Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:21][C:22]([OH:24])=O)=[C:4]([F:20])[C:5]([NH:8][CH2:9][C:10]([F:19])([F:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])=[N:6][CH:7]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[C:27]([CH2:26][NH:25][C:22](=[O:24])[CH2:21][C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][C:10]([F:18])([F:19])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[F:20])[CH:32]=1
Reactant: O=C(O)Cc1c(Cl)cnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CNC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.035 g (0.1 mmol) (5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetic acid 1-9 (mixed with LiCl) in 1 mL DMF was added 0.029 g (0.1 mmol) tert-butyl 2-[2-(aminomethyl)-4-chlorophenyl]ethylcarbamate, 0.03 g (0.15 mmol) EDC and 0.014 g (0.1 mmol) HOAt and the reaction mixture stirred at room temperature 4 h, then diluted with 50 mL EtOAc, washed with 50 mL saturated aqueous sodium bicarbonate solution, brine, then dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (2×12 cm silica gel, linear gradient 2-6% MeOH (containing 10% saturated ammonium hydroxide solution)/CH2Cl2 afforded tert-butyl 2-[4-chloro-2-({[(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetyl]amino}methyl)phenyl]ethylcarbamate 1-10. 1H NMR (400 mHz, CD3OD) δ8.60 (d, 1H, J=4.58 Hz); 7.89 (ddd, J=7.7, 7.7, and 1.47 Hz); 7.72 (s, 1H); 7.67 (d, 1H, J=7.87 Hz); 7.46 (dd, 1H, J=7.51 and 4.58); 7.29(d, 1H, J=1.83 Hz); 7.18 (m, 2H); 4.42 (s, 2H); 4.32 (t, 2H, J=13.9 Hz); 3.74 (d, 2H, J=1.46 Hz); 3.21 (t, 2H, J=7.14 Hz); 2.80 (t, 2H, J=7.4 Hz); 1.40 (s, 9H). Mass Spectrum (electrospray) M+H=612.3.
Reaction SMILES: OC1C=CC(C2C3C=C(N(C)C)C=CC=3S(=O)(=O)CCC2)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:40][CH2:41][CH2:42][CH2:43]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CC(C)=O>[S:37]([C:34]1[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][CH:35]=1)([O:40][CH2:41][CH2:42][CH3:43])(=[O:38])=[O:39]
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CN(C)c1ccc2c(c1)C(c1ccc(O)cc1)CCCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 21 h
Yield: 85.9 %

Procedure:
A solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N2 was treated with powdered K2CO3 (3.8 g, 27.2 mmol, 2.5 eq.) and 1,3-propanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting mixture was stirred at 65° C. for 21 hours. The cream-colored slurry was cooled to 25° C. and was filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×150 mL) and saturated aqueous NaCl (2×150 mL), and was dried (MgSO4) and concentrated in vacuo to provide a pale orange oil. Purification by flash chromatography (4.4×35 cm silica, 20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) as a white foam: 1H NMR (CDCl3) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.63 (m, 1H), 2.14 (m, 2H), 2.21 (m, 1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=49.0 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 4.10 (m, 1H), 4.26 (t, J=5.9 Hz, 2H), 5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51 (dd, J=8.9, 1.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H) , 7.88 (d, J=8.9 Hz, 1H)
Reaction SMILES: [CH3:1][CH:2]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:9]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:27])=[CH:21][CH:20]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC(NC1CCN(C)CC1)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N(C2CCN(C)CC2)C(C)c2ccccc2)cc1
Reaction time: 16 h
Yield: 69.9 %

