Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]1([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1C(C)C
Temperature: 200 °C

Procedure:
A mixture of Intermediate C (100 mg, 0.37 mmol), 2-phenyl-1H-imidazole (533 mg, 3.7 mmol), Cut (35 mg, 0.18 mmol), trans-1,2-bis(methylamino)cyclo-hexane (52.5 mg, 0.07 mL, 0.37 mmol) and solid K2CO3 (511 mg, 3.7 mmol) in 2 mL of DMF was heated in a microwave reaction apparatus for 2 h at 200° C. After this time the reaction was transferred to a round bottom flask with the aid of EtOAc, then evaporated. The residue was purified by reverse-phase HPLC (PLRPS C-18 column, eluting with a gradient of 20-25% acetonitrile in water over 30 min) to give the title compound. LCMS: 377.2 m/z (M+H)+; ret. Time: 2.56 min (Analytical Method A); 1H NMR (400 MHz, CDCl3) δ: 7.9-7.8 (dd, 2H), 7.6-7.3 (m, 6H), 4.3 (dd, 1H), 3.8 (m, 1H), 3.4 (s, 3H), 1.9 (dd, 1H), 1.7 (dd, 1H), 1.05 (d, 3H), 0.9 (d, 3H) and 0.8 (d, 3H) ppm.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(O)C>[N+:36](=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:6])=[N-:37]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of O-acetoacetyl-N-trifluoroacetyl-L-serine (232 mg) and triethylamine (0.41 ml) in ethanol (7 ml) was added p-toluenesulfonyl azide (193 mg) at 0° C. The mixture was stirred for an hour at 0° C. and for 4 hours at room temperature. The solvent was distilled off in vacuo and the residue was diluted with chloroform and washed successively with aqueous acetic acid, water and brine. After drying over sodium sulfate, the chloroform extract was filtered and concentrated. The residue was flash chromatographed on silica gel (10 g) eluting successively with chloroform and a 1:9 mixture of methanol and chloroform to give O-(2-diazo-1,3-dioxobutyl)-N-trifloroacetyl-L-serine (193 mg).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](OC=C)(=[O:23])[CH2:6][CH2:7][CH2:8][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][CH3:22].C[O-].[Na+]>>[C:5]([NH:4][CH2:3][CH2:1][OH:2])(=[O:23])[CH2:6][CH2:7][CH2:8][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][CH3:22]
Reactant: NCCO
Reactant: C=COC(=O)CCCCCCCCCCCCCCCCC
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)NCCO

Procedure:
In an exemplary embodiment, 20 mmol ethanolamine was reacted with 1 mmol vinyl stearate at 80° C. for 1 hour in the presence of 1% sodium methoxide. N-stearoylethanolamine with 96% purity was obtained after the removal of excess ethanolamine without further purification. In another exemplary embodiment, 20 mmol ethanolamine was reacted with 1 mmol vinyl palmitate at 60° C. for 1.5 hours in the presence of 1% sodium methoxide. N-palmitoylethanolamine with 98% purity was obtained after the removal of excess ethanolamine without further purification. More examples of reacting the alkanolamine and the vinyl ester of the fatty acid to prepare the high-purity fatty acid N-acylalkanolamine in a high yield are described in Examples 1-8.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]([F:68])([F:67])[C:16]1[CH:17]=[C:18]([CH:60]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:62]=1)[C:19]([N:21]1[CH2:25][C@@:24]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C:38]3([C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH2:50][C:51]([N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][NH:57][CH3:58])=[O:52])[CH2:37][CH2:36]2)([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:23][CH2:22]1)=[O:20]>>[F:66][C:63]([F:64])([F:65])[C:61]1[CH:60]=[C:18]([CH:17]=[C:16]([C:15]([F:14])([F:68])[F:67])[CH:62]=1)[C:19]([N:21]1[CH2:25][C@@:24]([CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][C:38]3([C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH2:50][C:51]([N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][N:57]([CH3:58])[C:11](=[O:13])[CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[O:52])[CH2:39][CH2:40]2)([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:23][CH2:22]1)=[O:20]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Product: CN(CCCN(C)C(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Yield: 94.2 %

