Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(OB(O)OC(=O)C)(=O)C.[CH:38]1([N:41]2[C:50]3[C:45](=[CH:46][C:47]([F:54])=[C:48](F)[C:49]=3[O:51][CH3:52])[C:44](=[O:55])[C:43]([C:56]([OH:58])=[O:57])=[CH:42]2)[CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:24]([NH:23][CH2:22][C@@H:20]1[O:19][C:18](=[O:27])[N:17]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3([OH:16])[CH2:15][CH2:14][N:13]([C:48]4[C:49]([O:51][CH3:52])=[C:50]5[C:45]([C:44](=[O:55])[C:43]([C:56]([OH:58])=[O:57])=[CH:42][N:41]5[CH:38]5[CH2:40][CH2:39]5)=[CH:46][C:47]=4[F:54])[CH2:12][CH2:11]3)=[C:2]([F:1])[CH:3]=2)[CH2:21]1)(=[O:26])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNCC3)c(F)c2)C(=O)O1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CC(=O)OB(O)OC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(N2CCC(O)(COc3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In analogy to example 5 with 114 mg N-[{(5S)-3[3-fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide. (MW: 381.40 0.3 mmol), 127 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid diacetylborate (Sakurai, Nobuhiro; Sano, Mitsuharu; Hirayama, Fumihiro; Kuroda, Tsuyoshi; Uemori, Satoru; Bioorg. Med. Chem. Lett.; 8; 16; 1998; 2185-2190) (MW: 423.137, 0.3 mmol) and 38 mg of ethyl diisopropylamine (MW: 129.25, 0.3 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 137 mg, 69.5%. MS: 658.2 (M+H)+, 655.8 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][C:27]1[NH:26][CH:30]=[CH:29][N:28]=1)=[O:22])[CH3:25]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (4.18 g, 10.0 mmol) and imidazole (1.5 g, 22.0 mmol) in acetonitrile (200 ml) was stirred at 80° C. for 2 h and overnight at 25° C. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (19:1) graduated to dichloromethane/methanol (1:9). The purified product was washed with water to give 2.0 g (49%) of the title compound. M.p. 187°-189° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=1[N:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=3[N:52]([CH3:54])[CH3:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1c(Cl)cncc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CN(C)c1c(Cl)cncc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-5-chloro-N,N-dimethylpyridin-4-amine hydrobromide and isolated as light-yellow gum. MS (m/e): 451.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]1[CH2:18][CH:17]([OH:19])[CH:16]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:10]1[CH2:11]2.CCN(C(C)C)C(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC(OC)(C)C>[OH:28][CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][CH:16]1[CH:10]2[CH2:11][C:12]3[C:7]([CH2:8][CH:9]2[CH2:18][CH:17]1[O:19][C:42]([CH:39]1[CH2:41][CH2:40]1)=[O:43])=[C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:29])[CH:15]=[CH:14][CH:13]=3
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)OC)CC21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: CCCCCC(O)CCC1C(OC(=O)C2CC2)CC2Cc3c(cccc3OCC(=O)OC)CC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
A solution of [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (32 mg, 0.06 mmol), DIPEA (31 μl, 0.18 mmol) and DMAP (1 crystal) in DCM (2 ml) was treated with cyclopropanecarbonyl chloride (8 μl, 0.08 mmol) and stirred for 24 hr at RT under nitrogen. The reaction mixture was diluted with MTBE and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography. This resulting material was dissolved in MeOH/THE (4 ml), treated with Amberlite IR120H and stirred 24 hr. The reaction mixture was filtered and concentrated to yield cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (32 mg) as an oil. 1HNMR: (400 MHz, DMSO-d6) δ 7.06 (d, 1H, J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.8); 4.78 (s, 2H); 4.1-4.2 (m, 1H); 4.05-4.50 (m, 1H); 3.68 (s, 3H); 2.6-2.8 (m, 2H); 2.4-2.5 (m, 2H); 2.20-2.35 (m, 1H); 2.10-2.20 (m, 1H); 1.8-1.95 (m, 1H); 1.10-1.16 (m, 15H); 0.95-1.10 (m, 1H); 0.70-0.90 (m, 7H); MS: m/z 495 [M+Na]+
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=1[C:1](=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: Fc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)/C=C/C(=O)c1cc(Cl)ccc1F
Reaction time: 8 h

