellow oil. This diester (0.79 mmol) was saponified with 2 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, 22 hr. Work-up as in example 4 gave crystalline 3-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid. Recrystallization from ethyl acetate-hexane gave 0.30 g (86%) of a colorless solid, mp 124°-125° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5])(=[O:29])=[O:28]
Reactant: CCCCCCCCCCCCC[C@@H](O)CC(N)=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC[C@H](CC(N)=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-hydroxyhexadecanamide (100 mg) and pyridine (210 μl) in dichloromethane (10 ml) was added methanesulfonyl chloride (144 μl). This mixture was stirred at room temperature overnight, and the resulting precipitate was filtered off. The filtrate was concentrated, and dissolved in ethyl acetate (20 ml). This solution was washed with 1N-hydrochloric acid (20 ml×3), saturated sodium carbonate (20 ml×2), and brine (20 ml). After drying over MgSO4 and concentration, the residue was chromatographed on a silica gel, eluting with a mixture of dichloromethane and methanol (50:1) to give (R)-3-methanesulfonyloxyhexadecanamide (40 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]O)[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.CS([Cl:39])(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:39][CH2:23][C:19]1[CH:18]=[C:17]([S:14]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cn(S(=O)(=O)c2cccc(CCl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 54.5 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(hydroxymethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (683 mg) in tetrahydrofuran (5 mL) were added methanesulfonyl chloride (174 mg) and diisopropylethylamine (215 mg) under ice-cooling, and the mixture was stirred at room temperature for 60 hr. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a pale-yellow oil (yield 386 mg, 55%).
Reaction SMILES: [OH:1][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:3].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:25]([O:3][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:1])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCO
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 250-mL round-bottom flask were added 2-methyl-acrylic acid 6-[4-(2-hydroxycarbonyl-vinyl)-phenoxy]-hexyl ester (4.98 g, 15.0 mmol), 1-pentanol (1.785 mL, 16.5 mmol) and 4-dimethylaminopyridine (DMAP,92 mg, 0.75 mmol) as solids and a stirbar. The flask was purged with N2, followed by the addition of CH2Cl2 (35 mL). The suspension was stirred at room temperature for 20 min to give a white slurry. The flask was cooled in an ice bath and N,N′-dicyclohexylcarbodiimide (DCC, 3.25 g, 15.75 mmol) was introduced. The mixture quickly became a light yellow solution, which was then removed from the ice bath and stirred at room temperature. After 20 h, the resulting white slurry was loaded on a SiO2 column (˜100 g) for quick purification. The product was eluted off with 10% EtOAc in hexanes. The fractions with the desired product were combined, concentrated and then dried in vacuo to a clear oil, which turned into a white solid (Addition Monomer 6) upon cooling (5.45 g, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][C@H:10]([NH:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:17]([F:20])([F:19])[F:18])[C:11]([O:13]C)=[O:12].[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][C@H:10]([NH:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:17]([F:20])([F:18])[F:19])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)[C@H](CSCc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](CSCc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of methyl 3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionate (0.64 g, 1.59 mmol) in methanol (9 mL) was added 1N sodium hydroxide (4.77 mL). The resulting solution was stirred for 2 h at ambient temperature and then methanol was removed in vacuo. The residue was portioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate and the combined organic layers were dried over magnesium sulfate. Removal of the solvents provided 3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (0.410 g, 1.06 mmol) as a white solid which was a mixture of diastereomers.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1.C(O)C.[ClH:19]>>[ClH:19].[OH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: CCO
Product: OCC1CNCCO1

Procedure:
N-Benzyl-2-hydroxymethylmorpholine prepared in the same manner as described in Synthetic Communication, Vol. 10 (1), pages 59-73, 1980 (1.3 g) is subjected to hydrogenolysis in hydrogen chloride-containing ethanol in the same manner as described in Reference Example 15 to give 2-hydroxymethylmorpholine hydrochloride (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2C=CC=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.ClC1C=C(Cl)N=C(C2C=CC=CC=2)N=1.ClC1C=C(Cl)N=C(CCC)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:3]=1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: CCCc1nc(Cl)cc(Cl)n1
Agent: Clc1cc(Cl)nc(-c2ccccc2)n1
Product: CCCc1nc(Cl)cc(OCCC(C)C)n1

Procedure:
The compound of Example 20 is prepared analogously to the compound of Example 3, with the 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-propylpyrimidine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][N:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(CCc1ccccc1)c1ccccc1
Yield: 53 %

Procedure:
According to GWM, 0.011 mol (=1.20 ml) of N-methylaniline and 0.011 mol (=1.00 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:3) as eluent, the product N-methyl-N-phenylethylaniline being obtained as a yellow liquid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].CN(C)C=O.[CH2:33](I)[CH3:34].[H-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([CH2:33][CH3:34])[C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27]
Reactant: COC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.8 %

