Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)(O)[O-].[Na+]>CO.O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(F)cc1N
Yield: 80.6 %

Procedure:
A stirred solution of 2-amino-4-fluorobenzoic acid (4.86 g, 31.3 mM) in anhydrous methanol (100 mL) was saturated with anhydrous hydrogen chloride and then refluxed for 4 days. During the reflux period, the reaction mixture was periodically resaturated with hydrogen chloride. After the reflux period, the reaction mixture was cooled and concentrated to leave a white solid. This material was dissolved in water and the resulting solution neutralized with aqueous sodium bicarbonate and extracted with diethyl ether. The combined extracts were dried (MgSO4), filtered and concentrated to leave (4.08 g, 80.6%) of the title compound as an off white solid, mp 66°-67° C.; MS(CI): 170 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:44]>>[NH2:44][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C

Procedure:
A suspension of 1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (65 mg, 0.103 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to the title compound (64 mg). MS (ESI): 558.6 [M+1-56]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(Br)cn2)=NO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
[3-(5-Bromo-pyridin-2-yl)-4,5-dihydro-isoxazol-5-yl]-methanol (38.8 g, 150.5 mmol) was added to anhydrous dichloromethane (200 ml) followed by addition of triethylamine (29.2 ml, 210.7 mmol). The solution was cooled to 0° C. followed by dropwise addition of methane sulfonyl chloride (12.3 ml, 180.6 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (30.5 g).
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:6][C:7]([N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)N1CCN(C)CC1)SC(C)=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]-carbonyl]heptanoic acid (E5, Isomer A; 226 mg, 0.5 mmol), N,N1 -dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (76 mg, 0.5 mmol) and N-methylpiperazine (0.05 ml, 0.5 mmol) in dichloromethane (8 ml) was stirred at 5° C. for 1 h, then at room temperature overnight. After cooling, the precipitated solid was filtered off. The solution was diluted with dichloromethane and extracted with 0.25 M citric acid. The extracts were washed with dichloromethane then basified with 10% sodium carbonate, and extracted with ether. The ether extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. Trituration of the oily residue with ether, followed by recrystallisation of the resulting solid from ethyl acetate/hexane gave the title compound as a single isomer (Isomer A), 98 mg (37%) mp 133°-138° C. (Found: C,60.48; H,8.15; N,10.40. C27H42N404S requires C,60.65; H,7.92; N,10.48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=[O:15])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.N1CCOCC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:18]3[C:17](=[C:26]4[N:25]=[CH:24][CH:23]=[CH:22][C:21]4=[CH:20][CH:19]=3)[O:16][CH:14]([OH:15])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: Oc1cccc2cccnc12
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2cccnc32)cc(Br)c1OC
Yield: 34 %

Procedure:
The title compound was prepared following the procedure as in Example 18 from 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (25 mg; 0.09 mmol) and 8-hydroxyquinoline (9 mg; 0.06 mmol) using morpholine (10 μl; 0.11 mmol) as base (yield: 34%). 1H NMR (acetone-d6): 8.85 (overlapping dd, J=1.8, 4.3 Hz; 1H), 8.20 (overlapping dd, J=1.8, 8.4 Hz; 1H), 7.47 (dd, J =4.1, 8.2 Hz, 1H), 7.34 (d, J=8.4 Hz) and 7.32 (d, J=8.4 Hz) (1H), 7.08 (d, J=2.1 Hz), 7.06 (d, J=2.1 Hz) and 7.05 (d, J=2.0 Hz) (2H), 6.98 (d, J=8.8 Hz) and 6.95 (d, J=8.8 Hz) (1H), 5.91 (t, J=2.7 Hz) and 5.70-5.72 (m) (1H), 4.50 (overlapping dd, J=6.3, 10.7 Hz; 1H), 3.85, 3.82, 3.81 and 3.80 (s each, 6H), 2.50-2.56 (m) and 2.20-2.37 (m) (2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([OH:13])([CH2:12][O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
After dissolving 120 mg of 6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2.5]octane in 10 ml of N,N-dimethylformamide, 67 mg of 2-methylphenol and 86 mg of potassium carbonate were added and the mixture was stirred at 150° C. for 5 hours. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (156 mg, 86% yield).
Reaction SMILES: [O:1]=[CH:2][CH:3]([CH2:5][OH:6])[OH:4].Cl.[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.O>[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:2]([CH:3]([CH2:5][OH:6])[OH:4])=[O:1])=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=CC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(=O)C(O)CO)cc1
Reaction time: 4 h

Procedure:
To a mixture of 3.6 g. of glyceraldehyde and 2.44 g. of 4-dimethylaminopyridine in an ice-bath is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. After 4 hours at room temperature, chloroform and water are added. The chloroform extract is chromatographed quickly and evaporated in vacuo to yield 4-(n-hexadecylamino)benzoyl glyceraldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([N:24]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])[CH3:25])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.O.O.[OH-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([N:24]([C@@H:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])[CH3:25])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.8 %

