Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.C(OC([N:46]1[CH2:51][CH2:50][CH:49]([C:52](O)=[O:53])[CH2:48][CH2:47]1)=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:52]([CH:49]3[CH2:50][CH2:51][NH:46][CH2:47][CH2:48]3)=[O:53])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 83 %

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 equiv.) were added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was taken up in purified by column chromatography. The Boc protecting group was removed using standard conditions to give the desired compound (83% yield). LCMS: 532.35 (M+1)+; HPLC: 99.04% (@ 254 nm) (Rt;5.006); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.83 (t, 1H), 8.47 (bs, 1H), 8.30 (s, 1H), 8.26 (bs, 1H), 7.86 (s, 1H), 6.92 (bs, 1H), 5.89 (s, 1H), 5.21-5.18 (m, 1H), 4.38 (d, 2H, J=4 Hz), 4.22 (bs, 2H), 3.75 (m, 2H), 3.32 (m, 3H), 2.96 (m, 2H), 2.80 (bs, 1H), 2.67 (bs, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 1.84-1.73 (m, 4H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: FC1C=C(C=CC=1S(C)=[N:21][C:22]#[N:23])CN1C(=O)C2C(=CC=CC=2)C1=O.[C:25]([O:29][C:30](=[O:42])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][CH3:40])=[CH:35][C:34]=1[F:41])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:42])[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:40])=[N:23][C:22]#[N:21])=[CH:35][C:34]=1[F:41])([CH3:28])([CH3:26])[CH3:27]
Reactant: CSc1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Reactant: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Product: CS(=NC#N)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1

Procedure:
The title compound is prepared following the procedure described for preparation 15b, using (2-fluoro-4-methylsulfanyl-benzyl)-carbamic acid tert-butyl ester (preparation 18b) as starting material. ESI mass spectrum: [M+H]+=312; r.t. HPLC: 0.68 min (5-95AB).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:49]([C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][C:61]=1[OH:62])[O:55][CH2:56][CH2:57][NH-:58])(=[O:51])[NH2:50].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:49]([C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][C:61]=1[OH:62])[O:55][CH2:56][CH2:57][NH-:58])(=[O:51])[NH2:50]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCOc1ccc(O)c(C(N)=O)c1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 132 mg of Z-Phe-His-OH, 95 mg of H-Leu-Val-2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl amide, 46 mg of HOBt and 72 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.21, Rf (B11)=0.56.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].Cl[C:11]1[C:16]([NH2:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCCCC)(=O)C.O>[NH2:17][C:16]1[C:11](/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: Nc1cc(F)cnc1Cl
Reactant: C=CC(=O)OCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCOC(=O)/C=C/c1ncc(F)cc1N
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A mixed solution of 150 mL of butyl acetate and 73 mL of butyl acrylate was refluxed with heating for 45 minutes under a nitrogen atmosphere. The reaction mixture was cooled to 30° C., 50.0 g of 2-chloro-5-fluoropyridine-3-amine, 3.8 g of palladium (II) acetate, 44.8 g of triphenylphosphine and 36.6 g of sodium carbonate were added thereto, and the mixture was refluxed for 13 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 150 mL of water and 700 mL of butyl acetate were added thereto, and the mixture was stirred for 1 hour. Insoluble matter was filtered out, and the filter residue was washed using 50 mL of butyl acetate. The filtrate and the wash liquid were combined, the organic layer was separated, and 800 mL of the solvent was evaporated under reduced pressure. To the obtained residue, 300 mL of cyclohexane and 30 mL of toluene were added dropwise, the mixture was cooled to 5° C., and the solid product was obtained by filtration and washed using a mixed solution of toluene-cyclohexane (1:2) and toluene to give 57.8 g of butyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].[NH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O.O>CN1CCCC1=O>[C:12]([C:5]1[N:6]=[C:7]([C:8]([CH3:10])=[CH2:9])[C:2]([NH:24][C@@H:25]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]2)=[N:3][C:4]=1[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=1)(=[O:13])[NH2:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
A mixture of 5-chloro-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (700 mg), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (1.05 mL), diisopropylethylamine (1.06 mL), and N-methylpyrrolidone (2.5 mL) was reacted in a microwave reaction device at 180° C. for 1 hour. To the reactant was added a mixed solution of saturated brine:water (1:1), followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-90:10, NH2 type: eluent; chloroform:methanol=99:1-95:5) to obtain tert-butyl (3R)-3-{[5-carbamoyl-6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-(prop-1-en-2-yl)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (928 mg) as a yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:4]([CH2:5][NH:15][CH3:14])[C:3]=1[OH:13]
Reactant: CN
Reactant: O=Cc1cc([N+](=O)[O-])cc(F)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc([N+](=O)[O-])cc(F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.5 %

