Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:17])=[C:7]([O:14][CH2:15][CH3:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:20])[CH3:19]>>[CH2:15]([O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:17])[N:3]=[C:2]([NH:20][CH2:18][CH3:19])[C:11]([CH:12]=[O:13])=[CH:10]2)[CH3:16]
Reactant: CCN
Reactant: CCOc1cc2cc(C=O)c(Cl)nc2cc1F
Product: CCNc1nc2cc(F)c(OCC)cc2cc1C=O
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 56 %

Procedure:
A solution of 2-chloro-6-ethoxy-7-fluoroquinoline-3-carbaldehyde SMA 44100 (110 mg, 0.43 mmol) in ethylamine (2.0 M in THF, 2.20 mL, 4.40 mmol) in a 10 mL microwave vial equipped with a magnetic stirrer was stirred for 3.5 h at 150° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=50:50 (10 mL) and the mixture was stirred for 30 min at RT. THF was then removed at 40° C. under vacuum and the residue was basified with a 10 N aq. NaOH solution (pH=8) before extraction with CH2Cl2 (40 mL). The separated organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 90:10) gave 6-ethoxy-2-(ethylamino)-7-fluoroquinoline-3-carbaldehyde SMA 44102 as a yellow solid (63 mg, 56% yield).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl[C:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>>[NH2:23][C:21]1[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=[C:13]([N:9]2[CH2:10][CH2:11][N:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH2:7][CH2:8]2)[N:22]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CC4)CC3)nc(N)c2cc1OC

Procedure:
N-(Cyclopropylcarbonyl)piperazine (3.08 g., 0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) are reacted according to the procedure of Example 127(a). The crude product crystallized from ethanol affords analytically pure 4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 283.5° C. (corr.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:33])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][C:12]=2[F:32])=[O:9])=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:32][C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]2)[CH:15]=[CH:16][C:11]=1[N:10]([C:8]([C:5]1[CH:6]=[N:7][C:2]([O:41][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[CH:3][CH:4]=1)=[O:9])[CH3:33]
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)c(F)c2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)c(F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 130 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate (D68) and 4-fluorophenol using a method similar to that described for D55 in Description 55 although only 1 eq of 4-fluorophenol was added initially, the reaction was heated at 130° C. over-weekend, further 4-fluorophenol (2 eq) and potassium carbonate (4 eq) were added and the reaction was heated at 130° C. overnight. The product was purified by column chromatography. δH (CDCl3, 400 MHz) 8.07 (1H, s), 7.73 (1H, dd), 7.04 (7H, m), 6.74 (1H, d), 4.19 (1H, br.s), 3.80 (1H, d), 3.43 (4H, m), 3.33 (1H, d), 3.08 (1H, td), 2.67 (1H, d), 2.49 (1H, d), 2.13 (1H, dd), 2.00 (1H, m), 1.45 (9H, s), 1.21 (3H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]([NH:11][NH:12][C:13](=O)[CH3:14])=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[S:26][C:13]([CH3:14])=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)NNC(=O)CNC(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Yield: 79.3 %

Procedure:
To a 37.5 mL THF solution of tert-butyl[2-(2-acetylhydrazino)-2-oxoethyl]carbamate (496 mg, 2.15 mmol) was added Lawesson's reagent (900 mg, 2.23 mmol). The resulting reaction mixture was heated to reflux for 3 hr. The reaction was concentrated and chromatographed on silica gel eluting with a gradient solvent mixture of AcOEt & dichloromethane to give the title compound as white crystalline solid (391 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>C(O)C>[CH:16]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:6](=[CH:5][CH2:4][CH2:3][N:2]([CH2:23][CH2:22][C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH3:1])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C=CC(=O)OCC
Reactant: CNCCC=C1c2ccccc2C=Cc2ccccc21
Solvent: CCO
Product: CCOC(=O)CCN(C)CCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 2.61 g of 5-[3-(methylamino)propylidene]-5H-dibenzo[a,d]cycloheptene, 1.20 g of ethyl acrylate, and 13 ml of ethanol was refluxed for 2 hours. After reaction was completed, the solvent was removed by distillation and the residue was purified by column chromatography on aluminum oxide [n-hexane-diethyl ether (1:1)] to give 3.22 g of slightly yellow viscous liquid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)C1C=CC=CC=1>[Pd].C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)[CH:11]=1
Reactant: Clc1ccc(OCc2ccccc2)c(-c2cncnc2)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(Cl)cc1-c1cncnc1
Reaction time: 24 h

