Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.C([O-])([O-])=O.[K+].[K+].[SH:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>CC#N>[C:25]1([C:4]2[C:3]([CH2:2][S:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[C:12]([C:13]([NH:15][C@H:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH3:18])=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Sc1ccncc1
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(CSc2ccncc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 74.3 %

Procedure:
3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (150 mg, 0.33 mmol) was dissolved in CH3CN (2 mL) under N2 and to this, with stirring, was added K2CO3 (140 mg, 0.99 mmol), then 4-mercaptopyridine (40 mg, 0.36 mmol). The suspension was allowed to stir overnight; concentrated; diluted with EtOAc; washed with 0.5 N NaOH, then H2O; dried over Na2SO4; filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/CH2Cl2) to afford the desired product as oil (120 mg, 74% yield). 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.30 (s, 2H), 8.14 (d, J=8.4 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.76-7.69 (m, 1H), 7.62-7.49 (m, 3H), 7.43-7.37 (m, 3H), 7.35-7.28 (m, 2H), 7.25-7.19 (m, 3H), 6.80 (d, J=4.4 Hz, 2H), 6.37 (d, J=7.9 Hz, 1H), 5.21 (q, J=7.6 Hz, 1H), 4.36-4.23 (m, 2H), 2.08-1.82 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); HRMS m/z 490.1931, calcd 490.1953.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=1[OH:21].C(N(CC)CC)C>ClCCl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:21][C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[O:11][CH3:10])=[O:4]
Reactant: CC(C)CC(Br)C(=O)Cl
Reactant: COc1cc(C)cc(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1OC(=O)C(Br)CC(C)C
Reaction time: 20 h
Yield: 76.1 %

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][CH2:9][CH:10]([CH3:11])[CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CC(C)CNc1cc(Cl)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CC(C)CNc1cc(Cl)nc(N)[n+]1[O-]
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
34.70 g of 2-amino-4-isobutylamino-6-chloropyrimidine are dissolved in 250 ml of ethanol. 81.50 g of metachloroperbenzoic acid, in solution in 350 ml of ethanol, are added dropwise and while keeping the temperature of the reaction mixture at 20° C. After stirring for 2 h 30 min, the precipitate formed is filtered on sintered glass, washed with 100 ml of ethyl ether and then taken up in 100 ml of water. The pH is adjusted to 8 by addition of concentrated sodium hydroxide solution. After stirring for 1 hour, the precipitate is filtered on sintered glass, washed with 3×50 ml of water and dried under vacuum over phosphorus pentoxide at 50° C. 11.30 g of 2-amino-4-isobutylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:14]#[CH:15].CCN(CC)CC>C(#N)C.CCOC(C)=O.[Cu]I.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>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:15]#[C:14][CH2:13][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C#CCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1C#CCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
Dissolve 1-iodo-2-methoxy-4-nitro-benzene (618 mg, 2.21 mmol) in acetonitrile (10 mL) and treat sequentially with 1-prop-2-ynyl-pyrrolidine (352 mg, 3.22 mmol), Et3N (2 mL), CuI (77 mg, 0.404 mmol) and Pd(PPh3)4 (360 mg, 0.311 mmol). Stir the mixture at room temperature for 3 h, then dilute with EtOAc (50 mL) and wash with saturated NaHCO3 (30 mL). Dry, filter and concentrate the organic solution. Purify the crude material by flash chromatography, using a linear gradient of 50% EtOAc/hexanes to 100% EtOAc, to give the title compound as an orange oil (292 mg, 51%). MS (ES+) 261.1 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.77 (dd, 1H, J=8.3, 2.2 Hz), 7.70 (d, 1H, J=2.2 Hz), 7.50 (d, 1H, J=8.3 Hz), 3.95 (s, 3H), 3.72 (s, 2H), 2.75-2.70 (m, 4H), 1.87-1.83 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-])=O)[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[C:13]([NH2:18])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(F)c([N+](=O)[O-])c3)nc12
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(N4CCN(C)CC4)c(N)c3)nc12
Reaction time: 0.25 h