Procedure:
To a solution of 17C (2.65 g, 14.32 mmol) in MeOH (100 mL), methylamine (33% in EtOH, 1.960 mL, 15.75 mmol) was added dropwise and stirred rt for 1 h. The reaction mixture was cooled to 0° C., sodium borohydride (0.596 g, 15.75 mmol) was added portionwise and the mixture was stirred at rt for 1 h. The reaction was quenched with 0.5 N HCl, extracted with EtOAc (3×20 mL), washed with water, brine, dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography to give 27A (3.8 g, 18.98 mmol, 133% yield) yellow solid. MS (ESI) m/z: 201.2 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCO.CCOC(C)=O.[Pt]>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1C(COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C (1.5 g), attached with a balloon of H2. More Pt/C (500 mg) was added after 3 h. Then the reaction mixture was stirred at rt for another 2 h. The reaction mixture was filtered over celite, concentrated down to give product (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) and went to next step without purification. To a solution of (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) (21.63 mmol) in HOAc/THF (80 ml, 1:1) was added KSCN at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then Br2 was added slowly, reacted at 0° C. The reaction was quenched by adding sat. NaHSO3, extracted by EtOAc, dried over MgSO4, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65H (2.3 g, 24% over 2 steps).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([CH2:18][CH2:19][NH2:20])[CH2:10]C(OC(C)(C)C)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>C1COCC1>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:20][CH2:19][CH2:18][N:9]([CH3:10])[CH2:8][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CC(C)(C)OC(=O)CCN(CCN)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN)CCC(=O)O

Procedure:
3-(Boc-aminoethyl-methyl-amino)-propionic acid tert-butyl ester (630 mg, 2.1 mmol) was treated with trifluoroacetic acid (6 mL) for 2 hours. 3-(Aminoethyl-methyl-amino)-propionic acid trifluoroacetic acid salt was isolated by recrystallisation from THF to give a white powder, 974 mg (quantitative).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:20])([F:22])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[CH:36][N:35]=[N:34]4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-[1,2,3]-triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M118) (0.33 g, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (115 mg, 44%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH2:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[C:18]=2[CH:27]=1.C1C[O:31][CH2:30]C1>CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH2:20][C:19]([CH2:30][OH:31])([C:23]([O:25][CH3:26])=[O:24])[C:18]=2[CH:27]=1
Reactant: C1CCOC1
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C1(CO)CCOc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mL (0.035 mole) of diisopropylamine in 100 mL of THF was cooled to 0° C. and 22.1 mL (0.35 mole) of 1.6M butyllithium in hexane was added dropwise. After stirring for 30 minutes at 0° C. the resulting solution was cooled to -78° C. A solution of 6.2 g (0.0295 mole) of Methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 20 mL of THF was then added dropwise while maintaining the temperature below -66° C. The resulting solution was stirred at -78° C. for 3 hours. Gaseous formaldehyde was then bubbled into the solution for 5 minutes. The reaction was allowed to warm to room temperature, then diluted with water and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated to give 7.6 g of crude product as an oil. NMR (CDCl3) ppm (delta): 2.20-2.60 (m, 2H), 3.8 (s, 3H), 4.26 (t, 2H, J=5 Hz), 4.90 (m, 2H), 6.80-7.20 (m,3H).
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=C=O)=O.[CH:10]([C:13]1[N:14]([O:27][CH3:28])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:26]=1)([CH3:12])[CH3:11].CO>ClCCl>[CH:10]([C:13]1[N:14]([O:27][CH3:28])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:5])[C:16]=2[N:26]=1)([CH3:12])[CH3:11]
Reactant: COn1c(C(C)C)nc2c[n+]([O-])c3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COn1c(C(C)C)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
Trichloroacetyl isocyanate (3.3 mL, 28 mmol) was added to a solution of 2-isopropyl-1-methoxy-5-oxido-1H-imidazo[4,5-c]quinoline (4.7 g, 118 mmol) in dichloromethane (100 mL), and the reaction was stirred three hours at room temperature. Methanol (20 mL) was added, and the mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (25 mL), and sodium methoxide (0.5 mL of a 4.5 N solution in methanol) was added. The mixture was stirred at room temperature for three days and concentrated under reduced pressure. The residue was stirred with dichloromethane (25 mL). A solid was present and was collected by filtration, recrystallized from methanol/water, and dried overnight in a vacuum oven at 70° C. to provide 0.878 g of 2-isopropyl-1-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as tan needles, mp 217-219° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27](O)=[O:28].Cl.[CH3:31][O:32][C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][NH:37][CH2:38]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][CH:41]=[CH:42][C:33]=2[O:32][CH3:31])[CH2:38]1)=[O:28]
Reactant: COc1cccc2c1CCNC2
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4c(cccc4OC)C3)c2cc1OC
Yield: 41.6 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 116 (41.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.84 and 2.90 (2t, 2H), 3.52-4.09 (m, 20H), 4.45 and 4.96 (2s, 2H), 6.45-7.26 (m, 4H), 7.45 and 7.49 (2s, 1H), 7.76 and 7.82 (2s, 2H); MS (ESI) m/z 546 ([M+H]+).
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[C@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][CH:13]=2)[C@@H:3]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@H:2]1[OH:32].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40]>CO.O>[CH3:35][CH:34]([O:30][C:29]([CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[CH2:23][C@@H:3]1[C@@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[C@H:5]([OH:6])[CH2:1][C@@H:2]1[OH:32])=[O:31])[CH3:42].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CO
Solvent: O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Reaction time: 0.5 h

