Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)C[N:4]1[CH2:8][C:7](=[O:9])[NH:6]C1C1C=CC=CC=1.[OH:17][CH:18]([CH3:23])[CH2:19][C:20]([O-:22])=O>CS(C)=O.O>[CH2:19]1[C:20](=[O:22])[N:4]([CH2:8][C:7]([NH2:6])=[O:9])[CH2:23][CH:18]1[OH:17]
Reactant: CC(O)CC(=O)[O-]
Reactant: CC(C)CN1CC(=O)NC1c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
A solution of 0.65 g 2-methylpropyl 2-phenyl-4-oxoimidazolidine-β-hydroxybutanoate in 1.5 ml dimethyl sulfoxide and 0.5 ml water is heated at reflux for 16 h. After evaporating, the residue is chromatographed on silica, eluting with 7:3 ethyl acetate/methanol. Oxiracetam is obtained as a white powder, m.p. 167°-70° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][O:41][CH2:42][C@H:43]([O:45][CH2:46][CH3:47])[CH3:44])=[CH:36][CH:35]=2)[C@H:13]([CH2:48][NH2:49])[CH2:12]1)=O)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl>[CH2:46]([O:45][C@H:43]([CH3:44])[CH2:42][O:41][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C@@H:14]2[C@@H:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=4[CH:33]=3)[CH2:16][NH:11][CH2:12][C@H:13]2[CH2:48][NH2:49])=[CH:39][CH:38]=1)[CH3:47]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CN(C(=O)OCc3ccccc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
1.4 mmol of 4-nitrophenylformiate are added to a solution of 1 mmol of (3R,4R,5R)-3-aminomethyl-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (example 6a) in 10 ml of CH2Cl2 under argon followed by the addition of 1 mmol of Et3N. After 60 min, the reaction mixture is evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.[CH3:28][NH2:29].CO>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:29][CH3:28])[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: CN
Solvent: CO
Product: CNc1cc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Yield: 44 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.100 g, 0.000240 mol) and 1M Methylamine in methanol (4 mL, 0.004 mol) 0.000163 mol) was heated at 80° C. for 5 hours. The solvent was removed and the residue was purified using a silica gel chromatography (12 g), elution DCM to 5% MeOH in DCM over 20 minutes to afford the title compound (0.045 g, 44%). LCMS: (FA) ES+, 427, 429. 1H NMR (400 MHz, d4-Methanol) 8.38 (s, 1H), 8.12-8.07 (m, 1H), 7.60 (dd, J=1.56, 0.77 Hz, 1H), 7.44-7.42 (m, 2H), 6.94 (dd, J=4.67, 1.66 Hz, 1H), 6.93 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH:32]1[CH2:33][CH2:34][C@@H:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:14]5=[CH:15][C:16]6[O:20][CH2:19][O:18][C:17]=6[CH:21]=[C:13]5[O:12][CH2:11]4)[C:2]3=[O:1])=[CH:28][CH:27]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(CN3C(=O)C4(COc5cc6c(cc54)OCO6)c4ccccc43)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(Cc2ccc(N[C@@H]3CCNC3)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 79.4 %

Procedure:
A solution of tert-butyl (3R)-3-({4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]phenyl}-amino)pyrrolidine-1-carboxylate (0.53 g, 0.94 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (5 mL) was stirred at ambient temperature for 70 min. The reaction was made basic with 1 M sodium hydroxide (50 mL) and extracted with dichloromethane (4×30 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol/ammonium hydroxide (14:1:0.15) afforded 1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.34 g, 78%) as an off-white solid: mp 118-121° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.23-7.13 (m, 4H), 7.00 (dd, J=7.5, 7.5 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H), 6.52 (s, 1H), 6.12 (s, 1H), 5.87 (d, J=1.2 Hz, 1H), 5.85 (d, J=1.2 Hz, 1H), 4.99-4.94 (m, 2H), 4.71-4.66 (m, 2H), 3.94-3.85 (m, 1H), 3.83 (br s, 1H), 3.15-3.04 (m, 2H), 2.97-2.88 (m, 1H), 2.83 (dd, J=11.1, 3.0 Hz, 1H), 2.21-2.09 (m, 1H), 1.98 (br s, 1H), 1.67-1.57 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.9, 148.8, 147.2, 142.3, 132.3, 128.85, 128.80, 124.3, 123.8, 123.3, 119.6, 113.4, 109.6, 103.1, 101.5, 93.6, 80.5, 58.3, 53.9, 53.6, 45.7, 43.8, 33.6; MS (ES+) m/z 456.2 (M+1).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[O:5]1[C:9]2([CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[C:18]([C:20]4[CH:21]=[C:22]([NH:27][C:28]5[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=5)[CH:23]=[C:24]([CH3:26])[CH:25]=4)[CH:17]=[N:16]3)[CH2:11][CH2:10]2)OCC1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:26][C:24]1[CH:25]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([CH:12]3[CH2:11][CH2:10][NH:1][C:9](=[O:5])[CH2:14][CH2:13]3)[CH:19]=2)[CH:21]=[C:22]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][N:29]=2)[CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCNC(=O)CC3)c2)c1
Temperature: 65 °C

