Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:10]=[C:9]([N:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]2=[O:25])[CH:8]=1>O.C1COCC1>[CH3:24][C:21]1[CH:22]=[CH:23][N:18]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([N:13]3[CH:17]=[N:16][N:15]=[N:14]3)[CH:10]=2)[C:6]([OH:26])=[O:5])[C:19](=[O:25])[CH:20]=1
Reactant: COC(=O)c1cc(-n2cnnn2)cc(-n2ccc(C)cc2=O)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(C(=O)O)cc(-n3cnnn3)c2)c(=O)c1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of LiOH.H2O (95 mg, 2.25 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (500 mg, 1.61 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the aqueous solution was acidified by addition of 10% HCl to pH=2. The resulting precipitate was collected and dried to afford 3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid as yellow solid (453 mg, 95%). MS (M+H)=298.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH:13]([CH3:14])[O:15][C:10]1=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: CC1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC1CC(=Cc2ccccc2O)C(=O)O1
Yield: 66.9 %

Procedure:
Salicylaldehyde (15.2 g) and γ-valerolactone (25 g) were dissolved in toluene (150 ml). By the reactions as in the same manner as in Example 307, the title compound (17 g) was obtained, melting point 112-114° C.
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.Cl>C(O)(=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[O:6][C:5]([CH3:7])=[C:2]([CH3:1])[N+:3]=2[O-:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1

Procedure:
50.6 g of Diacetylmonoxime and 66.7 ml of 4-methoxy-benzaldehyde are added to 100 ml of glacial acetic acid, and HCl gas is introduced for 30 minutes, with ice-cooling. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in water and the pH is made alkaline using ammonia. The mixture is extracted three times with in each case 200 ml of dichloromethane, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 82.1 g of 2-(4-methoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide as a white solid. C12H13NO3 (219.24), MS (ESI)=220 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[OH:12])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of the product from Example 179A (10.0 g, 27.6 mmol) in EtOH (220 mL) was added sodium borohydride (2.190 g, 57.9 mmol) in several portions over 1 h. The resulting mixture was stirred at rt for 1 h, filtered through celite, and concentrated in vacuo. The residue was dissolved in EtOAc and washed by 1N aq. HCl. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (9.29 g, 92%)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 100.5 %

Procedure:
Prepared from rac-2-chloro-N-[2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 42 step A) (50 mg, 0.133 mmol, HPLC 1.056 min) and morpholine (231 ul, 2.66 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (57 mg, 100%, HPLC 0.525 min 100%), MS (ISP) m/e=427.1 [(M+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[N:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: COc1ccc(N)cc1
Solvent: CO
Product: COc1ccc(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Reaction time: 8 h

Procedure:
3,5-di(Tert-butyl)-4-hydroxybenzaldehyde (1 g, 4.11 mmol) was dissolved in methanol (30 ml). To this solution was added p-anisidine (0.51 g, 4.11 mmol). The resultant reaction solution was stirred at room temperature under nitrogen for two (2) hours and the solution was taken to dryness in vacuo. The resultant oil was azeotroped with methanol (2×), ether (1×), a mixture of ethyl acetate/hexane (1×), and methanol (1×). The oil was left in vacuo overnight which began crystallization of the oil. The crystals were then dissolved in a mixture of ether and hexane. Dark flakes of p-anisidine were filtered out of the solution, the mother liquor was reduced with low heat, resulting in crystals of the title product which were collected by filtration: 1H NMR (300 MHz, CDCl3); δ 8.38 (S, 1H), 7.72 (S, 2H), 7.19 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 5.58 (S, 1H), 3.83 (S, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[NH:5][O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].Cl.O1CCOCC1>>[CH2:1]([NH:3][C:4](=[O:15])[NH:5][O:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)NOCC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)NOCC(=O)O
Yield: 98.7 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-9, tert-butyl 2-(3-ethylureidooxy)acetate (Compound V-8) (33 mg, 0.15 mmol) was reacted with 4N HCl/dioxane (2 ml) to obtain the title compound (24 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cu][C:41]#[N:42]>CN1C(=O)CCC1>[O:33]([CH2:32][C:3]1[CH:4]=[C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:6]=[CH:7][C:2]=1[C:41]#[N:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N#C[Cu]
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Br)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Alternatively, the compound described above is synthesized starting from 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene using copper(I) cyanide (2 equivalents) in NMP at 210° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=O)[N:3]=[CH:2]1.[CH2:11]([CH2:13][NH2:14])[OH:12]>>[OH:12][CH2:11][CH2:13][NH:14][C:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:8]
Reactant: NCCO
Reactant: CCOC(=O)c1cscn1
Product: O=C(NCCO)c1cscn1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 4-thiazolecarboxylate (24.49 g) and monoethanolamine (28.0 ml) was heated at 100° C. with stirring for 1 hour 20 minutes. After being cooled, the mixture was subjected to column chromatography on silica gel (245 g) and eluted with chloroform. The fractions containing the objective compound were combined and concentrated under reduced pressure to give a light brown oil of N-(2-hydroxyethyl)-4-thiazolecarboxamide (25.93 g).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH3:13])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 4-methylbenzyl bromide (8.5 g, 46 mmol), 8.2 g of the product was isolated. Yield, (85%); white solid; MS: 210.1 (M+H)+.
Reaction SMILES: [ClH:1].C([NH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[N:11]=1)(=O)C>C(O)C>[ClH:1].[ClH:1].[NH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[N:11]=1
Reactant: CC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: Cl
Solvent: CCO
Product: NCc1nc(-c2csc(N=C(N)N)n2)cs1

