Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(CO)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(COc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
The product from Example 193a (1.00 g, 4.9 mmol), and the product from Example 197b (0.90 g, 5.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMF (20 mL) were heated at 100° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with H2O. The resulting solid was collected by filtration, washed with H2O, and dried in vacuum to give brown crystal, which was purified by silica gel column chromatography eluting with 5:2 EtOAc/hexane to give the title compound as a dark orange crystal (0.47 g, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Yield: 55.3 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 39(B)(b), 135 mg, 0.32 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 68 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (71.4 mg, 54.8%) as a pale yellow solid: EI-HRMS m/e calcd for C19H21N3O5S (M) 403.1201, found 403.1188.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[OH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([C@@H:21]2[CH2:25][C@H:24]([S:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:23][N:22]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[C:3]([O:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([C@@H:21]2[CH2:25][C@H:24]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:23][N:22]2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])=[O:20])[CH2:17][CH2:18]1)(=[O:4])[NH2:5]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.5 h

Procedure:
1.43 ml of trichloroacetyl isocyanate were added, whilst ice-cooling, to a solution of 5.59 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 50 ml of dry methylene chloride, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 120 ml of methanol. This solution was then stirred at room temperature for 4.5 hours in the presence of 35 g of silica gel (Merck, silica gel 60, 230-400 mesh). The silica gel was removed by filtration and the filtrate was freed from the solvent. The residue was purified by column chromatography through silica gel, using a 8:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 5.76 g of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:24](=[O:25])[NH:23][CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (108 mg, 0.4 mmol, example 27) in dichloromethane (2 mL) was added isopropyl isocyanate. The mixture was stirred for 1 h and quenched with water. After aqueous workup with water and dichloromethane, the organic layers was dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give 4-(1-isopropylcarbamoyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[CH:11][N:12](C)C)[C:7](=[O:15])[C:6]=2[CH:16]=1.[C:17]([O:21][C:22]([N:24]([CH3:26])N)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C>CO.O1CCCC1>[C:17]([O:21][C:22]([N:24]([CH3:26])[NH:12][CH:11]=[C:8]1[C:7](=[O:15])[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:10][CH2:9]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C)C=C1CSc2ccc(Cl)cc2C1=O
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CN(NC=C1CSc2ccc(Cl)cc2C1=O)C(=O)OC(C)(C)C
Yield: 129.2 %

