Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24].F[C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1>>[CH3:20][O:21][C:22](=[O:33])[C@@H:23]([NH:24][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1)=[O:16])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1.[CH3:20][O:21][C:22](=[O:33])[C@@H:23]([NH:24][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(C#N)cc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 75 %
Yield: 66 %

Procedure:
3-(4-Hydroxy-phenyl)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (664 mg, 75%) was prepared starting from 4′-trifluoromethyl-biphenyl-4-carboxylic acid (532 mg, 2.0 mmol) and tyrosine methyl ester (462 mg, 2.0 mmol) according to general procedure A. The above compound (443 mg, 1.0 mmol) was treated with 1-fluoro-4-cyanobenzene (181 mg, 1.5 mmol) following general procedure B to give 3-[4-(4-cyano-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (360 mg, 66%). The ester was hydrolyzed following general procedure C to give the title compound (345 mg, 99%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([NH2:8])[CH:5]([CH3:7])[CH3:6].[F:10][C:11]([F:17])([F:16])[CH:12](OC)O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([N:8]=[CH:12][C:11]([F:17])([F:16])[F:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: COC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](N=CC(F)(F)F)C(C)C
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride (6.72 g, 40 mmol) in water (50 mL) was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford (S)-2-amino-3-methyl-butyric acid methyl ester (40 mmol). A solution of (S)-2-amino-3-methyl-butyric acid methyl ester (40 mmol), 2,2,2-trifluoro-1-methoxy-ethanol (5.2 g, 3.8 mL, 40 mmol) and 4-toluenesulfonic acid hydrate (100 mg) in toluene (125 mL) was heated at reflux using a Dean-Stark apparatus for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 10:1 to 5:1 to afford the title compound (4.79 g, 56%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.94 (d, J=7.1 Hz, 3H), 0.97 (d, J=7.1 Hz, 3H), 2.32-2.44 (m, 1H), 3.73-3.77 (m, 4H), 7.67 (q, J=3.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH:32]([NH2:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:25])[CH2:22][CH2:23]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:4])[CH3:3]
Reactant: CC(C)N
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Yield: 8.3 %

Procedure:
A solution of 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxylic acid (Compound 244, 80 mg, 0.189 mmol), isopropylamine (22 mg, 0.378 mmol), EDCI (72 mg, 0.378 mmol), and HOBT (13 mg, 0.095 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 20-30% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (7.3 mg, 8%). 1H NMR (DMSO-d6) δ: 10.88 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.74 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.42 (s, 1H), 6.34 (d, J=2.3 Hz, 1H), 4.43-4.50 (m, 3H), 3.84 (dd, J=14.3, 6.4 Hz, 2H), 3.07 (br. s., 2H), 1.73-1.87 (m, 4H), 1.45 (s, 6H), 1.05 (d, J=6.6 Hz, 6H). ESI-MS: m/z 465.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(=O)n(C)c1C
Product: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Temperature: 100 °C
Yield: 44.5 %

Procedure:
5-Acetyl-3,4-dimethyl-3H-thiazol-2-one (4.64 g, 27.10 mmol) and dimethylformamide dimethyl acetal (8.4 mL, 59.62 mmol) were mixed in a dry, argon-flushed flask, and heated at 100° C. for 3 h. The mixture was cooled, producing some precipitation, which was enhanced by the addition of an equal volume of Et2O. The resulting orange solid was filtered and washed with Et2O to give 2.73 g of 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one. 1H-NMR (d6-DMSO): δ: 2.52 (s, 3H), 2.82 (bs, 3H), 3.11 (bs, 3H), 3.22 (s, 3H), 5.10 (d, 1H, J=12.2 Hz), 7.61 (d, 1H, J=11.7 Hz). IR (ATR): 1669 and 1630 cm−1 (CO str).
Reaction SMILES: [C:1](O)(=O)CC(O)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)O[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13]/[C:12]/2=N/CC1C=CC=CC=1.CCO.[OH2:34].Cl.[OH2:36]>O1CCOCC1>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:34][C:14]([CH3:1])([C:19]([F:20])([F:21])[F:22])[CH2:13][C:12]2=[O:36]
Reactant: FC(F)(F)c1c/c(=N/Cc2ccccc2)c2cc(Br)ccc2o1
Reactant: O=C(O)CC(=O)O
Reactant: O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC1(C(F)(F)F)CC(=O)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of malonic acid (1.2 ml, 19 mmol) and (Z)-N-(6-bromo-2-(trifluoromethyl)-4H-chromen-4-ylidene)(phenyl)methanamine (6.63 g, 17 mmol) in dioxane was heated to reflux for 18 h until the reaction was completed. The mixture was cooled to RT and treated with 50% EtOH/H2O (20 ml) followed by conc. HCl (5.0 ml). The resulted mixture was left to stand at RT for 40 min, and then diluted with water (500 ml). The product was extracted with hexane (3×300 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (2-10% EtOAc/hexane) to afford the title compound as yellow oil. MS m/z: 310 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][C@@H:24]4[CH2:28][CH2:29][CH2:30][C@@H:23]34)[N:19]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)[C:4]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:6][C:7]=1[C:8](=[N:10][OH:11])[NH2:9].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[C:3]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][C@@H:24]4[CH2:28][CH2:29][CH2:30][C@@H:23]34)[N:19]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]3)[C:4]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:6][C:7]=1[C:8]1[NH:9][C:39](=[O:40])[O:11][N:10]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (33.3 mg, 0.06 mmol) in acetonitrile (2 mL) were added 1,1′-carbonyldiimidazole (19.3 mg, 0.119 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL, 0.238 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford 3-{7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd for C28H31Cl2N7O3 [M+H]+=584. found=584. 1H NMR (600 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.92 (d, J=1.2 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.46 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.77-3.86 (m, 2H), 3.56-3.62 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.87 (m, 1H), 2.31 (m, 1H), 1.86 (m, 1H), 1.71 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.81 (m, 1H), 0.65-0.74 (m, 6H), 0.46 (m, 1H), 0.30-0.42 (m, 2H).
