Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.Cl.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(#N)C>[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[C:7]3=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]3[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccn2ncnc(Cl)c12
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)cc3)c12
Yield: 35.8 %

Procedure:
A solution of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (47 mg, 0.281 mmol) (Ref. WO 03/042172 A2) and 4-(3-fluoro-benzyloxy)-phenylamine hydrochloride (70 mg, 0.299 mmol) and NaHCO3 (600 mg, 7.14 mmol) in dry acetonitrile (2 ml) was heated at 80° C. for 8 hr. Filtration followed by removal of the solvent from the filtrate and purification by preparative HPLC afforded the title product (35 mg, 37%) as an oil. Analytical HPLC retention time=1.41 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=331.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:27]C(OC(C)(C)C)=O)[C:11]([O:13][C@H:14]([CH3:26])[C@H:15]([O:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:35]>O1CCOCC1>[ClH:35].[NH2:27][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][C@H:14]([CH3:26])[C@H:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH3:16])=[O:12]
Reactant: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
(1R,2R)-1-methyl-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (1.8 g, 2.7 mmol) was dissolved in 40 mL of 4M HCl in dioxane. The mixture was stirred at room temperature for 30 min. The dioxane was evaporated completely under reduced pressure. The resulting a white solid was dissolved in acetonitrile (5 mL), and ether added until the solution became slightly cloudy. The solution was refrigerated overnight, and the product crystallized. The white crystalline solid was collected and dried under vacuum to afford 1.0 g (87%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 1.12 (d, J=6 Hz, 3H), 1.24 (d, J=6 Hz, 3H), 2.85 (dd, J=8, 14 Hz, 1H), 3.02 (dd, J=5.2, 14 Hz, 1H), 4.15 (t, J=5.6 Hz, 1H), 5.06 (m, 2H), 6.46 (dd, J=2, 8 Hz, 1H), 6.61 (d, J=2 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.65 (t, J=7.6 Hz, 1H), 7.90 (m, 2H). MS (ESI) m/z 374.11 (M+H)+ and 372.08 (M−H)−.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][CH:4]([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[O:13]CC2C=CC=CC=2)[CH2:3]1>C(O)C.[Pd]>[F:21][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[OH:13])[CH2:3]1
Reactant: Fc1ccc(OCc2ccccc2)c(C2CC(F)(F)C2)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(F)cc1C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 2-(3,3-difluorocyclobutyl)-4-fluorophenyl ether (C20) (60 mg, 0.20 mmol) in ethanol (15 mL) was treated with palladium (50 mg, 0.47 mmol) and shaken on a Parr hydrogenator (50 psi) at room temperature for 2 hours. The mixture was filtered through Celite and concentrated in vacuo to afford the title compound as a yellow oil. Yield: 20 mg, 0.065 mmol, 100%. GCMS m/z 202 (M+). 1H NMR (400 MHz, CDCl3) δ 2.60-2.78 (m, 2H), 2.92-3.07 (m, 2H), 3.46-3.58 (m, 1H), 6.61-6.95 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[O:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:41][NH2:42]>>[O:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:41][NH:42][C:30](=[O:31])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:28][CH:27]=1)[CH3:33]
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: NC[C@@H]1CCCO1
Product: CC(C(=O)NC[C@@H]1CCCO1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and 1-[(25)-tetrahydrofuran-2-yl]methanamine. LCMS (M+H)+: m/z=567.3
Reaction SMILES: [C:1]1([C:7](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:38].[OH-]>O>[C:1]1([C:7](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([NH2:38])=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCC(N)=O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a solution of 34 (100 mg, 0.26 mmol) and CH2Cl2 (mL) was added oxalyl chloride (90 uL, 1.06 mmol) and the mixture was stirred at RT for 2 h. To this solution 10 mL of NH4OH (30% aqueous) was slowly introduced and stirred for 6 h. The mixture was poured into H2O (100 mL) and then extracted with EtOAc (2×100 mL). The organic layer was worked-out to give the crude product, which upon purification gave 11 mg (11%) of the desired product 35 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (br s, 1H), 7.35 (br s, 1H), 7.27 (app. J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.2 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 1.91 (s, 2H), 1.87 (s, 2H), 1.25 (s, 2H), 0.88 (s, 6H), 0.87 (s, 6H). LCMS (ESI): m/z 378 (M+H)+.
Reaction SMILES: FC(F)(F)C(N1CCC([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)CC1)=O.IC1C=NN([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:52][CH2:51][O:50][C:49]3=[O:53])[CH2:44][CH2:43]2)C=1>>[CH3:33][N:31]1[CH:32]=[C:28]([C:24]2[CH:23]=[C:22]([C:19]3[N:20]=[CH:21][C:16]([C:14]4[CH:13]=[N:12][N:11]([CH:42]5[CH2:43][CH2:44][CH:45]([N:48]6[CH2:52][CH2:51][O:50][C:49]6=[O:53])[CH2:46][CH2:47]5)[CH:15]=4)=[CH:17][N:18]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[N:30]1
Reactant: O=C1OCCN1[C@H]1CC[C@H](n2cc(I)cn2)CC1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCC(N6CCOC6=O)CC5)c4)cn3)c2)cn1
Yield: 51 %

