Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([CH2:20][NH:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]([Br:26])=[CH:16][N:15]=1>ClCCCl>[Br:26][C:17]1[CH:16]=[N:15][C:14]2[NH:13][C:1](=[O:2])[N:21]([CH2:22][CH2:23][O:24][CH3:25])[CH2:20][C:19]=2[CH:18]=1
Reactant: COCCNCc1cc(Br)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COCCN1Cc2cc(Br)cnc2NC1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
1,1′-Carbonyldiimidazole (0.74 g, 4.60 mmole) was added to a solution of 2-amino-5-bromo-3-[(2-methoxyethyl)aminomethyl]pyridine (1.00 g, 3.80 mmole) in 1,2-dichloroethane (35 mL) at RT. The reaction was heated at 65° C. with stirring overnight, then was concentrated in vacuo. Flash chromatography on silica gel (5% MeOH/CHCl3) gave title compound (0.90 g, 83%) as a yellow solid after drying in vacuo: MS (ES) m/e 286/288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([CH3:49])[CH:16]=[C:17]([S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([C:37](=[O:48])[C:38]6[CH:43]=[CH:42][CH:41]=[C:40](CC(=O)C)[CH:39]=6)[CH2:33][CH2:32]5)=[O:30])[CH:24]=4)(=[O:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:50]([NH2:52])=[O:51])[CH:6]=[CH:7][CH:8]=1.[CH2:53]([O:60][C:61]1[CH:62]=[CH:63][C:64]([C@@H:72]([O:88][Si:89]([C:92]([CH3:95])([CH3:94])[CH3:93])([CH3:91])[CH3:90])[CH2:73][NH:74][C:75]([CH3:87])([CH3:86])[CH2:76]C2C=C(C=CC=2)C(O)=O)=[C:65]2[C:70]=1[NH:69][C:68](=[O:71])[CH:67]=[CH:66]2)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:53]([O:60][C:61]1[CH:62]=[CH:63][C:64]([C@@H:72]([O:88][Si:89]([C:92]([CH3:95])([CH3:94])[CH3:93])([CH3:90])[CH3:91])[CH2:73][NH:74][C:75]([CH3:86])([CH3:87])[CH2:76][C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[C:37]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([C:25]3[CH:24]=[C:23]([S:20]([C:17]4[CH:18]=[C:19]5[C:14](=[C:15]([CH3:49])[CH:16]=4)[N:13]=[CH:12][C:11]([C:50]([NH2:52])=[O:51])=[C:10]5[NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=3)=[O:30])[CH2:32][CH2:33]2)=[O:48])=[C:65]2[C:70]=1[NH:69][C:68](=[O:71])[CH:67]=[CH:66]2)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)=O)c6)CC5)c4)cc23)c1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(OCc8ccccc8)c8[nH]c(=O)ccc78)c6)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 97, using Intermediate 101 in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C64H72N7O9SSi+ 1142.5. Found m/z=1142.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:32][N:33]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32][N:33]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3ncc(CCC(=O)OC)o3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3ncc(CCC(=O)O)o3)c2)c1

Procedure:
Methyl 3-(2-{3-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]phenyl}-1,3-oxazol-5-yl)propanoate (70 mg, 0.12 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) in 2:1:1 tetrahydrofuran/methanol/water (6 mL) is stirred at room temperature 1.5 h. The reaction is concentrated under reduced pressure. The residue is washed with 1N hydrochloric acid (aq), then chloroform, and the solid is dried under reduced pressure to give the title compound. ESI MS m/z 578.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CCCc1ccccc1
Temperature: 85 °C

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol (1.76 g, 5.69 mmol), iodobenzene (0.638 mL, 5.69 mmol), and triethylamine (1.59 mL, 11.38 mmol) were dissolved in ACN (17 mL) and the solution was purged with bubbling N2 (g). Palladium(II) acetate (0.064 g, 0.28 mmol) was added, the reaction vessel was sealed, and the reaction was heated to 85° C. overnight. After cooling, the reaction was submitted to standard aqueous workup then purified on silica gel (0-30% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>Cl.C(O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1
Reactant: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCOCC2)cc1

