Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])=[O:34])=[CH:28][CH:27]=1
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)Nc1ccc(F)cc1
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.15 mmol) and triethylamine (0.01 mmol) in anhydrous dichloromethane was added 1-fluoro-4-isocyanatobenzene (0.14 mmol) at ambient temperature. The mixture was stirred for 16 h, diluted with of dichloromethane (5.00 mL), washed with 10% HCl solution and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (0.05 g) in 82% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.35-7.25 (m, 3H), 7.19 (d, 1H), 7.11 (d, 1H), 7.06-6.91 (m, 3H), 6.67 (s, 1H), 6.52 (t, 1H), 5.94-5.84 (ABq, 2H), 4.74 (d, 1H), 4.61 (d, 1H), 3.91-3.69 (m, 2H), 3.49-3.34 (m, 2H); MS (ES+) m/z 462 (M+1), 484 (M+23).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH3:22])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH3:22])=[O:19]
Reactant: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 98 (0.17 g, 0.56 mmol) and 5% Pd/C (0.2 g) in methanol (15 mL) was hydrogenated at 10 psi for 1 h. The mixture was filtered through Celite pad and concentrated to provide (2S,5R)-6-hydroxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 99 (0.12 g, quant. yield) as a white foam.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]1[CH:10]2[CH2:11][C:12]3([NH2:15])[CH2:14][CH:8]([CH2:9]2)[CH2:7][CH:6]1[CH2:13]3.[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:20]=2[O:19][CH2:18][CH2:17]1>O>[C:12]12([NH:15][C:26]([C:25]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[O:27])[CH2:14][CH:8]3[CH2:9][CH:10]([CH2:5][CH:6]([CH2:7]3)[CH2:13]1)[CH2:11]2
Reactant: O=C(Cl)c1cccc2c1OCCO2
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cccc2c1OCCO2
Yield: 25.7 %

Procedure:
200 ml of chloroform and 37.5 g of adamantamine were introduced into a balloon flask provided with an agitator and a thermometer, and then 50 g of 1,4-benzodioxane-5-carbonyl chloride was added in portions at a temperature of from 5°-10° C. After agitation at ambient temperature 1500 ml of water was added and then chloroform was removed under vacuum. The base which was precipitated by ammonia was extracted by means of methylene chloride. After removal of the solvent the residue was dissolved in hydrochloric ethanol. The crystals formed by cooling were dried off, washed and then dried. 20 g of N-(1-adamantyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 137° C.; yield: 25%).
Reaction SMILES: [K+].[Br-].CO[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:25]2[NH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH2:16][CH2:15][NH:14]1.[CH3:26][O:27]C1C=C(C2C3NC4C(=CC=CC=4)C=3CCN2)C=CC=1OC.COC1C=C(OC)C=CC=1C1C2NC3C(=CC=CC=3)C=2CCN1>>[CH3:26][O:27][C:10]1[CH:5]=[C:6]([CH:13]2[C:25]3[NH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[CH2:16][CH2:15][NH:14]2)[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1OC
Reactant: COc1ccc(OC)c(C2NCCc3c2[nH]c2ccccc32)c1
Agent: COc1ccc(C2NCCc3c2[nH]c2ccccc32)c(OC)c1
Agent: [Br-]
Agent: [K+]
Product: COc1cc(OC)cc(C2NCCc3c2[nH]c2ccccc32)c1

Procedure:
Pale yellow solid; C19H20N2O2; IR (KBr) v max 3420, 2910, 1605, 1465, 1350, 1305, 1155, 1065, 845, 785 cm−1; 1H-NMR (CDCl3) δ 5.03 (1H, s, H-1), 3.11(1H, m, H-3a), 3.35 (1H, m, H-3b), 2.91 (2H, m, H-4), 7.15 (3H, overlap, H-5,6,7), 7.56 (1H, d, J=7 Hz, H-8), 8.13 (1H, s, H-9), 6.47 (2H, d, J=2.1 Hz, H-2′,6′), 6.44 (1H, d, J=2.1 Hz, H-4′), 3.71 (6H, s, OMe); 13C-NMR (CDCl3) δ 58.3 (d, C-1), 43.0 (t, C-3), 22.3 (t, C-4), 109.8 (s, C-4a), 127.3 (s, C-4b), 121.6 (d, C-5), 119.2 (d, C-6), 118.1 (d, C-7), 110.8 (d, C-8), 144.1 (s, C-8a), 135.8 (s, C-9a), 134.2 (s, C-1′), 106.5 (d, C-2′,6′), 161.1 (s, C-3′,5′), 100.0 (d, C-4′), 55.3 (q, OMe); EIMS m/z 308 (100, M+), 307 (64), 279 (38), 278 (37), 264 (11), 249 (17), 248 (30), 233 (10), 220 (9), 217 (9), 204 (21), 191 (10), 171 (85), 154 (13), 144 (17), 130 (10), 115 (16), 102 (13), 95 (9), 77 (10).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: Sc1ccc(Cl)cc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccc(SC2CCCCO2)c(Br)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of 2-bromo-4-chlorothiophenol (3.74 g, 16.8 mmol), p-toluene sulfonic acid (0.427 g, 1.7 mmol) and 3,4-dihydro-2-H-pyran (0.985 ml, 16.8 mmol) in CH2Cl2 (30 mL) was stirred at 23° C. for 18 hours. After the addition of NaOH, the organic phase was separated, dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellow oil, (4.91 g, 95%) 1H NMR (CDCl3) δ7.6-7.5 (m, 2H), 7.35-7.2 (m, 1H), 5.37 (t, J=4.5 Hz, SCHO, 1H), 4.25-4.1 (m, CH2O, 1H), 3.7-3.55 (m, CH2O, 1H), 2.2-2.05 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.6 (m, 3H): IR 1566, 1542, 1450, 1367, 1257, 1188, 1101, 1037, 1024, 1008, 867, 809, 783 cm−1; Anal. Calcd. for C11H12BrClOS: C, 42.95; H, 3.93. Found: C,43.15; H, 3.91.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)=[O:2].[OH:11]O>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)([OH:11])=[O:2]