Procedure:
Finely pulverized maleic anhydride (3.0 g) is added portionwise to a mixture of 1-chloro-4-fluorobenzene (24.6 g) and anhydrous aluminium chloride (11.56 g). A gas bubbler is attached to the top of the condenser and the mixture is heated in an oil bath at 80°-85° C. for 2 hours at which time little hydrogen chloride gas evolution is evident. The mixture is cooled and the excess 1-chloro-4-fluorobenzene is recovered by distillation at water aspirator pressure. The resultant mixture is quenched with ice and then steam distilled to remove the last traces of the 1-chloro-4-fluorobenzene. Concentrated hydrochloric acid (10 mL) is added to the cooled mixture and the resultant solid collected by filtration (9.2 g). This material is taken up in boiling benzene (50 mL), treated with decolorizing charcoal and filtered through a celite bed. On standing overnight, the yellow solid is collected by filtration (2.45 g). A second recrystallization from benzene (40 mL) leads to 4-(2'-fluoro-5'-chlorophenyl)-4-oxo-2E-butenoic acid (2.1 g) as pure regioisomer.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)nn1-c1ccccn1
Yield: 85 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 44 of Example C-18 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8]2)=[N:3]1>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[CH:6][C:7]([C:11]([F:12])([F:14])[F:13])=[CH:8]2)=[N:3]1
Reactant: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (76 mg, 0.151 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 2 mL) and stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 64 mg (quant.) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.84 (s, 1H), 7.41 (m, 2H), 7.34 (m, 2H), 7.28 (s, 1H), 7.21 (m, 1H), 4.83 (s, 2H), 4.18 (s, 3H), 3.57 (s, 2H), 2.90 (m, 2H), 2.76 (m, 2H), 2.20 (m, 2H), 1.95 (m, 2H), 1.85 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 147.6, 144.4, 129.4, 128.3, 127.3, 126.1, 125.5, 124.9 (q, J=272 Hz), 124.2 (q, J=32 Hz), 120.7, 118.7, 117.5 (q, J=4.8 Hz), 80.2, 68.7, 42.9, 42.0, 40.7, 33.7. Mass spec.: 404.10 (MH)+. Accurate mass spec.: m/z 404.1936 [MH]+, Δ=3.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:22][CH2:21][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: OCCCN1CCCC1
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 3-Pyrrolidin-1-yl-propan-1-ol. LC/ESI-MS: m/z=322 [M+H].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:18][C:19](=[N:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C:18]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=[N:27][N:28]2[CH2:32][CH2:31][CH2:30][C:29]=12
Reactant: Cc1cccc(C(Cc2ccnc3ccc(Br)cc23)=NN2CCCC2=O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4ccc(Br)cc24)CCC3)n1
Temperature: 100 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a mixture of (1.2 eq.) cesium carbonate and 1-[2-(6-bromo-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one (33.3 g, 78.7 mmol) add 300 mL dry N,N-dimethylformamide. Stir the mixture 20 hours at 100° C. The mixture may turn dark during the reaction. Remove the N,N-dimethylformamide in vacuo. Partition the residue between water and methylene chloride. Extract the aqueous portion with additional methylene chloride. Filter the organic solutions through a 300 mL silica plug, eluting with 1.5 L methylene chloride, 1.5 L ethyl acetate and 1.5 L acetone. Combine the appropriate fractions and concentrate in vacuo. Collect the resulting precipitate by filtration to yield 22.7 g (71.2%) of the desired subtitled intermediate as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([CH3:7])([CH3:6])[CH3:5].F[C:10]1[C:11]([CH3:30])=[N:12][C:13]2[C:18]([N:19]=1)=[C:17]([C:20]1[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=1)[CH:16]=[CH:15][CH:14]=2.CO.C(Cl)Cl>CN(C=O)C.[NH4+].[Cl-]>[CH3:30][C:11]1[C:10]([O:8][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]2[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=2)[N:12]=1
Reactant: CC(C)(C)CO
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1OCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
NaH (60% w/w in mineral oil; 37.8 mg, 0.945 mmol) was added to a solution of neopentyl alcohol (Aldrich; 0.103 mL, 0.945 mmol) in DMF (1.0 mL), and the resulting suspension was stirred at 25° C. for 10 min. 2-(3-Fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol) was added, and the resulting solution was heated at 100° C. for 17 h. The mixture was cooled to 25° C., diluted with half-saturated aq. NH4Cl (30 mL), and extracted with DCM (2×40 mL). The combined organic extracts were washed with water (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-(neopentyloxy)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (15.3 mg, 0.042 mmol, 31% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.03 (1H, br. s.), 8.00 (1H, d, J=7.6 Hz), 7.79 (1H, d, J=8.0 Hz), 7.56 (1H, t, J=7.8 Hz), 7.18 (1H, d, J=2.0 Hz), 5.43 (1H, br. s.), 4.12 (2H, s), 3.68 (2H, td, J=6.5, 1.4 Hz), 2.96 (2H, t, J=6.8 Hz), 2.71 (3H, s), 1.18 (9H, s). m/z (ESI, +ve) 365.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].Cl.[OH-].[Na+]>O>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCOc1ccc(N)cc1

Procedure:
N,N-Diethyl-2-(4-nitrophenoxy)ethylamine (4.0 g) (prepared by the method described in Helv. Chim. Acta. 1960, 43, 1971) was dissolved in IMS (70 ml), water (10 ml) and concentrated hydrochloric acid (2 ml). The mixture was boiled under reflux and then reduced iron powder (4.6 g) was carefully added in portions. The mixture was boiled under reflux for 7 hours then hot filtered. The filtrate was basified with 5M sodium hydroxide solution and then evaporated under reduced pressure. The residue was partitioned between water and ether. The organic layer was separated, dried and evaporated to give 4-[2-(N,N-diethylamino)ethoxy]aniline as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 0.67 h
Yield: 60.6 %