Procedure:
Crude 6-chloro-2-(4-fluoro-3-nitrophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine (Example 252) (333 mg) and 1-methylpiperazine (1.0 ml) were mixed and left at room temperature for 15 min, whereupon it was diluted with EtOAc (50 ml) and washed with water (100 ml). The aqueous phase was extracted with EtOAc (50 ml) and the combined organic phase was evaporated in vacuo. The yellow oily residue was dissolved in methanol (100 ml) and hydrogenated in a Parr apparatus (Raney nickel, 60 psi, 5 h). The catalyst was removed by filtration and the solvent removed in vacuo. The residue was purified by semi-preparative HPLC-C18 affording the product as a trifluoroacetate. The salt was dissolved in EtOAc (10 ml) and washed with aqueous 10% NaHCO3 solution (5 ml), brine (5 ml) and dried (MgSO4). Evaporation of the solvent yielded the product as an off-white powder (67 mg, 25%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[F:28][C:29]([F:35])([F:34])[S:30](Cl)(=[O:32])=[O:31]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:30]([C:29]([F:35])([F:34])[F:28])(=[O:32])=[O:31])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)C(F)(F)F)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and trifluoromethanesulfonyl chloride.
Reaction SMILES: Br.S([O-])(O)=O.[Na+].[CH2:7]([N:11]([CH2:35][CH2:36][CH2:37]O)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)=[S:13])[CH2:8][CH2:9][CH3:10]>O>[CH2:7]([N:11]1[CH2:35][CH2:36][CH2:37][S:13][C:12]1=[N:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN(CCCO)C(=S)Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCN1CCCSC1=Nc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Yield: 38 %

Procedure:
To 75 parts of a hydrobromic acid solution 48% in water was added a small amount of sodium hydrogen sulfite. Then there were added 1.7 parts of N-butyl-N-(3-hydroxypropyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea. The whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.6 parts (38%) of 4-[4-[4-[(3-butyltetrahydro-1,3-thiazin-2-ylidene)amino]phenyl]-1-piperazinyl]phenol; mp. 143.0° C. (45).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:45])([CH3:44])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH2:42])=[CH:31][CH:30]=2)[C:17]1=[O:43])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH3:53][N:54]=[C:55]=[O:56]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:45])([CH3:44])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:55]([NH:54][CH3:53])=[O:56])=[CH:33][CH:34]=2)[C:17]1=[O:43])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(F)ccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CN=C=O
Agent: O=C([O-])C(F)(F)F
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3cc(F)ccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Step G) and methyl isocyanate according to the procedure described in Example 35, Step I. 1H NMR (400 MHz, CDCl3): δ 1.44 (s, 3H), 1.45 (s, 3H), 1.78 (m, 1H), 1.85 (s, 1H), 2.30-2.60 (m,3H), 2.57 (d, 4 Hz, 3H), 4.18 (d, 5 Hz, 2H), 4.40 (m, 1H), 4.62 (m, 1H), 4.80 (m, 2H), 5.00 (s, 2H), 5.17 (d, 15 Hz, 1H), 540 (s, 1H), 6.85 (m, 1H), 6.96 (m, 1H), 7.08-7.35 (m, 13H), 7.39 (m, 1H). FAB-MS: calculated for C38H40FN5O5 665; found 666 (M+H, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]#[N:17])[S:15][C:8]=23)=[C:4]([F:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[C:32]([C:35](O)=[O:36])=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[C:16]([C:14]1[S:15][C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:18]=[CH:19][C:2]([NH:1][C:35]([C:32]3[C:33](=[O:34])[N:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[N:29]=[CH:30][CH:31]=3)=[O:36])=[CH:3][C:4]=2[F:20])[CH:13]=1)#[N:17]
Reactant: N#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Product: N#Cc1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Yield: 83 %

