Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:5]1[C:4]([CH2:3][CH2:2][O:1][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:12][N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCc1cn2ccccc2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.80 g of 2-(2-hydroxy-ethyl)imidazo[1,2-a]pyridine (prepared as described in Preparation 26), 2.79 g of 5-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 1.7 ml of tributylphosphine, 1.51 g of 1,1'-(azodicarbonyl) dipiperidine and 30 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:4 to 0:1 by volume as the eluent, to give 0.97 g of the title compound, melting at 135.5-142.4° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19](OC)=[O:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnn2cc(Cl)nc(OCc3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
A solution of methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate 5.35 (427 mg, 1.34 mmol) in THF (6 mL) was cooled to 0° C. under argon. A solution of lithium aluminum hydride in THF (1 M, 1.52 mL, 1.52 mmol) was then added slowly and mixture was warmed to rt and stirred for 18 hours. Mixture was diluted with ether and cooled to 0° C. It was then quenched by addition of 0.060 mL water, 0.060 mL 15% NaOH (aq), and 0.18 mL of water and warmed to room temperature. After 15 minutes, MgSO4 was added and mixture stirred for 20 minutes. Mixture was filtered and filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate/hexanes) to yield (4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazin-3-yl)methanol 5.51 (143 mg).
Reaction SMILES: [OH:1][C:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].Br[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=2)[CH:25]=[C:24]([CH3:39])[CH:23]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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].CN(C)C(=O)C>[OH:1][C:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)([C:4]1[S:5][C:6]([C:22]2[CH:23]=[C:24]([CH3:39])[CH:25]=[C:26]([NH:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][N:30]=3)[N:27]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2nccs2)C1
Agent: [Pd]
Agent: CC(C)(C)C(=O)O
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)C3)s2)c1
Temperature: 130 °C

Procedure:
tert-Butyl 3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidine-1-carboxylate (100 mg, 0.335 mmol), 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (112 mg, 0.337 mmol), butyl di-1-adamantylphosphine (25 mg, 0.070 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.3 mg, 0.018 mmol), pivalic acid (0.018 mL, 0.157 mmol), potassium carbonate (140 mg, 1.013 mmol) and N,N-dimethylacetamide (1 mL) were combined and the mixture was evacuated and purged with nitrogen 3 times then heated to 130° C. for 7 hours. The mixture was filtered then extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)-pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate, which was used in a subsequent step without further purification. MS ESI calc'd. for C26H30F3N5O3S [M+H]+ 550. found 550.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH2:39]([O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1)[CH2:40][CH2:41][CH3:42]>>[CH2:39]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH:48]([OH:49])[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[CH:50][CH:51]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CCCCOc1ccc(C(O)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1