Procedure:
A mixture of the product from step (iii) (0.28 g), 10% palladium on carbon (0.04 g) in ethanol (20 ml) was hydrogenated at 2 Bar for 24 h. After filtration the solvent was evaporated under reduced pressure. Yield 0.19 g
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH:11]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([CH3:13])[CH3:12]>>[F:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH:11]([CH3:13])[CH3:12])[CH:20]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: CC(C)Oc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 53.8 %

Procedure:
The title compound (0.34 g) was prepared from 4-Bromo-2,6-difluoro aniline (0.5 g, 2.4 mmol) and 3-isopropoxyphenylboronic acid (0.337 g, 3.1 mmol) as a red liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.30-7.22 (m, 3H), 7.16-7.07 (m, 2H), 6.89 (dd, J 2.3, 8.1, 1H), 5.32 (s, 2H), 4.68 (septet, J 6, 1H), 1.26 (d, J 6, 6H).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]>N1C(C)=CC(C)=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: Cc1cc(C)nc(C)c1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C

Procedure:
Methyl pheophorbide-a (1, 1.0 g) was obtained from alga Spirulina destridratada by following the procedure described in K. M. Smith, D. A. Golf and D. J. Simpson, J. Am. Chem. Soc, 1985, 107, 4941-4954; and R. R. Pandey, D. A. Bellnier, K. M. Smith and T. J. Dougherty, Photochem. Photobiol, 1991, 53, 65-72 both of which are incorporated herein by reference The methyl pheophorbide-a was heated under reflux in collidine (100 ml) for 90 min during slow passage of a stream of nitrogen. See G. W. Kenner, S. W. McCombie and R. M. Smith. J. Chem. Soc. Perkin Trans. 1973, 1, 2517-2523, incorporated herein by reference. The solution is evaporated (0.1 mm Hg) and the residue was recrystallized from dichloromethane/methanol. Yield 820 mg; 91%, m.p. 217-219° C. lit. 220-225° C.; H. Fisher and A. Stern, Die Chemie des Pyrrole, vol II, Part 2, pp. 64 and 74, Akademische Verlag, Leipzig incorporated herein by reference. Vis: (max) 410 (112 000); 508 (11 000); 536 (9 600) 610 (8 200) 666 (45 000); NMR, ppm; 9.50. 9.38, 8.52 each s, 3H, 3 meso. H); 7.95-8.05 (m, 1H, CH═CH2); 6.30 and 6.15 (each s, 1H, CH-CH2), 5.27 to 5.12 (q, 2H, 10-CHz); 4.50 (m, 8-HO; 4.28 (m, 7-H); 3.70 (q, 2H, CH2CH2) 3.68 (s, 3H, CHCHCO2CH3); 3.62, 3.40, 3.22(each s, 3H, 3CH3); 2.70 (7a-H); 2.31(7a′-H); 2.56 (7b-H); 2.29 (7b′-H); 1.82 (d, 3H, 8-CH3); 1.70 (t, 3H, CH3CH3); −1.70 (s, 2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][NH:9]1.F[C:20](F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][N:9]1[CH3:20]
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2Cl)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1cn(C)n(-c2ccccc2Cl)c1=O
Yield: 81 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2-chlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.4 g, 12 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (2.8 g, 81%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1>CC#N>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1[Br:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1
Solvent: CC#N
Product: COC(=O)c1ccc2c(Br)c(NC(=O)OC(C)(C)C)ccc2c1
Yield: 90.9 %