Procedure:
A solution of 6-chloro-2,3-dihydro-3-dimethylaminomethylene-4H-1-benzothiopyran-4-one (34.13 g), 1-t-butoxycarbonyl-1-methylhydrazine (59.14 g), and acetic acid (23.14 ml) in methanol (2 l) and tetrahydrofuran (1 l) was stirred at ambient temperature for 6 hours and then evaporated in vacuo. To the residue was added aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 3-(2-t-butoxycarbonyl-2-methylhydrazinomethylene)-6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one (61.65 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([OH:21])=O)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1.ClC(OCC)=O.[NH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][C@H:31]1[O:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([NH:28][CH2:29][C@@H:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][C@H:31]2[O:41][CH2:42][CH3:43])=[O:21])[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: O=C(O)c1cc(Cl)cc2c1OCCO2
Reactant: CCOC(=O)N1CC[C@@H](CN)[C@H](OCC)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)cc3c2OCCO3)[C@H](OCC)C1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
At a temperature below 10° C., triethylamine (0.01 mol) was added to 7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (0.01 mol) in chloroform (40 ml). Ethyl chloroformate 01 mol) was added at a temperature below 10° C. and the mixture was stirred for 30 minutes at a temperature below 10° C. This mixture was added to a solution of intermediate (14) (0.01 mol) in chloroform (20 ml), at a temperature below 10° C. The reaction mixture was stirred for 30 minutes then washed with a 5% HCl solution, with water, dried, filtered and the solvent was evaporated, yielding 4 g of (trans)-ethyl 4-[[[(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)carbonyl]-amino]methyl]-3-ethoxy-1-piperidinecarboxylate (intermediate 15).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[CH:5]=1.[NH2:23][C@H:24]([C:40]([NH:42][C@H:43]([C:53]([C:55]([O:57][CH3:58])=[O:56])=[O:54])[CH2:44][O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl.C(Cl)(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:40]([NH:42][C@H:43]([C:53]([C:55]([O:57][CH3:58])=[O:56])=[O:54])[CH2:44][O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:41])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:31]=1)=[O:12])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[CH:5]=1
Reactant: Cn1cnc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Reactant: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1cn(C)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of Cbz-His(1-Me) (from Step 1 above, 0.36 g, 1.2 mmol), Tyr(OBn)-Ser(OBn)-CO2Me.HCl (from Example 8, Step 1 above, 0.60 g, 1.2 mmol), DCC (0.30 g, 1.4 mmol), and HOBT (0.19 g, 1.4 mmol) in CH2Cl2 was added Et3N (0.17 mL, 1.2 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with CHCl3, washed with saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (1% MeOH:CHCl3) provided the title compound as a white solid, mp 161.5°-163.5° C.; FAB-MS 748 (m+1).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)Nc1cnc(C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
Sodium hydride (14.26 mg, 0.36 mmol) was added to (S)-2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y12) (64 mg, 0.24 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (86 mg, 0.32 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (75 mg, 63.4%). 1H NMR (400 MHz, CDCl3) δ 1.16 (d, 3H), 2.52 (s, 3H), 3.33-3.48 (m, 5H), 3.80-3.89 (m, 1H), 4.16-4.27 (m, 2H), 6.01 (t, 1H), 7.45-7.55 (m, 3H), 7.60-7.64 (m, 1H), 8.11-8.12 (m, 1H), 8.41 (s, 1H), 8.59 (s, 1H), 8.94 (s, 1H), 9.42 (d, 1H). m/z (ESI+) (M+H)+=498.36; HPLC tR=2.19 min.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=[O:14].[F:16]C1C=C(F)C=C2C=1CCC2(CC(O)=O)O>>[F:16][C:10]1[CH:2]=[C:3]2[C:7](=[CH:8][CH:9]=1)/[C:6](=[CH:12]/[C:13]([OH:15])=[O:14])/[CH2:5][CH2:4]2
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Product: O=C(O)/C=C1\CCc2cc(F)ccc21
Yield: 68 %

Procedure:
This compound was prepared in an analogous manner to (E)-2-(4,6difluoro-1-indanylidene)acetic acid in Example 5e by substituting 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid(14.70 g, 0.069 mol) for 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid. Recrystallization from acetonitrile: 2-propanol mixtures gave 9.05 g (68%) of (E)-2-(5-fluoro-1-indanylidene)acetic acid as a white solid: m.p., 240°-242° C.;
Reaction SMILES: C1COCC1.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[C-:16])=[CH:11][CH:10]=1)([O-])=O.O.C(=O)=O>CO>[NH2:6][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[C-:16])=[CH:11][CH:10]=1
Reactant: [C-]#[N+]c1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: [C-]#[N+]c1ccc(N)cc1
Yield: 76.2 %

Procedure:
Under nitrogen, 11.6 g (12.8 mmol) lithium-cobalt (I) phthalocyanine x 4.5 THF and 296 mg (2 mmol) p-nitro-phenyl isonitrile are agitated in 65 ml methanol for 72 hours at 20° C. The green reaction mixture is mixed with 5 ml water; CO2 and air are passed in for 5 min., and the blue precipitate is centrifuged which is washed with ethanol. The centrifugate collected is concentrated and the residue separated into ether and water. Concentration of the ether phase, dried with sodium sulfate, produces 180 mg (76%) p-aminophenylisonitrile.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[CH:30]=[CH:31][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:26][C:27]3[CH:28]=[C:29]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[CH:30]=[CH:31][CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1cccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 150 °C
Yield: 73.2 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), tert-butyl 1-(3-aminophenyl)ethylcarbamate (124 mg, 526 mol), xantphos (60.9 mg, 105 mol), Pd2(dba)3 (32.1 mg, 35.1 mol) and cesium carbonate (229 mg, 702 mol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 20-40% ethyl acetate in hexanes) gave tert-butyl 1-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)ethylcarbamate (150 mg, 257 mol, 73%) as a yellow gum. (EI/CI) m/z: 583.5 [M+H].
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[C:18]([O-:21])(=[S:20])[CH3:19].[K+].CCOC(C)=O.O>CN(C=O)C>[C:18](=[O:21])([S:20][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])[CH3:19]
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)SC(C)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 55.6 %