Procedure:
(4-Nitrophenyl)acetic acid (52 mg, 0.287 mmol) and the compound (186 mg, 0.239 mmol) obtained in Example 1k were used to give the title compound (212 mg; yield, 94%) as a colorless oily substance according to the method described in Example 41a.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[C:13]=4[CH:12]=[C:9]3[C:10]=2[CH:11]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:19][C:14]1[C:13]2[CH:12]=[C:9]3[N:8]([C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:6][C:5]1[N:4]=[CH:3][C:2]([C:37]2[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]4[O:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=4[CH:36]=2)=[CH:11][C:10]3=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ncc(Br)cc2-1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 40.8 %

Procedure:
A mixture of 2-bromo-11-fluoro-5,6-dihydroindolo[2,1-f][1,6]naphthyridine (50 mg, 0.16 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (87 mg, 0.17 mmol), potassium carbonate (43 mg, 0.32 mmol) and Pd(dtbpf)Cl2 (10 mg) in 1,4-dioxane/water (1/0.1 mL) was stirred at 100° C. for 6 hours under nitrogen atmosphere. The mixture was filtered through Celite pad and concentrated, and then the residue was diluted with water and EA. After extraction with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the desired product (40 mg, yield: 41.7%) through the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 8.19 (s, 1H), 7.93˜7.96 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.19˜7.24 (m, 2H), 7.15˜7.17 (m, 2H), 7.02 (s, 1H), 6.77˜6.82 (m, 1H), 5.88 (br s, 1H), 4.41˜4.44 (m, 2H), 3.45˜3.49 (m, 2H), 3.18 (s, 3H), 2.99 (d, J=4.80 Hz, 3H), 2.84 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20](=O)[CH2:21]Br)[C:5]([NH:7][CH:8]1[C:18](=[O:19])[N:10]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6].[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].C(OC(C)C)(C)C>CO>[NH2:27][C:25]1[S:26][CH:21]=[C:20]([C:4](=[N:3][O:2][CH3:1])[C:5]([NH:7][CH:8]2[C:18](=[O:19])[N:10]3[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH2:13][S:14][C@H:9]23)=[O:6])[N:24]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 5 h
Yield: 118.7 %

Procedure:
7-(2-Metoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 10 g.) was added to a solution of thiourea (2.81 g.) and sodium acetate (2.22 g.) in methanol (50 ml) and stirred at 30° C. for 5 hours. To the resultant solution was added diisopropyl ether (200 ml.) and stirred at 30 minutes. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 11.2 g.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][C:8]2[CH:26]=[CH:25][C:11]([C:12]([N:14]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13])=[CH:10][C:9]=2[N+:27]([O-])=O)=[CH:2]1.O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:27][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:8]=1[NH:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[C:12]([N:14]([CH2:20][C:21]([F:22])([F:23])[F:24])[CH2:15][C:16]([F:18])([F:19])[F:17])=[O:13]
Reactant: O=C(c1ccc(NCc2ccoc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(C(=O)N(CC(F)(F)F)CC(F)(F)F)ccc1NCc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[(3-Furylmethyl)amino]-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (108 mg, 0.254 mmol) was dissolved in 5 mL of DMF. Tin(II) chloride dihydrate (860 mg, 1.27 mmol) was added and the solution was stirred under nitrogen at RT for 24 h. The solvent was evaporated and the residue was taken up in EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was used directly for the next step. Yield: 80 mg (80%); MS (ESI) 396.11 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][C@H:21]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:29]([O:28][C:27](=[O:33])[NH:26][CH2:25][C@H:23]1[CH2:24][C@H:21]([O:20][C:4]2[C:5]3[C:10]([C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:22]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(-c2cccnc2)cn3COCC[Si](C)(C)C)C1
Temperature: 70 °C

