Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.Cl[CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccncc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccncc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (710 mg, 1.19 mmol), 4-(chloromethyl)pyridine hydrochloride (794 mg, 4.84 mmol), potassium carbonate (1.337 g, 9.67 mmol) in acetone (21 mL) and water (7 mL). Stir and heat at reflux for 24 h. Allow reaction mixture to cool to room temperature, and remove the acetone under vacuum. Add ethyl acetate, separate the organic layer and extract with saturated aqueous NaCl solution. Dry the organic layer over anhydrous Na2SO4, filter and concentrate in vacuo. Chromatograph the residue on silica gel eluting with 30% methanol/ethyl acetate to give the title compound: Rf=0.16 (silica gel, 20% methanol/ethyl acetate).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Br[CH2:9][CH:10]1[CH2:12][CH2:11]1>[OH-].[Na+].O1CCOCC1>[NH2:1][C@@H:2]([CH2:3][S:4][CH2:9][CH:10]1[CH2:12][CH2:11]1)[C:5]([OH:7])=[O:6]
Reactant: N[C@@H](CS)C(=O)O
Reactant: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N[C@@H](CSCC1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ice water bath cooled solution of L-cysteine in 1N sodium hydroxide (740 mL) and dioxane (740 mL) was treated with bromomethylcyclopropane (50 g, 370 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Dioxane was removed under reduced pressure and the resulting aqueous solution was adjusted to pH 6 with 6N HCl and placed in a refrigerator for 20 h. The product was collected by vacuum filtration, washed with hexanes and lyophilized to give 2(R)-amino-3-cyclopropylmethylsulfanylpropionic acid (57.28 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([CH:19]([CH:26]2[CH2:28][CH2:27]2)[NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]1([CH:19]([C:15]2[CH:16]=[N:17][CH:18]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH:14]=2)[NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH2:28][CH2:27]1
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccccc2OC)c1)C1CC1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
A mixture of 3-methoxyphenylboronic acid (48 mg, 0.31 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (100 mg, 0.31 mmol), PdCl2(PPh3)2 (18 mg, 0.02 mmol) and Na2CO3 (2 M in water, 0.39 mL, 0.78 mmol) in DMF(2 mL) was heated at 100° C. for 2 h. After concentration, the resulting residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (38 mg, 35%); ESI-MS m/z: 347 [M+1]+. 1H-NMR (MeOD, 400 MHz) δ 8.75 (1H, bs), 8.61 (1H, bs), 8.17 (1H, bs), 7.46 (1H, t, J=8.0 Hz), 7.27 (1H, dd, J=8.0, 2.4 Hz), 7.24 (1H, t, J=2.4 Hz), 7.05 (1H, dd, J=8.0, 2.4 Hz), 3.94 (1H, d, J=9.2 Hz), 3.91 (3H, s), 3.03-2.89 (2H, m), 1.35-1.29 (1H, m), 1.29 (3H, t, J=7.2 Hz), 0.81-0.75 (1H, m), 0.676-0.60 (2H, m), 0.53-0.48 (1H, m)
Reaction SMILES: [Li].[CH:2](/Cl)=[CH:3]\[CH3:4].C(/[Li])=C\C.[C:10]1([C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.CCOCC>[C:10]1([C:16](/[CH:2]=[CH:3]/[CH3:4])([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: C/C=C/Cl
Agent: Cl
Agent: [Li]
Agent: [Li]/C=C/C
Solvent: CCCCCC
Solvent: CCOCC
Product: C/C=C/C(O)(C(=O)OC)c1ccccc1
Reaction time: 1 h

Procedure:
Lithium ribbon (1.0% Na content) 6.9 g., 1.0 g. at.) was cut into strips (1.0 cm.=0.089 g.), degreased in hexane and cut into thin strips into ether (200 ml.) under helium. The reaction flask was equipped with dry-ice condenser and trans-propenyl chloride (25.5 g., 0.30 mole) was introduced dropwise during 60 minutes to the rapidly stirred suspension. The reaction was exothermic and was controlled by the addition of the halide. After addition the mixture was stirred for an additional 60 minutes. The trans-propenyllithium slurry was subsequently siphoned (in spurts during 30 minutes by He.pressure) into a stirred solution containing methyl phenylglyoxylate (55.0 g., 0.3 mole) in ether which was cooled to -78°. After 30 minutes of additional stirring, the reaction was warmed to -10° and poured onto 30 ml. of concentrated HCl and ca. 200 g. of ice. The ether layer was separated and the aqueous layer was further extracted with 3×50 ml. of ether. All ether layers were combined and dried over Drierite for 18 hours. After the solvent was stripped, the crude product weighting 58.1 g. (94%) was obtained which on distillation afforded 35 g. (57%) of pure material, b.p. 100° (0.05 mm.).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.Cl.Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:23])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)(Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared by treating the ester from Step A with 2-(choromethyl)quinoline hydrochloride under the conditions of Step D and effecting hydrolysis under the conditions of Example 1 (Step B), m.p. 193°-194° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH:34]([CH3:37])[CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]([CH3:37])[CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(Br)CO
Product: CC(CO)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 24.7 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo propan-1-ol (96 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-1-methyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (28 mg, 25%). MS (ESI) m/z 493.4 (M+H)+
