Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](C#CCCOC(C3CCCCO3)=O)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][C@H:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:40][CH:39]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCCC#CC1CCC(COc2ccc(F)cc2)O1)C1CCCCO1
Reactant: O=S(=O)(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S)(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4H), 3.85-5.0 (m, 4H), 6.70-7.05 (m, 4H), 7.45-7.72 (m, 3H), 7.77-8.0 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:9]1(/[CH:14]=[C:15](\I)/[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1(/[CH:14]=[C:15](\[C:2]2[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=2)/[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Fc1ccc(Br)cn1
Reactant: COC(=O)/C(I)=C/C1CCCC1
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(F)nc1

Procedure:
Reaction of 5-bromo-2-fluoropyridine (1.50 g, 8.5 mmol) with (Z)-methyl 3-cyclopentyl-2-iodoacrylate (2.60 g, 9.3 mmol), according to the cross-coupling conditions described above in Step 2 of Preparation 9, gave (E)-methyl 3-cyclopentyl-2-(6-fluoropyridin-3-yl)acrylate: m/z (ES+)=250.1 [M+H]+. Step 2: A solution of this α,β-unsaturated ester (1.50 g, 6.0 mmol) in EtOAc was treated with a suspension of Pd (10% on C, 300 mg, 0.3 mmol) in EtOH (0.5 mL). The reaction was stirred under a H2 atmosphere for 4 d and then filtered through Celite. The solvents were removed under reduced pressure, then the residue was purified by column chromatography to give methyl 3-cyclopentyl-2-(6-fluoropyridin-3-yl)propionate: m/z (ES+)=252.2 [M+H]+. Step 3: A solution of this ester (1.48 g, 5.9 mmol) and LiOH.H2O (0.49 g, 11.8 mmol) in THF-H2O (5:1, 24 mL) was stirred at 20° C. for 18 h. The THF was removed in vacuo, then the remainder was partitioned between saturated aqueous Na2CO3 (150 mL) and Et2O (75 mL). The pH of the aqueous layer was adjusted to 3 with 2M HCl. The remainder was extracted with EtOAc (100 mL+75 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES+)=238.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[NH2:6].[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[C:3]([CH:4]=1)[CH2:2][NH:1][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 3-(aminomethyl)-4-(ethylsulfonyl)aniline (1.1 g, 5.1 mmol) in DMF (5 mL) and TEA (2.75 mL) was added benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.4 g, 5.7 mmol) in DCM (15 mL). The solution was stirred for 18 h before quenching with water (25 mL). The reaction mixture was extracted with DCM (2×30 mL), washed with brine and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 28A (1.0 g, 59%) as an oil. MS (ESI) m/z 349.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[C:25]([F:44])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[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])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[C:25]([F:44])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-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: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Yield: 58 %

Procedure:
Prepared in 58% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-19-fluoro-4,22,28-trimethyl-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 8.09 (s, 1H), 7.99-7.95 (m, 2H), 7.56 (t, J=7.7 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.31 (s, 1H), 7.30-7.26 (m, 2H), 7.22-7.16 (m, 1H), 5.94 (br. s., 1H), 4.31 (br. s., 1H), 3.99-3.89 (m, 1H), 3.57 (t, J=11.4 Hz, 1H), 3.49-3.39 (m, 2H), 3.07 (d, J=9.5 Hz, 1H), 2.75-2.70 (m, 1H), 2.41 (s, 3H), 1.98-1.53 (m, 10H), 1.22 (s, 3H), 1.19 (s, 9H), 0.77 (d, J=6.2 Hz, 3H); LCMS (ESI, M): 643.3.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>>[C:19]([C:18]1[CH:22]=[CH:23][C:15]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][CH:17]=1)(=[O:20])[NH2:21]
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: NC(=O)c1ccc(F)cc1
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(C(N)=O)cc1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzamide instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]1[CH2:19][O:18]1>C(#N)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:10][N:11]([CH2:19][C@H:17]([OH:18])[C:16]([F:21])([F:20])[F:15])[CH2:12][CH2:13][O:14]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Clc1cc(Cl)cc(C2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Solvent: CC#N
Product: O[C@@H](CN1CCOC(c2cc(Cl)cc(Cl)c2)C1)C(F)(F)F
Reaction time: 72 h
Yield: 98.1 %