Procedure:
A mixture of tert-butyl {trans-3-[(2-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4yl)oxy]cyclobutyl}methylcarbamate (450 mg, 0.7 mmol), pyridin-3-ylboronic acid (95 mg, 0.8 mmol), 1,4-dioxane (10 mL), water (3 mL), sodium carbonate (94 mg, 0.9 mmol), PdCl2(dppf) (54 mg, 0.07 mmol) was stirred and heated at 70° C. for 1 hr. The reaction was diluted with ethyl acetate (60 mL) and water (15 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a residue, which was purified via flash chromatography (eluting with a gradient of 0%-100% EtOAc in heptanes) to give the title compound (304 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (d, J=1.83 Hz, 1H) 8.53 (dd, J=4.71, 1.41 Hz, 1H) 8.12 (dt, J=8.01, 1.86 Hz, 1H) 7.98 (s, 1H) 7.48 (dd, J=7.82, 4.89 Hz, 1H) 5.58 (s, 2H) 5.40 (t, J=6.60 Hz, 1H) 4.67 (br. s., 1H) 3.52-3.65 (m, 2H) 2.78 (s, 3H) 2.59-2.71 (m, 2H) 2.21-2.37 (m, 2H) 1.38 (s, 9H) 0.82-0.93 (m, 2H) −0.06 (s, 9H). m/z (APCI+) for C27H38ClN5O4Si 560.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: CCCCSCCCC
Reactant: Brc1ccc(I)cc1
Product: CCCCSc1ccc(Br)cc1

Procedure:
The general procedure was used to convert 4-iodo bromobenzene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (450 mg, 92% yield). 1H NMR (300 MHz, CDCl3) δ 7.39–7.36 (d, J=8.6, 2H; Ha, Ha′), 7.19–7.15 (d, J=8.28, 2H; Hb, Hb′), 2.91–2.86 (t, J=7.1, 2H; Hc), 1.57–1.47 (m, 2H; Hd), 1.41–1.31 (m, 2H; He), 0.94–0.89 (t, J=7.3, 3H; Hf). 13C NMR (75 MHz, CDCl3) δ 136.2 (C4), 131.7 (C1, C1′), 130.2 (C2, C2′), 119.2 (C3), 33.2 (C5), 30.9 (C6), 21.8 (C7), 13.5 (C8). Anal. Calcd. for C10H13Br C, 48.99; H, 5.34; S, 13.08; Found C, 49.09; H, 5.44; S, 12.96.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:11]=[C:12]=[O:13]>[Sn].O>[CH2:4]([N:11]=[C:12]=[O:13])[CH2:5][CH2:6][CH2:6][CH2:5][CH2:4][N:11]=[C:12]=[O:13].[CH3:1][CH2:2][O:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [N-]=C=O
Agent: [Sn]
Solvent: O
Solvent: CCOCCC(=O)OCC
Product: O=C=NCCCCCCN=C=O

Procedure:
In order to prepare the test coating, 100 grams of the above oligomer were mixed with 0.1 gram of T-12 tin catalyst, and 20 grams of EEP solvent. A second component was prepared from 126.4 grams of isocyanate multifunctional oligomer biurets formed by the reaction product between hexamethylene diisocyanate and water and 20 g of EEP solvent. Three mil wet films were cast from the mixed components which dried hard in two hours and had a Sward hardness of 10 in 24 hours.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.[CH2:28](O)/[CH:29]=[CH:30]/[CH3:31].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:28]/[CH:29]=[CH:30]/[CH3:31])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: C/C=C/CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Solvent: ClC(Cl)Cl
Product: C/C=C/COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.83 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid (50.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (45.8 g) in chloroform (500 ml) was added 4-dimethylaminopyridine (29.3 g), and the mixture was stirred for 50 minutes. To the mixture was added (E)-but-2-en-1-ol (22.1 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 10% aqueous potassium bisulfate solution (500 ml), and the mixture was extracted with chloroform. The separated organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution (400 ml) and saturated aqueous sodium chloride solution (350 ml). The separated aqueous layer was extracted with chloroform (300 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/1) to give the titled compound (57.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]2)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]4)=[CH:29][CH:28]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)NC(=O)CC4)nn12