Procedure:
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 eq.) and trans-3-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-oxazolidin-2-one (intermediate 27; 231 mg; 0.63 mmol; 1.0 eq.). The crude was triturated in acetonitrile and the suspension filtered and dried under vacuum to afford the title compound as a brown solid (151 mg, 51%). 1H NMR (300 MHz, DMSO) δ 9.21 (s, 2H), 8.58 (d, J=3.6 Hz, 2H), 8.38-8.10 (m, 3H), 7.98 (s, 1H), 7.86-7.44 (m, 2H), 4.32 (dd, J=14.8, 6.5 Hz, 3H), 3.95 (s, 3H), 3.78-3.46 (m, 4H), 2.23 (s, 2H), 2.08-1.57 (m, 7H). HPLC (Condition A): Rt 3.39 min (purity 97.9%). MS (ESI+): 470.4.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH:11]=[CH2:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 100 °C
Yield: 47 %

Procedure:
4-Fluorobenzaldehyde (3.8 mL, 35.1 mmoles) was added to a solution of the product from Example 60A (4.39 g, 29.3 mmoles) and K2CO3 (8.90 g, 64.4 mmoles) in DMF (29.3 mL). The resulting mixture was heated to 100° C. for 2.5 days and then cooled to room temperature. The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage column (hexane→9:1 hexane:ethyl acetate) on silica gel to provide the title compound (3.50 g, 81%) as a clear colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16].[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])=[O:32]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCC1CCCN1)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCCN1C(=O)Nc1ccc(-n2ccccc2=O)cc1F)c1ccc(Cl)s1

Procedure:
75.3 Using general method H, rac-5-chloro-thiophene-2-carboxylic acid (pyrrolidin-2-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give rac-2-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 475.1 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH:14]=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][N:16]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1)[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C=C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C=C1CCN(CCN(C)C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred solution of 2-(N-benzyloxycarbonyl-N-methylamino)acetaldehyde (2.07 g, 10.0 mmol) and ethyl 4-piperidinylideneacetate (1.69 g, 10.0 mmol) in MeOH—AcOH (10:1, v/v, 22 ml) was added NaBH3CN (1.32 g, 20 mmol) and the stirring was continued overnight. The mixture was quenched by addition of sat. NaHCO3 (200 ml) and extracted with CHCl3 (3×150 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica-gel with CHCl3-EtOH (40:1, v/v) to give ethyl 1-[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-4-piperidinylideneacetate (1.71 g, 47%) as a colorless oil. 1H-NMR (CDCl3) δ 1.25 (t, J=7.3 Hz, 3 H), 2.16 (m, 2 H), 2.57 (m, 4 H), 2.95 (m, 7 H), 3.44 (m, 2 H), 4.13 (q, J=7.3 Hz, 2 H), 5.12 (s, 2 H), 5.49–5.53 (m, 1 H), 7.35 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#[N:14])=[CH:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCC=C2C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1[N+](=O)[O-])CCCC2C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of 6-methoxy-5-nitro-3,4 -dihydronaphthalene-1-carbonitrile (0.41 g, 1.8 mmol) in 10 ml of EtOH was added NaBH4 (0.20 g, 5.3 mmol) and the resulting reaction mixture was stirred for 30 min at 25° C. The solvent was removed in vacuo to yield an oily residue which was dissolved in EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield the desired product as a colorless oil (0.42 g, >95%) which was subjected to a following reaction without purification. 1H NMR (300 MHz, CDCl3):δ 1.86 (m, 2H), 2.04 (m, 2H), 2.62 (q, 2H, J=6.3 Hz), 3.83 (s, 3H), 4.17 (t, 1H, J=6.3 Hz), 7.10 (d, 1H, J=8.9 Hz), 7.45 (d, 2H, J=8.9 Hz).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=S)[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:3].N.OO>CO>[O:3]=[C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:1]1
Reactant: Cc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Agent: N
Agent: OO
Solvent: CO
Product: Cc1ccc(C(=O)Nc2nc(=O)c3ccccc3[nH]2)cc1
Reaction time: 8 h
Yield: 16.9 %