Procedure:
5-((4-Butoxyphenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 4-butoxybenzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]([F:21])([F:20])[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)(=[O:10])=[O:9].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]3[CH2:40][O:39]3)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>O1CCOCC1.C(OCC)(=O)C>[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]([OH:39])[CH2:40][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[S:8]([C:7]([F:20])([F:6])[F:21])(=[O:9])=[O:10])[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3
Reactant: COc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
N-butyllithium (2.5 M in hexanes, 48 ml) was added dropwise to an ice-cooled solution of 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (22.07 g, 86.5 mmol) in dry dioxane (145 ml) over a 40 minute period. The solution was then stirred at ambient temperature for 15 minutes before addition of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (25.05 g, 65.7 mmol) followed by heating at 90° C. for an hour. The reaction was cooled then diluted with 1.2 L ethyl acetate and washed several times with water and finally brine. The organic layer was dried over MgSO4, filtered and condensed to give an orange viscous mixture. The residue was dissolved in 150 ml of 60% methylene chloride/hexanes, then concentrated to yellow foam to which a further 150 ml of 60% methylene chloride/hexanes was added and stirred overnight. The mixture was filtered and washed several times with 60% methylene chloride/hexanes until the solid was white giving 20.1 g of 99%
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:12][C:13](=[O:33])[C:14]([OH:32])([CH3:31])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)O)[CH3:11].C([SiH](CC)CC)C>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:33])[C:14]([OH:32])([CH3:31])[CH2:15][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[CH3:11]
Reactant: CCOC(=O)C(C)(O)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Boron trifluoride etherate was added to a 0° C. solution of 3-(4-Benzyloxy-phenyl)-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (12.9 g, 38.96 mmol) and triethylsilane (28 mL, 175.3 mmol, d=0.728) in anhydrous CH2Cl2, then the reaction is allowed to gradually warm to ambient temperature over 3 h. The reaction is quenched with a saturated aqueous solution of sodium bicarbonate and extracted with additional CH2Cl2. The organic layer is dried, concentrated, and separated by chiral chromatography to provide the title compound (11.7 g, 96%). 1H NMR (400 MHz, CDCl3): δ 7.44-7.33 (m, 5H), 7.12 (d, 2H, J=6.85 Hz), 6.90 (d, 2H, J=6.85 Hz), 5.04 (s, 2H), 4.22-4.14 (m, 2H), 3.03 (d, 1H, J=13.69 Hz), 2.87 (d, 1H, J=13.69 Hz), 1.48 (s, 3H), 1.27 (t, 3H, J=7.34 Hz). Rf=0.60 in 50% acetone in hexanes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:16]1[NH:20][N:19]=[C:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([Cl:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:17]=1)[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[CH:8]=1.[I-].[Na+]>CC(C)=O>[Cl:33][C:31]1[N:30]=[CH:29][N:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:18]3[N:17]=[C:16]4[CH:6]([C:7]5[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[CH:8]=5)[CH2:5][CH2:4][CH2:3][CH2:2][N:20]4[N:19]=3)=[CH:23][C:24]=2[O:34][CH3:35])[CH:32]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(Cl)c1
Yield: 17 %

Procedure:
A solution of 5-(5-chloro-1-(3,4,5-trifluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.66 g, 5.06 mmol), sodium iodide (3.79 g, 25.3 mmol), and diisoproplylethylamine (1.77 mL, 10.1 mmol) in acetone (40 mL) was heated in a sealed vessel at 100° C. for 2 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (35-50% EtOAc/chloroform, linear gradient) to afford 420 mg (17% yield) of the titled compound as a pale yellow solid. The solid was recrystallized from EtOH to afford an analytical sample. LC-MS (M+H)+ 489.2. 1H NMR (500 MHz, chloroform-d) δ ppm 7.52 (d, J=1.53 Hz, 1 H) 7.39 (d, J=2.14 Hz, 1H) 7.11 (d, J=8.55 Hz, 1 H) 7.03 (d, J=1.22 Hz, 1H) 6.79-6.92 (m, 3 H) 6.59 (s, 1 H) 4.24-4.35 (m, 1 H) 4.10-4.24 (m, 2 H) 3.82 (s, 3H) 1.94-2.20 (m, 4 H) 1.78-1.94 (m, 2 H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[CH3:21])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: Cc1ccccc1CCN
Product: COc1cc(CNCCc2ccccc2C)ccc1Oc1ccc(C(N)=O)cn1
Yield: 81.1 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-methylphenethylamine (0.0248 g, 0.184 mmol) gives the title compound (0.0584 g, 81.2%): TOF MS ES+ 392.2 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1966, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.5 min, 97.6% purity.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+].C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[S:10][C:9]=12
Reactant: OB(O)c1ccncc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccncc4)sc23)c(F)c1
Yield: 74.5 %

Procedure:
A mixture of the nitro compound 50 (890 mg, 2.41 mmol), pyridin-4-ylboronic acid (593 mg, 2 eq, 4.82 mmol), CsF (1.1 g, 3 eq, 7.23 mmol) and Pd(PPh3)4 (278 mg, 0.1 eq, 0.241 mmol) were suspended in DME (30 ml) and NaHCO3 (607 mg, 3 eq, 7.23 mmol), dissolved in the minimum amount of water, was added. The mixture was de-aerated by bubbling N2 through the solution for 10 min, heated to reflux for 4 hrs and concentrated to dryness. The formed residue was dissolved in DCM and washed with water. The DCM was collected, dried over sodium sulfate, filtered and the DCM was removed by evaporation. The resultant solid was triturated with Et2O to afford the title compound 63 (660 mg, 75% yield), which was used without further purification. MS (m/z): 368.0 (M+H).
Reaction SMILES: C(OC([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1C[CH2:50][O:49][CH2:48][CH2:47]1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:39][CH2:50][O:49][CH2:48][CH2:47]3)=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: C1COCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (249 mg) described in Example 769 and morpholine (42 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (60 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:5]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Cc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl [4-(aminomethyl)phenyl]acetate (1.00 g) in acetonitrile (15.0 mL) were added tert-butyl bromoacetate (0.668 mL) and triethylamine (0.693 mL), followed by stirring at room temperature for 4 hours. The reaction suspension was concentrated under reduced pressure, and then to the residue was added ethyl acetate. The organic layer was washed with 0.1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[4-(2-tert-butoxy-2-oxoethyl)benzyl]glycinate (747 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Product: CC(C)=CCCC(C)=CC=O