Procedure:
A mixture of ester 147 (977 mg, 3.24 mmol) and NBS (664 mg, 3.73 mmol) in CH3CN (25 mL) was stirred at reflux for 45 min, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed with 10% aqueous Na2SO3 and water (×2), dried, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give methyl 2-[(tert-butoxycarbonyl)amino]-1-bromo-6-naphthoate (148) (1.12 g, 91%) as a white solid: mp (petroleum ether) 130-131° C.; 1H NMR [(CD3)2SO] δ 8.93 (s, 1H), 8.65 (d, J=1.6 Hz, 1H), 8.64 (d, J=8.9 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H), 8.11 (dd, J=8.9, 1.7 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 3.93 (s, 3H), 1.50 (s, 9H). Anal. (C17H18BrNO4) C, H, N, Br.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].C(N(C(C)C)CC)(C)C.C(#N)C.[F:47][C:48]1[CH:71]=[CH:70][C:51]([CH2:52][N:53]2[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[N:55]=[C:54]2[C:62]([CH:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)=[O:63])=[CH:50][CH:49]=1>C(OCC)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:67]2[CH2:68][CH2:69][CH:64]([C:62]([C:54]3[N:53]([CH2:52][C:51]4[CH:50]=[CH:49][C:48]([F:47])=[CH:71][CH:70]=4)[C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=4[N:55]=3)=[O:63])[CH2:65][CH2:66]2)([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(benzo[1,3]dioxol-5-yl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.64 g, 1.26 mmol), diisopropylethylamine (0.33 g, 2.6 mmol), acetonitrile (14 mL), and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.64 g, 1.9 mmol). Heat to reflux. After 48 hours, partition the reaction mixture between ethyl acetate and water. Extract 2 times with water, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10/1 ethyl acetate/methanol to give a residue. Partition the residue between dichloromethane and water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo at 70° C. to give the title compound: Rf=0.54 (silica gel, 10/1 ethyl acetate/methanol); mp; 94-97° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].O.Cl.[CH3:10][CH:11]([CH3:15])[C:12]([NH2:14])=[NH:13]>C(OCC)C>[CH3:5][O:4][C:2]([NH:14][C:12](=[NH:13])[CH:11]([CH3:15])[CH3:10])=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COC(=O)NC(=N)C(C)C
Yield: 86 %

Procedure:
165 parts of methyl chloroformate and 141.8 parts of sodium hydroxide in 590 parts of water are added via two inlets to 221 parts of 2-methylpropionamidine hydrochloride in 1,000 parts of diethyl ether, at from 25° to 30° C., in the course of 40 minutes, while stirring. The mixture is stirred at room temperature for one hour, and the organic phase is separated off. The aqueous phase is extracted again with 200 parts of diethyl ether, and the solvent is removed from the combined organic extracts to give 223 parts (86% of theory) of N-methoxycarbonyl-2-methylpropionamidine of melting point 127°-130° C.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=4[Cl:39])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)=[O:8])(=[NH:5])[NH2:4].C1COCC1.[ClH:45]>CCO>[ClH:39].[ClH:45].[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=4[Cl:39])[CH2:27][CH2:28]3)=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)=[O:8])(=[NH:4])[NH2:5]
Reactant: COC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CNC(=O)NC(=N)N)c4)cn3)CC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N=C(N)NC(=O)NCc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1M aqueous NaOH solution was added to a mixture of methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg), THF (2 ml), and EtOH (2 ml), followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitated solid was collected by filtration. A 4M hydrogen chloride/dioxane solution (1 ml) was added to a mixture of the obtained solid and dioxane (3 ml), followed by stirring at room temperature overnight. The insoluble matter was collected by filtration to obtain 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoic acid dihydrochloride (112 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (265 g., 1.50 mole) and isovaleryl chloride (200 g., 1.64 mole) in methylene chloride (1.2 1.) is cooled to 5° C. and treated with aluminum chloride (220 g., 1.64 mole) during a two-hour period. The reaction is allowed to warm to 25° C. and after 24 hours is poured into ice water (3 l.) and hydrochloric acid (600 ml.). The organic phase is washed with 10% sodium hydroxide and water and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane affording 295 g. of 2',3'-dichloro-4'-methoxyisovalerophenone which melts at 49°-54° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=S1(=O)CCN(c2ccc(Br)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1,4-dibromobenzene (118 mg, 0.5 mmol), thiomorpholine-1,1-dioxide (68 mg, 0.5 mmol), Pd2 dba3 (12 mg, 2.5 mol %), BINAP (24 mg, 7.5 mol %), sodium 2-methylpropan-2-olate (72 mg, 0.75 mmol) and toluene (2 mL) was stirred at 80° C. for overnight. The reaction mixture was cooled down to room temperature and worked-up. The residue was purified on slilica gel flash column chromatography (eluent: 0-50% EtOAc in hexane) to afford 4-(4-bromophenyl)thiomorpholine-1,1-dioxide as a white solid.
Reaction SMILES: [CH3:1][C:2](/[CH:8]=[CH:9]\[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>O>[CH3:1][C:2](/[CH:8]=[CH:9]\[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)C=C(C)/C=C\CC(C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C

