Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])[C:38]2=[N:47][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:52][CH2:51][C:16]([CH3:53])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:50])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:49])=[CH:28][C:29]=2[C:30]2[CH:48]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:43][CH:44]([CH3:45])[CH3:46])[C:38]2=[N:47][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:53])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:50])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:49])=[CH:28][C:29]=2[C:30]2[CH:48]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:51][CH2:52]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CNC(C)C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1CNC(C)C)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 47.7 %

Procedure:
Prepared in 47.7% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-{[(propan-2-yl)amino]methyl}-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.94 (s, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.21 (d, J=9.2 Hz, 1H), 7.12 (d, J=5.9 Hz, 2H), 5.72 (br. s., 1H), 4.55 (br. s., 1H), 4.43 (d, J=12.5 Hz, 1H), 4.32 (d, J=11.7 Hz, 1H), 3.79 (br. s., 1H), 3.52-3.31 (m, 6H), 2.63 (d, J=8.4 Hz, 1H), 2.42 (s, 3H), 1.91-1.54 (m, 10H), 1.42 (d, J=5.5 Hz, 3H), 1.30 (d, J=6.2 Hz, 3H), 1.16 (s, 3H), 1.13 (s, 9H), 0.97 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 715.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH:4]([CH3:16])[CH:3]1[CH3:17].C[OH:20]>>[CH:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:13])[C:5]([CH3:15])([CH3:14])[CH:4]([CH3:16])[CH:3]([CH3:17])[C:2]2([CH3:18])[CH3:1])=[O:20]
Reactant: CO
Reactant: Cc1cc2c(cc1C)C(C)(C)C(C)C(C)C2(C)C
Product: Cc1cc2c(cc1C=O)C(C)(C)C(C)C(C)C2(C)C
Temperature: 50 °C

Procedure:
To prepare the corresponding 6-carboxaldehyde, 16 portions of Ce(NH4)2 (NO3)6 (16×16.0 g=256.0 g) in methanol (16×100 ml) is added to a solution of 1,1,2,3,4,4,6,7-octamethyl-1,2,3,4-tetrahydronaphthalene (16.0 g) in methanol (700 ml), over 8 hrs, while maintaining the temperature at 50° C. After about 1/2 of the methanol is evaporated, the resulting product is extracted with petroleum ether 30° C.-50° C./saturated NaCl. After crystallizing in ethanol, treating the mother liquors and recrystallizing, the desired 6-carboxaldehyde, 6-formyl-1,1,2,3,4,4,7-heptamethyl-1,2,3,4-tetrahydronaphthalene is obtained.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[OH:39][CH:37]([CH3:38])[CH2:36][NH:35][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CC(O)CN
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCC(C)O)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19 60 mg, 0.105 mmol) and 1-amino-propan-2-ol using a similar method to that employed in Example 48 (16 mg).
Reaction SMILES: [C:1]([C:3]1([CH2:18][CH2:19]Br)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[ClH:21].[CH:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][NH:23]2.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)(C)C.C(OCC)C>[ClH:21].[C:1]([C:3]1([CH2:18][CH2:19][N:23]2[CH2:24][CH:25]3[CH2:28][CH2:29][CH:22]2[CH2:27][CH2:26]3)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2]
Reactant: N#CC1(CCBr)c2ccccc2CCc2ccccc21
Reactant: C1CC2CCC1CN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: N#CC1(CCN2CC3CCC2CC3)c2ccccc2CCc2ccccc21

Procedure:
A mixture of 6.5 parts 5-cyano-5-(2-bromoethyl)10,11-dihydro-5H-dibenzo[a,d]cycloheptene, 4.0 parts 2-azabicyclo[2.2.2]octane hydrochloride and 4.0 parts potassium carbonate in 88 parts N,N-dimethylsulfoxide and 20 parts water is heated at reflux for about 4 hours. After cooling, the reaction mixture is diluted with water, resulting in the formation of an oil. The water layer is decanted and the oil dissolved in ethyl ether. The ethereal solution is washed twice with water, once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The solvent is removed to give an oil which is treated with a solution of hydrogen chloride in isopropanol. Addition of ethyl ether results in a precipitate that is separated, washed with ether and dried to afford-5-cyano-5[2-(2-azabicyclo[2.2.2]oct-2-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride. This compound is represented by the following structural formula. ##STR14##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Li]CCCC.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:7]([NH:9][CH3:10])=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CNC(=O)c1ccc(OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(OC)cc1C(O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a −78 C solution of 4-methoxy-N-methylbenzamide (2.0 g) in THF was added n-BuLi (10 mL, 2.5 M in hexanes). The reaction was stirred for 10 min at −78° C., warmed to 0 C, then cooled back to −78 C. 3-fluorobenzaldehyde (1.90 mL) was added as a solution in THF via cannula. The reaction was warmed to room temp, then quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, concentrated, and purified by flash chromatography (5% MeOH in CH2Cl2) to give 2-[(3-fluorophenyl) (hydroxy)methyl]-4-methoxy-N-methylbenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33]C)=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:35])[CH2:11][C@H:10]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([O:48][CH3:49])=[CH:40][N:39]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]([O:48][CH3:49])=[CH:40][N:39]=3)[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([OH:33])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:35])[CH2:11][C@H:10]1[CH3:36])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cnc(F)c2ccccc12
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: CC(C)(C)[O-]
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Solvent: CS(C)=O
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Reaction time: 4 h