Procedure:
The (2-amino-ethyl)-carbamic acid tert-butyl ester (5.00 g, 31.2 mmol) and 4-chloro-benzaldehyde (4.61 g, 32.77 mmol) were dissolved in 60 mL of 1,2-dichloroethane at room temperature. The reaction mixture was allowed to stir for 40 minutes prior to treatment with sodium triacetoxyborohydride (9.90 g, 46.8 mmol). The mixture was allowed to stir overnight to completion and quenched with a saturated NaHCO3 solution. The aqueous was extracted with DCM, separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with hexanes/EtOAc plus 2% triethyl amine) to afford the pure [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester as a viscous yellow oil (5.38 g, 61%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.92 (brs, 1H), 3.75 (s, 2H), 3.23 (appd, J=5.6 Hz, 2H), 2.73 (appt, J=6.0 Hz, 2H), 1.44 (s, 9H), 1.36 (brs, 1H). LCMS (APCI+) m/z 285 [M+H]+; Rt=2.30 min.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]=[CH:6]1)(=O)C>P([O-])([O-])([O-])=O>[C:12]([O:11][C@@H:10]1[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]=[CH:6][C@H:5]1[OH:4])(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=P([O-])([O-])[O-]
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1OC(C)=O
Yield: 90 %

Procedure:
7.0 g (30 mmol) of tri-O-acetylglucal in 70 ml of 0.25M phosphate buffer (pH=7) are stirred with 7 g of lipase from Pseudomonas spec. (lipase P, from Amano Pharmaceutical Co., Ltd., Nagoya, Japan) (free or immobilized on SiO2) at room temperature. After the reaction is complete (about 5-7 h) the reusable enzyme is separated off. The desired 4,6-di-O-acetylglucal is obtained either by extraction of the aqueous solution with CHCl3 or ethyl acetate or after freeze-drying and subsequent taking up in organic solvents such as ethyl acetate and filtering off the insoluble concomitants, The 4,6-di-O-acetylglucal which results in about 90% yield can be used without further purification for further reactions.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[O:8][N:7]=1)([CH3:5])[CH3:4].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>>[CH:3]([C:6]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:22]2[O:24][CH2:23]2)[O:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: BrCC1CO1
Reactant: CC(C)c1cc(C=Cc2ccccc2O)on1
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This compound is prepared by the method described for Example VI, from 3.4 g of 55% strength sodium hydride (0.078 mole), 18 g (0.078 mole) of 3-isopropyl-5-(2-hydroxystyryl)-isoxazole and 10.8 g (0.078 mole) of epibromohydrin. 21.5 g (97% of theory) of a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone 0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methoxyacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxyacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH2:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40].Cl>O1CCCC1>[CH2:39]([S:41]([N:23]1[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:24]1)(=[O:43])=[O:42])[CH3:40]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile (0.100 g, 0.244 mmol) in tetrahydrofuran (2 mL) containing N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) was added ethanesulfonyl chloride (0.023 mL, 0.24 mmol). After stirring for 1.5 hours, the reaction mixture was poured into dilute HCl and extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford product, used without further purification in Step 5 (111 mg, 91%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[C:3]1[CH3:13].C1(C)C=CC=CC=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8](=[O:12])[CH:9]([C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]#[N:11])=[C:3]1[CH3:13]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(C(=O)CC#N)c(C)n1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C(C#N)C(=O)Nc2ccccc2)c(C)n1C
Reaction time: 8 h

Procedure:
The suspension of 1.0 g of 1,2,5-trimethyl-β-oxo-3-pyrrolpropionitrile, 40 ml of toluene and 0.7 g of triethylamine is treated with 0.75 g of phenylisocyanate and warmed for 5 minutes on the steam cone until all is dissolved. After standing overnight, the precipitate formed is collected, taken up in methanol, and the solution added to the mixture of 3 ml of 5 N hydrochloric acid and 250 ml of water. The crude product formed is collected, washed with water, dissolved in 5% aqueous sodium hydroxide, filtered, and the alkaline filtrate acidified with 5 N hydrochloric acid. The precipitate is collected, washed with water, air-dried and recrystallized from ethanol, to yield the 1,2,5-trimethyl-β-oxo-α-phenylcarbamoyl-3-pyrrolpropionitrile melting at 158°-160°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][N:30]3[CH2:31][CH2:32][C@@H:28]([F:27])[CH2:29]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: F[C@@H]1CCNC1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CC[C@@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and (R)-3-fluoropyrrolidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.682 min, m/z=516.9; 1H NMR (CDCl3) 1.42 (d, 3H), 1.82-2.30 (m, 9H), 2.52-2.64 (m, 1H), 2.67-2.88 (m, 3H), 4.93-5.13 (m, 1H), 5.53 (m, 1H), 6.71 (d, 2H), 6.98 (m, 2H), 7.18 (m, 2H), 7.19 (m, 1H).