Reaction SMILES: [I:1]I.[CH2:3]([S:10]/[C:11](/[Sn](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:12]\[CH:13]=[C:14](/[S:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[Sn:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:3]([S:10]/[C:11](/[I:1])=[CH:12]\[CH:13]=[C:14](/[S:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[Sn:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: II
Reactant: C(/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: I/C(=C/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
Iodine (56 mg, 0.22 mmol) in CH2Cl2 (10 mL) was added over a period of 2 h at 0° C. to 4 (200 mg, 0.20 mmol) in CH2Cl2 (20 mL) under argon. Analysis by TLC (1:2 CH2Cl2 :hexanes) indicated the disappearance of 4. The solution was slowly warmed to room temperature and then washed with NaHSO3 (2×25 mL) and KF solution (1×25 mL), dried (MgSO4), concentrated in vacuo and the residue purified by flash column chromatography (1:6 CH2Cl2 :hexanes) to afford 5 as a pale yellow oil (0.15 g, yield 97%): 1H NMR δ 6.6-7.8 (m, 27 H), 3.78 (s, 2 H), 3.75 (s, 2 H); 13C NMR δ 127-146 (several), 42.24, 40.46; Anal. Calcd for C36H31IS2Sn, C, 55.91; H, 4.04. Found, C, 56.12; H, 4.19.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:31])([OH:30])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:31][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[O:30][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(S)-1-(2-Chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]propan-2-ol prepared in Example 253 (1.06 g, 2.3 mmol) was dissolved in DMF (15 ml). To the solution, sodium hydride (110 mg, 2.76 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethylphenoxy)piperidin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (431 mg, yield 44%) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:27]([S:31]([NH:1][C@@H:2]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To an ice-cold solution of the product of step (a) (6.9 g) and triethylamine (3.64 ml) in dichloromethane (100 ml) was added, with stirring, dropwise over 15 minutes a solution of butanesulphonyl chloride (4.1 g) in dichloromethane (10 ml). The reaction mixture was stirred at low temperature for 2 hours and then at ambient temperature for a further 2 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and washed with water, dilute KHSO4 (aq.), dilute NaHCO3 (aq.), brine, dried (MgSO4) and evaporated. The solid residue was collected and washed with hexane containing a small volume of ether to give t-butyl (2S)-2-(n-butylsulphonylamino)-3-(4-nitrophenyl)propionate (6.65 g) as an off-white solid: NMR Spectrum (CDCl3) 0.90 (3H, t), 1.36 (2H, m), 1.45 (9H, s), 1.68 (2H, m), 2.88 (2H, m), 3.18 (2H, m), 4.28 (1H, m), 5.01 (1H, d), 7.43 (2H, d), 8.19 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11]([CH:20]=[CH:21][CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.II.C>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1C=CC=O
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (390 mg) as an E:Z (1:1) mixture in carbon tetrachloride (150 ml) was added iodine (0.1 g) and the reaction mixture was heated under reflux for 18 h using a 200W-tungsten lamp. After this period, activated charcoal (6 g) was added and heating was continued for a further 1 h. The mixture was filtered and the resulting pale yellow solution was evaporated to yield the title compound (384 mg) as a dull-white solid whose spectroscopic properties were in accord with those described above for Intermediate 11a.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[S:37][C:36]([NH2:38])=[N:35][CH:34]=2)=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:27]=[CH:28][C:29]([O:32][C:33]2[S:37][C:36]([NH:38][C:14](=[O:15])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:12][CH:11]=3)[O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:35][CH:34]=2)=[CH:30][CH:31]=1
Reactant: O=C(O)C(O[C@@H]1CCOC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: COC(=O)c1ccc(Oc2cnc(N)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 72 %

Procedure:
The compound of example A77 was obtained by similar method described in example A75 using (4-Cyclopropanesulfonyl-phenyl)-[(R)-(tetrahydro-furan-3-yl)oxy]-acetic acid (preparation 15) (0.150 g, 0.46 mmol), 4-(2-Amino-thiazol-5-yloxy)-benzoicacid methyl ester (0.140 g, 0.55 mmol), HOBt (0.075 g,0.55 mmol), and EDCI (0.106 g, 0.55 mmol), N-methyl morpholine (0.055 g, 0.55 mmom) in DMF (10 mL) to provide the title compound (185 mg).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([NH:17][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:19][CH:20]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 21.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and p-toluidine (35 mg, 0.33 mmol) to provide 238 (14 mg, 21% yield) as a black solid. LC-MS (M+H=302, obsd.=302). 1H NMR (400 MHz, d6-DMSO): δ 11.64 (s, 1H), 8.82 (s, 1H), 8.44 (m, 2H), 8.12 (d, 1H), 7.78 (d, 1H), 7.27 (m, 1H), 7.22 (dd, 1H), 7.19 (s, 3H), 2.30 (s, 4H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].CO.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Sodium borohydride (325 mg) was added to a solution of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (5.00 g) in tetrahydrofuran (30 ml)-methanol (30 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water to give crystals. Recrystallization from acetone-ethyl acetate gave 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.17 g, yield 83%) as colorless prisms. m.p. 155-156° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][N:20](C(OCC4C=CC=CC=4)=O)[C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][NH:20][C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H](c3ccc(F)cc3)Nc3ccccc3[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
