Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[C:4]([CH2:13][OH:14])[CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[C:4]([CH:13]=[O:14])[CH:3]=1
Reactant: O=C1COc2c(F)cc(CO)cc2N1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cc(F)c2c(c1)NC(=O)CO2
Reaction time: 8 h

Procedure:
Intermediate 23 was reacted to form 8-fluoro-6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one in an analogous manner to intermediate 3. 1H NMR (DMSO-d6) δ 4.34 (s, 2H), 4.59 (s, 2H), 6.66 (s, 1H), 6.74 (s, 1H), 6.7 (s, 1H), 10.86 (bs, 1H). To a solution of 8-fluoro-6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one (4.75 g, 24.09 mmol) in dichloromethane (250 mL) at room temperature was added 4-methylmorpholine-N-oxide (4.23 g, 36.1 mmol), TPAP (tetraproplyammonium perruthenate) (0.042 g, 1.2 mmol), and 4A molecular sieves (0.500 g). The reaction was stirred for overnight. The reaction mixture was then filtered through a pad of celite. The celite cake was washed with dichloromethane (100 mL). The solution was then concentrated under reduced pressure to yield a dark oil. This solution was then filtered through SiO2 and washed with ethyl acetate to remove final traces of the TPAP catalyst to yield the title compound. MS: M+−1=194.1 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][CH:43]=[CH:42][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1.O[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57]>>[C:56]([NH:55][CH2:54][CH2:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:42]=[CH:43][CH:44]=[CH:45][C:2]=3[Cl:1])=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)(=[O:58])[CH3:57]
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOc3ccccc3Cl)cc2)cc1
Reactant: CC(=O)NCCc1ccccc1O
Product: CC(=O)NCCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2ccccc2Cl)cc1

Procedure:
Analogously to Method G, 0.28 g of tert-butyl 4-{4-[3-(2-chlorophenoxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 123b) and 0.15 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.65 (EtOAc); Rt=5.73.
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[C:6](=[O:14])[NH:7][C:8]([N:11]([CH3:13])[CH3:12])=[N:9][N:10]=1>O>[CH3:12][N:11]([CH3:13])[C:8]1[NH:7][C:6](=[O:14])[C:5]([NH:2][NH2:3])=[N:10][N:9]=1
Reactant: NN
Reactant: CN(C)c1nnc(Br)c(=O)[nH]1
Solvent: O
Product: CN(C)c1nnc(NN)c(=O)[nH]1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
With stirring, hydrazine monohydrate (1.44 ml, 30 mmol) was added at 25° C. to a solution of the bromide (X) (2.20 g, 10 mmol) in water (80 ml). The reaction mixture was heated to reflux, cooled to room temperature and, for crystallization, allowed to stand for several hours. The crystals were filtered off, washed with water and dried in the air, giving the hydrazine (XI) (1.08 g, 63%) as a white solid of melting point 264-266° C. (from ethanol): IR spectrum vmax (NaCl/nujol/cm−1) 3324s, 3301s, (NH), 1641s (C═O), 1575s, 1516s, 1397s, 1304w, 1260w, 1204w, 1165w, 1133w, 1068w, 1050s, 1005w, 923s, 833w, 786s, 709s, 683s; NMR spectrum: δH (270 MHz, DMSO-d6): 11.25 (2H, bs, NH2), 7.18 (1H, bs, NH), 2.96 (6H, s, NCH3);
Reaction SMILES: [C:1]([O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=1)\[NH2:7])(=O)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:2][C:1]1[O:4][N:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=2)[N:7]=1
Reactant: COC(=O)CCC(=O)Nc1ccc(/C(N)=N/OC(C)=O)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1ccc(-c2noc(C)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of methyl 4-[[5-[(Z)—N′-acetoxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butanoate (obtained in step 2, 0.18 g, 0.58 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (1.0 mol/L) in THF (0.053 g, 0.058 mL, 0.058 mmol, 0.1 equiv.) at room temperature. The mixture was stirred for 4 h at room temperature. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried on magnesium sulfate, and then concentrated under vacuum. The residue was purified by flash chromatography, eluted with a gradient of ethyl acetate and cyclohexane to give methyl 4-[[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-pyridyl]amino]-4-oxo-butanoate A75 (0.062 g, 37% yield). LC-MS (Method F) RT 0.72, 291 (M+H+).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:30])=[C:16]([C:25](OCC)=[O:26])[C:17](=[O:24])[C:18]2([CH2:22][CH3:23])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:32]([O:36][C:37](=[O:40])[CH2:38][NH2:39])([CH3:35])([CH3:34])[CH3:33]>O1CCOCC1>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:30])=[C:16]([C:25]([NH:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])=[O:26])[C:17](=[O:24])[C:18]2([CH2:22][CH3:23])[CH3:21])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(CC)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 85.4 %