Reactant: OO
Reactant: O=Cc1ccc(CO)cn1
Solvent: O
Product: O=C(O)c1ccc(CO)cn1
Yield: 97 %

Procedure:
2-Formyl-5-hydroxymethylpyridine (5.7 g, 0.042 mol) was dissolved in 40 mL of H2O and treated with 10 mL of aqueous 30% H2O2 at room temperature for 16 h. The mixture was concentrated to about 20 mL and cooled, and the precipitated acid was collected by filtration. 2-Carboxy-5-hydroxymethylpyridine was obtained in 97% yield (6.1 g). A portion was recrystallized from H2O to obtain an analytical sample. These white crystals sublimed at about 220° C., IR (mull) 3200, 1670, 1600, 1380, 1070, 870, 850, 800 cm-1 ; 1H NMR (Me2SO-d6) δ4.73 (s, 2, CH2OH), 7.9-8.2 (m, 2, 3', 4'--H), 8.67 (m, 1, 6'--H); MS calcd for C7H7NO3 153.0426, found 153.0429.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.O1CCOCC1>C(Cl)Cl>[ClH:20].[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:33][CH3:34])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[F:21])[CH2:25]1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1

Procedure:
A mixture of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (14 mg, 0.028 mmol) in methylene chloride (0.2 mL) was treated with 4.0 M hydrogen chloride in dioxane (0.2 mL, 0.8 mmol) at room temperature for 1 hour and then the solvent removed to give 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine HCl salt. To a mixture of the crude HCl salt in acetonitrile (0.1 mL)/methanol (0.1 mL)/tetrahydrofuran (0.1 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), followed by acetone (0.050 mL, 0.68 mmol). The mixture was stirred for 30 minutes before the addition of sodium triacetoxyborohydride (0.030 g, 0.14 mmol). The reaction was stirred at room temperature overnight, then quenched and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product as TFA salt. The product was isolated as a racemic mixture. LCMS calculated for C21H27ClFN6O (M+H)+: m/z=433.2; Found: 433.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:4]=1.[CH:38]([N:41]([CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][NH:44][C:45](N1C=CN=C1)=[O:46])([CH3:40])[CH3:39]>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH2:22][NH:21][C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:45]([NH:44][CH2:43][CH2:42][N:41]([CH:52]([CH3:54])[CH3:53])[CH:38]([CH3:39])[CH3:40])=[O:46])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[CH:25][CH:26]=1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: Cc1ccc(C(CNc2nc(CN)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(CNc2nc(CNC(=O)NCCN(C(C)C)C(C)C)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from (2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(4-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 60) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) using a similar procedure to that used in Example 36.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:1][C:2]3[O:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Sc1nc2ccccc2o1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4o3)C(=O)O)cc2)cc1

Procedure:
Example 27 is prepared from 2-mercaptobenzoxazole and 1d using the procedure described for compound 20.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2)[CH3:20]
Reactant: CCOC(=O)c1cc(O)c2[nH]ncc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c2[nH]ncc2c1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
To a solution of ethyl 7-hydroxy-1H-indazole-5-carboxylate (918 mg, 4.45 mmol) in DMF (35 mL) at 0° C. was added 60% oil dispersion of NaH (178 mg, 4.45 mmol). The mixture was aged for 1 hour at 0° C. before dropwise addition of a solution of iodoethane (694 mg, 0.36 mL, 4.45 mmol) in DMF (15 mL). The mixture was aged at 0° C. for several hours before removal of the ice bath. The reaction was allowed to warm to room temperature and aged overnight. The mixture was diluted with EtOAc, washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered concentrated. Purify by silica gel chromatography (40 g column) eluting with 0-30% EtOAc/hexanes gradient to afford ethyl 7-ethoxy-1H-indazole-5-carboxylate (400 mg, 38%).