A mixture of benzyl (3aR*,4R*,9bR*)-4-(4-fluorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (500 mg, 1.24 mmol) and 10% palladium on carbon (50% aqueous, 0.3 g) in ethanol (20 ml) was stirred at room temperature under hydrogen atmosphere for 2 hrs. The catalyst was filtered off, and the mixture was washed with ethanol. The solvent was evaporated under reduced pressure to give the title compound (350 mg, ca. 100%) as an oil.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][C:18]([CH3:25])([CH3:24])[C:19](OCC)=[O:20])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[AlH4-].[Li+]>O1CCCC1>[OH:20][CH2:19][C:18]([CH3:25])([O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:8]=[CH:9]2)=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of ethyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)-2-methylpropanoate (63.4 mg, 0.185 mmol) in tetrahydrofuran (3 mL, 40 mmol) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.20 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by sequential addition of 9 μL water, then 9 μL 15% aq NaOH, then 26 μL water. The resulting mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane, dried with MgSO4, filtered through celite, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 4.8 mg (9%) of N-(7-(1-hydroxy-2-methylpropan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=3.414, M+H=301.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.03 (s, 1H), 8.38 (s, 1H), 7.76 (d, J=8.9 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.39 (dd, J=8.9, 2.3 Hz, 1H), 4.93 (t, J=5.6 Hz, 1H), 3.45 (d, J=5.7 Hz, 2H), 3.27 (s, overlapping water non-integratable), 2.12-1.97 (m, 1H), 0.83 (dt, J=10.1, 5.4 Hz, 4H).
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[C:10](=[O:15])[N:9]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:8]2[CH2:23][CH2:24]OS(C)(=O)=O.[C-:30]#[N:31].[K+]>O>[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[C:10](=[O:15])[N:9]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:8]2[CH2:23][CH2:24][C:30]#[N:31]
Reactant: [C-]#N
Reactant: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1ccc(F)cc1)C2=O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1C)C(CCC#N)N(c1ccc(F)cc1)C2=O
Yield: 97.8 %

Procedure:
To a 80% ethanol solution of the product of above-mentioned (4-b) (0.23 g, 0.63 mmol) was added potassium cyanide (0.12 g, 1.9 mmol) and heated under reflux for 4 hrs. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled away under reduced pressure to give 0.19 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-cyanoethylisoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propanenitrile].
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2]N.CO[Si](CCC[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(OC)OC.C=O>C1(C)C=CC=CC=1>[O:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:2]=[CH:1][NH:4]1
Reactant: NCCN
Reactant: CO[Si](CCCc1ccccc1O)(OC)OC
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
The desired benzoxazine was prepared from the reaction of ethylene diamine (0.9 g, 15 mmole), 2-[(trimethoxysilyl)propyl]phenol (7.68 g, 30 mmole, prepared as described in Example 12A), paraformaldehyde (2.1 g, 70 mmole), and toluene (20 ml). The final product was a viscous liquid. The yield was 65% of theory.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1([CH2:19][OH:20])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([OH:18])[CH2:12][NH:11]1>CO.O>[C:1]([NH:8][CH2:9][C:10]1([CH2:19][OH:20])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([OH:18])[CH2:12][NH:11]1)(=[O:3])[CH3:2]
Reactant: NCC1(CO)NCC(O)C(O)C1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)NCC1(CO)NCC(O)C(O)C1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5.1 ml of acetic anhydride are added to a solution of 6.5 g of crude 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxy-piperidine in 65 ml of methanol/water (1:1) at 0° C. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 18 hours. The solution is concentrated in vacuo, the residue is dissolved in a little water and, to remove the acetic acid formed, the solution is filtered through an anion exchanger in the OH⃝ form and the column is washed with water. The filtrate is concentrated, the residue is dissolved in a little water and the solution is discharged onto a cellulose column 120 cm long and 3 cm wide which contains butanol as the mobile phase. The column is eluted with butanol, 95% pure butanol and 90% pure butanol and the individual fractions are investigated by thin layer chromatography to determine their content of the required compound. The fractions containing the desired product are collected and concentrated. The residue is dissolved in hot methanol and the solution is filtered and concentrated down to a volume of 30 ml. The product crystallises out. The crystallisation is brought to completion by leaving the mixture to stand overnight. The product is filtered off and washed with methanol. 2.7 g of colourless crystals of melting point 196° C. (decomposition) are obtained.