Procedure:
DIPEA (0.253 mL, 1.45 mmol, 1.2 eq) was added to a mixture of ethyl 7-chloro-1-ethyl-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (373 mg, 1.21 mmol) and glycine tert-butyl ester hydrochloride (0.243 g, 1.45 mmol) in dioxane (8 mL). The reaction mixture was stirred at 80° C. for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica flash chromatography (0-75% DCM/hexane) to give the desired compound as a white solid (407 mg). MS (m/e)=338.1 (M+H-tBu)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C=O)[CH:12]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl.[NH2:24][OH:25]>C(O)C>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:11]2[CH2:12][C:13](=[N:24][OH:25])[CH:14]=[CH:15][CH:16]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: C#CCn1c(-c2cccc(C=O)c2)nc(CC)c(CC)c1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C#CCn1c(C2=CC=CC(=NO)C2)nc(CC)c(CC)c1=O
Yield: 60.9 %

Procedure:
To a 100 mL RBF were charged 1.1 g (3.7 mmol) of 5,6-diethyl-2-(3-formyl-phenyl)-3-propargyl-4(3H)-pyrimidinone, 0.52 g (7.5 mmol) of hydroxylamine hydrochloride and 50 mL of ethanol. The reaction mixture was refluxed for 17 hours. The ethanol was removed in vacuo and ether and ethyl acetate were added to the residue. The organics were washed 3 times with water. The organic layer was gravity filtered to remove 0.22 g of 5,6-diethyl-2-(3-hydroxyiminophenyl)-3-propargyl-4(3H)-pyrimidinone (compound 139). The organic layer was dried over MgSO4 and concentrated to yield a further 0.67 g of 5,6-diethyl-2-(3-hydroxyiminophenyl)-3 -propargyl-4(3H)-pyrimidinone (compound 139) as a white solid. A combined yield of 77.6% was obtained. 1H-NMR (CDCl3) 1.25(6H,m); 2.35(1H,t); 2.65(4H,m); 4.6(2H,d); 7.49-8.15(4H,m); 8.7(1H,s)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].CN1CCCN(C)C1=O>C1COCC1>[CH2:16]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2cc(O)cnc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1cc2cc(OCc3ccccc3)cnc2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-hydroxy-6,7-dimethoxyquinoline (150 mg; 0.73 mmol) in 3 mL THF is added benzyl bromide (0.13 mL; 188 mg; 1.10 mmol) and NaH (59 mg; 1.46 mmol). This is stirred at room temperature for 1 hour and 25 mg of NaH added followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) (255 mg; 2.07 mmol) and stirred at room temperature for 31/2 hours. The reaction mixture is partitioned between EtOAc and distilled H2O and extracted 2× with EtOAc. The latter is washed with brine, dried (MgSO4), filtered, evaporated to dryness and chromatographed with 1% MeOH/CHCl3 to obtain 3-benzyloxy-6,7-dimethoxyquinoline m.p. 146.5°-148.5° C.).
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:30]([O:37][CH2:38][C@H:39]1[CH2:41][O:40]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C1COCC1>[CH2:30]([O:37][CH2:38][C@H:39]([OH:40])[CH2:41][C:26]1[N:25]([C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:29]=[CH:28][N:27]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H](COCc1ccccc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In an argon atmosphere, n-butyllithium (1.6 M solution in hexane, 6.9 ml) was added drop by drop to a solution of 1-tritylimidazole (3.10 g) in THF (80 ml) under ice cooling. After stirring at the same temperature for 30 minutes, (R)-2-[(benzyloxy)methyl]oxirane (1.52 ml) was added. After stirring under ice cooling for 1.5 hours and at room temperature for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saline and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane 1:1) to yield the titled compound (1.402 g) as a pale-yellow oily substance.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].C=O.Cl>O>[C:1]([CH:9]1[CH2:14][O:12][C:11](=[O:13])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1CC(C(=O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 84.1 %