Procedure:
2-(3,5-Dichlorophenyl)morpholine oxalate (1 g) from Chem-Impex was added to 5% aq NaOH and dichloromethane and extracted (3×100 mL dichloromethane). Combined extracts were dried over Na2SO4, filtered and concentrated to afford 728 mg of 2-(3,5-dichlorophenyl)morpholine as the free-base. In a 100 mL round-bottom flask, 2-(3,5-dichlorophenyl)morpholine (728 mg, 3.14 mmol) and (S)-2-(trifluoromethyl)oxirane (527 mg, 4.7 mmol) were combined with acetonitrile (10.0 ml) to give a yellow solution. Stirring was continued at room temperature for 3 days. Reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 20% EtOAc in hexanes) to afford (2S)-3-(2-(3,5-dichlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (1.06 g, 98%) as a colorless oil. (M+H)+=344, 346 m/e. Used as is.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: Cc1csc(S(=O)(=O)Cc2cc(Cl)nc(Cl)n2)n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1csc(S(=O)(=O)Cc2cc(N3CCOC[C@@H]3C)nc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a cooled (ice/water bath) solution of 2,4-dichloro-6-[(4-methyl-1,3-thiazol-2-yl)sulfonylmethyl]pyrimidine (901 mg, 2.78 mmol) in DCM (12 mL) was added triethylamine (0.45 mL, 3.23 mmol). The resulting solution was treated dropwise, over 3 minutes, with a solution of (3S)-3-methylmorpholine (319 mg, 3.15 mmol) in DCM (2.5 mL). The reaction mixture was stirred, under nitrogen for 24 hours, allowing reaction to warm to RT. Water (20 mL) was added to reaction mixture and stirred for 15 minutes. The organic layer was then separated, dried (MgSO4) and evaporated to give crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material (615 mg).
Reaction SMILES: [O:1]=[C:2]1[C:5]([O:6][CH:7]([CH3:9])[CH3:8])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:14]=[C:13]3[CH2:29][CH2:30][CH2:31][O:32][Si](C(C)C)(C(C)C)C(C)C)[C:3]1=[O:43]>C(#N)C>[O:1]=[C:2]1[C:5]([O:6][CH:7]([CH3:9])[CH3:8])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([Si:19]([CH:20]([CH3:22])[CH3:21])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])[CH:14]=[C:13]3[CH2:29][CH2:30][CH2:31][OH:32])[C:3]1=[O:43]
Reactant: CC(C)Oc1c(-c2ccc3c(c2)c(CCCO[Si](C(C)C)(C(C)C)C(C)C)cn3[Si](C(C)C)(C(C)C)C(C)C)c(=O)c1=O
Solvent: CC#N
Product: CC(C)Oc1c(-c2ccc3c(c2)c(CCCO)cn3[Si](C(C)C)(C(C)C)C(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 5-[1,2-dioxo-4-(1-methylethoxy)-3-cyclobuten-3-yl]-3-(3-triisopropylsiloxypropyl)-1-triisopropylsilylindole (11) (0.315 g, 0.50 mmol) in 5 mL of acetonitrile was added 48% HF (10% in MeCN, 0.35 mL, 1.0 mmol) and the mixture was stirred at room temperature for 30 min. The reaction was then quenched with 10% aqueous Na2CO3, ethyl acetate was added and the mixture was washed (10% aq. Na2CO3, brine), dried (Na2SO4) and evaporated to give a yellow gum. Flash chromatography (SiO2 /hexane-ethyl acetate, 1:1) of this gum afforded the title compound (0.209 g, 89%) as a yellow foam: IR (neat) 3480 (br), 1782, 1735, 1585, 1390 cm- ; 1H NMR (CDCl3, 200 MHz) δ 8.43 (d, J=1.4 Hz, 1H), 7.82 (dd, J=8.7, 1.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.10 (s, 1H), 5.64 (hept, J=6.2 Hz, 1H), 3.74 (t, J=6.4 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.09-1.95 (m, 2H), 1.69 (hept, J=7.5 Hz, 3H), 1.57 (d, J=6.2 Hz, 6H), 1.14 (d, J=7.5 Hz, 18H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[K+].[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20](S)[C:19]=3[CH:26]=[CH:27][CH:28]=2>C(O)C>[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:19]=3[CH:26]=[CH:27][CH:28]=2
Reactant: NCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCn1ccnc1)=N2
Reaction time: 18 h

Procedure:
A mixture of 4.2 g of 4-(1H-imidazol-l-yl)butanamine dihydrochloride in 75 ml of ethanol was treated with 2.2 g of potassium hydroxide and stirred for 18 hours. A 5.2 g portion of 6-bromo-benz(cd)indole-2-thiol and 6.4 g of mercuric acetate were added and the reaction proceeded as described in Example 1, giving 3.7 g of the desired product, mp 145° C.-147° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:38][CH2:39][N:40]=[C:41]=[O:42].CC([O-])(C)C.[Na+].C(O)=O>C1COCC1>[CH3:2][CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:24]([N:25]4[CH2:38][CH2:39][NH:40][C:41]4=[O:42])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3]
Reactant: O=C=NCCCl
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(N)cc3)CC2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(N4CCNC4=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)aniline (82 mg, 0.221 mmol) in THF (2.5 ml) at room temperature under nitrogen was added DIPEA (0.155 ml, 0.885 mmol), followed by 2-chloroethyl isocyanate (0.038 ml, 0.443 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and NaOtBu (2M solution in THF) (0.443 ml, 0.885 mmol) was added dropwise. The ice bath was removed and the mixture was stirred for 30 minutes at room temperature. The mixture was quenched with formic acid (0.068 ml, 1.771 mmol) and then concentrated under reduced pressure. The residue was dissolved in DMF and filtered. The residue in DMF was then purified by RP HPLC on a Gilson, SunFire-5C18 OBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes, hold at 100% for 1 minute, at 20 ml/min flow rate. The fractions containing product were combined, frozen and then lyophilized from MeCN/water to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:4]=2[O:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(N(CCCC)CCCC)CCC>CN(C)C1C=CN=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:6]2[C:5]3[CH:9]=[CH:10][C:11]([N:13]([S:18]([CH3:21])(=[O:19])=[O:20])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:4]=3[O:3][C:2]([CH3:22])([CH3:1])[C:7]2=[O:8])=[CH:26][CH:25]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2NC1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Temperature: 20 °C
Reaction time: 26 h
Yield: 95.4 %