Procedure:
To a mixture of (2R,6S,7R,13aS,14aR,16aS,Z)-methyl 6-((tert-butoxycarbonyl)amino)-2-hydroxy-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (152 mg, 0.3 mmol),1-fluoro-4-methoxyisoquinoline (128 mg, 0.720 mmol), and t-BuOK (168 mg, 1.500 mmol) was added DMSO (5 mL) and then sonicated for 15 min. The resulting solution was stirred for 4 h. The reaction was quenched with water, acidified with 6 N HCl, extracted with EtOAc, washed with brine, dried over MgSO4. After concentration, the residue (2R,6S,7R,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-2-((4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid was obtained as a solid (150 mg) that will be used as it is. LC/MS: MS m/z (M+H)+ 651.23.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m/e: 456.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc(CC(=O)Nc2ccc(Cl)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCNc2ccc(Cl)cc2)c1

Procedure:
22.1 g of N-(4-chlorophenyl)-3-methoxyphenylacetamide are reduced with lithium aluminum hydride in THF. After destroying the reagent with water, filtering, drying and evaporating in a rotary evaporator, the oily residue is taken up in diethyl ether, and the desired product is precipitated as the hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N:23](C)[CH3:24])[CH:19]=3)[C:14]2=[O:26])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][CH3:24])[CH:19]=3)[C:14]2=[O:26])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)OCc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CNc1ccc2c(c1)CCN(c1cccc(Br)c1COC(C)=O)C2=O
Reaction time: 4 h
Yield: 47.7 %

Procedure:
To a solution of acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (224 mg, 0.482 mmol) in 5 mL 1,4-dioxane was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (109 mg, 0.48 mmol). After stirring for 4 hours, this was partitioned between ethylacetate and 1M aq. NaOH. The organic layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 40 to 50% ethylacetate/hexanes) to yield acetic acid 2-bromo-6-(6-methylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (93 mg, 0.23 mmol). MS (ESI) 404.8 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:17][NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21]>>[CH:1]1([C:6]2[C:15]3[C:10](=[C:11]([CH2:17][NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(NCO)C(Cl)Cl
Reactant: c1ccc2c(C3CCCC3)nccc2c1
Product: O=C(NCc1cccc2c(C3CCCC3)nccc12)C(Cl)Cl

Procedure:
1-Cyclopentylisoquinoline (obtained from 1-cyano-2-benzoyl-1,2-dihydroisoquinoline and cyclopentyl bromide) and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to obtain 1-cyclopentyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 151.0° to 152.3° C. The product was successively reacted in the same way as in steps (c), (d), (e), and (f) of Example 18 to afford 1-cyclopentylisoquinoline-5-acetonitrile having a melting point of 99.4° to 100.0° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cnc2ccc(O)cc2c1
Temperature: 140 °C
Yield: 97.1 %