Procedure:
A mixture of 3-benzoylpropionic acid (18 g, 101 mmol), potassium carbonate (10 g, 75 mmol), water (45 mL) and formaldehyde (36% in water, 7.8 mL, 101 mmol) is stirred at room temperature for 5 days, warmed to 30° C. and stirred for 3 additional days. To this mixture is added concentrated hydrochloric acid (10 mL) to pH 5.0, heated at 50° C. for 30 min. and cooled to room temperature. The mixture is extracted with chloroform (4×200 mL) and the combined organic extracts washed with sodium carbonate (10% in water, 3×100 mL). The solution is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated in vacuo to yield 4-benzoyl-dihydro-furan-2-one (12 g) as a colorless liquid.
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:9]2)[CH:3]=1>C(O)(=O)C.O.[Fe]>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:9]2)[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccc[n+]([O-])c2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2cccnc2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 85 °C

Procedure:
To a solution of ethyl 1-(1-oxidopyridin-3-yl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (300 mg, 0.78 mmol) in glacial acetic acid (15 mL) is added iron powder (175 mg, 3.12 mmol). The reaction mass is heated to 85° C. for 1 h under nitrogen. The reaction progress is monitored by TLC. The solvent is removed completely under reduced pressure. The crude material obtained is diluted with water and is extracted with ethylacetate. The organic layer is separated and is dried using sodium sulphate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ=8.85-8.84 (d, J=4.7 Hz, 1H), 8.79-8.78 (m, 1H), 8.07-8.03 (m, 2H), 7.70-7.59 (m, 3H), 6.87-6.85 (d, J=7.84 Hz, 1H), 5.00 (s, 2H), 4.40-4.35 (q, 2H), 1.35-1.32 (t, J=7.12 Hz, 3H). MS (ESI+): 370.2. HPLC (max plot): 97.29%; Rt 3.24 min.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH3:28][C:25]([CH3:29])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]#[N:27]
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: CC(C)(C#N)CCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridinone (6.3 g), 6-bromo-2,2-dimethylhexanonitrile (2.60 g) (prepared according to the method of M. Larcheveque et al., Bull. Soc. Chim. Fr., 1710 (1974)), silver carbonate (3.5 g) and toluene (300 cc). The product is purified by chromatography under pressure on silica gel (30-60 mm); eluent: n-hexane-ethyl acetate 9.5-0.5),yellowish solid. (m,p.=71° C.)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.I[CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:1]=[C:2]1[O:3][C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:7]1[CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:39])([CH3:40])[O:33]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of (2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate (4.69 g, 13.27 mmol) and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (d 1.38, 5.96 mL, 8.23 g, 26.5 mmol, 2 equiv) in THF (66 mL, 0.2 M) and HMPA (6.6 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (14.6 mL, 1.0 M, 1.1 equiv) drop wise over 5 min and stirred for 1 h. After warming to room temperature and stirring for an additional 2 h, the solution was cooled to 0° C. and quenched with 0.5 NHC (2-3 equiv). The resulting solution was diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as a white solid (6.66 g, 94%); ESI-LCMS m/z calcd for C31H42BNO2: expected 535.3. found 536.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]2)=[CH:12][CH:11]=1>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][NH:35][C:36]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[S:37])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: NCc1cccnc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)NCc4cccnc4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 1 part of 3-pyridinemethanamine, 3.9 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 45 parts of tetrahydrofuran was stirred for 4 hours at room temperature. The reaction mixture was evaporated in vacuo. The residue was purified by column-chroratography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 3.4 parts (65.7%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-(3-pyridinylmethyl)thiourea; mp. 147.2° C. (compound 102).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH:10]([C:13]1[CH:19]=[C:18](Br)[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[C:14]=1[NH2:15])([CH3:12])[CH3:11]>C1(C)C(C)=CC=CC=1.[Cu](Cl)Cl>[CH:10]([C:13]1[CH:19]=[C:18]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[C:14]=1[NH2:15])([CH3:12])[CH3:11]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Reactant: Oc1ccccc1
Agent: Cl[Cu]Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N

