Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][OH:17])[CH2:12][C@H:11]([OH:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:19](C1NC=CN=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][O:17][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12][C@H:11]([OH:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1[C@H](CO)C[C@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)c1ncc[nH]1
Solvent: ClCCl
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
The compound of Example 16H (574 mg, 2.1 mmol) was dissolved in 35 mL of dichloromethane and tert-butyldimethylsilylimidazole (0.54 mL, 2.8 mmol) was added. After stirring overnight, the reaction was diluted with dichloromethane and washed twice with 10% NaCl, then dried over MgSO4, filtered and concentrated in vacuo. After a second run using 340 mg of the starting diol, the combined unpurified product mixtures were purified by silica gel chromatography (200 mL of SiO2, elution with a gradient of 1:4 ethyl acetate:hexanes to ethyl acetate) to afford the titled compound (940 mg) contaminated with a small amount of a regioisomeric bis-TBS ether.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:22]=3[NH:23][N:24]=2)=[CH:16][CH:15]=1)=[C:12]=[O:13]>C1COCC1>[NH:23]1[C:22]2[C:25]3[C:30]([CH2:31][C:21]=2[C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:11][C:12](=[O:13])[O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[N:24]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: CCN(CC)CCO
Reactant: O=C=Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCOC(=O)Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of N,N-diethyl ethanol amine (0.368 mL, 2.75 mmol) in THF (5 mL) was added NaH (60% in mineral oil, 113 mg, 2.75 mmol). The reaction mixture was stirred at about 20° C., for about 1 hour then solid 3-(4-isocyanatophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 2 (58 mg, 0.22 mmol) was added. The reaction mixture was heated to about 45° C., for about 3 hours. The reaction mixture was quenched by addition of H2O and the product was extracted into EtOAc. The crude material was purified by flash chromatography on SiO2 (MeOH/CH2Cl2, 10/90) to give 51 mg (62%) of pure product. LC/MS 391 (M+1); LC retention time 2.68 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH2:27]([OH:30])[C:28]#[CH:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]2[O:30][CH2:27][C:28]#[CH:29])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: C#CCO
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and propargyl alcohol with pyridine there is obtained isopropyl 2-chloro-4-fluoro-5-[6-oxo-2-(2-propynyloxy)-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate, m.p. 117°-119° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CO
Reactant: O=C(O)CCc1conc1-c1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
A mixture of 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid (3.15 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (3.11 g, yield 95%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 57–58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 48 was prepared from bis(4-fluorophenyl) acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: O[C@H:2]([CH3:18])[C@H:3]([NH:7][C:8]([O:10][C:11]1([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9])[C:4]([OH:6])=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:17][C:11]1([O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[C@@H](O)[C@H](NC(=O)OC1(C)CCCCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1(C)CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a round bottomed flask equipped with a magnetic stirrer and a dropping funnel (2S,3R)-3-hydroxy-2-[(1-methylcyclohexoxy)carbonylamino]-butanoic acid (0.503 g, 1.95 mmol) was dissolved in anhydrous CH2Cl2 (50 mL). The clear yellow solution was cooled to 0° C., PyBOP (1.22 g, 2.34 mmol) was added, followed by a dropwise addition of Et3N solution (0.815 mL, 5.85 mmol) in anhydrous CH2Cl2 (5 mL), over a period of 10 min. The crude mixture was stirred at 0° C. for 1 h then overnight at rt. The reaction was quenched by addition of 5% NaHCO3 solution (50 mL) and the corresponding mixture was vigorously stirred for 10 min. The two phases were separated and the organic one collected, dried over Na2SO4 and concentrated to dryness to leave an oil, which was purified by typical chromatography eluting with petroleum ether/AcOEt mixtures (from 9:1 to 7:3). The title compound was obtained as white solid (0.070 g, 15%). m.p.: 92-93° C. MS (ESI) m/z: 242.2 [M−H]+; (ESI) m/z: 240.1 [M−H]−. 1H NMR (DMSO-d6): δ 1.15-1.60 (m, 8H) 1.35 (d, J=6.3 Hz, 3H), 1.42 (s, 3H), 2.02 (m, 2H), 4.83 (m, 1H), 5.35 (dd, J=9.2, 6.3 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:20].Br[CH2:22][CH2:23][CH2:24][Cl:25].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[O:20][CH2:22][CH2:23][CH2:24][Cl:25]