Procedure:
Concentrated hydrochloric acid (72.4 ml) was added slowly to a suspension of 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (6.58 g) in ethanol (280 ml). The mixture was refluxed for 2 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (6.98 g).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.CC(O)=O.[Pt](=O)=O>[CH:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: C=CC
Reactant: c1ccncc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCCCC1
Yield: 137.9 %

Procedure:
A solution of O-protected pyridine propene (1.5 g, 5.7 mmol) and platinum(IV) oxide (258 mg) in MeOH (20 mL) and AcOH (4 ml) was hydrogenated 6 h at 40 psi. The final solution was filtered over CELITE, rinsed with MeOH then concentrated. The residue was diluted with 1 N NaOH, extracted with DCM and AcOEt, and the combined organic layers were dried over Na2SO4 and concentrated. The residue was quickly passed through a plug of silica gel (eluting hexanes/AcOEt 8:2) to provide 1.0 g (65%) of O-protected isopropyl piperidine.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43](=[O:55])[O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]=2[CH3:54])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43]([O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([B:25]([OH:27])[OH:26])=[CH:49][C:48]=2[CH3:54])=[O:55])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2C)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(B(O)O)cc2C)cc1C#N
Yield: 68 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 31A (745 mg, 1.66 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 31B (468 mg, 68%) as a tan foam. 1H NMR (400 MHz, MeOD) δ ppm 1.25 (t, J=7.33 Hz, 3 H) 2.34-2.40 (m, 3 H) 3.03 (t, J=6.95 Hz, 2 H) 3.35 (q, J=7.33 Hz, 2 H) 4.39 (t, J=7.07 Hz, 2 H) 7.20 (d, J=7.33 Hz, 1 H) 7.30-7.43 (m, 2 H) 7.86 (dd, J=8.84, 1.77 Hz, 1 H) 7.99 (d, J=8.84 Hz, 1 H) 8.11 (d, J=2.02 Hz, 1 H) 10.05 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:28]4[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC1CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: OC1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 72.6 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (420 mg, 1.30 mmol, 1 wt), 4-hydroxypiperidine (268 mg, 2.60 mmol), absolute ethanol (17 ml, 40 vol), activated 3 Å molecular sieves (420 mg), titanium (IV) isopropoxide (1.94 ml, 4.62 vol) and STAB (2.34 g, 11.1 mmol) was reacted in accordance with the general procedure D. The isolated waxy solid was purified by preparative HPLC, eluting with acetonitrile/water/0.1% TFA as a gradient, to give the title compound as a white solid (380 mg, 73%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.75 (dt, 2H), 3.59-3.47 (m, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.35 (s, 2H), 2.33-2.25 (m, 2H), 2.13-1.96 (m, 6H), 1.93-1.83 (m, 2H), 1.82-1.76 (m, 4H), 1.72-1.59 (m, 3H), 1.47-1.29 (m, 3H).
Reaction SMILES: [N+](C1C=CC(CO[C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])=CC=1)([O-])=O.[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CCOC(C)=O>[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][N:29]([CH3:28])[C:10](=[O:11])[NH:12][C:13]2[CH:25]=[CH:24][C:16]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc2sc3ccccc3c2c1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CNCCc1ccncc1
Solvent: CCOC(C)=O
Product: CN(CCc1ccncc1)C(=O)Nc1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Nitrobenzoxycarbonylamino)dibenzothiophene (Example 1; 501 mg, 1.35 mmol) was suspended in EtOAc (10 ml) and 4-[2-(methylamino)ethyl]pyridine (408 mg, 3.0 mol) added in one portion. The resulting mixture was stirred at ambient temperature for 16 hours then further EtOAc (50 ml) added. The solution was washed with 1 M sodium hydroxide (3×25 ml), water (2×25 ml) and brine (25 ml), dried and evaporated in vacuo. NMR 8.44 (m, 3H), 8.34 (d, 1H), 8.13 (m, 1H), 7.96 (m, 1H), 7.82 (d, 1H), 7.55 (dd, 1H), 7.47 (m, 2H), 7.28 (d, 2H), 3.61 (t, 2H), 2.96 (s, 3H), 2.86 (t, 2H); m/z 362.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Fc1ccc2nnc(N3CCCCCC3)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.2 %

