Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:39])[CH2:21][C:22]3[CH:38]=[CH:37][C:25]4[N:26]=[C:27]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH3:36])[O:28][C:24]=4[CH:23]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.ClCCl.O>FC(F)(F)C(O)=O>[C:31]1([CH3:36])[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:27]1[O:28][C:24]2[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([C:8]4([CH2:7][C:6]([OH:40])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:18][CH:17]=3)=[O:39])[CH:38]=[CH:37][C:25]=2[N:26]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)OC(C)(C)C)CCCC4)cc3)cc2o1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)CCCC4)cc3)cc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
A solution of [1-{4-[2-[2-o-tolylamino-benzoxazol-6-yl]-acetylamino]-phenyl}-cyclopentyl]-acetic acid tert-butyl ester [0.36 g, Reference Example 1(a)] in a mixture of trifluoroacetic acid (12 mL), dichloromethane (2.25 mL) and water (1.5 mL) was stirred at room temperature for 1.5 hours. The resulting turquoise solution was evaporated and the residue was chased with toluene to yield an amber gum which was recrystallised from a mixture of acetonitrile and water to give the title compound (0.25 g) as an off white solid, m.p. 123–126° C. LC-MS: RT=3.51 minutes, MS(ES+): 506.6(M+Na)+, 484.6(M+H)+; MS(ES−): 482.4(M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19].Cl>C1COCC1>[Br:1][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[C:4]([F:9])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: Cc1ccc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Br)c(C(=O)O)c1F
Reaction time: 1.17 h
Yield: 49.2 %

Procedure:
50 ml (0.385 mol) of 4-bromo-2-fluorotoluene were dissolved in 750 ml of THF, and 231 ml (0.462 mol) of a 2 M solution of LDA in THF were added dropwise at −70° C. After 70 minutes, 37.2 g (0.846 mol) of carbon dioxide were passed in, and the batch was allowed to thaw. After acidification using conc. hydrochloric acid, the solution was extracted with MTB ether, and the combined organic phases were washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallisation of the crude product from 1-chlorobutane gave 44.1 g (49%) of 6-bromo-2-fluoro-3-methylbenzoic acid as white crystals.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4](#[N:8])[CH2:5][C:6]#[N:7].[F:9][C:10]([F:18])([F:17])/[CH:11]=[CH:12]/[C:13](OC)=[O:14]>CO>[CH3:1][O:2][C:6]1[NH:7][C:13](=[O:14])[CH2:12][CH:11]([C:10]([F:18])([F:17])[F:9])[C:5]=1[C:4]#[N:8]
Reactant: COC(=O)/C=C/C(F)(F)F
Reactant: C[O-]
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CO
Product: COC1=C(C#N)C(C(F)(F)F)CC(=O)N1

Procedure:
With ice cooling, 7.47 g (138.39 mmol) of sodium methoxide in methanol (85 ml) were initially charged, and 6.04 g (91.44 mmol) of malononitrile were added. With stirring, 11.84 g (76.84 mmol) of methyl 4,4,4-trifluorocrotonate were then added dropwise, and the mixture was stirred at RT for 30 min and then heated at reflux for 1 h. Under reduced pressure, the mixture was then concentrated to dryness. Water was added to the residue, and the mixture was extracted four times with ethyl acetate. The combined organic phases were dried with sodium sulphate, filtered and concentrated. Further purification was carried out by chromatography on silica gel (cyclohexane/ethyl acetate 3:1). This gave 1.95 g of the title compound (11% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].Cl.[C:16](Cl)(Cl)=[O:17]>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:16]([OH:17])=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Product: CC1(C)C(=O)Nc2cc3[nH]c(O)nc3cc21
Reaction time: 0.17 h

Procedure:
Into a solution of 4.00 g. (0.021 mole) 5,6-diamino-3,3-dimethylindolin-2-one in 60 ml. 2N hydrochloric acid is passed phosgene at ambient temperature for 1 hour. Thereafter, nitrogen is passed through the solution for 10 minutes and the solution then left to stand for 15 hours. The precipitate is filtered off and crystallised from methanol. There are obtained 2.80 g. (62% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@H:26]([O:34]C(=O)C)[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.[C-]#N.[K+]>O.CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C@@H:26]([OH:34])[C:27](=[O:33])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:32])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in Syn., 1973, 790, (3β,5α,12α,25R)-3,12-di(acetoxy)spirostan-11-one was saponified with potassium cyanide in water, methanol and THF to give the title compound.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:20]=[CH:19][C:15]([CH:16]=[N:17][OH:18])=[CH:14][CH:13]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[CH2:29][CH:28]([C:27]3[CH:30]=[CH:31][C:24]([NH2:23])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:14][CH:13]=1