Reactant: Oc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ClCCCOc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A suspension of 2-chloro-4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]phenol i66 (0.13 g, 0.44 mmol, 1 eq), 1-bromo-3-chloropropane (57 μl, 0.58 mmol, 1.3 eq) and potassium carbonate (0.12 g, 0.89 mmol, 2 eq) is stirred at 50° C. overnight. The carbonate is then filtered off and the resulting solution is concentrated under reduced pressure to give 0.12 g of crude 1-({2-[3-chloro-4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)piperidine i71 as an oil, which is directly used in the next step.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].N1C=CN=C1.FC(F)(F)S(O[Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])(=O)=O>C(Cl)Cl.CCCCCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.25 g, 4.1 mmol) in MeCl2 (17 ml) containing imidazole (2.55 g, 48.7 mmol) was cooled to 0° C. and treated with triisopropylsilyl trifluoromethanesulfonate (7.41 g, 24.2 mmol). The reaction mixture was allowed to warm to RT and stirred for 16 hrs. The reaction mixture was diluted with MeCl2 (20 ml) and n-hexane (40 ml). The resultant suspension was filtered and the filtrate was passed over SiO2. Elution with n-hexane/ethyl acetate (3:1) yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.35 g, 86.3%). Mass Spec: C49H83NO12Si(906.29) FAB:928(M+Na), 756, 678, 511, 266.
Reaction SMILES: S(=O)(O)[O-].[Na+:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[S:15]([O-:18])(=[O:17])=[O:16].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[S:15]([O-:18])(=[O:16])=[O:17])(=[O:22])[CH3:21].[Na+:5]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)([O-])c1cc2ccccc2[nH]1
Agent: O=S([O-])O
Agent: [Na+]
Product: CC(=O)n1c(S(=O)(=O)[O-])cc2ccccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a round-bottom-flask containing 60 mL acetic anhydride was added 5 g sodium bisulfite and 5 g sodium indole-2-sulfonate. The mixture was heated and stirred at 70° C. for 1 hr and then at 90° C. for 2 hrs. Upon cooling, the solid was filtered, washed with ether, and dried to yield 5.7 g of sodium 1-acetylindole-2-sulfonate product (93%) as a white solid. The sodium 1-acetylindole-2-sulfonate product was used in the next step without further purification. MP>320° C.; IR (KBr, cm−1) 3480, 3010, 1660, 1490, 1400, 1385, 1150, 1050, 980, 760.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[CH3:25].C(N(C(C)C)CC)(C)C.[CH2:35]([NH:37][C:38]1([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:36]>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:8][N:7]3[C:2]([N:41]4[CH2:40][CH2:39][C:38]([NH:37][CH2:35][CH3:36])([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]4)=[C:3]([CH3:25])[CH:4]=[N:5][C:6]=23)=[CH:12][CH:13]=1
Reactant: CCNC1(C(N)=O)CCNCC1
Reactant: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC1(C(N)=O)CCN(c2c(C)cnc3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine (I-3A-1d; 31.3 mg, 0.0806 mmol) and diisopropylethylamine (0.025 ml, 0.14 mmol) in THF (1 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1g; 18.5 mg, 0.108 mmol). The mixture was stirred at 50° C. for 20 hours. After cooling to room temperature, the reaction was extracted from saturated aqueous NaHCO3 with ethyl acetate, the combined organic layers were dried (MgSO4), concentrated and purified on a Biotage™ Flash 12S column using 0–5% methanol in methylene chloride as eluant to afford, after trituration from hexanes/methylene chloride, product 3A-1 as a solid (29 mg, 69%): +ESI MS (M+1) 523.4; 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.48–7.34 (m, 6H), 7.21 (d, J=8.7 Hz, 2H), 3.82–3.74 (m, 2H), 3.66–3.58 (m, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.39 (s, 3H), 2.28–2.20 (m, 2H), 1.88–1.80 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].[CH2:24]([NH2:26])[CH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:18])([F:17])[F:19])[C@H:10]([C:12]([NH:26][CH2:24][CH3:25])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:20]([F:22])([F:21])[F:23])#[N:2]