Procedure:
(S)-methyl 2-(3-(4-(3-(2-fluorophenyl)ureido)phenyl)-N-methylisoxazole-5-carboxamido)-3-methylbutanoate (80 mg, 0.17 mmol) was dissolved in THF and water in 2:1 ratio. Lithium hydroxide monohydrate (14 mg, 0.341 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to yield 30 mg (39%) of the title compound. MS: ES (−): m/z 453 (M−1); ES (+): m/z 455(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.427(s, 1H), 8.713 (d, 1H), 8.171 (m, 1H), 7.905-7.851 (d, 2H), 7.677-7.524 (m, 3H), 7.283 (m, 1H), 7.183 (t, 1H), 7.068 (m, 1H), 4.661-3.949 (d, 1H), 3.161-2.977 (s, 3H), 2.314 (m, 1H), 1.335-1.065 (d, 3H(×2)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COC(CBr)OC
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNCC(OC)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 2-methoxyethanamine (100 mg, 1.33 mmol) in DMF (2 mL) was added K2CO3 (276 mg, 1.99 mmol) and 2-bromo-1,1-dimethoxyethane (236 mg, 1.39 mmol). The mixture was stirred at 80° C. for 3 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated to give 2,2-dimethoxy-N-(2-methoxyethyl)ethanamine as a yellow oil in 91% yield and used in the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][C@@H:6]([NH:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:24][N:23]=[C:22]([N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])[N:21]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:20]([NH:19][C@@H:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH2:5][C:4]([OH:41])=[O:3])=[N:21][C:22]([N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])=[N:23][CH:24]=1
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(OC(=O)N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)Oc1ccc([C@@H](CC(=O)O)Nc2nc(N(C)C3CCCCC3)ncc2-c2ccccc2F)cc1
Temperature: 22 °C
Reaction time: 6 h

Procedure:
To a solution of (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)propanoic acid ethyl ester (1.0 eq) in 3:1 MeOH/H2O was added 1M NaOH (2.5 eq). The mixture was stirred at 22° C. for 6 hr, and then the MeOH and H2O were evaporated. The residue was partitioned between Et2O and H2O, and then the separated aqueous layer was acidified to pH=3 by addition of 0.1 M H3PO4. The aqueous layer was extracted three times with 3:1 CHCl3/iPrOH, and then the CHCl3/iPrOH extracts were treated with MgSO4, filtered and evaporated to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)propanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: Cc1cc[nH]c1C(=O)O
Product: Cc1cc[nH]c1C(=O)Nc1ccccc1
Yield: 47.7 %

Procedure:
Prepared following the experimental method described in preparation 1a starting from 1.38 g (11.3 mmol) of 3-methyl-1H-pyrrole-2-carboxylic acid and 1.13 g (12.13 mmol) of aniline. After purification by flash chromatography (0-40% AcOEt in hexane), 1.08 g (49% yield) of the title compound were obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[C:23]2[NH:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:24]2=[N:25][CH:26]=1.[H-].[Na+]>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]2[N:29]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[CH2:28][C:27]([CH3:31])([CH3:30])[C:24]2=[N:25][CH:26]=1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 60 °C

Procedure:
Prepared according to procedure M using 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (86 mg, 0.32 mmol) (described herein), 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (86 mg, 0.38 mmol) (described herein), and sodium hydride (25 mg, 0.63 mmol) in DMF (10 mL). Reaction was heated at 60° C. for 18 h, affording 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as an orange solid. Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].CO[C:9](OC)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C1C=CC=CC=1>[C:10]1([C:9]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:1][CH2:2][CH:3]([CH2:4][OH:5])[O:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC(O)CS
Reactant: COC(OC)(c1ccccc1)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: OCC1CSC(c2ccccc2)(c2ccccc2)O1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
3-Mercapto-1,2-propanediol(3.26 g, 30.00 mmol) was dissolved in benzene (60 mL). Benzophenone dimethyl ketal (13.48 g, 60.0 mmol, 2 equiv.) and CSA (0.70 mg, 3.00 mmol, 0.1 equiv.) were added. The solution was heated with an oil bath to reflux. Benzene/methanol was collected and removed while more benzene was added to the refluxing reaction. After about 200 mL benzene/methanol was distilled out, the reaction was cooled to room temperature, applied directly onto a silica gel column. The column was then eluted was 20%-40% etherlpetroleum ether to afford a thick oil as the desired product (3.78 g, 46). Rf =0.25, 20% ether/petroleum ether. 1H NMR (400 MIHz, C6D6) δ=2.56 (dd, J 6.3, 10.2 Hz, 1 H), 2.83 (dd, J=7.7, 10.2 Hz, 1 H), 3.35 (br dd, J=5.3, 11.6 Hz, 1 H), 3.44 (br dd, J=3.5, 11.6 Hz, 1 H), 3.88-3.95 (m, 1 H), 6.94-7.20 (m, 6H), 7.54 (d, J=7.5 Hz, 2 H), 7.70 (d, J=7.5 Hz, 2 H). 13C NMR (100 MHz, C6D6) δ=35.90, 63.97, 83.29, 100.20, 126-129 (m).
Reaction SMILES: [CH:1]1([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Cl)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:20]>CC[N+](CC)(CC)CC.[Br-]>[C@@H:1]1([N:8]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([OH:20])[C:14]=3[N:15]=[CH:16]2)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)S1
Reaction time: 34 h
Yield: 79 %