Procedure:
N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-(methylsulfonyl)methanesulfonamide (7.50 g), 4-fluorophenylboronic acid (5.27 g), 4-dimethylaminopyridine (0.53 g), tributylamine (3.20 g) and copper(II) acetate monohydrate (0.43 g) were added to dimethylsulfoxide (56 mL), and the mixture was stirred at 20° C. for 26 hours under blowing air (7 to 10 mL/min) thereto. The reaction mixture was added dropwise to a mixed solution of dimethylsulfoxide/concentrated hydrochloric acid/water (19 mL/4.5 g/34 mL) at about 15° C., and washed with dimethylsulfoxide (7.5 mL). The mixture was stirred at 10° C. for 3 hours, then the precipitated crystals were successively washed with dimethylsulfoxide/water (12 mL/3 mL) and water (75 mL), and then dried to obtain the title compound (9.09 g) as white crystals (yield: 95%, purity: 92%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:4](Cl)[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(CC3CCOC3)c2n1
Reactant: C1COCCN1
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1

Procedure:
2,6-Dichloro-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (41 g) was dissolved in ethanol (200 ml) followed by the addition of morpholine (20 ml) and the resulting mixture was heated to reflux for 2 hours. The solvent was evaporated under reduced pressure, the residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 5:5 to 2:8 to 0:10) to give the title compound (41 g) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29](OCC)=[O:30])[C:11]1=[O:34].[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[O:35]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:30])[C:11]1=[O:34]
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1 H), 8.55 (s, 1 H), 7.85 (s, 1 H), 7.23 (m, 2 H), 6.99 (t, J=8.7 Hz, 2 H), 4.37 (t, J=7.2 Hz, 2 H), 4.10 (s, 2 H), 3.64 (q, J=5.2 Hz, 2 H), 3.58 (m, 2 H), 3.43-3.35 (m, 4 H), 3.41 (s, 3 H), 2.95 (t, J=6.1 Hz, 2 H), 2.17 (m, 2 H), 1.57 (m, 2 H); MS m/z 533 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20]OS(C4C=CC(C)=CC=4)(=O)=O)[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH2:33].[OH-].[Na+]>>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:33][CH3:32])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(S(=O)(=O)c4ccccc4)cc3O2)cc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 100 °C

Procedure:
A solution of toluene-4-sulfonic acid (R)-7-benzenesulfonyl-chroman-2-ylmethyl ester (274 mg, 0.6 mmol) and MeNH2 (2M in THF, 5 mL) was heated at 100° C. under microwave conditions for 6 hours. MeNH2 (40% in water, 2 mL) was then added and the mixture was heated at 100° C. under microwave conditions overnight. NaOH (10%) was added and the mixture was extracted 3 times with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography to afford the desired product (172 mg). The product was recrystallized from DCM affording 8 mg ((R)-7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine with 79% ee and from the evaporation of the mother liquors were recovered an additional 164 mg. Recrystallation from ethanolic HCl yielded the corresponding hydrochloride salt, Mp 271.8-273.0° C.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH2:11])[CH:3]=[CH:2]1.C1C2C(C3CC2CC3N)CC=1>CO.[Pd]>[CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH2:11])[CH2:3][CH2:2]1
Reactant: NC1CC2CC1C1C=CCC21
Agent: [Pd]
Agent: NC1CC2CC1C1CC=CC21
Solvent: CO
Product: NC1CC2CC1C1CCCC21

Procedure:
3.3 g of a mixture of 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-ylamine and 3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-ylamine (example Amine 1, a2) were dissolved in 30 ml of methanol and reduced under an atmosphere of hydrogen in the presence of 0.5 g Pd/C (10%). After 4 hours the catalyst was filtered off and washed with methanol. The filtrate was concentrated in vaccuo to give 3 g of the desired product as an oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(#N)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating and NaOH (0.28 g) was added. The mixture was stirred at about 60EC for 1 h, cooled to room temperature, heated again to about 75EC for 2 h, then cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.07 g (34.9%) of fluvastatin sodium crystal Form I.