Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[F:15]C12CC3CC(CC(N)(C3)C1)C2>>[F:1][C:2]12[CH2:11][CH:6]3[CH2:7][C:8]([F:15])([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC12CC3CC(C1)CC(F)(C3)C2
Reactant: O=C(O)C12CC3CC(CC(F)(C3)C1)C2
Product: O=C(O)C12CC3CC(F)(CC(F)(C3)C1)C2

Procedure:
The procedure of Example 2 for the conversion of 3-fluoroadamantane-1-carboxylic acid to 3-fluoroadamantan-1ylamine was utilized. 4.32 g (20 mmol) of 3,5-difluoroadamantane-1-carboxylic acid provided after 96 hours crude product which was chromatographed on silica gel using 4:1 hexane:EtOAc to afford 4.7 g (73%) of benzyl carbamate: mp 71.9-72.9° C.; 1H NMR (CDCl3) 1.80-1.90 (7H, m), 2.02-2.25 (6H, m) 2.40-2.50 (1H, m), 4.84 (1H, bs),5.04 (2H, bs), 7.30-7.40 (5H, m); 13C NMR (CDCl3) 29.07, 38.98, 40.15, 45.54, 47.16, 54.25, 66.37, 92.24 (188.67), 128.09, 128.17, 128.52, 128.56, 136.26, 154.18. Anal. Calc'd for C18H2NO2F2 : C, 67.27; H, 6.59; N, 4.36; F, 11.82; Found: C, 66.96; H, 6.54; N, 4.33; F, 11.71. Hydrogenation (HOAc/Pd/C/50 PSI) of 7.84 g (24.4 mmol) of this intermediate for a period of 5 hours provided 7.8 g (>100%) of 3, 5-difluoro-adamantan-1ylamine as its acetate salt.
Reaction SMILES: [C:1]1([C:8]([OH:10])=O)([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C1COCC1.C(OCC)(=O)C>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:8]([C:1]2([C:5]([OH:7])=[O:6])[CH2:2][CH2:3][CH2:4]2)=[O:10])=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)O)CCC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a mixture of cyclobutane-1,1-dicarboxylic acid (10.0 g, 69.4 mmol, 1.0 eq.) in anhydrous THF (100 mL) under nitrogen was added dropwise triethylamine (7.02 g, 69.4 mmol, 1.0 eq.) with stirring for 30 minutes at 0° C., followed by the addition of thionyl chloride (8.25 g, 69.4 mmol, 1.0 eq.) with stirring for another 30 minutes at 0° C. To the resulting mixture under nitrogen was added dropwise a solution of 4-fluoroaniline (8.48 g, 76.3 mmol, 1.1 eq.) in anhydrous THF (50 mL) with stirring for 1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetate and extracted with 2N NaOH. The aqueous phase was titrated with 2N HCl to pH 1-2 and then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated in vacuo to give 1-(4-fluoro-phenylcarbamoyl)-cyclobutanecarboxylic acid as a light pink solid (5.75 g, 34.9%). 1H NMR (400 MHz, CDCl3 w/1 drop CD3OD): 7.53-7.48 (m, 2H), 7.06-7.00 (m, 2H), 2.81-2.63 (m, 4H), 2.14-2.02 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+]>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:12]([CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:13]
Reactant: [C-]#N
Reactant: ClCc1cccc2nnsc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CCc1cccc2nnsc12
Reaction time: 8 h

Procedure:
18.4 g of 7-chloromethylbenzo-1,2,3-thiadiazole are dissolved in 50 ml of chloroform, 0.5 g of tetrabutylammonium iodide are added, the mixture is heated to 50°-55° C. and treated dropwise in the course of 0.5 hours with a solution of 5.6 g of sodium cyanide in 20 ml of water, with stirring. Heating is continued overnight at the same temperature, on the following day the mixture is cooled, treated with water and extracted several times using dichloromethane. The extracts are washed with water, dried over sodium sulfate and filtered over Hyflo, and the filtrate is evaporated. The residue is purified on silica gel (hexane/ethyl acetate) resulting in the title compound of m.p. 78°-80° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:20])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N+:17]([C:13]1[CH:12]=[C:11]([C:8]2[NH:7][C:6](=[O:20])[C:5]([CH:2]([NH:1][C:26]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: CCC(N)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Reactant: O=C(Cl)C1CCCC1
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 3.0 g (10.9 mmol) 6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one, 2.2 g (16.3 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([NH:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22](O)([CH3:24])[CH3:23])[CH3:18])(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:9]([NH:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])([CH3:23])[CH3:24])[CH3:18])(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCC(=O)NC(C)CCCC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCC(=O)NC(C)CCCC(C)(C)c1ccc(O)cc1O
Reaction time: 0.5 h