Procedure:
48.9 g of phenol are dissolved in 500 ml of xylene, and to this solution are added 30.2 g of pulverised potassium hydroxide in an atmosphere of nitrogen. The reaction mixture is stirred and heated to boiling point, while continuously distilling off the water that is formed. After addition of 0.6 g of copper chloride and 100 g of 2,6-diisopropyl-4-bromoaniline, the mixture is stirred for 8 hours at 150°-155° C., then cooled, and filtered with suction. The filtrate is washed with 15% sodium hydroxide solution (150 ml) and with two 150 ml portions of water. The organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation and the product is distilled, affording the compound of the formula ##STR5## with a boiling point of 103°-104° C./0.01 torr and a melting point of 71°-72° C. (after recrystallisation from hexane).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]2[CH:2]=[C:3]([CH2:4][C@@H:5]3[CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:26]=[C:22]2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CC(=O)CBr
Reactant: Cc1ccnc(N)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2cc(C[C@@H]3CCCCN3C(=O)OC(C)(C)C)nc2n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.300 g, 0.94 mmol) in DMF (2 ml) was added 4-methyl-2-pyrimidinamine (0.153 g, 1.41 mmol) and the mixture was stirred at 80° C. for 1.5 h. To the reaction mixture was added brine and a saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash cromatography on silica gel (Biotage 25+M, DCM/MeOH from 100/0 to 90/10). Collected fractions gave the title compound (0.350 g slightly contaminated with residual 4-methyl-2-pyrimidinamine). UPLC: rt=0.53, peak observed: 331 (M+1). C18H26N4O2 requires 330.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Yield: 83 %

Procedure:
Treatment of (−)-[7-bromo-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.0 g, 5.22 mmol) with 2-methylphenylboronic acid (1.06 g, 7.83 mmol) generally according to described for Intermediate 37 provided 1.71 g (83%) (−)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. [α]D25=−44.6 (c 10.0 in methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH:19]([CH2:26]CCO)[C@@:18]([CH2:40][F:41])([C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=2F)[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1C[O:47][CH2:46]C1.CN(C=O)C>>[F:41][CH2:40][C@@:18]12[C:30]3[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=3[O:47][CH2:46][CH2:26][C@@H:19]1[S:20](=[O:24])(=[O:25])[C:21]([CH3:23])([CH3:22])[C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:15])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:17]2
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(CCCO)S(=O)(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc([N+](=O)[O-])ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-2-(3-hydroxypropyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (1.95 g, 3.30 mmol) in THF:DMF (10:1, 44 mL) at 0° C. was added NaH (264 mg, 6.60 mmol, 60% suspension in mineral oil) portion wise. The reaction mixture was stirred at RT for 1 h and an additional amount of NaH was added (264 mg, 6.60 mmol, 60% suspension in mineral oil). The reaction mixture was stirred at RT for 1 h, quenched with satd. aqueous NH4Cl, and diluted with EtOAc. Water was added to dissolve solids, and the organic layer was separated. The organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using a 0-25% EtOAc/hexanes gradient to afford the less polar cis-isomer, tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (647 mg, 34%) as a white solid, LC/MS (ESI+) m/z=594 (M+Na), and the more polar trans-isomer, tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (594 mg, 31%) as a white solid. LC/MS (ESI+) m/z=594 (M+Na).