Procedure:
A mixture of 1 g. of trans/cis methyl 3,7,11-trimethyldodeca-2,4-dienoate, 60 ml. of methanol, 0.5 g. of sodium hydroxide and 6 ml. of water is stirred at about 30° for about 56 hours. The mixture is then diluted with water, neutralized and extracted with ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to yield trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:33](O)(=[O:36])[CH:34]=[CH2:35]>C1COCC1.O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH:25][C:33](=[O:36])[CH:34]=[CH2:35])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Reactant: C=CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncn(-c3cncc(N[C@@H](C)c4ccccc4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (67 mg, 0.2 mmol) in anhydrous THF (2 mL) under N2 was added triethylamine (67 μl, 0.48 mmol), EDACHCl (46 mg, 0.24 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (17 mg, 0.24 mmol). The resulting mixture then stirred at RT overnight and was the diluted with H2O (10 mL) and the mixture extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous Na2CO3, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2-94:6) as eluant to separate the pure product (25 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.2 %

Procedure:
In a flask were placed 3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) and N,N-dimethylformamide (1 mL), followed by stirring at room temperature for 24 hours. After filtering off the insoluble matters by filtration, the filtrate was purified by HPLC, to give the title compound (8 mg).
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[O:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1)([F:6])[CH3:5].CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:13][CH2:12][C:10]1[N:11]=[C:7]([C:4]([F:6])([F:3])[CH3:5])[O:8][CH:9]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(F)(F)c1nc(CO)co1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(F)(F)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(1,1-difluoroethyl)oxazol-4-yl)methanol (505 mg, 3.10 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.56 mL, 4.03 mmol) followed by DMAP (38 mg, 0.31 mmol) and Ms-Cl (0.31 mL, 3.91 mmol). After stirring at 0° C. for 1.5 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×) The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 695 mg of crude (2-(1,1-difluoroethyl)oxazol-4-yl)methyl methanesulfonate as a yellow solid. A solution of this crude material in DMF (8 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (3.08 g of a 10% solution in acetone, 2.70 mmol) in DMF (10 mL) pre-treated for 30 min with DIPEA (0.9 mL, 5.39 mmol) and the reaction mixture was stirred overnight at 50° C. Water (30 mL), followed by EA (50 mL) were added. The aq. layer was extracted with EA (50 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1→2:1 hept-EA) gave the title compound as a yellow solid: TLC:rf (1:2 hept-EA)=0.4. LC-MS-conditions 01: tR=0.89 min, [M]+=259.11.