Procedure:
To travoprost free acid ((+)-fluprostenol free acid) 3 in MeOH/H2O was added L-Arginine (>98%) (Sigma-Aldrich Cat. A5006) and the solution was stirred for 30 minutes. The solvents were evaporated then azeotroped with Et2O and hexanes to give white crystalline travoprost-L-Arginine salt 4 (quantitative).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]C1C=CC(C(O)=O)=C(I)C=1.N1C=CN=N1>>[CH3:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:12]=[CH:13][CH:14]=[N:15]2)[CH:4]=1
Reactant: Cc1ccc(C(=O)O)c(I)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: c1c[nH]nn1
Product: Cc1ccc(C(=O)O)c(-n2nccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+1]+.
Reaction SMILES: BrC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[C:35]1(/[CH:43]=[CH:44]/C2C=CC=CC=2)[CH:40]=[CH:39][C:38](C=O)=[CH:37][CH:36]=1.C1C=CC2C(=NO[N+]=2[O-])C=1.[OH-].[Na+]>CO.C(#N)C.C(OCC)(=O)C>[CH:17]1([N:16]2[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=[C:12]2[C:9]2[CH:10]=[CH:11][C:6](/[CH:44]=[CH:43]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:7][CH:8]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Agent: [Na+]
Agent: [O-][n+]1onc2ccccc21
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(/C=C/c3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.5 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (500 mg) obtained in Example 1, Step 3, was dissolved in methyl alcohol (6 ml) and trans-4-stilbenecarbaldehyde (397 mg) was added under ice-cooling. The mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled and benzofuroxan (259 mg) dissolved in acetonitrile (2 ml) was added. The mixture was stirred for 7 hr at 50° C. The reaction mixture was ice-cooled. After 1N sodium hydroxide was added, ethyl acetate was added and the mixture was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate=4:1) to give the title compound (540 mg, yield 63%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 120 °C
Yield: 56 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (1.50 g, 4.46 mmol) in 1,4-dioxane (25 mL) containing 4-amino-1-methylpyrazole (0.520 g, 5.35 mmol) and p-toluenesulfonic acid (0.085 g, 0.45 mmol) was heated under microwave irradiation at 120° C. for 7 hours. The volatiles were removed in vacuo and the residue was adsorbed onto silica gel and the product was separated using silica column chromatography (Combiflash Rf, 40 g SiO2 Cartridge, 60-100% EtOAc in cyclohexane and then 0-5% MeOH in DCM) to give the title compound 13 as a light orange foam (1.01 g, 56%). 1H NMR (300 MHz, d6-DMSO) δ 9.64 (s, 1H), 8.37 (s, 1H), 7.87 (s, 1H), 7.46 (s, 1H), 7.22-7.36 (m, 4H), 7.00 (brs, 1H), 6.01 (brs, 1H), 3.81 (s, 3H), 3.09 (brs, 4H), 1.45-1.44 (m, 2H), 1.00-0.99 (m, 2H). LCMS-B: rt 6.318 min; m/z 397 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].Cl.[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:39])[C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[O:20][C:19](=[O:38])[CH:18]=1>>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:39])[C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:1][C@@H:2]([CH3:3])[C:4]([O:6][CH3:7])=[O:5])=[O:36])[C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[O:20][C:19](=[O:38])[CH:18]=1
Reactant: COC(=O)[C@H](C)N
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from Ala-OMe•HCl and 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (Example 44) following the procedure outlined in Example 94. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 8.20 (d, 1H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 4.22 (m, 1H), 3.96 (t, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 2.11 (t, 2H), 1.68 (m, 2H), 1.54 (m, 2H), 1.43 (m, 2H), 1.23 (d, 3H); MS (ESI): 552.0.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[OH-].[CH2:27]([N+:43]([CH3:46])([CH3:45])[CH3:44])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:23]([O-:25])=[O:24])(=[O:20])=[O:21].[CH2:27]([N+:43]([CH3:46])([CH3:44])[CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: CCCCNc1cc(C(=O)[O-])cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
In a similar manner to Example 9, bumetanide can be reacted with cetyltrimethylammonium hydroxide in water to yield cetyltrimethylammonium 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.