Procedure:
47AKU-36 (218 mg, 1.0 mmol) was dissolved in 10 ml dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40° C.). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 256 mg (70%) 47AKU-37. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.5. HPLC-MS (Method A): M+=367.3 (UV/MS(%)=100/99).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]([O:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:13]([O:20][CH2:21][CH2:22][O:23][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccnc(Br)c1
Reactant: OCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccnc(OCCOCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-bromoisonicotinate (575 mg, MATRIX) in THF (25 ml) was added with ethylene glycol monobenzyl ether (710 μl, TCI), cooled to 0° C., and added with potassium t-butoxide (420 mg, TCI), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with purified water (15 ml), and extracted with ethyl acetate (30 ml×2). The organic layers were combined, washed with saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Flash, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate ii-01).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:26]=[CH:25][C:18]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[N:39]1[C:43](=[O:44])[CH2:42][S:41]/[C:40]/1=[N:45]\[C:46](=O)[O:47]C1C=CC([N+]([O-])=O)=CC=1)([CH3:31])[CH3:30]>>[CH2:22]([N:21]([CH2:20][CH2:19][C:18]1[CH:25]=[CH:26][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:27])[F:28])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:46](/[N:45]=[C:40]1\[S:41][CH2:42][C:43](=[O:44])[N:39]\1[C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[CH:29]([CH3:30])[CH3:31])=[O:47])[CH:23]=[CH2:24]
Reactant: C=CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)prop-2-en-1-amine (CB26) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.040 g, 43%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[CH:28]=[CH:29][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.99 min, MH+ 393. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.13,(1H, s), 8.86,(1H, t), 8.34,(1H, d), 8.21,(1H, s), 8.07,(1H, d), 7.81,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.29,(1H, d), 3.21,(2H, t), 2.45,(3H, s), 1.07,(1H, m), 0.47,(2H, m), 0.27,(2H, m).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][CH:41]3[CH2:50][CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH2:50]([C@H:41]1[CH2:42][N:43]([CH:46]2[CH2:47][O:48][CH2:49]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][C:22]5[N:21]6[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]6)=[CH:15][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1)[CH3:51]
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(cc6n5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of 123a (105 mg, 0.15 mmol) and lithium hydroxide (36 mg, 1.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 123 (40 mg, 40%) as a pale pink solid. MS: [M+H]+ 682.3. 1H NMR (500 M, CHCl3) δ 8.55 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.29 (d, J=3.5 Hz, 1H), 7.15-7.12 (m, 1H), 6.94 (dd, J=3.5 Hz, 10.5, 1H), 6.81 (d, J=10.0 Hz, 1H), 6.30 (s, 1H), 4.77-4.74 (m, 4H), 4.72-4.70 (m, 1H), 4.57-4.55 (m, 1H), 4.29-4.24 (m, 1H), 4.12-4.05 (m, 1H), 3.90-3.78 (m, 4H), 3.70 (s, 3H), 3.52-3.50 (m, 1H), 3.32-3.30 (m, 1H), 3.12-3.10 (m, 2H), 3.04-2.83 (m, 2H), 2.81 (m, 2H), 2.57-2.50 (m, 1H), 2.43-2.33 (m, 2H), 2.05-2.00 (m, 2H), 1.87-1.85 (m, 2H), 1.49-1.35 (m, 2H), 0.81 (t, J=8.5 Hz, 3H).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][SH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:18][C:19]([F:33])([F:32])[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=2)[O:22][CH2:21]1.O>CN(C)C=O.C(O)(=O)C>[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][S:14][CH2:21][C:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)([OH:22])[C:19]([F:18])([F:32])[F:33])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOc1ccc(C2(C(F)(F)F)CO2)cc1
Reactant: SCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(C(O)(CSCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a suspension of sodium hydride (0.1 g) in N,N-dimethylformamide (10 cm3) at 0° C. was added 3-phenoxybenzyl thiol (0.28 g). After stirring for 30 minutes, 1,1,1-trifluoro-2-(4-ethoxyphenyl)-prop-2-ene oxide (0.3 g) was added. The reaction mixture was stirred for ten minutes before being added to water (25 cm3) and neutralised with acetic acid. The product was extracted into diethyl ether (200 cm3). The organic layer was dried over anhydrous sodium sulphate and the solvent removed by evaporation under reduced pressure. The resulting oil was purified by chromatography to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-2-hydroxyprop-3-yl 3-phenoxybenzyl sulphide as a colourless oil (0.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:24]([O:16][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 75 ml of N,N-dimethylformamide are suspended 7.5 g of 3-(3-ethoxy-3-oxopropyl)-4-hydroxybenzoic acid, 17.5 g of potassium carbonate and 7.4 ml of acetic anhydride. The mixture thus obtained is stirred at ambient temperature for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 1.8 g of 4-(acetyloxy)-3-(3-ethoxy-3-oxopropyl)benzoic acid as a light brown-colored solid product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]([OH:21])=O)[CH:10]=2)[S:3]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:19](=[O:21])[CH2:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:10]2)=[CH:47][CH:46]=1
Reactant: O=C(O)Cn1cc(C=C2SC(=O)NC2=O)c2ccccc21
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(Cn1cc(C=C2SC(=O)NC2=O)c2ccccc21)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]acetic acid (example 300, 90.7 mg, 0.3 mmol) was dissolved in NMP (1 mL) and added to a mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (86.4 mg, 0.45 mmol) and 1-hydroxybenzotriazol (68.8 mg, 0.45 mmol) in NMP (1 mL). The resulting mixture was shaken at RT for 2 h. 4-Chlorobenzylamine (51 mg, 0.36 mmol) and DIPEA (46.4 mg, 0.36 mmol) in NMP (1 mL) were added to the mixture resulting mixture shaken at RT for 2 days. Subsequently ethyl acetate (10 mL) was added and the resulting mixture washed with 2×10 mL water followed by saturated ammonium chloride (5 mL). The organic phase was evaporated to dryness giving 75 mg (57%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])=[N:17][CH:16]=2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCc2ccc(Cl)nc2)ccc(C(C)=O)c1O
Reactant: O=C(O)c1cccc(S)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2ccc(Sc3cccc(C(=O)O)c3)nc2)ccc(C(C)=O)c1O
Reaction time: 0.17 h