Procedure:
11.0 Parts of resorcinol, 12.2 parts of 2-hexanoylamino-6-hydroxy-6-methyl-heptane and 0.5 parts of p-toluene sulphonic acid are sealed for 4 days in a glass Carius tube. The reaction mixture is then poured into 500 parts of water and stirred for 30 minutes on a steam-bath. After removing the water by decantation, the above washing procedure is repeated twice again before taking up the residual oil in ether. The ether solution is then dried and stripped down under reduced pressure (16 mb) on a rotary evaporator at 100° C. to give 2-hexanoylamino-6-(2,4-dihydroxyphenyl)-6-methylheptane as an amber oil with the following percentage composition by weight
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][CH2:8][N:9]([CH3:10])[C:4]=2[CH:3]=1.[N:13]([O-])=O.[Na+]>C(O)(=O)C>[CH3:10][N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([NH2:13])=[CH:3][C:4]1=2
Reactant: CN1CCOc2ccc(I)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCOc2ccc(N)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine [S12-5]. To solution of S12-4 (2.1 g, 12.8 mmol) in 50 mL of acetic acid cooled in ice bath was added NaNO2 (1.77 g, 26.9 mmol) slowly in portions. The resulting mixture was stirred at 0° C. for 10 min and was added KI (4.24 g, 38.4 mmol) in portions. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm up to rt and stirred for 2 h. The resulting mixture was quenched with 100 mL of water, extracted with ethyl acetate (3×150 mL). The organic layer was combined, treated with Na2S2O3, washed with brine, dried over MgSO4 and purified by flash chromatography to give S12-5 (1.86 g, 53%) as a yellow solid. 1H NMR (CDCl3, 500 MHz) δ 6.64 (d, J=8.3 Hz, 1H), 6.56 (s, 1H), 6.48 (d, J=8.4 Hz, 1H), 4.25 (m, 2H), 3.24 (m, 2H), 2.85 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 138.1, 126.6, 120.5, 117.6, 111.9, 83.7, 64.8, 48.7, 36.5.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH:59][C:8](=[O:10])[CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[S:56][C:46]=2[C:47]([N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[N:48][CH:49]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12

Procedure:
From tetrahydropyran-4-yl-acetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 393 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCCN1CCCC1
Reactant: CN(C)CC1(c2cccc(O)c2)CCOCC1
Product: CN(C)CC1(c2cccc(OCCCN3CCCC3)c2)CCOCC1

Procedure:
Alkylation of 3-[4-(dimethylamino)methyltetrahydro-2H-pyran-4-yl]phenol (0.1 g, 0.425 mmol) with 1-(3-chloropropyl)pyrrolidine (0.125 g, 0.85 mmol) according to general procedure B gave the desired compound after purification by flash chromatography (0.030 g, 20%). 1H NMR (400 MHz, CDCl3) δ7.27-7.18 (m, 1H), 6.92-6.84 (m, 2H), 6.75 (dd, 1H), 4.05 (t, 2H), 3.8-3.7 (m, 2H), 3.55 (t, 2H), 2.65 (t, 2H), 2.6-2.5 (m, 4H), 2.4 (s, 2H), 2.15-1.85 (m, 6H), 2.0 (s, 6H), 1.85-1.75 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[O:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(CC3CCNCC3)oc2c1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(Br)cc4o3)CC2)nc1
Temperature: 90 °C
Yield: 83.7 %