Procedure:
A solution of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.9 g, 1 equivalent) and potassium thioacetate (0.61 g, 1.5 equivalents) in 4 mL of DMF was stirred at room temperature for 1 hour. The resulting solution was worked up with EtOAc and water. The crude product was purified by silica gel flash column chromatography to give S-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl ethanethioate (0.58 g, 55% yield) as a yellow solid. Compound 1081.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:59]=[CH:58][C:45]([C:46]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:47])=[CH:44][C:43]=1[CH3:60]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:59]=[CH:58][C:45]([C:46]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)=[O:47])=[CH:44][C:43]=5[CH3:60])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N(C)CCN2CCOCC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)CCN4CCOCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-bromo-3,N-dimethyl-N-(2-morpholin-4-yl-ethyl)-benzamide (114 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,N-dimethyl-N-(2-morpholin-4-yl-ethyl)-benzamide was obtained, and further PMB group was removed according to the above Deprotection method 3, to obtain the desired compound (D-205) as a brown oil (68 mg, 66%).
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].CN(C=O)C.C(NC(C)C)(C)C>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.[Cu]I>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])=[C:3]([O:27][CH2:28][C:29]3([CH3:33])[CH2:32][O:31][CH2:30]3)[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: CC1(COc2ccc3c(c2Br)[C@]2(COC(N)=N2)c2cc(-c4cccnc4)ccc2O3)COC1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1c(OCC2(C)COC2)ccc2c1[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 90 °C

Procedure:
A resealable tube was charged with (S)-1′-bromo-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (300 mg, 0.590 mmol), 2-methyl-3-butyn-2-ol (248 mg, 2.95 mmol), tetrakis(triphenylphosphine)palladium (68.2 mg, 0.059 mmol) and copper(i) iodide (22.48 mg, 0.118 mmol). To this were added DMF (1180 μL, 0.590 mmol) and diisopropylamine (1241 μL, 8.85 mmol). The reaction was flushed with argon, sealed and heated at 90° C. for 1.5 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% CH2Cl2 to 10:1 methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-4-(2-amino-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-yl)-2-methylbut-3-yn-2-ol as a light yellow solid. MS m/z=512.2 [M+H].
Reaction SMILES: C(OC([N:11]([CH:22]1[CH2:25][N:24]([CH:26]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[C:27]([OH:29])=[O:28])[C:23]1=[O:35])[C:12](=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:14])=O)C1C=CC=CC=1.[H][H].C(OCC)(=O)C.C(#N)C>CO.[Pd].O>[C:15]1([CH:13]([C:12]([NH:11][CH:22]2[CH2:25][N:24]([CH:26]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:27]([OH:29])=[O:28])[C:23]2=[O:35])=[O:21])[NH2:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: NC(C(=O)N(C(=O)OCc1ccccc1)C1CN(C(C(=O)O)c2cccs2)C1=O)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: NC(C(=O)NC1CN(C(C(=O)O)c2cccs2)C1=O)c1ccccc1
Yield: 14.5 %

Procedure:
2-[3-(N-Benzyloxycarbonyl-2-phenylglycinamido)-2-oxo-1-azetidinyl]-2-(2-thienyl)acetic acid (0.19 g.) was dissolved in methanol (10 ml.), and to the solution, there was added 10% palladium on carbon (0.15 g.) as a catalyst. The mixture was subjected to catalytic reduction in a stream of hydrogen gas at ordinary temperature and ordinary pressure. A calculated volume of hydrogen gas was absorbed into the mixture in the course of 6.5 hours. The catalyst was filtered off from the reaction mixture and the filtrate was evaporated to dryness under reduced pressure to give an oily residue, which was pulverized with ethyl acetate. The powder (0.09 g.) obtained was treated with a mixture of acetonitrile and water (volume ratio, 20:1) to give 2-[3-(2-phenylglycinamido)-2-oxo-1-azetidinyl]-2-(2-thienyl)acetic acid (0.02 g.).