Procedure:
Dissolve 3-mercapto-benzoic acid (482 mg, 3.13 mmol, commercially available) in dimethylformamide (20 mL) at 0° C. Add washed sodium hydride (300 mg), and stir the mixture for 10 minutes. Add 1-[4-(6-chloro-pyridin-3-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.13 mmol). Stir the mixture at room temperature for 2 hours; then stir at 65° C. for 2 hours and finally stir at 120° C. overnight. Dilute in ethyl acetate, and wash with water twice. Extract the organic layer with saturated aqueous sodium bicarbonate. Acidify the aqueous layer with 2N hydrochloric acid hydrochloric acid to pH 3. Extract with ethyl acetate, wash with brine, dry and concentrate to afford 620 mg of a crude red solid. Purify the residue via chromatography, eluting with 1:1 hexane:ethyl acetate to afford the title compound as a light yellow powder (120 mg): 1H NMR (DMSO-d6) δ 0.84 (s, 3H), 1.44 (sextet, 2H), 2.55 (t, 2H), 2.58 (s, 3H), 5.24 (s, 2H), 6.74 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.75 (d, 1H), 7.81-7.84 (m, 2H), 8.02 (d, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 12.84 (s, 1H), 13.21 (bs, 1H); MS (APCI-neg mode) m/z (rel intensity) 436 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][C:13]([C:20]([OH:22])=O)=[C:12]2[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[CH:28]([NH:29][C:20]([C:13]1[N:14]=[C:15]([Cl:19])[C:16]2[C:11]([C:12]=1[OH:23])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:18][CH:17]=2)=[O:22])[CH3:30]
Reactant: O=C(O)c1nc(Cl)c2ccc(OCc3ccccc3)cc2c1O
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Product: COC(=O)C(C)NC(=O)c1nc(Cl)c2ccc(OCc3ccccc3)cc2c1O

Procedure:
6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester hydrochloride, 0.150 g, analogously to Example A-1 a). 0.205 g of off-white, solid product were obtained, MS-(+)-ion, M+1=415.0 amu.
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])[C:9]([Cl:15])=[N:8][CH:7]=[CH:6]2.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(Cl)(Cl)Cl>[ClH:15].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc2ccnc(Cl)c2cc1OC
Reactant: COc1ccccc1CN
Solvent: ClC(Cl)Cl
Product: COc1ccccc1CNc1nccc2cc(OC)c(OC)cc12
Product: Cl
Reaction time: 1.5 h