Reactant: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCN
Product: CCNC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)alanine and ethylamine: 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.96 (dd, J=8.8, 2.8 Hz, 1H), 5.95 (bs, 1H), 4.26 (q, J=7.1 Hz, 1H), 4.10 (m, 2H), 3.28 (m, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.06 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 3229) in 2 mL of CDCl3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 3230.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[NH4+:39].[OH-]>O=S(Cl)Cl.O>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH2:39])=[O:21])[C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: NC(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Temperature: 25 °C

Procedure:
A solution of 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid (40 mg, 0.077 mmol) in SOCl2 (1 mL) was heated at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and poured into a 50% aqueous solution of NH4OH (15 mL). The resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography (silica gel, 5% MeOH/CH2Cl2) to give the title compound 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamide as a white solid. 1H NMR (CDCl3) δ (ppm) 8.67 (s, 1H), 8.29 (t, 1H), 8.15 (br s, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.71 (t, 1H), 7.64 (d, 2H), 7.58 (d, 3H), 7.46 (br s, 2H), 7.44 (m, 6H), 7.37 (m, 1H); HPLC-MS calculated for C30H20ClN5O2 (M+H+): 518.1. Found 518.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([OH:25])=O)[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:41](=[O:57])([O:43][CH2:44][CH:45]([NH2:56])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53])[NH2:42].Cl>CN(C=O)C>[C:41](=[O:57])([O:43][CH2:44][CH:45]([NH:56][C:23](=[O:25])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:53])[F:54])[NH2:42]
Reactant: NC(=O)OCC(N)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A quantity of 30 mg (0.08 mmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (preparation according to WO2007/134862, Example 154A) was dissolved in 1 ml of DMF, and the solution was admixed with 21 mg (0.11 mmol) of EDC and with 15 mg (0.11 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. Then 23 mg (0.09 mmol) of the compound from Example 180A were added and the mixture was left with stirring at room temperature for 16 h. For work-up, 50 μl of 1N hydrochloric acid were added and the crude product was purified directly by preparative HPLC [Method 19]. This gave 34 mg (69% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH2:11][NH:12][C@@H:13]([CH3:21])[CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:12]([CH2:11][C:8]2[C:6]3=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]3[S:10][CH:9]=2)[C@@H:13]([CH3:21])[CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1csc2ccc(Cl)nc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccc(Cl)nc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-((5-chlorothieno[3,2-b]pyridin-3-yl)methyl)-1,1-diethoxypropan-2-amine (Compound IX-7) 996 mg (3.03 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:22]1([CH2:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:7][N:6]4[CH:8]=3)=[CH:14][CH:15]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2nc(COc3ccc(CCCn4ccnc4)cc3)cn2c1
Product: c1ccc(-c2ccc3nc(COc4ccc(CCCn5ccnc5)cc4)cn3c2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 135, 6-bromo-2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]imidazo[1,2-a]pyridine was allowed to react with phenylboronic acid to give 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-6-phenylimidazo[1,2-a]pyridine. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 106-107° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]=[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH2:23]>>[O:20]=[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH:23][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCC(=O)c1ccccc1
Product: CCc1cc(-c2cncc(C(=O)NCC(=O)c3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-oxo-2-phenyl-ethyl-amine to afford the title compound. MS: m/e=376 (M+H). 1H NMR (δ ppm): 11.74 (s, 1H); 9.13 (t, 1H, J=5.5 Hz); 8.99 (d, 1H, J=2.2 Hz); 8.72 (d, 1H, J=2.2 Hz); 8.19 (t, 1H, J=2.2 Hz); 8.05 (m, 2H); 7.70 (m, 1H); 7.58 (m, 2H); 7.32 (s, 1H); 4.85 (d, 2H, J=5.5 Hz); 2.42 (q, 2H, J=7.4 Hz); 2.20 (s, 3H); 1.12 (t, 3H, J=7.4 Hz).