Procedure:
To a stirred mixture of 9.3 g of the above benzamide, 100 ml of methanolic ammonia and 100 ml of methanol was added dropwise 10 ml of 30% hydrogen peroxide over 3 minutes. When the exotherm subsided to 40° C., 15 ml of 30% hydrogen peroxide was added. The mixture was stirred overnight, the solid collected, partially dissolved in 800 ml of hot acetonitrile filtered and the filtrate chilled, giving 1.4 g of the desirred product as white crystals, mp 238°-239° C. (dec.).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:20]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:44][CH:45]=1)[C:19]2=[O:70])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:46][C:43]1[S:44][CH:45]=[C:41]([C:40](=[N:66][O:67][CH3:68])[C:39]([NH:38][CH:20]2[C:19](=[O:70])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][O:27][S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:29])=[O:30])=[C:17]3[C:15]([OH:16])=[O:14])=[O:69])[N:42]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Yield: 85.2 %

Procedure:
2-Benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) 1.5 g) is dissolved in a mixture of formic acid (30 cc) and distilled water (10 cc). The solution is heated at 50° C. for 30 minutes. After cooling, the precipitate is filtered off and the filtrate is concentrated to dryness under reduced pressure (10 mm Hg) at 30° C. The residue is triturated with diethyl ether (50 cc). The solidifed product is filtered off, washed with diethyl ether (2×25 cc) and then dried under reduced pressure (5 mm Hg) at 25° C. 7-[2-(2-Amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (syn isomer, E-form) (0.75 g) is obtained as a solvate with formic acid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2Cl)(=[O:9])[CH3:8].[CH3:22][O:23][C:24]1[N:29]=[C:28]2[S:30][C:31]([NH2:33])=[N:32][C:27]2=[CH:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:7]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:33][C:31]1[S:30][C:28]2[C:27]([N:32]=1)=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[N:29]=2)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: COc1ccc2nc(N)sc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2nc(Nc3ncnc4ccc(OC(C)=O)cc34)sc2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Cesium carbonate (880 mg, 2.7 mmol) and 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (168 mg, 0.27 mmol) and tris(dibenzylideneacetone)dipalladium(0) (123 mg, 0.14 mmol) were successively added to a toluene solution (10 ml) of 4-chloro-6-quinazolinyl acetate (300 mg, 1.35 mmol) and 5-methoxy[1,3]thiazolo[5,4-b]pyridine-2-amine (244 mg, 1.35 mmol), and stirred under a nitrogen atmosphere at 120° C. for 2 hours. The reaction solution was cooled to room temperature, filtered, and washed with chloroform and methanol. The obtained filtrate was concentrated under reduced pressure to obtain 4-[(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)amino]-6-quinazolinyl acetate (196 mg, yield: 40%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:25]1([CH2:24][N:20]2[C:21](=[O:23])[NH:22][C:18]([CH2:17][CH2:16][CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:31])=[O:3])=[CH:14][CH:13]=3)=[N:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccccc3)c(=O)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(CCCc2nn(Cc3ccccc3)c(=O)[nH]2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