Procedure:
To a solution of Intermediate A (137 mg, 0.84 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 68 mg, 1.7 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 67a (197 mg, 0.84 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (175 mg, 55%). LCMS (Method 3): Rt 2.22 min, m/z 378 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH2:14][OH:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([N:10]2[CH2:9][C@H:8]([CH2:14][OH:15])[N:7]([CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][C@H:11]2[CH3:13])=[O:33])=[CH:28][CH:27]=1
Reactant: C[C@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1C(=O)COc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a solution of (2R,5S)-1-(4-fluorobenzyl)-2-(hydroxy)methyl-5-methylpiperazine (1.6 g, 6.7 mmol) in CH2Cl2 (30 mL) was added triethylamine (excess) and 4-chlorophenoxyacetyl chloride (1.5 g, 7.4 mmol, dropwise in 10 mL solution of CH2Cl2). The resultant mixture was stirred at ambient temperature. After 20 minutes, analysis by analytical TLC showed complete consumption of starting material had occurred. The mixture was concentrated of volatiles in vacuo and the residue taken up in CH2Cl2. This was washed with saturated aqueous NaHCO3 solution, then water, then brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 2.16 g (79% yield) of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((hydroxy)methyl)piperazine, as a solid yellow foam: NMR (DMSO-d6) 7.7 (br s, 2), 7.3 (m, 4), 6.9 (d, 2), 5.0-4.2 (m, 5), 4.0-3.2 (m, 7), 1.2 (m, 3) ppm; MS (LSIMS) 406.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:13]=2)=[C:9]([CH3:11])[N:10]=1)=[O:4].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3](=[O:4])[NH:5][C:6]2[S:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[N:13]=3)=[C:9]([CH3:11])[N:10]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
A solution of 2-chloro-N-{4-methyl-5-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-thiazol-2-yl}-acetamide (40 mg, 0.1 mmol) in DMF (2 mL) was cooled on an ice bath. Piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.21 mmol) was added. After stirring at room temperature for 16 h, the reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound (20 mg) as a light yellow solid. Anal. RP-HPLC: tR=16.9 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >97%). 1H-NMR (CD3OD) δ: 2.65 (s, 3H, CH3), 2.87 (m, 4H, CH2), 3.36 (m, 4H, CH2), 4.66 (s, 2H, CH2), 7.71 (m, 1H, pyrimidinyl-H), 7.89 (t, 1H, J=8.1 Hz, Ph-H), 8.15 (m, 1H, Ph-H), 7.42 (m, 1H, Ph-H), 7.67 (m, 2H, pyrimidinyl-H & Ph-H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH2:15][C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].Cl>O>[C:16]([CH2:15][N:14]1[C:12](=[O:13])[CH:2]2[CH:3]([CH:4]3[CH2:7][CH2:8][CH:1]2[CH:6]=[CH:5]3)[C:9]1=[O:11])([OH:18])=[O:17]
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CN1C(=O)C2C3C=CC(CC3)C2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
To a suspension of bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (688 mg, 3.9 mmol) in H2O (10 mL) was added glycine (348 mg, 4.6 mmol), and a solution of K2CO3 (321 mg, 2.3 mmol) in H2O (2 mL). The mixture was heated to reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the mixture was acidified with conc. HCl until the pH reached 1 and extracted with ethyl acetate (EtOAc). The organic layer was washed with brine and dried over Na2SO4. Removal of the solvent gave a colorless solid which was recrystallized from EtOAc/hexane to yield the product as colorless crystals: 653 mg (72% yield), mp=142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[C:21]1([CH2:20][N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.0 g) in dry acetonitrile (70 ml) was added milled potassium carbonate (3.7 g) followed by benzyl chloride (2.2 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 5 hrs, warmed under reflux for 2 hrs, and cooled to ambient temperature. The reaction mixture was filtered through a pad of celite, and the solids washed with ethyl acetate. The combined filtrates were concentrated to give 4.3 g (96%) of 1-phenylmethyl-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[C:10]2([C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16][C:43](=[O:45])[CH3:44])[C:10]2([C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CO)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.3 g, 0.56 mmol) in tetrahydrofuran (2 mL) at 0° C. was added pyridine (44 mg, 0.56 mmol) and acetyl chloride (44 mg, 0.56 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous CuSO4, brine, dried over MgSO4, and concentrated to give as rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester as a yellow oil (0.24 g, 74%)