Procedure:
Prepared from 7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carbonitrile and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C) according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 73 mg (83%) of the desired product. LRMS (APCI pos) m/e 502.2 (M+1). 1H-NMR (400 MHz, CDCl3) δ 11.89 (s, 1H), 8.64 (d, 1H), 8.42 (d, 1H), 8.25 (d, 1H), 8.11 (s, 1H), 7.99 (dd, 1H), 7.60 (m, 2H), 7.43 (d, 1H), 7.27 (m, 3H), 7.67 (d, 1H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −111.3, −126.0.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:24]1[CH:25]=[CH:26][C:27]([OH:38])=[C:28]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=1)[CH3:23]>>[C:30]([C:28]1[CH:29]=[C:24]([CH2:22][CH3:23])[CH:25]=[CH:26][C:27]=1[O:38][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)(=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: CCc1ccc(Oc2cccc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(C(=O)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (5-ethyl-2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.220 g (50%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C31H28O5 481.2015, found 481.2032 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19]C(=O)C(C)(C)C)=[N:4][C:5]([NH:12]C(=O)C(C)(C)C)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+]>CO>[NH2:12][C:5]1[N:4]=[C:3]([NH2:19])[C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)nc1N
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a colorless solution of methyl 5-chloro-2,6-bis[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 1, Step 2, 153.9 g, 416 mmol) in methanol (1.5 L) was added a solution of potassium tert-butoxide (185 g, 1.65 mol) in methanol (500 mL) dropwise during the period of 20 min at room temperature under nitrogen atmosphere. Dissolving potassium tert-butoxide in methanol was exothermic, so potassium tert-butoxide must be added portionwise from powder addition funnel to methanol during the period of 2 h with ice-cold water bath. After the addition was completed, the reaction solution was stirred at reflux temperature for 1 h under nitrogen atmosphere, and cooled to room temperature. The resulting suspension was evaporated and ca. 1.3 L of methanol was removed (ca. 700 mL of methanol was remained). To this mixture was added water (1.2 L) and stirred at room temperature for 1 h with water bath (internal temperature was maintained at 20° C.), then the resulting suspension was filtered through paper filter and the pale yellow solid was dried under reduced pressure at 50° C. for 12 h to give 74.3 g (368.9 mmol, 89%) of the title compound as a pale yellow crystal.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:20][O:21]S(C)(=O)=O)(COS(C)(=O)=O)[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:10]1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.[Na+].[Cl-].C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([O:8][C@H:9]1[C@@H:10]2[O:21][CH2:20][C@@H:13]1[O:12][C@H:11]2[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OS(=O)(=O)C(F)(F)F)[C@H]1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H]2CO[C@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
Pure 62 (100 mg, 0.128 mmol) was dissolved in THF (7 ml), cooled to 0° C. and added 1 M LiOH (1.3 ml, 10 equiv.). The reaction mixture was allowed to slowly reach r.t. When LCMS confirmed full conversion of 62 to 63, the reaction was neutralized with 1 M HCl satd. with NaCl (1.3 ml), diluted with DCM (20 ml) and brine (10 ml). Layers were separated and the aqueous layer was extracted with DCM (2×20 ml). Comb. organic layers were dried (Na2SO4), filtered and the solvent removed in vacuo to afford a clear oil (63)2 (quantitative yield). Rf=0.49 (Eluent: EtOAc). ESI-MS m/z found 552.2 ([M1-1]+, calcd 552.1); 1H-NMR (CDCl3, 400 MHz): 8.64 (1H, s, N—H), 8.44 (1H, s, Adenin), 7.95 (2H, d, J=7.1 Hz, Bz), 7.50 (1H, t, J=7.3 Hz, Bz), 7.40 (1H, t, J=7.3 Hz, Bz), 7.07-6.79 (5H, m, OBn), 6.11 (1H, s, H-1′), 4.66 (1H, d, J=11.5 Hz, CH2), 4.61 (1H, d, J=11.5 Hz, CH2), 4.48 (1H, d, J=1.8 Hz, H-2′/H-3′), 4.30 (1H, d, J=11.9 Hz, CH2), 4.12 (1H, d, J=11.9 Hz, CH2), 4.07 (1H, d, J=1.8 Hz, H-3′/H-2′), 4.02 (1H, d, J=8.6 Hz, CH2), 3.94 (1H, d, J=8.6 Hz, CH2), 3.02 (3H, s, OMs); 13C-NMR (CDCl3, 100 MHz): δ 165.31, 152.03, 150.45, 148.54, 141.99, 135.38, 132.90, 132.84, 128.63, 128.37, 128.26, 127.98, 127.88, 121.34, 87.90, 86.16, 79.84, 76.29, 73.45, 72.51, 67.76, 64.47, 37.48 (OMs). 2Compound 63 is also described in JACS 124, p. 2164-2176 (2002) but not as an isolated product.
Reaction SMILES: O1C2C=CC=CC=2OC[C@@H]1CN1CCC[C@@](CO)(C)C1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][CH:22]1[CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][C:34]([CH3:45])([CH2:38][O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:33]1>>[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][C@@H:22]1[CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][C@:34]([CH3:45])([CH2:38][O:39][CH2:40][C:41]([F:43])([F:42])[F:44])[CH2:33]1
Reactant: CC1(COCC(F)(F)F)CCCN(CC2COc3ccccc3O2)C1
Agent: C[C@]1(CO)CCCN(C[C@H]2COc3ccccc3O2)C1
Product: C[C@]1(COCC(F)(F)F)CCCN(C[C@H]2COc3ccccc3O2)C1