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][C:42]23[CH2:52][CH:51]2[CH2:50][C:45]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:44][CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][C:42]34[CH2:52][CH:51]3[CH2:50][C:45]3([O:46][CH2:47][CH2:48][O:49]3)[CH2:44][CH2:43]4)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCC4(CC2C3)OCCO4)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC4(CC2C3)OCCO4)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate of tert-butyl 5-chloro-2-fluoro-4-(spiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate, the title compound was obtained as a colorless solid (1.30 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=8.3 Hz, 1H), 6.42 (d, J=12.7 Hz, 1H), 3.95-3.86 (m, 4H), 3.84-3.70 (m, 2H), 2.22-1.98 (m, 4H), 1.82-1.72 (m, 2H), 1.64-1.57 (m, 2H), 1.56 (s, 9H), 1.49-1.35 (m, 2H), 1.11-1.04 (m, 1H), 0.80-0.75 (m, 11H), 0.65-0.60 (m, 1H), 0.56 (t, J=5.3 Hz, 1H); MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][C@@H:10](I)[C@@H:9]2[CH2:13][C@H:6]1[C:7](=[O:14])[O:8]2)=[O:4].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][C@@H:9]2[CH2:13][C@H:6]1[C:7](=[O:14])[O:8]2)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](I)[C@@H]2C[C@H]1C(=O)O2
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of compound 2 (1.24 g, 1.0 eq.) in toluene (12 mL) was added tris(trimethylsilyl)silane (1.48 mL, 1.2 eq.) with stirring, followed addition of 1,1′-azobis(cyclohexanecarbonitrile) (AIBN) (98 mg, 0.1 eq.). The reaction mixture was stirred at 90° C. for 1.5 hrs. The solution was cooled down to room temperature, quenched with 5% citric acid solution, and extracted with EtOAc (50 mL). Organics were washed sequentially with H2O (30 mL), saturated NaHCO3 aqueous solution (30 mL), and brine (30 mL), and concentrated under reduced pressure to yield a colourless oil. Crude material was purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 3 as white crystals in 71% yield. 1H NMR (CDCl3, 400 MHz) δ 1.68-1.73 (m, 4H), 2.05-2.18 (m, 2H), 2.82-2.85 (m, 2H), 3.60 (s, 3H), 4.71 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:17][CH:16]=1>>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:19][CH:20]=2)[N:4]=1
Reactant: N#CCCCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCCC#N)cc1

Procedure:
According to the method described for Reference Example 45, 4-chloromethyl-2-(furan-2-yl)-5-methyloxazole was allowed to react with 4-(4hydroxyphenyl)butyronitrile to give 4-[4-[2-(furan-2yl)-5-methyl-4-oxazolylmethoxy]phenyl]butyronitrile as an oily product. NMR(δ ppm in CDCl3): 1.85-2.05(2H,m), 2.31(2H,t,J=7Hz), 2.42(3H,s), 2.72(2H,t,J=7.5Hz), 4.97(2H,s), 6.52(1H,dd,J=3.5&2Hz), 6.9-7.0(3H,m), 7.10(2H,d,J=9Hz), 7.53(1H,dd,J=2&1Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12](OC)=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:11])[CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)alaninate (1-3, 0.774 g, 3.341 mmol) was treated with DIBAL (6.682 mL, 6.682 mmol) in anhydrous THF (100 mL) at −78° C. The resulting solution was warmed to 25° C. while stirring over 1 h. The resulting solution was treated with a saturated aqueous solution of NH4Cl (1.0 mL) and ether (300 mL) then allowed to stir 30 min. MgSO4 was added and stirred for 20 min then reaction mixture was filtered. The filtrate was concentrated under vacuum to yield 2-[(3-chloro-4-fluorophenyl)amino]propan-1-ol (1-4). 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 6.94 (dd, J=8.8, 8.8 Hz, 1H), 6.67 (dd, J=6.1, 3.0 Hz, 1H), 6.49 (dd, J=8.8, 5.8, 3.0 Hz, 1H), 3.74 (m, 1H), 3.55 (m, 2H), 1.19 (d, J=6.1 Hz, 3 H). MS 204.2 found, 204.6 (M+H+) required.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:38])=[C:11]2[C:16](=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[N:18]=1)[N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:31])[C:13]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:12]2)=[O:8].