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Reactant: C=Cc1ccc(N)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ccc(C2CC(c3ccc(OC(F)(F)F)cc3)=NO2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of NCS (85 μL, 0.634 mmol) and pyridine (4 μL) in chloroform (2.5 mL) was added p-trifluoromethoxybenzaldehyde oxime (130 mg, 0.634 mmol). The reaction was heated at 50° C. for 3 h. 4-Aminostyrene (93 μL, 0.793 mmol) was then added followed by a solution of triethylamine (93 μL, 0.666 mmol) dissolved in chloroform (0.5 mL) dropwise. The reaction was stirred at 50° C. for 3 h. The cooled solution was diluted with chloroform (15 mL) and washed with water (2×10 mL). The organic phase was then dried over MgSO4, filtered and concentrated. The residue was purified via radial chromatography using a 2:1 hexane/EtOAc solution as the eluent (Rf=0.18) to afford 4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-isoxazol-5-yl]-phenylamine (125 mg; 61%): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.2 Hz, 2H), 5.65 (dd, J=10.9, 8.9 Hz, 1H), 3.55-3.75 (br s, 2H), 3.67 (dd, J=16.8, 10.9 Hz, 1H), 3.30 (dd, J=16.8, 8.9 Hz, 1H); EIMS m/z 322 (M+).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Cl.[N:49]1(C(N)=N)[CH:53]=CC=[N:50]1>CN(C)C=O>[O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:53]=[N:49][NH2:50])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCN)CC[C@]314
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCNC=NN)CC[C@]314
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous dimethylformamide (2 ml) was added to a mixture of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-aminopropylmorphinan (0.2 g, 0.359 mmol), diisopropylethylamine (0.07 ml, 0.39 mmol), and 1H-pyrazole-1-carboxamidine hydrochloride (0.06g, 0.39 mmol) and the reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was evaporated to dryness under reduced pressure, and the crude product was chromatographed on silica gel (yield=0.155 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:13](=O)(OC1C=CC=CC=1)[O:14]Cl.[CH3:24][C@H:25]1[CH2:30][NH:29][C@H:28]([CH3:31])[CH2:27][N:26]1[C:32]1[CH:39]=[C:38]([O:40][CH3:41])[C:35]([C:36]#[N:37])=[C:34]([F:42])[CH:33]=1>N1C=CC=CC=1>[C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:13]([N:29]3[CH2:30][C@H:25]([CH3:24])[N:26]([C:32]4[CH:39]=[C:38]([O:40][CH3:41])[C:35]([C:36]#[N:37])=[C:34]([F:42])[CH:33]=4)[CH2:27][C@H:28]3[CH3:31])=[O:14])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)#[N:12]
Reactant: O=C(OCl)Oc1ccccc1
Reactant: N#CC1(c2ccc(N)cc2)CC1
Reactant: COc1cc(N2C[C@@H](C)NC[C@@H]2C)cc(F)c1C#N
Solvent: c1ccncc1
Product: COc1cc(N2C[C@@H](C)N(C(=O)Nc3ccc(C4(C#N)CC4)cc3)C[C@@H]2C)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
Into 10 ml of pyridine was dissolved 475 mg of 1-(4-aminophenyl)cyclopropanecarbonitrile, and then 493 mg of chloro phenyl carbonate was added thereto under ice-cooling, followed by 24 hours of stirring at room temperature. Then, 5 ml of a pyridine solution of 790 mg of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-fluoro-6-methoxybenzonitrile was added dropwise thereto, followed by 1 hour of stirring at 100° C. After the reaction solution was evaporated and the resulting residue was dissolved in ethyl acetate, the solution was washed with a saturated sodium bicarbonate aqueous solution and then water. After the solution was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. The residue was subjected to silica gel column chromatography to obtain 751 mg of the title compound from an eluate using ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([C:6]1[C:7]([OH:13])=[CH:8][CH:9]=[CH:10][C:11]=1[OH:12])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19](Cl)=O.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19]1[O:13][C:7]2[C:6]([C:4](=[O:5])[CH:3]=1)=[C:11]([OH:12])[CH:10]=[CH:9][CH:8]=2
Reactant: CC(=O)c1c(O)cccc1O
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3c(O)cccc3o2)cc1OC