Procedure:
To a mixture of methyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate (0.400 g, 0.00100 mol), N,N-dimethylformamide and ethyl iodide (0.980 g, 0.00628 mol) is added sodium hydride (60%, 0.0900 g, 0.00225 mol) in portions. The mixture is stirred 5 days at room temperature, diluted with methylene chloride, washed sequentially with 8% hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel with ether:hexanes:methylene chloride to give the title compound (0.260 g, 60.9%) which is identified by NMR spectral analysis.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[C:15]([NH:22][CH2:23][CH2:24][CH2:25][NH2:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:18]([O:17][C:15]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
A mixture of methyl 3-fluoro-4-nitrobenzoate (5.8 g, 1 eq), N-Boc-1,3-diaminopropane (5.75 g, 1.1 eq) and potassium carbonate (8.04 g, 2 eq) in acetonitrile (200 ml) is heated under reflux for 2 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (100 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is washed with petroleum ether and dried (10.2 g; 99% yield).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=4)=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-trifluoromethylphenyl isocyanate (0.184 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 248 mg (70.5%) of the desired product as a solid.
Reaction SMILES: Br[C:2]([CH3:11])=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:28][N:29]1[CH2:42][CH2:41][C:32]2[NH:33][C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][C:39]=3[C:31]=2[CH2:30]1>CN(C=O)C.[Cu]I>[CH3:28][N:29]1[CH2:42][CH2:41][C:32]2[N:33](/[C:2](=[C:3](/[C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)\[CH3:4])/[CH3:11])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][C:39]=3[C:31]=2[CH2:30]1
Reactant: CC(Br)=C(C)c1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C(/C)n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(3-Bromobut-2-en-2-yl)pyridine (127 mg, 0.59 mmol) was dissolved in DMF (5 mL) and potassium phosphate (212 mg, 1 mmol) was added followed by copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.5 mg, 0.1 mmol). 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was added and nitrogen gas purged for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the reaction mixture filtered to obtain the solid mass under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. The compound was further purified through reverse phase chromatography. Yield: 5 mg (TFA salt). 1H NMR (CD3OD, free base) δ (ppm): 8.60 (d, 2H), 7.50 (d, 2H), 7.24 (s, 1H), 7.12 (d, 1H), 6.99 (d, 1H), 3.78 (s, 2H), 2.98 (m, 2H), 2.90 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 1.92 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:13]([CH2:17][CH3:18])[C:14](O)=[O:15]>>[CH:1]1([NH:8][C:9]2[S:10][CH:13]([CH2:17][CH3:18])[C:14](=[O:15])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(Br)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: CCC1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cycloheptylthiourea and 2-bromobutyric acid according to Method C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16]([C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1)[CH3:17]>CS(C)=O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][C:22]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:16][CH3:17])[CH:23]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CCc1cc([N+](=O)[O-])ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cc(Oc2ccc(Br)cc2F)ccn1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro-4-bromophenol (0.576 ml, 5.258 mmol) in DMSO (8 ml) was added K2CO3 (1.451 g, 10.516 mmol) and 2-ethyl-4-nitropyridine [CAS. 101860-96-2] (0.800 g, 5.258 mmol). The reaction mixture was heated at 100° C. for 2 days. Then the reaction mixture was refilled with 2-fluoro-4-bromophenol (0.115 ml) and heated at 100° C. for 6 hours more. After cooling to r.t. the reaction mixture was washed with NaHCO3 (aqueous sat. solution), then extracted with DCM. The organic layer was separated, dried (Na2SO4) evaporated to dryness. The crude product was purified by column chromatography (silica gel; DCM to heptane/DCM from 100/0 to 30/70 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D55 (0.985 g, 63%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
0.80 g of 5% palladium-carbon was added to a mixture of 3.94 g of ethyl 3-(4-benzyloxyphenyl)-2-(phenylamino)propionate obtained in Reference example 5(a), 40 ml of ethanol and 20 ml of tetrahydrofuran, and the mixture was stirred at 50° C. under hydrogen at normal pressure for 6 hours. The catalyst was removed by filtration from the reaction mixture, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 2.95 g of the desired compound as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)CN1CCOCC1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (65 mg, 36%). The mother liquid was evaporated to dryness and the residue was purified by flash chromatography to give additional 2N (70 mg, 39%). 1H NMR (DMSO-d6) δ 2.28 (m, 1H), 2.32 (m, 1H), 2.40 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.31 (m, 1H), 3.55 (m, 4H), 3.78 (m, 1H), 4.73 (brs, 1H, OH), 6.82 (dd, J=4.5, 8.4 Hz, 1H), 6.90 (td, 2J=2.8, 3J=10.0 Hz, 1H), 7.53 (m, 1H), 7.70 (s, 1H), 7.74 (dd, J=2.0, 9.6 Hz, 1H) (aromatic and vinyl), 10.87 (s, 1H, CONH), 13.66 (s, 1H, NH). LC-MS (m/z) 441.4 (M−1).