Procedure:
100 parts of 3-methyl-2-buten-1-ol is brought to refluxing temperature (140° C.) and 100 parts of 3,3-dimethylacrolein in which 2 parts of dibenzoyl peroxide has been dissolved is introduced in the course of one hour while stirring. The reaction mixture is then heated for another three hours at 140° C., while the water formed is continuously removed using pentane as entrainer. Working up gives 105 parts of citral. The yield is thus 86% of theory based on 3,3-dimethylacrolein at a conversion of 67%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@@H:18]([CH3:23])[CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:25].[ClH:25].[ClH:25].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@@H:18]([CH3:23])[CH2:17]2)[CH2:10][CH2:9]1
Reactant: C[C@H]1CN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1O
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 16 (3.07 g, 8.98 mmol) with 4M-HCl in dioxane (11.2 ml, 44.8 mmol) as described for amine 7.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([C:16]([F:19])([F:18])[F:17])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(O)(=O)C.O>C(O)C.[Zn]>[OH:1][CH:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]([O:20][Si:21]([CH2:24][CH3:25])([CH2:26][CH3:27])[CH2:22][CH3:23])([C:16]([F:18])([F:19])[F:17])[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)c2ccccc2C(=O)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)c2ccccc2C(O)c2ccccc21
Temperature: 110 °C
Yield: 58 %

Procedure:
A solution of 50 mg (0.13 mmol) of 9,10-dihydro-9-oxo-10-triethylsiloxy-10-trifluoromethylanthracene in 0.5 mL of absolute ethanol was treated successively with 42 mg (0.65 mmol) of zinc dust and 0.5 mL of a solution of 90% acetic acid - 20% water. The mixture was heated to reflux in a 110° C oil bath for 2 hours, allowed to cool to room temperature, and poured into 10 mL of water. The resulting aqueous mixture was extracted with three 5 mL portions of diethyl ether. Combination, drying, and concentration of the ether layers gave a residue which was purified by PTLC (one 1 mm silica gel plate eluted with 50% dichloromethane -50% petroleum ether) to give 34 mg of 87% pure (58% yield) 9,10-dihydro-9-hydroxy-10-triethysiloxy-10-trifluoromethylanthracene as a white solid: mass spectrum (70 eV) m/z (relative intensity) 363 (8, M-C2H5), 211 (100), 183 (21), 77 (25); TMS derivative 466 (M+), 368 (27), 246 (24), 196 (22), 193 (90), 165 (21), 105 (40), 87 (28), 77 (47), 73 (100), 59 (20), 45 (21).
Reaction SMILES: CCN(CCNC(C1C=CC(N)=C(Cl)C=1)=O)CC.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][C:21]=1[Cl:31].C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)=O>C1COCC1.CO.C(Cl)Cl>[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[Cl:31]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Agent: CCN(CC)CCNC(=O)c1ccc(N)c(Cl)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C=O
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 35 °C
Reaction time: 1 h