Procedure:
(+,−) cis 7-Benzyloxy-4-[4-(morpholinoethyloxy)-phenyl]-3-phenyl-chroman (139 mg, 0.27 mmol) was dissolved in a solution of 1% hydrochloride in ethanol (5 ml). The solution was added to a 10% palladium on carbon catalyst, and hydrogenated (1 atm.) overnight. The reaction mixture was filtered and evaporated. The evaporated product was dissolved in acetone and evaporated to give a glassy solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O1CCCC1.CO.O>C(O)(=O)C>[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[C:27](\[CH3:33])/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
1.5 g (2.5 mmol) of sodium hydroxide are added to a solution of 1.2 g (2.5 mmol) of ethyl (E)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylate in 30 mL of an 8/2 tetrahydrofuran/methanol mixture. The reaction medium is stirred at room temperature for 4 hours. After addition of water and acidification to pH4 with acetic acid, the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. The product is recrystallized from an isopropyl ether/pentane mixture. 456 mg (40%) of (E)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a solid with a melting point of 79° C.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]=1[S:21]C(=O)N(C)C)=[CH:18][CH:17]=[C:16]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:15]=2)=[O:10])CCC>CO.O.Cl>[CH3:4][O:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]=1[SH:21])=[CH:18][CH:17]=[C:16]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:15]=2)=[O:10]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1SC(=O)N(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 6.5 ml of 0.5 N sodium methoxide in methanol was added 460 mg of 4-Dimethylcarbamoylsulfanyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester. The resultant solution was heated to 50-60° C. for 8 hours, cooled to room temperature, and diluted with 10 ml water and 7.0 ml 1 N HCl. The resulting yellow precipitate was collected by filtering the solution through a (medium) porous buchner filter funnel to give 307 mg of product; MS (+) m/z 312.08 (M+1)
Reaction SMILES: COC1C=C(C=CC=1OC)CCNC(OCC1C=CC=CC=1)C(C1C=CC=CC=1)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:56]=[CH:57][C:58]=1[O:59][CH3:60])[CH2:36][CH2:37][NH:38][CH2:39][C:40]([OH:55])([O:47]CC1C=CC=CC=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:56]=[CH:57][C:58]=1[O:59][CH3:60])[CH2:36][CH2:37][NH:38][CH2:39][C:40]([OH:55])([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccc(CCNCC(O)(OCc2ccccc2)c2ccccc2)cc1OC
Agent: COc1ccc(CCNC(OCc2ccccc2)C(=O)c2ccccc2)cc1OC
Product: COc1ccc(CCNCC(O)(O)c2ccccc2)cc1OC

Procedure:
The α-(3,4-dimethoxyphenethylamino)-monobenzyloxyacetophenone (III) or α-(3,4-dimethoxyphenethylaminomethyl)-monobenzyloxybenzylalcohol (IV) is then subjected to catalytic hydrogenation to give the α-(3,4-dimethoxyphenethylaminomethyl)-monohydroxybenzylalcohol (I). Said catalytic hydrogenation is carried out by shaking a solution of the compound (III) or (IV) in the presence of a catalyst in a hydrogen atmosphere. Preferred examples of the catalyst include platinum dioxide, platinum and palladium-carbon. A lower alkanol (e.g., methanol, ethanol, propanol, isopropanol) or a mixture of the lower alkanol and water is suitable as the reaction solvent. It is preferred to carry out the reaction at 5° to 20° C under atmospheric pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]4[O:20][CH2:19][N:18]([CH3:21])[CH2:17]4)[CH:13]=[CH:12][N:11]3[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]([OH:20])[CH2:17][N:18]([CH3:21])[CH3:19])[CH:13]=[CH:12][N:11]3[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C4CN(C)CO4)ccn23)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C(O)CN(C)C)ccn23)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A 100 mL round bottom flask was charged with oxazolidine 41 (1.65 g, 3.91 mmol), ethanol (50 mL), and sodium borohydride (450 mg, 11.9 mmol), and stirred at room temperature for 3 hours. The reaction was then quenched with 16 mL of a 20% NH4Cl aqueous solution and concentrated under reduced pressure, then diluted with water and neutralized with an aqueous solution of potassium carbonate. The solution was then extracted with methylene chloride (3×50 mL). The organic extracts were then pooled, dried over MgSO4, filtered and concentrated under reduced pressure to give (dimethylamino)ethanol 42 (crude yield: 1.31 g, 78%). The crude product was then dissolved in a minimum volume of CH2Cl2, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 42: 1.01 g (60% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 6H), 2.49 (m, 2H), 2.58 (s, 3H), 4.77 (m, 1H), 5.40 (bs, 1H), 6.86 (d, J=5.6 Hz, 1H), 7.16 (dd, J=7.2, 1.6 Hz, 1H), 7.29 (t, J=8.8 Hz, 2H), 7.64 (m, 3H), 8.45 (d, J=5.6 Hz, 1H), 9.32 (d, J=7.2 Hz, 1H). MS (ESI+) 424.2.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16](/[CH:19]=[CH:20]/[C:21]#[N:22])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.C1(C2CCC(=CC(OCC)=O)CC2)N=NN2C=1C1C=CNC=1N=C2>>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][C:21]#[N:22])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: N#C/C=C/[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: CCOC(=O)C=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Product: N#CCC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1