2-(4-{3-[1-(Phenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methylpropionic acid ethyl ester (557 mg, 1.20 mmol) was dissolved in ethanol (5 mL) and 1N aq. NaOH (3.6 mL, 3.6 mmol) was added in one portion and the solution was stirred at room temperature for 16 h. The solution was then concentrated to a hazy colorless oil. This oil was diluted with water (5 mL) and washed with t-butyl methyl ether (5 mL). The pH of the aqueous layer was adjusted to <1with conc. HCl and the aqueous was extracted with ethyl acetate (10 mL, then 5 mL). This solution was washed with 1 N aqueous HCl (5 mL) and sat'd aq. NaCl (5 mL), dried (MgSO4), and concentrated in vacuo to afford the title compound as a clear colorless oil (442 mg, 84.5%). 1H NMR (DMSO-d6) δ 12.9 (br s, 1H), 7.30 (t, 2H, J=7 Hz), 7.25 (d, 1H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 7.04 (d, 2H J=8 Hz), 6.72 (d, 2H, J=8 Hz), 4.83 (s, 2H), 3.47 (t, 2H, J=7 Hz), 2.54 (t, 2H, J=8 Hz), 2.49 (t, 2H, J=8 Hz), 1.83 (quint, 2H, J=7 Hz), 1.53, (m, 2H), 1.46 (s, 6H), 0.80 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 175.8, 154.1, 146.0, 138.1, 135.2, 129.7, 129.2, 128.0, 119.3, 79.0, 48.5, 42.8, 34.0, 27.9, 25.7, 24.8, 22.5, 11.5; IR (CHCl3) 2938, 1509, 1468, 1233, 1155 cm−1; Anal. Calcd. For C25H31N3O4: C, 68.63; H, 7.14; N, 9.60. Found: C, 68.24; H, 6.95; N, 9.40.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Br:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Br.C(O)(=O)C>C(OCC)C>[BrH:28].[CH2:25]([C:22]1[CH:21]=[N:20][C:19]([N:18]([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:24][CH:23]=1)[CH3:26]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: BrCCCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1cnc(N(CCCc2ccccc2)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and (3-bromopropyl)benzene as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>CO.C1COCC1.C(O)(=O)C.[Zn]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-chloro-3-nitrobenzoate (2.1 g, 9.7 mmol) in methanol (100 mL) and THF (20 mL) was added zinc powder (1.9 g, 29 mmol), ammonium formate (3.1 g, 49 mmol), and a few drops of acetic acid. The mixture was allowed to stir at RT for 18 hours. Most of the volatiles were removed under reduced pressure. The residue was redissolved in EtOAc (200 mL), washed with brine, concentrated and purified by MPLC to provide methyl 3-amino-2-chlorobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[Cl:24][C:25]1[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=1>>[Cl:24][C:25]1[N:30]=[C:29]([C:31]([NH:23][C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])=[N:15][C:16]=23)=[O:32])[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C(O)c1cccc(Cl)n1
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)c1cccc(Cl)n1
Yield: 31 %

Procedure:
Prepared by the method as described in Example 68, substituting (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine with (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B), and substituting picolinic acid with 6-chloropicolinic acid, to provide the final product as a yellowish solid (9.1 mg, 31% yield). MS (apci) m/z=455.2 (M+H).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]#[CH:15]>>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:15]#[C:14][CH2:13][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:3][CH:4]=1
Reactant: C#CCOCCCCCCNCc1ccccc1
Reactant: CN(C)C(=O)c1ccc(I)cc1
Product: CN(C)C(=O)c1ccc(C#CCOCCCCCCNCc2ccccc2)cc1
Yield: 83 %

Procedure:
From 4-iodo-N,N-dimethylbenzamide (2.5 g) and N-[6-[(2-propynyl)oxy]-hexyl]benzenemethanamine (2.23 g). FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as an orange oil (2.96 g), t.l.c. (Ethyl acetate+few drops triethylamine) Rf 0.15.