Procedure:
3-chloro-procainamide, free base, [N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide, free base] (1b). The acid (2), 10 g (0.058 moles) was dissolved in 800 mL of anhydrous THF. Carbonyl diimidazole, 11.1 g (0.067 moles), was added in one portion and the mixture was warmed to 35° C. CO2 began to slowly evolve and then increased rapidly. After one hour, all evolution of gas ceased and the mixture was warmed to 45° C. for fifteen minutes to insure that all of the acid had reacted. N,N′-diethylenediamine, 7.5 g (0.65 moles) was added dropwise over five minutes and then the reaction mixture was warmed to 55° C. After 30 minutes, a TLC of the mixture (CH2Cl2:MeOH, 3:1) showed that the reaction was complete, producing the desired product (Rf 0.4) along with a minor nonpolar impurity (Rf 0.8) and polar impurities (Rf 0.1). The TCL did not change after stirring overnight at 55° C. The solvent was removed on a rotary evaporator at 50° C. and then 100 mL of water was added to destroy any unreacted carbonyl diimidazole, producing a biphasic mixture. The free base was extracted into CH2Cl2 (3×100 mL), and dried over anhydrous K2CO3, and evaporated to give 20 g (>100%) of a brown oil. Attempts to prepare a crystalline salt (sulfate, succinate, tosylate, and adipate) failed. Simple chromatography on 25 g of silica, eluting with hexane:EtOAc (2:1) gave 14.3 g (91%) of 1b as clear tan oil, homogeneous by TLC. The structure of the free base (1b) is shown in FIG. 5. 1H NMR (CDCL3) d 7.75 (d, J=0.8 Hz, 1H, ArH), 7.52-7.48 (dd, J=0.8 Hz, 1H, ArH), 6.84 (bs, 1H, NH), 6.77-6.74 (d, J=2.8 Hz, 1H, ArH), 3.49-3.43 (q, 2H, J=1.8 Hz, CH2NHCO), 2.66-2.54 (m, 6H, (CH2)3N, 1.07-1.02 (t, J=2.4 Hz, 6H, N(CH2CH3)2). IR (KBr) cm−1, 3475, 3320 (NH2, m), 1620, 1600 (C═O, s). MS (El) m/e 269 (M+), 271 (M+2), 240 (M=−Et), 197 (M+−NEt2), 154 (M+−NCH2CH2NEt2), 86 (base peak, M+−CH2NEt2) Anal. Calc'd for C13H20N3—OCl: C, 57.88; H, 7.47; N, 15.58. Fd. C, 58.05; H, 7.56; N, 15.30.
Reaction SMILES: C(O)(=O)C.FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:30]3[C:25](=[C:26]([CH3:35])[C:27]([O:33][CH3:34])=[C:28]([CH3:32])[C:29]=3[CH3:31])[CH:24](O)[C:23]3([CH2:39][CH2:38][CH2:37]3)[CH2:22]2)=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O.CCCCCC.O.C(OC(=O)C)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:30]3[C:25](=[C:26]([CH3:35])[C:27]([O:33][CH3:34])=[C:28]([CH3:32])[C:29]=3[CH3:31])[CH2:24][C:23]3([CH2:39][CH2:38][CH2:37]3)[CH2:22]2)=[CH:17][CH:16]=1
Reactant: COc1c(C)c(C)c2c(c1C)C(O)C1(CCC1)CN2c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C)c(C)c2c(c1C)CC1(CCC1)CN2c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
To a 2 mL mixture of acetic acid and trifluoroacetic acid (1:1, v/v) cooled in ice bath, was added NaBH4 (71 mg) in portions, followed with 1′-(4-chlorophenyl)-6′-methoxy-5′,7′,8′-trimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol (65 mg) in THF (0.5 mL). After 20 min, the mixture was taken up by ethylacetate and water. After separation of the two phases, the aqueous phase was extracted with more ethylacetate, and the combined organic phases were washed with brine, dried and evaporated to yield a thick oil, which was passed through a silica column (EtOAc/Hexane: 0-5% in 30 min) to give 1′-(4-chlorophenyl)-6′-methoxy-5′,7′,8′-trimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (34.6 mg). 1H-NMR (300 MHz, CDCl3) δ=7.2-6.933 (d, 2H); 6.783-6.428 (d, 2H); 3.68 (s, 3H); 3.64 (s, 2H); 2.72 (s, 2H); 2.21 (s, 3H); 2.16 (s, 3H); 1.75 (s, 3H); 1.988-1.542 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=152.86, 150.26, 136.97, 129.12, 128.7, 128.11, 128.03, 126.65, 123.67, 119.89, 60.78, 60.39, 40.19, 38.65, 32.78, 15.92, 15.51, 13.02, 12.02 ppm.