Procedure:
Prepared from {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol as described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-(2,2,2-trifluoroethoxymethyl)piperidine.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C)C=O.O>[CH:11]1([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(O)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OC2CCCC2)cc1
Reaction time: 0.33 h

Procedure:
Sodium hydride (50% in oil; 4.8 g) was added in portions to a solution of 4-aminophenol (10.9 g) in dimethylformamide (150 ml). After 20 minutes, cyclopentyl bromide (14.9 g) was added dropwise. After 2 hours at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 3:1). The product with the molecular weight of 177.25 (C11H15NO); MS (ESI): 178 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.N1C(C)=CC=CC=1C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:23][CH2:22][C@@H:21]([OH:24])[CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C@H:3]([OH:27])[CH2:2][Cl:1])=[CH:11][CH:10]=2)([CH3:14])[CH3:13])=[CH:26][CH:25]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)OC[C@@H](O)COc1ccc(C(C)(C)c2ccc(OC[C@H](O)CCl)cc2)cc1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (1000 mg, 2.53 mmol) in anhydrous dichloromethane (8.0 mL) at −78° C. were successively added 2,6-lutidine (590 μL, 5.06 mmol) and acetic chloride (144 μL, 2.02 mmol) dropwise. After 1 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to provide the title compound (300 mg, 27%) as a sticky solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CC[O-].[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>CCO>[C:18]([CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)#[N:19]
Reactant: N#CCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCCOc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 126.8 %

Procedure:
4-Hydroxybenzaldehyde (20 mmol) was dissolved in absolute EtOH (150 mL) and treated with solid NaOEt (24 mmol). After stirring for 15 minutes, 4-bromobutyronitrile (24 mmol) was added and reaction mixture was heated overnight at 90° C. in an oil bath. After letting the reaction cool to room temperature, volatiles were removed, the residue was taken up in ice, adjusted to pH 6 with 1N sulfuric acid, and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO4 and concentrated. Chromatography over silica gel (eluant, 5% EtOAc in hexanes) gave the 4-(3-cyanopropoxy)benzaldehyde (4.8 g, 58%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]Cl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1F
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Oc2ccccc2F)cc1
Temperature: 120 °C
Yield: 66.4 %

Procedure:
Mix under argon atmosphere 4-bromobenzonitrile (2.0 g, 11.3 mmol), 2-fluorophenol (2.5 g, 22.6 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (203 mg, 1.1 mmol), and cesium carbonate (7.4 g, 22.6 mmol) in anhydrous NMP (19 mL). Degas the flask, fill with argon and add copper(I) chloride (554 mg, 5.6 mmol) quickly. Degas the flask then fill with argon and heat at 120° C. for 3 h. Cool to ambient temperature, dilute with EtOAc, filter and wash the filtrate sequentially with 2M aqueous HCl, 0.3M aqueous HCl, 2M aqueous NaOH and brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate (1.6 g, 66%). MS (ES+) m/z: 231 (M+NH4)+.