Procedure:
The reactions in Synthetic Examplea 438 were carried out in substantially the same manners except that (E)-3-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acrylonitrile obtained in Synthetic Examplea 440 was used instead of ethyl 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetate to give the title compound as a colorless solid (7.30 mg, yield 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O)=[CH:6]N(C)C)[CH3:2].[N+]([O-])(O)=O.[NH2:22][C:23]([NH2:25])=[NH:24].C([O-])(=O)C.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:24][C:23]([NH2:25])=[N:22][CH:6]=1)=[O:17])[CH3:2]
Reactant: N=C(N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccco1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N)nc1-c1ccco1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
Following the method of Sansebastiano et al. (Il Farmaco 1993, 48, 335), to a stirred solution of 2.44 g (10.3 mmol) 3-dimethylamino-2-(furan-2-carbonyl)-acrylic acid ethyl ester and 2.26 g (18.5 mmol) guanidine nitrate in 20 ml DMF was added 1.51 g (18.5 mmol) sodium acetate and the mixture heated at 90° C. for 36 h. The reaction mixture was then partitioned between ether and water. The phases were separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was recrystallised from ether/ethyl acetate/hexane to afford 669 mg (28%) 2-amino-4-furan-2-yl-pyrimidine-5-carboxylic acid ethyl ester as a white crystalline solid. Chromatography (ethyl acetate/hexane 2/1) of the mother liquor afforded a further 150 mg (6%) product. ES-MS m/e (%): 234 (M+H+, 100), 206 ([M—C2H4]+, 35), 188 ([M+H-EtOH]+, 42).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8](#[N:11])[CH:9]=[CH2:10]>C(Cl)Cl>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:9][C:8]#[N:11]
Reactant: OC[C@H]1CCCN1
Reactant: C=CC#N
Solvent: ClCCl
Product: N#CCCN1CCC[C@@H]1CO
Temperature: 25 °C

Procedure:
(R)-2-hydroxymethylpyrrolidine (Tokyo Kasei Kogyo Co., Ltd.) (50 g) was dissolved in methylene chloride (500 mL), and acrylonitrile (36 mL) was added dropwise to the solution with stirring at room temperature. Subsequently, the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated to give (R)-3-(2-hydroxymethylpyrrolidin-1-yl)propionitrile (76 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:6][N:5]1[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.4 %