[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:24]([N:15]1[C:16]2[C:11](=[C:10]([OH:38])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-propionic acid methyl ester (28 mg, 0.052 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 11 mg of the title compound. MS: (+) m/z 527.33 (M+1).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[CH3:19][C:20]1([C:35](OCC)=[O:36])[CH2:25][CH2:24][CH2:23][N:22]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:21]1>C(Cl)Cl>[CH:1]1([NH:7][C:35]([C:20]2([CH3:19])[CH2:25][CH2:24][CH2:23][N:22]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:21]2)=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(C)CCCN(S(=O)(=O)c2ccccc2)C1
Reactant: NC1CCCCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C(=O)NC2CCCCC2)CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
At r.t., to a solution of cyclohexanamine (19.1 mg, 0.19 mmol) in methylene chloride (0.1 mL) was added 2.0 M of trimethylaluminum in toluene (96 ul, 0.19 mmol). After stirring for 30 min, to the solution was added a solution of ethyl 3-methyl-1-(phenylsulfonyl)piperidine-3-carboxylate (35 mg, 0.11 mmol) in methylene chloride (0.1 mL). The mixture was stirred at r.t for 10 min, then, at 40° C. overnight. After cooling to r.t., the mixture was purified with combi-flash. The product was further purified with prep. HPLC. 1.3 mg final product was obtained. Yield: 3.2%. LCMS: m/z 365.1 (M+H)+; 751.3 (2M+Na)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([S:27][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Reactant: Sc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cnc(Sc2cccc(Cl)c2)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (167 mg), 3-chlorobenzenethiol (98 mg), cesium carbonate (221 mg), and N,N-dimethyl formamide (2 mL) was stirred at room temperature for 15 hours, and then at 70° C. for 10 hours. To the reaction liquid was added ethyl acetate (30 mL), followed by washing with saturated brine (20 mL) and a saturated aqueous ammonium chloride solution (20 mL) in this order, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate) to obtain 4-({2-[(3-chlorophenyl)sulfanyl]-4-(trifluoromethyl)pyrimidin-5-yl}carbonyl)morpholine (183 mg) as a colorless solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:60]=[CH:59][C:11]([C:12]([O:27][CH2:28][C@@:29]2([CH:51]=[CH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58])[O:33][C@@H:32]([N:34]3[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[CH2:31][C@@H:30]2[O:43][SiH2:44][C:45]([CH3:50])([CH3:49])[CH:46]([CH3:48])[CH3:47])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([O:27][CH2:28][C@@:29]2([CH:51]=[CH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][S:2]([CH3:1])(=[O:4])=[O:3])[O:33][C@@H:32]([N:34]3[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[CH2:31][C@@H:30]2[O:43][SiH2:44][C:45]([CH3:49])([CH3:50])[CH:46]([CH3:47])[CH3:48])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]2[CH:59]=[CH:60][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCOS(C)(=O)=O)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Methanesulfonyl chloride (96 μL, 1.22 mmole) was added dropwise to Compound (4) (250 mg, 0.32 mmole) in dry pyridine (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 hours and the reaction was quenched by the dropwise addition of methanol (1.5 mL). The yellow solution was poured into water (20 mL) and the layers were separated. The organic phase was washed with brine (20 mL), dried over magnesium sulfate and concentrated to a white solid (0.41 g) under reducedpressure. (Routinely, this crude material was used directly in the next step). The crude product (0.41 g) was purified by column chromatography onsilica gel using ethyl acetate/hexane mixtures for elution. 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-methanesulfonyloxy-1-hepten-1-yl)-thymidine (241 mg, 87.5%) was obtained as a white solid. Recrystallization from hexane/dichloromethane gave a sample with m.p. 72°-75° C.