Procedure:
A mixture of 6-bromo-2-(piperidin-4-ylmethyl)benzo[d]oxazole (0.13 g, 0.440 mmol), 2-chloro-5-propylpyrimidine (0.083 g, 0.529 mmol), and K2CO3 (0.122 g, 0.881 mmol) in DMF (4.4 mL) was heated in 90° C. oil bath for 12 h. It was cooled to rt, quenched with H2O (5 mL), and extracted with EtOAc-Et2O (3×4 mL, 1:1 v/v). The combined organic layers were washed with H2O (3×4 mL) and brine (4 mL). The solvent was evaporated to afford crude product, which was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0-60% EtOAc) to afford the desired product as a colorless oil (153 mg, 83% yield). 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 2H), 7.66 (d, J=1.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 1.8 Hz, 1H), 4.73 (d, J=13.4 Hz, 2H), 3.04-2.77 (m, 4H), 2.48-2.32 (m, 2H), 2.24 (s, 1H), 1.85 (d, J=12.6 Hz, 2H), 1.67-1.49 (m, 2H), 1.37 (ddd, J=25.0, 12.4, 4.2 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H). LCMS (m/z)=415 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8](O)=[O:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[OH:57][C@@H:58]([CH3:62])[CH2:59][O:60][NH-:61]>C1COCC1>[OH:57][C@@H:58]([CH3:62])[CH2:59][O:60][NH:61][C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:9]
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Reactant: C[C@H](O)CO[NH-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
A suspension of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (100 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol), DIPEA (0.06 mL, 0.34 mmol) and (S)-2-hydroxy-propoxy-amide hydrochloride (44 mg, 0.34 mmol) in THF (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (5 mL) and 1M HCl, the organic layer was isolated and washed with saturated aqueous NaHCO3 (2×5 mL) and brine (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was subjected to reverse-phase preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (13 mg, 8%). LCMS (method A): RT=8.13 min, [M+H]+=489. 1H NMR (DMSO-d6): 11.51 (1 H, broad), 8.95 (1 H, broad), 8.25 (1 H, s), 7.60 (1 H, s), 7.55 (1 H, d, J=10.7 Hz), 7.27 (1 H, d, J=8.4 Hz), 6.82 (1 H, d, J=11.1 Hz), 6.32 (1 H, t, J=8.8 Hz), 4.66 (1 H, broad), 3.64 (1 H, m), 3.43 (2 H, d, J=5.8 Hz), 0.94 (3 H, d, J=6.3 Hz).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Yield: 57.1 %

Procedure:
1.46 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 15 ml of toluene, and 0.35 g of concentrated aqueous sulfuric acid solution was added thereto. The resulting mixture was refluxed for 15 minutes with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 1.15 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =4.2 : 1) were obtained (purity: 68.0%). The yield was 57.1%. Percent recovery of the starting material was 32.0%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.N1C=CC=CC=1>C1COCC1>[N:15]1([S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.5 %

Procedure:
To a mixture of 5-chlorosulfonyl-2-oxindole (5 g, 21.6 mmol) and indoline (2.9 mL, 26 mmol) in THF (20 mL) was added pyridine (3.4 g, 43 mmol). After stirring at room temperature for one day, the precipitate was collected by filtration, washed with water in ethanol (20%), dried, washed with 60 mL of hot ethanol and dried under vacuum to give 7.5 g (over 100%) of 5-(2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][NH:18][OH:19].[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C.[OH-].[Li+]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][N:18]([OH:19])[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CNO)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(=O)N(O)Cc1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 43.4 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxybenzenemethanamine (1.00 g, 3.4 mmol) is reacted with acetyl chloride (0.58 g, 7.4 mmol), triethylamine (1.0 g, 10.1 mmol), and lithium hydroxide (0.40 g, 16.8 mmol) according to the procedure of Example 48 to give 0.5 g (43% yield) of N-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide; mp 155°-156° C.
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][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:44](=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) in dry tetrahydrofuran (20 ml) was treated with triethylamine (0.1 ml, 0.72 mmol) and the mixture heated gently until all components had dissolved. The solution was then cooled to room temperature, treated with a solution of benzoyl chloride (28 mg, 0.20 mmol) in dry tetrahydrofuran (2 ml) and the mixture stirred for 1.5 hr. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5), to give the product which was then triturated with a mixture of diethyl ether and pentane, filtered off and dried to afford the title compound as a solid (80 mg). MS: 595 (MH+).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(C(C)=O)C(C)C>[CH3:5][C:4](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: CC(CC(C)C)=NNC(=O)c1ccccc1
Temperature: 5 °C