Procedure:
6,7-Dimethoxy-1-chloroisoquinoline (J. Am. Pharm. Assoc., Sci. Ed. (1952), 41, 643-50; C.A. 47, 11205d.) (1.0 gm, 0.00447 mol) and 2-methoxybenzylamine (1.22 gm, 0.00894 mol) were mixed at room temperature and heated, with stirring, in an oil-bath at 140° for 1.5 hours. After cooling the mixture was dissolved in chloroform and the solution washed with saturated NaHCO3 solution and water, dried and evaporated. The resulting oil was chromatographed on silica gel, using chloroform as eluent. Fractions were monitored by t.l.c. and those containing pure product were combined, evaporated to dryness and the residue (0.25 g) dissolved in ethanol containing ethanolic hydrogen chloride. This solution was evaporated to dryness and the residue crystallised from ethanol/diethyl ether to give the title compound as its hydrochloride salt (0.22 gm), m.p. 225°-229°.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH:8][C:9](=[O:33])[CH2:10][N:11]([CH2:19][C:20](=[O:32])[NH:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)=[O:24])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]([CH3:7])[CH3:6].COC(N1CC(=O)N2C(C(OCC)=O)CCC2C1)=O>>[Br:31][C:28]1[CH:27]=[CH:26][C:25]([C:23](=[O:24])[CH2:22][NH:21][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C:9]([NH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:34])=[O:2])=[O:33])=[O:32])=[CH:30][CH:29]=1
Reactant: COC(=O)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(C)C
Agent: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Product: CC(C)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(=O)O

Procedure:
2-[2-({[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid was prepared using method 801 substituting 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid methyl ester for 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester. C22H30BrN3O7 calculated 527.1 observed [M+1]+ 528.1; rt=2.39 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9](=[NH:13])[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.[O:16]([C:23]([N:25]=[C:26]=[S:27])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9](=[NH:13])[C:10]([C:11]#[N:12])=[C:26]([SH:27])[NH:25][C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(CSC(=N)CC#N)cc1
Reactant: O=C(N=C=S)Oc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(CSC(=N)C(C#N)=C(S)NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of of 2-cyano-thioacetimidic acid 4-methoxy-benzyl ester (42 g, 0.19 mol) in 191 mL of ethyl acetate at 0° C. was added phenoxycarbonylisothiocyanate (34 g, 0.19 mol), and the mixture was stirred at 0° C. for 24 hours. The mixture was diluted with ether and filtered. The solids were washed with ether, collected and dried in vacuo, affording 56 g (73%) of 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid 4-methoxy-benzyl ester as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.81(s, 1H), 9.01 (s, 1H), 8.68 (s, 1H) 7.28-6.99 (m, 7H), 6.69 (d, 2H, J=8.8 Hz), 4.17 (s, 2H), 3.64 (s, 3H) ppm; MS (APCl, m/z): 400 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]>CN(C(OC)OC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[C:10]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])=[CH:10][N:11]([CH3:19])[CH3:12]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O

Procedure:
1 mmol of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dion was heated to 80° C. in neat N,N-dimethylformamidedimethyl acetal for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether to obtain 2-{2-(2,4-dichlorophenyl)-1-[(dimethylamino)methylene]-2-oxoethyl}isoindoline-1,3-dione.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:2]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2Br)cc1
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(F)c2)cc1
Yield: 72 %

Procedure:
In a similar manner to that in Example 28, from 3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (240 mg, 0.64 mmol) and 2-fluoropyridin-4-ylboronic acid (271 mg, 1.92 mmol) after heating to 100° C. for 1.5 hours was formed N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (180 mg, 72%) as a greenish solid. 1H NMR (CDCl3): δ 8.12 (d, 1H), 7.56 (m, 2H), 7.27 (m, 1H), 7.13–7.02 (m, 4H), 6.90 (s, 1H), 6.05–6.01 (m, 2H), 4.02 (m, 1H), 2.16 (m, 2H), 1.86–1.68 (m, 6H); 19F NMR (CDCl3) δ −68.65, −113.06; MS m/z 391 (M+1).