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.080 g, 0.21 mmol) and 7-Amino-3,4-dihydro-1H-quinolin-2-one (0.043 g, 0.27 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. Upon completion, the product was triturated and washed with acetone. LC/MS: 386 (M+H); HPLC: 2.920 minutes, 99% purity, MP: 310-313° C. 1H NMR (400 MHz, CDCl3 , 6, ppm): 8.56 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.65 (dd, J=7.8, 8.3 Hz, 1H), 7.47 (s, 1H), 7.23-7.16 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.96 (d, J=5.9 Hz, 1H), 3.88 (s, 3H), 2.93 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([CH2:8][F:9])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:17]>CCOCC>[NH2:1][C@H:2]([C:6]([CH2:8][F:9])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)CF
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@H](N)C(=O)CF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Boc-ValCH2F (0.48 g, 2.06 mmol) in ether (10 mL) was added a saturated solution of HCl in ether (25 mL). The mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under reduced pressure at room temperature. The residue was quickly triturated with ether (2×30 mL) and then was pumped dry, giving 0.24 g of ValCH2F hydrochloride. Boc-Ala-Ala-ProOH (Enzyme Systems Products, 0.503 g, 1.41 mmol) was dissolved in THF (5 mL) and was cooled to -20° C. NMM (0.155 mL, 1.41 mmol) was added, followed by IBCF (0.183 mL, 1.41 mmol) After 5 minutes, this mixture was charged with a solution of ValCH2F hydrochloride (0.24 g, 1.41 mmol) in DMF (2 mL). A second equivalent of NMM (0.155 mL, 1.41 mmol) was added. The mixture was stirred at -15° C. for 15 minutes. 1 molar HCl (15 mL) was added. The product was extracted with ethyl acetate (2×15 mL). The combined extracts were washed with saturated aqueous NaHCO3 (15 mL), brine (15 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was slowly crystallized at -20° C. from CH2Cl2 /hexane, giving 0.47 g (47% from Boc-ValCH2F of Boc-Ala-Ala-Pro-ValCH2F.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([Si](C)(C)C)=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[K+].[Br-:24].CO.ClN1C(=O)CCC1=O>C(O)(=O)C>[Br:24][C:16]1[CH:17]=[CH:18][C:13]([C:2]2([OH:1])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc([Si](C)(C)C)cc2)C1
Reactant: [Br-]
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Br)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A mixture of tert-butyl 3-hydroxy-3-(4-(trimethylsilyl)phenyl)azetidine-1-carboxylate (Preparation 3, 45 g, 0.14 mol) and KBr (25 g, 0.21 mol) in acetic acid (10 and MeOH (100 mL) was heated at 60° C. for 20 minutes. Then N-chlorosuccinimide (22.4 g, 0.17 mol) was added to the reaction mixture and stirred at 60° C. for 2 hours. LC/MS indicated the reaction was complete (only product peak). After cooling to ambient temperature, the mixture was poured into ice-water (1 L). The mixture was extracted with CHCl3 (2×800 mL). The combined organics were washed with 3M NaOH (2×600 mL), water (600 mL), dried over sodium sulfate, filtered and concentrated. The crude product was washed with ether to afford the desired product (35 g, 76% yield). 1H NMR (CDCl3) δ 7.5 (d, 2H), 7.4 (d, 2H), 4.2 (s, 4H), 3.4 (s, 1H), 1.4 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]([O:30][CH2:31][CH3:32])[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[CH:21][C:20]([O:26][C:27](=[O:29])[CH3:28])=[CH:19][CH:18]=3)(=[O:10])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[C:27]([O:26][C:20]1[CH:19]=[CH:18][C:17]2[C:16]([CH2:4][CH2:3][C:2]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:1])([O:30][CH2:31][CH3:32])[C:15]3[C:24]([O:23][C:22]=2[CH:21]=1)=[CH:25][C:12]([O:11][C:8](=[O:10])[CH3:9])=[CH:13][CH:14]=3)(=[O:29])[CH3:28]
Reactant: CCOC1c2ccc(OC(C)=O)cc2Oc2cc(OC(C)=O)ccc21
Reactant: OC1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC1(CCC(=O)N2CCC(O)CC2)c2ccc(OC(C)=O)cc2Oc2cc(OC(C)=O)ccc21
Yield: 104 %