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (19.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2,6-dihydroxyacetophenone (6.6 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 3,4-dimethoxybenzoyl chloride (6 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 3′,4′-dimethoxy-5-hydroxyflavone. 1H NMR (250 MHz, CDCl3): δ=4.00 (d, 6 H), 6.60–7.60 (md, 7 H), 12.65 (s, 1 H); 13C NMR CDP (250 MHz, CDCl3): δ=54.71 (s), 103.48 (s), 105.57 (s), 107.45 (s), 109.76 (s), 118.93 (s), 122.24 (s), 133.80 (s), 147.93 (s), 151.06 (s), 159.39 (s), 163.17 (s), 182.04 (s); EI-MS (70 eV) m/e (rel. abund.)=298; UV (2-propanol): λ=248 nm, 342.5 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][S:25][CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][S:25][CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)CSCSC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)CSCSC1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (154 mg, 0.95 mmol) with compound 526 (250 mg, 0.73 mmol) in THF (4 mL) in the presence of LiHMDS (2.2 mL, 2.2 mmol) afforded compound 132 as a white solid material after purification by column chromatography (45-55% EtOAc in light petroleum). LC-MS: RT=4.39 min.; m/z 472.15, 474.14 (M+H)+. 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.42 (1H, d, J 8.9), 6.88 (1H, d, J 8.9), 4.64 (2H, s), 4.43 (2H, s), 4.24 (2H, s), 3.85 (3H, s), 3.84 (2H, s), 2.91 (4H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[CH:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.C(O)C.II>COCCOC.C(O)(=O)C>[CH3:9][N:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[N:1]=[C:11]1[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:27][CH:28]=1
Reactant: CNc1ncccc1N
Reactant: O=CCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: II
Solvent: COCCOC
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 3 %

Procedure:
A procedure similar to that described in Example 18 was repeated, except that 0.94 g of 3-amino-2-methylaminopyridine (prepared as described in Preparation 105), 2.10 g of 5-[4-(3-oxopropoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 107), 6 ml of ethanol, 3 ml of acetic acid, 2.32 g of iodine and 30 ml of 1,2-dimethoxyethane were used. After working up the product as described in Example 18, the resulting crude product was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 85 mg of the title compound, melting at 96-100° C.
Reaction SMILES: C1(NN=[CH:9][C@@H:10]([C@@H:12]([C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11])C=CC=CC=1.O.C(=[O:28])C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C(O)C>[OH:19][C@@H:18]1[O:11][C@@H:10]([CH2:9][OH:28])[C@H:12]([OH:13])[C@@H:14]([OH:15])[C@H:16]1[OH:17]
Reactant: O=Cc1ccccc1
Reactant: OC[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=NNc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: CCO
Product: OC[C@@H]1O[C@@H](O)[C@H](O)[C@H](O)[C@H]1O

Procedure:
The hydrazone (20 g.) was then refluxed for 3 hours with a solution containing water (200 ml.), ethanol (40 ml.), benzaldehyde (25 ml.) and benzoic acid (2.5 g.). The solution was cooled and then decanted from benzaldehyde phenylhydrazone, extracted three times with chloroform, decolorized with carbon and concentrated at reduced pressure. The resulting syrup was further evaporated with several portions of absolute ethanol to remove residual water and the resulting syrup (10 g.) was left to crystallize. The crystals were filtered with ethanol to give α-L-mannopyranose, m.p. 125°-126°, [α]D -26.9°→-14.4° (24 hr., c 2.0, water) compared to m.p. 128°-132°, [α]D -14.5° (equilibrium, c 3.4, water).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:14]1[C:19]([CH2:20][OH:21])=[CH:18][C:17]([Cl:22])=[CH:16][N:15]=1)[CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([Cl:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH:8]([CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)[C:14]1[C:19]([CH2:20][O:21][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])=[CH:18][C:17]([Cl:22])=[CH:16][N:15]=1)=[O:23])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:14]1[C:19]([CH2:20][Cl:40])=[CH:18][C:17]([Cl:22])=[CH:16][N:15]=1)[CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(c1ncc(Cl)cc1CO)C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(c1ncc(Cl)cc1CCl)C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2cc(Cl)cnc2C(NC(=O)OC(C)(C)C)C2CCOC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %
Yield: 32 %

Procedure:
To a solution of tert-butyl((5-chloro-3-(hydroxymethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate (600 mg, 1.74 mmol) in anhydrous CH2Cl2 (25 mL) was added Et3N (0.5 mL, 2.62 mmol) and p-toluenesulfonyl chloride (400 mg, 2.1 mmol) at 0° C. The mixture was stirred at rt for 2 h. The mixture was then washed with water (3×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography column on silica gel (eluting with 10% EtOAc in petroleum ether, gradient to 20%) to afford (2-(((tert-butoxycarbonyl)amino)(tetrahydrofuran-3-yl)methyl)-5-chloropyridin-3-yl)methyl4-methylbenzenesulfonate (470 mg, 54%) as a colorless oil and tert-butyl((5-chloro-3-(chloromethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate (200 mg, 32%) as a white solid. LCMS: tR=0.947 min in 5-95AB—1.5 min chromatography (MK RP18e 25-2 mm), MS (ESI) m/z 519.1 [M+Na]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Cl>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=3[Cl:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1ccc(CCl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.0 g, 3.19 mmol)/THF (40 mL) at 0° C., was added NaH (153 mg, 60 w/w % in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resulting foaming mixture was stirred in an ice bath for 30 min, followed by addition of 2-chloro-4-fluorobenzyl chloride (572 mg, 3.19 mmol). The resulting mixture was stirred at 0° C. for 30 min then warmed to ambient overnight. The reaction failed to proceed at room temperature and it was warmed in a 60° C. oil bath for 20 h. An aliquot indicated that the reaction was over. It was quenched with aq. NH4Cl (50 mL). Volatiles were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. The oil was purified by SiO2 (Biotage 40+M cartridge, eluted by EtOAc/hexanes, gradient; 5% to 40%). The titled compound was obtained as a colorless glassy material. LC-MS: 456.12 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.77 (s, 2H), 7.46 (dd, J=8.7, 6.0 Hz, 1H), 7.17 (dd, J=8.4, 2.5 Hz, 1H), 7.03 (m, 1H), 5.68 (d, J=8.2 Hz, 1H), 4.83 (d, J=15.6, 1H), 4.36 (d, J=15.3 Hz, 1H), 4.06 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:8][CH2:7]1.[CH2:32]=O.[C:34]([BH3-])#[N:35].[Na+]>CO>[CH3:32][N:35]([CH3:34])[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:8][CH2:7]1
Reactant: [BH3-]C#N
Reactant: Nc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Reactant: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
To a solution of 200 mg (0.48 mmol) of 3-[1-(3-aminobenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)quinazolinone in 20 mL of methanol were added 415 mg (4.85 mmol) of formaldehyde and 243 mg (3.88 mmol) of sodium cyanoborohydride and the mixture was stirred for 12 hours at ambient temperature. Then, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and the mixture was adjusted to pH 10 with aqueous ammonia and extracted with chloroform. The organic layer separated was dried on potassium carbonate, and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9:90 aqueous ammonia:methanol:chloroform) to give 210 mg (0.47 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])OCCCl)=[C:6]([NH2:15])[N:5]=[C:4]([N:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[N:17]2)[N:3]=1.[CH3:33][O-:34].[Na+].[CH3:36]O>>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[N:17]2)[N:5]=[C:6]2[C:7]=1[N:8]([CH2:36][CH2:33][OH:34])[C:9](=[O:14])[NH:15]2
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1NC(=O)OCCCl
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc2[nH]c(=O)n(CCO)c12
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
120 mg (0.263 mmol) of the carbamate from example 51A were initially charged in methanol (5.0 ml), 100 μl (0.525 mmol) of sodium methoxide solution (25% w/w in methanol) were added and the mixture was stirred at 65° C. for 30 min. The solvent was removed under reduced pressure, the residue was separated by means of preparative HPLC and the product fractions were concentrated. This gave 53.1 mg (48% of theory) of the title compound in solid form.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)N.[C:16](=O)(O)[O-].[Na+].C=O.[C:23]([BH3-])#[N:24].[Na+]>O.C(#N)C>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[N:24]([CH3:23])[CH3:16]
Reactant: [BH3-]C#N
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)N(C)C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
To a solution of L-tyrosine methyl ester hydrochloride (1 g) in water (1.5 ml) was added sodium bicarbonate (0.363 g) under ice-cooling and stirred for 10 minutes, and then acetonitrile (7 ml), 37% formaldehyde aqueous solution (0.637 ml) and sodium cyanoborohydride (0.182 g) was added thereto at -5° C. The mixture was stirred for 2 hours at -5° C. The resultant insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give N,N-dimethyl-L-tyrosine methyl ester (0.21 g).