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a Dean-Stark type reflux condenser and a stirrer was charged with 68.0 g (0.5 mol) of benzohydrazide and 600 ml of methyl isobutyl ketone and then heated under reflux for 5 hours. The reaction liquid was cooled down to 5° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Cl:13][CH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:13][CH2:14][CH2:15][C@@H:16]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[C:3]1=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)N([C@H](CCCl)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To a mixture of 3,3-dimethyloxindole (409 mg, 2.53 mmol), (S)-3-chloro-1-phenyl-1-propanol (376 mg, 2.20 mmol) and triphenylphosphine (664 mg, 2.53 mmol) in tetrahydrofuran (5 mL) under nitrogen was added slowly diisopropyl azodicarboxylate (490 μL, 2.53 mmol) via a syringe. The resulting solution was stirred at room temperature overnight. Solvent was removed under reduced pressure and the viscous brown liquid residue was purified using Isco CombiFlash Companion chromatography (RediSep 12-g silica column, 0-12% ethyl acetate/hexane) to give 236 mg (34%) of 1-[(1R)-3-chloro-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a viscous colorless liquid. MS (ES) m/z 314.1 ([M+H]+); HRMS: calculated for C19H20ClNO+H+, 314.1306; found (ESI, [M+H]+), 314.1299.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](OC)([O:10]C)[CH2:8][CH2:7][O:6][CH2:5]1)[CH3:2].Cl>C1COCC1.O.CCOC(C)=O>[CH2:1]([O:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][O:6][CH2:5]1)[CH3:2]
Reactant: CCOC1COCCC1(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC1COCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 3-ethoxy-4,4-dimethoxytetrahydro-2H-pyran (2.1 g, 11 mmol) in THF/water (50 mL/10 mL) was added concentrated HCl (6 mL). After being stirred at room temperature for 1 h, the mixture was diluted with EtOAc. The organic layer was separated and the aqueous layer was extracted with ether five times. The combined organic layers were dried over MgSO4, filtered and concentrated to give 1.55 g (97%) of the desired product 1H NMR (CDCl3) δ 4.30-3.50 (7H, m), 2.62-2.57 (2H, m), 1.30-1.20 (3H, t, J=5 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: OCCCCl
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCO)CC1

Procedure:
1-(3-Hydroxypropyl)-4-piperidone is prepared from 4-piperidone and 3-chloro-1-propanol essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: O[C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[N:7]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OCc1nc(O)c2c3c(sc2n1)CCCC3
Product: CC(=O)OCc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 85 %

Procedure:
The acetic acid 4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (4 g, 0.014 mol) in 20 ml of POCl3 was refluxed for 2 h. The excess of POCl3 was distilled off; the reaction mixture was quenched with ice, and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with bicarbonate solution, dried over anhydrous sodium sulphate, concentrated and dried to give acetic acid 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (3.5 g, 85%) as brown solid. 1H NMR (400 MHz, CDCl3): δ 1.85-1.95 (m, 4H), 2.20 (s, 3H), 2.84-2.90 (m, 2H), 3.04-3.10 (m, 2H), 5.30 (s, 2H); LC-MS: [M+H]=297.2 & 299.1 m/z.
Reaction SMILES: S(Cl)([Cl:3])=O.N[C@H](C(O)=O)[C@@H](C)O.[ClH:13].[CH3:14][O:15][C:16](=[O:22])[C@H:17]([C@@H:19]([CH3:21])O)[NH2:18]>CO>[ClH:3].[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH2:18])[CH:19]([Cl:13])[CH3:21]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)C(C)Cl

Procedure:
Using thionyl chloride and methanol, threonine was derivatized into threonine methyl ester hydrochloride, which was then treated with thionyl chloride to give α-amino-β-chlorobutyric acid methyl ester hydrochloride. This was then converted to α-amino-β-chloropropionic acid hydrochloride by hydrolyzing with hydrochloric acid. The α-amino-β-chloropropionic acid hydrochloride was crystallized and isolated by the same technique as mentioned in Example 8.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C1(C)C=CC(S(O[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)=CC=1.[I-].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[Cl:9][C:5]1[C:6]([O:8][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 100 °C
Yield: 99.7 %

Procedure:
A round-bottomed flask (50 cc) equipped with a mechanical stirrer was charged with 5-amino-2-chloro-4-fluorophenol (1.02 g, 6.29 mmol), cyclopentyl p-toluenesulfonate (1.56 g, 6.50 mmol), tetrabutylammonium bromide (242 mg, 0.75 mmol) and potassium iodide (262 mg, 1.57 mmol) to prepare a solution in toluene (20 mL). Subsequently, 40% sodium hydroxide in aqueous solution (20 mL) was added slowly and the mixture was stirred under heating at 100° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (10 mL) was added, followed by extraction with ethyl acetate (20 mL×3). The organic layers were combined, washed with water (10 mL) and saturated brine (10 mL) and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline (1.44 g, 6.27 mmol; yield=99.6%).