Procedure:
A solution of 4-hydroxypiperidine (506 mg, 5.00 mmol, 2.5 eq, Aldrich) and 9-(2-(N-succinimidyloxy-carbonyl))ethyl)-3,6-diacetoxy-9-ethoxy-9H-xanthene, 7a (1.023 g, 2.00 mmol, prepared according to Prober, et al., EP-A No. 252,683) in dry dichloromethane (20 ml) was stirred for 30 min. The reaction was added to 1M aqueous potassium phosphate buffer (30 mL; pH=7) and extracted with dichloromethane (3×30 mL). The organic extracts were dried over calcium sulfate, concentrated, and dried under vacuum overnight to afford crude amide 8a (1.039 g, 104%) as an off-white foam. This material was>90% pure according to NMR and TLC and was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[C:3]=1[C:17]#[N:18].[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21]>>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20](=[O:21])[C:19](=[O:25])[NH:1][C:2]=2[C:3]=1[C:17]#[N:18]
Reactant: COc1ccccc1-c1ccc(N)c(N)c1C#N
Reactant: CCOC(=O)C(=O)OCC
Product: COc1ccccc1-c1ccc2[nH]c(=O)c(=O)[nH]c2c1C#N

Procedure:
This crude 3,4-diamino-2′methoxy-biphenyl-2-carbonitrile was stirred in diethyl oxalate (5 mL) at reflux for 5 h. The solution was concentrated in vacuo to give 320 mg (quantitative yield) of the title compound as an insoluble solid. MS (ES) [m+H] calc'd for C16H11N3O3, 294; found 294.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:21][C:20]3[C:19]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][CH:27]=[CH:26]5)=[N:18][CH:17]=[N:16][C:15]=3[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-ethylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 171-182° C.; LC-MS: 371 (MH+); HPLC RT: 5.13 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[N:10]=NC1C=CC=CC=1.[H][H].C>CO>[OH:9][C:6]1[CH:5]=[CH:4][C:3]([NH2:10])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: Oc1ccc(N=Nc2ccccc2)c(F)c1F
Reactant: [H][H]
Solvent: CO
Product: Nc1ccc(O)c(F)c1F
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
At room temperature, 3.5 g (0.015 mol) of (2,3-difluoro-4-hydroxyphenyl)-phenyldiazene are dissolved in 30 ml of methanol in a 100 ml three-neck flask fitted with internal thermometer, stirrer and gas inlet tube. The flask is flushed with argon, and 1.5 g of Raney nickel and 25 μl of bis(2-hydroxyethyl) sulphide are then added. 692 ml of hydrogen (0.03 mol) are then applied at room temperature with a pressure of about 1 bar. The reaction mixture is admixed with activated charcoal, stirred for a further 15 minutes and filtered over a bed of silica gel. The solvent is distilled off and the residue is washed with n-hexane, affording 2.0 g (91.9% of theory) of 4-hydroxy-2,3-difluoroaniline.