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OC2CCCCC2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OC2CCCCC2)ccc1C(=O)O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.077 mL of 2.0 mol/L aqueous sodium hydroxide was added drop-wise to a mixed solution of 1 mL of methanol and 1 mL of tetrahydrofuran containing 35 mg of methyl 2-(benzamido)-4-(cyclohexyloxy)benzoate at room temperature and stirred at the same temperature overnight and at 40° C. for 6 hours and 30 minutes. 0.050 mL of 2.0 mol/L aqueous sodium hydroxide was added at room temperature and stirred at she same temperature for 4 hours and 30 minutes. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 25 mg of 2-(benzamido)-4-(cyclohexyloxy)benzoic acid as white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[C:12]3[N:17]=[CH:18][NH:19][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH3:30]>C(#N)C.ClCCl.O>[CH2:29]([N:19]1[C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=3)[N:14]=[C:13]([C:15]#[N:16])[C:12]=2[N:17]=[CH:18]1)[CH3:30]
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc2[nH]cnc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCn1cnc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
To a stirring solution of 6-(3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg, 0.17 mmol) in acetonitrile (1 ml) was added cesium carbonate (62 mg, 0.19 mmol) and iodoethane (15 μl, 0.19 mmol). The resulting suspension was stirred at room temperature overnight. Reaction mixture was diluted with dichloromethane (5 ml) and water (5 ml) and filtered through a hydrophobic frit and concentrated in vacuo. Residual orange oil was triturated with ether (5 ml) and resulting precipitate was filtered and dried to give the title compound as a pale yellow solid (4 mg). 1H NMR (MeOD): δ 8.56 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 7.71-7.74 (m, 2H), 4.46-4,51 (q, 2H), 1.57-1.61 (t, 3H). MS m/z 317.0 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>>[C:3]([C:2]([NH:1][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][CH:20]=1)=[O:25])([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(Cl)c2n1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(Cl)c2n1)NC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 15, and 4-biphenyl carbonyl chloride, the title compound was isolated as a white solid (32 mg). MS (ES): M/Z [M+H]=450. NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.55 (d, J=13.3 Hz, 1H), 7.43 (m, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.70-7.78 (m, 3H), 7.81 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.18 (d, J=1.6 Hz, 1H) and 8.83 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH2:21][C:22]([O:24]C)=O)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:34]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([CH2:21][C:22]([NH2:34])=[O:24])(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: N
Solvent: CCO
Product: NC(=O)CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The ester of Example 38 (40 mg, 0.07 mmol) in ethanol (1.5 ml) was treated with NH3 (1 ml of 25% aqueous solution). The reaction mixture was stirred at ambient temperature for 2 h and evaporated to give a residue (40 mg) which was purified using preparative plate thin layer chromatography eluting with ethyl acetate:hexane 2:1 to yield the desired product (10 mg).