Procedure:
To a solution of the α/β anomers of 20 (82 mg, 0.3 mmol) in 20 mL of a 0.75 M TEAB buffer was added 3 μL adenosine deaminase. The reaction was stirred 34 h followed by lyophilization. The residue was purified by preparative TLC with 6:1 chloroform-methanol containing 1% acetic acid. The crude product was recrystallized from methanol/carbontetrachloride to give 30.5 mg (79%) of 21; mp. 195°-197 C.; [α]D25 -13.9° (c=0.1, H2O); FAB MS 253 (M+H)+ ; 1H NMR (D20) δ 8.5 (s, 1, H-2), 8.2 (s, 1, H-8), 6.2 (m, 1, 1'-H), 3.95 (m, 1, 5'-H), 3.8 (m, 2, 4'-H, 5'-H), 2.5 (m, 2, 2'-H's), 2.3 (m, 1, 3'-H), 1.9 (m, 1, 3'-H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[C:16]1([CH2:22][O:23][C:24](=[O:33])[NH:25][CH2:26][C@H:27]2[C@@H:31]([OH:32])[CH2:30][NH:29][CH2:28]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[C:16]1([CH2:22][O:23][C:24](=[O:33])[NH:25][CH2:26][C@H:27]2[C@@H:31]([OH:32])[CH2:30][N:29]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:28]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2n1
Yield: 96 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.73 g, 3.60 mmole) in EtOH (5 mL) was added (±)-phenylmethyl{[cis-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (0.90 g, 3.60 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (1.57 g, 96%) as a light yellow foam: LC-MS (ES) m/e 455 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:29][C:28]([CH2:30][NH:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1

Procedure:
5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde (0.05 g) was reacted with 2-(methanesulphonyl)ethylamine (0.075 g) according to procedure D. Acidification with acetic acid (0.5 ml) followed by purification using a ion-exchange (SCX) Bond Elut™ cartridge, eluting with methanol-ammonia (9:1), concentration and trituration with diethylether afforded an off-white solid; δH [2H6] DMSO 8.44 (1H, d), 8.41 (1H, d), 8.11 (1H, s), 7.85 (1H, d), 7.44-7.35 (4H, m), 7.18-7.03 (6H, m), 6.79 (1H, d), 6.47 (1H, d), 3.82 (2H, s), 3.01 (2H, t); m/z 514 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:16])[CH:22]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2c(C(C)O)oc(=O)c3ccccc23)ccn1
Yield: 47.8 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.5 g, 1.86 mmol), 2-methylpyridin-4-ylboronic acid (0.38 g, 2.79 mmol), Pd(PPh3)4 (0.107 g, 0.093 mmol) and Cs2CO3 (0.78 g, 2.41 mmol). The crude was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%; Phase B ACN 99.9%, formic acid 0.1%) to afford the title compound (0.25 g, 48%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:32])(=[O:31])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1>>[CH2:24]([N:22]([CH3:23])[S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=2)[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1)(=[O:31])=[O:32])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCNCC2)cc1

Procedure:
Using general procedure H with the above amine (790 mg, 1.72 mmol) and α-bromo-m-tolunitrile (660 mg, 3.37 mmol) and then using general procedure C gave N-benzyl-4-[(3-cyano-benzyl)-piperidin-4-yl-amino]-N-methyl-benzenesulfonamide as a white foam (202 mg, 25% over 2 steps).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([I:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([I:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:15][C@@H:5]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[Cl:14])[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.19 min. MS (ESI−): mass calcd. for C22H15Cl2IN4O5S2, 677.32; m/z found, 675/677 [M−H]−. H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.34 (d, J=7.1, 1H), 8.21 (d, J=8.8, 1H), 8.07-8.05 (m, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.40-7.39 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.22 (m, 2H), 6.94 (d, J=8.3, 1H), 6.53 (d, J=7.5, 1H), 5.02-4.95 (m, 1H), 3.53-3.44 (m, 1H), 3.34-3.24 (m, 1H).