Procedure:
6-Methoxyquinoline-3-carboxylic acid (0.75 g, 3.69 mmol) was placed in a 20 mL microwave vial fitted with a stirbar. The solid was suspended in acetic acid (7 mL) and hydrobromic acid (48% in water, 3.5 mL) was added. The vial was capped and the suspension was carefully heated under microwave irradiation at 140° C. for 1 h. After reaction, the vial was thoroughly cooled to room temperature and very carefully vented with an 18 g needle in a fume hood prior to opening. The solids were collected by filtration and washed with ethyl acetate to afford the title product as a solid (0.678 g, 91%). LC-MS: (FA) ES+ 190; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.68 (br s, 1H), 9.26 (d, J=1.9 Hz, 1H), 9.14 (d, J=1.3 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.62 (dd, J=9.1, 2.7 Hz, 1H), 7.52 (d, J=2.7 Hz, 1H).
Reaction SMILES: ClCCl.[C:4]([OH:12])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.O[C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1>O.C(OCC)C>[C:5]1([C:4]([O:12][C@H:30]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29]2)=[O:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a dichloromethane (100 mL) solution of benzoic acid (4.03 g, 33.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.4 g, 54.0 mmol) was added tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5.62 g, 30.0 mmol). The reaction mixture was stirred for 6 hours at room temperature, diluted with water (200 mL) and charged with diethyl ether (200 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. This crude product was used in the subsequent step without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH:40]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH3:41])[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH:40]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH3:41])[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)ncn1)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)O)c2)ncn1)c1cccc(C(F)(F)F)c1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(4-(piperidin-1-yl)-2-(6-(1-(3-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)phenylcarbamoyl)benzylthio)-propanoate (90 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (4 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at 30° C. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 46.1 mg (55%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.78 (s, 1H), 7.71 (m, 4H), 7.53 (m, 6H), 7.27 (m, 2H), 6.93 (s, 1H), 5.40 (s, 1H), 3.92 (s, 2H), 3.48 (m, 4H), 2.61 (m, 4H), 1.59 (m, 10H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([NH:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[N:16]=1.[N:29]([C@@H:32]1[C@@H:36]([CH2:37][OH:38])[O:35][C@@H:34](N2C=C(C)C(=O)NC2=O)[CH2:33]1)=[N+:30]=[N-:31]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:34]2[O:35][C@H:36]([CH2:37][OH:38])[C@@H:32]([N:29]=[N+:30]=[N-:31])[CH2:33]2)=[C:17]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Nc1nc(NCC2CC2)c2nc[nH]c2n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C
Yield: 85.8 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-(cyclopropylmethylamino)-9H-purine (0.204 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase (Example 2b) with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Six days later, 0.204 g, 0.8 mmol, of 2-amino-6-cyclopropylmethylpurine was added to the reaction. Twenty-one days after the reaction was started, another 0.204 g, 0.8 mmol, of 2-amino-6-cyclopropylpurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. The reaction was stopped after thirty-three days by heating to 80° C. to precipitate the enzyme. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered and the solvent was removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (97:3, v/v). The product containing fractions were combined and the solvent was removed in vacuo to give the product as a foam 0.237 g, 29% yield. mp=104°-106° C.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2c(C(C)O)oc(=O)c3ccccc23)cn1
Solvent: ClCCl
Product: COc1ccc(-c2c(C(C)Br)oc(=O)c3ccccc23)cn1
Yield: 38.5 %

Procedure:
1M PBr3 in DCM (1.80 mL, 1.80 mmol) was added 3-(1-hydroxyethyl)-4-(6-methoxypyridin-3-yl)-1H-isochromen-1-one (intermediate B17, 225 mg, 0.76 mmol) in DCM (9 ml) at RT. The reaction mixture was straightforward purified on Biotage SNAP 25 g silica cartridge with a gradient of hexane and EtOAc to give the title compound (105 mg, 38.5%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[NH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[N:21]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]nc2c(Br)cccn12
Reactant: C=Cc1ccc2ccccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=c1n(CCc2ccc3ccccc3n2)nc2c(Br)cccn12
Temperature: 160 °C
Yield: 55.6 %

Procedure:
2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 1-5 (250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP (3 mL). To the mixture was added catalytic powdered KOH (13 mg, 0.234 mmol), and the vial was capped and heated at 160° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 20-100% EtOAc/hexanes. The fractions containing the desired product (1-6) were pooled, and after solvent removal in vacuo, 240 mg (52%) of a fluffy yellow solid were obtained. 1H NMR (300 MHz, CHCl3-d) δ 8.07 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.77 (app t, J=8.0 Hz, 2H), 7.68 (t, J=7.7 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.38-7.30 (m, 2H), 6.39 (dd, J=7.2, 6.7 Hz, 1H), 4.61 (t, J=7.6 Hz, 2H), 3.57 (t, J=7.6 Hz, 2H); HRMS (ES) 369.0345 (M+H) found, 369.0349 required.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH:32](B1OC(C)(C)C(C)(C)O1)=[CH2:33].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:32]=[CH2:33])=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(I)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)cc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(4-iodo-3-methyl phenoxy)-2-propylbenzene (265 mg, 0.471 mmol) was dissolved in N,N-dimethylformamide (4.7 mL) and water (0.9 mL). The resultant mixture was sequentially added with vinylboronic acid pinacol ester (280 μL, 1.65 mmol), tetrakis triphenylphosphine palladium (54 mg, 0.0471 mmol), and sodium carbonate (300 mg, 2.83 mmol), and stirred at 80° C. for 1 hour. After completion of the reaction, the reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/chloroform), and 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(3-methyl-4-vinylphenoxy)-2-propylbenzene (218 mg, yield >100%) was obtained as a yellow oil.