Reaction SMILES: [CH3:1][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.C(Cl)C[Cl:18].[N:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)N(O)N=1.C(N(CC)CC)C.N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[ClH:18].[NH2:24][C@H:23]1[CH2:25][CH2:26][CH2:27][C@@H:28]1[NH:20][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:11]1[N:15]=[CH:14][CH:13]=[N:12]1
Reactant: On1nnc2cccnc21
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: ClCCCl
Agent: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 6; 254 mg, 1.25 mmol) in dry DCM (4.16 ml) was added EDC (359 mg, 1.87 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (255 mg, 1.87 mmol), triethylamine (6.9 ml, 4.99 mmol) and tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 250 mg, 1.25 mmol). The solution was stirred at room temperature under an atmosphere of nitrogen for 72 hours and then partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford a pale white solid. This Boc protected intermediate was dissolved in HCl in 1,4-dioxane (4M, 3 ml) and stirred at room temperature for 17 hours. The reaction was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28].[N:32]1C=CC=CC=1.[OH-].[NH4+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]2[C:15]([C:26](=[O:30])[C:27]([NH2:32])=[O:28])=[C:14]([CH2:16][CH3:17])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc2c(OCC(=O)OC)nc(C)nc2n1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(C)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 715 mg (2.10 mmol) of [[2-methyl-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 15 mL of chloroform was added 0.55 mL of oxalyl chloride followed by 0.25 mL of pyridine. The reaction was stirred for 18 hours at ambient temperature then poured into a solution prepared from 1.7 mL of concentrated ammonium hydroxide and 5.8 mL of water. The reaction was partitioned by the addition of 15 mL of methylene chloride and a small amount of solid residue was removed by filtration. The organic phase was dried with sodium sulfate and concentrated to an off-white solid. The solid was purified by flash chromatography (100 g of silica, ethyl acetate) to provide 740 mg (86%) of [[2-methyl-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.10 (t, J=7.5 Hz, 3H), 2.59 (s, 3H), 2.91 (q, J=7.5 Hz, 2H), 3.76 (s, 3H), 5.04 (s, 2H), 5.50 (s, 2H), 6.25 (s, 1H), 6.66 (s, 1H), 7.13 (d, J=6.9 Hz, 2H), 7.28 (m, 3H)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[N:31]1([CH2:38][CH2:39][OH:40])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:34]3[CH2:35][CH2:36][CH2:37][N:31]([CH2:38][CH2:39][OH:40])[CH2:32][CH2:33]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: OCCN1CCCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(CCO)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 2-(1,4-diazepan-1-yl)ethanol.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[O:12]2)=[C:4]([NH:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[N:3]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1.CS(C)=[O:40]>>[CH:18]([OH:22])=[O:40].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[N:19]=4)[O:12]3)=[C:4]([NH:24][CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[N:3]=2)[CH2:33][CH2:32]1
Reactant: CS(C)=O
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Product: CCC(CC)Nc1nc(N[C@H]2CC[C@H](N)CC2)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Product: O=CO
Temperature: 85 °C

Procedure:
Intermediate 11 (0.069 g, 0.163 mmol) and trans-1,4-diaminocyclohexane (0.093 g, 0.815 mmol) were dissolved in DMSO (0.03 ml) and heated at 80-90° C. for 66 h in a sealed vial (eg Reacti vial™), a further portion of trans-1,4-diaminocyclohexane (0.093 g, 0.815 mmol) was added after the first 20 h. The product was purified by Autoprep. to give the title compound after freeze drying as a brown solid (0.063 g). LC/MS system B Rt=2.12 min, m/z=502 MH+.
Reaction SMILES: BrC1C=CC(S(NC2C=CN=C(Cl)C=2)(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=2)[CH2:21]1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]>>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:33][C:29]2[CH:28]=[C:27]([N:22]3[CH2:23][C@H:24]([CH3:26])[NH:25][C@H:20]([CH3:19])[CH2:21]3)[CH:32]=[CH:31][N:30]=2)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]
Reactant: C[C@@H]1CN(c2ccnc(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Product: C[C@@H]1CN(c2ccnc(NS(=O)(=O)c3ccc(Br)c(F)c3)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a manner similar to 4-bromo-N-(2-chloro-4-pyridinyl)benzenesulfonamide (D3) using 4-[cis-3,5-dimethyl-1-piperazinyl]-2-pyridinamine (D21) and 4-bromo-3-fluorobenzenesulfonyl chloride as the starting materials. MS (ES+) m/e 443, 445 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: CN
Product: CNCCCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-[4-(4-bromobutoxy)benzoyl]-2-phenylbenzofuran with methylamine according to the procedure described in Example 4 gives 3-[4-(4-methylaminobutoxy)benzoyl]-2-phenylbenzofuran.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(=S)=S>[C:19]([CH2:18][CH2:17][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2][CH:3]=1)=[O:22])([OH:21])=[O:20]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 18 g. of methyl phenylacetate, 26 g. of aluminum chloride and 150 ml. of carbon disulfide, 20 g. of succinic anhydride are added. The reaction mixture is allowed to stand for two hours at 35° C.; then it is added to a liter of ice water and extracted with methylene chloride. The extracts are combined, washed, dried, and evaporated to give methyl p-(3'-carboxy-1'-oxopropyl)-phenylacetate. This derivative is reduced with sodium borohydride and dehydroxylated with palladium charcoal catalyst by the procedures described in Part A of Example 2 to afford methyl p-(3'-carboxypropyl)-phenylacetate. This derivative is refluxed in 50 ml. of thionyl chloride for three hours and then it is evaporated. The residue, containing methyl p-(3'-chlorocarbonylpropyl)-phenylacetate, is taken up in 175 ml. of benzene containing 40 g. of aluminum chloride. The resulting mixture is stirred for two hours at 20° C.; then it is added to a liter of ice and water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, and evaporated to give 7-(methoxycarbonylmethyl)-1-tetralone.