Procedure:
To a suspension of 10.7 g of (2S, 4R)-4-hydroxy-1-(2-nitrobenzoyl) proline methyl ester and 5.7 g of imidazole in 100 ml of N,N-dimethylformamide, there was added 6.6 g of tert-butyldimethylsilyl chloride at room temperature in a nitrogen gas atmosphere and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate three times, water washing of the organic phase, drying and concentration thereof under reduced pressure. The resulting residue was subjected to silica gel column chromatography, then eluted with a 1/1 ethyl acetate/hexane mixed solvent, followed by recrystallization from ethyl acetate-hexane to give 10.6 g (yield 71.6%) of (2S, 4R)-4-(tert-butyldimethylsilyloxy)-1-(2-nitrobenzoyl) proline methyl ester as colorless needles.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH2:9][PH3+].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:29]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[CH:29]=[CH:9]\[C:8]1[CH:7]=[C:6]([O:5][CH3:4])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(/C=C\c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a stirred suspension of sodium hydride (0.75, 31.4 mmol) in N,N-dimethylimidazolidinone (10 ml) was added 3,4,5-trimethoxy-benzyl-phosphonium bromide (8.26 g 15.71 mmol) under argon. The aldehyde (4.0 g, 1258 mmol) from Example 40 was added to the deep red solution followed by 2 ml of N,N-dimethylimidazolidinone. Before adding ice (10 g)-water (75 ml) the mixture was stirred overnight. Upon extraction with ethyl acetate (3×100 ml), the organic phase was washed with water (3×75 ml), dried and evaporated to a dark colored mass (9.0 g). The crude product in hexane-ethyl acetate (9:1) was chromatographed on a column of silica gel (200 g) to afford a mixture of E- and Z-isomers (3.70 g, 61% yield). A 1.1 g sample of the mixture was rechromatographed on a column of silica gel and eluted with hexane-ethyl acetate (19:1) to furnish Z-isomer (0.25 g) and E-isomer (0.32 g). The Z-isomer was further purified by preparative TLC (hexane-ethyl acetate, 7:3) to yield 3',4'-Dibenzyloxy-3,4,5-trimethoxy-(Z)-stilbene as a chromatographically homogeneous and viscous oil: IR υmax 1581, 1509, 1462, 1454, 1412, 1265, 1237, 1128, 1007 cm-1 ; 1H-NMR (400 MHz) 3.731 (6H, s, 2×OCH3), 3.856 (3H, s, OCH3), 4.856 (2H, s, ArCH2), 5.121 (2H, s, ArCH2), 6.589 (2H, s, ArH) , 6.600 (3H, m, ArH), 6.747 (1H, d, J=8.6 Hz, ArH), 6.758 (1H, brs, ARH), 7.273-7.407 (10H, ArH).
Reaction SMILES: [C:1]([NH:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N+:17]=[N-:18])=[C:12]([F:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[C:20]([O:24][CH3:25])(=[O:23])[C:21]#[CH:22]>C1C=CC=CC=1>[C:1]([NH:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:22]=[C:21]([C:20]([O:24][CH3:25])=[O:23])[N:18]=[N:17]3)=[C:12]([F:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CC(c2ccc(N=[N+]=[N-])c(F)c2)=NO1
Reactant: C#CC(=O)OC
Solvent: c1ccccc1
Product: COC(=O)c1cn(-c2ccc(C3=NOC(NC(C)=O)C3)cc2F)nn1
Temperature: 105 °C
Yield: 70 %

Procedure:
5-Acetamido-3-(4-azido-3-fluorophenyl)isoxazoline (277 mg) is combined with methyl propiolate (0.356 ml) in 3 ml benzene in a screw cap pressure tube under nitrogen. The reaction is warmed to 105° C. for 1 hour, is cooled to room temperature, and is washed into a recovery flask with ethyl acetate. The volatiles are removed in vucuo. The crude material is recrystallized from ethyl acetate to provide 252 mg (70%/) of 5-acetamido-3-(4-(4-carbomethoxy-1,2,3-triazol-1-yl)-3-fluorophenyl)isoxazoline as an off-white solid, mp 221° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1ccccc1F
Product: O=C1C=C(Nc2ccccc2F)CCC1
Yield: 80.9 %

Procedure:
2-Fluoroaniline (10 g) and cyclohexane-1,3-dione (10 g) were heated together under nitrogen at 120° for 1 h. The cooled mixture was triturated with ether and filtered to give the title compound (14.8 g), m.p. 116°-118°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]=[O:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[OH:18]OS([O-])=O.[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:18])=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:6]=2[N:7]=1
Reactant: O=Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (2.69 g, 11 mmol) in DMF is added oxone (7.2 g, 12 mmol) and stirred for 6 h. After the reaction is complete, water is added and a yellow solid is precipitated to give 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2.69 g, 85%). MS (ESI) m/z 266.4 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:17]1=[O:25])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:16]1[CH2:21][CH2:20][N:19]([C:36](=[O:37])[C@H:35]([NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH2:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:17]1=[O:25])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: C=CC[C@@H]1NCCN([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)C1=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)[C@@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a solution of (S,S)-2-(3-allyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 5, (500 mg, 1.42 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (473 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (960 mg, 1.85 mmol) and triethylamine (169 mg, 1.67 mmol). The reaction mixture is stirred for 20 h, quenched with 10% NaHCO3 aqueous solution and extracted with EtOAc. The extract is dried over Na2SO4, filtered and concentrated. The residue is purified over silica gel (hexanes/ethyl acetate, 4:1 to 3:2) to afford 0.745 g (85% yield) of the desired product.