Procedure:
Sodium azide (155 mg, 2.39 mL) was added to a solution of N-{3-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (732 mg, 1.59 mmol) in chloroform (8.0 mL) followed by methanesulfonic acid (1.24 mL, 19.1 mmol). The reaction was heated to 65° C. for 2 h. The reaction was cooled to room temperature and water was added, followed by NaOH (1N). The organic layer was extracted with EtOAc (3×). The combined layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10% methanol/dichloromethane) to afford racemic 5-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]azepan-2-one as a white solid. MS ESI calcd. for C21H21F3N6O [M+H]+ 431. found 431.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>ClCCl.N1C=CC=CC=1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=4[N:7]4[C:3]([CH2:2][NH:1][C:34](=[O:36])[CH3:35])=[CH:4][CH:5]=[C:6]34)[CH2:12][CH2:13]2)=[O:18])=[CH:20][C:21]=1[CH3:29])([CH3:27])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CN)ccc23)ccc1OC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccc2n1-c1ccccc1OC21CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Crude (1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone (49 mg, 0.11 mmol) was dissolved in a solution of dry dichloromethane (0.5 mL) and pyridine (0.3 mL) and was cooled to 0° C. Acetic anhydride (52 μL, 0.55 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by the addition of methanol (0.5 mL), concentrated, and purified by reverse phase HPLC [10-99% acetonitrile in water (HCl modifier)] to give N-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)acetamide. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.9 Hz, 1H), 7.33-7.21 (m, 2H), 7.13 (d, J=4.2 Hz, 2H), 7.10-7.02 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.26 (d, J=3.4 Hz, 1H), 5.99 (d, J=3.5 Hz, 1H), 5.68 (s, 1H), 4.71 (d, J=4.7 Hz, 2H), 4.64-4.50 (m, 1H), 3.50 (s, 2H), 2.22 (s, 3H), 2.17-1.76 (m, 7H), 1.67 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 487.6. found 488.5 (M+1)+; Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:13]=2[CH:12]=[CH:11]1>>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][N:20]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=3)[S:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:13]=2[CH:12]=[CH:11]1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3occc3c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3occc3c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-(benzofuran-5-ylmethyl)sulfamoyl)benzoate (step-1 of Example 1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:33])[CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(cc(NC3CCN(C)CC3)c3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.42 h

Procedure:
To a mixture of 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (50. mg, 0.13 mmol, from Example 206) and formaldehyde (37 wt % solution in water, 12 mg, 0.15 mmol, Aldrich) in DCM (2.6 mL) was added Na(OAc)3BH (42 mg, 0.20 mmol, Aldrich). After 25 minutes, volatile solvent was removed in vacuo. The mixture was diluted with water and methanol, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (24.8 mg, 49%).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: Clc1ncccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12

Procedure:
[7-(2-Chloro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 2-chloro-3-pyridineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow foam (48 mg, 40%). LCMS (m/e) 407 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.50-8.44 (m, 1H), 8.23 (d, 1H, J=7.6 Hz), 7.43 (d, 2H, J=7.8 Hz), 7.41-7.34 (m, 1H), 7.10-7.05 (m, 1H), 6.88-6.80 (m, 3H), 6.67 (s, 1H), 3.91-3.82 (m, 4H), 3.13-3.06 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:37])[N:7]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]([C@H:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][C:40]=1[CH3:47]>>[NH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([F:38])=[C:40]([CH3:47])[CH:41]=1)[C@@H:12]([C:8]1[N:7]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6](=[O:37])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][CH3:14]
Reactant: CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: Cc1cc(C=O)ccc1F
Product: CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccc(F)c(C)c1

Procedure:
This compound was synthesized as described in general procedure C except 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-propylamino]-propyl}-isoindole-1,3-dione was used instead of (R)-2-(3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propyl)isoindoline-1,3-dione and 4-fluoro-3-methyl benzaldehyde was used instead of 4-methyl benzaldehyde. LCMS: m/e 508.04 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Br:18]Br>C(Cl)(Cl)Cl.[W]>[Br:18][CH:5]([C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:3][CH2:1][CH3:2])=[O:17]
Reactant: CCOC(=O)Cc1ccccc1C(=O)OCC
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccccc1C(Br)C(=O)OCC
Temperature: 20 °C
Yield: 50.2 %

Procedure:
A solution of ethyl 2-[2-(ethyloxy)-2-oxoethyl]benzoate (4.15 g, 17.5 mmol) in chloroform (70 ml) was treated with bromine (1.3 ml, 25 mmol) and stirred at reflux, whilst irradiating with a 120 W tungsten bulb, for 5 hrs. The mixture was cooled to 20° C., evaporated and purified by automated flash silica-gel column chromatography (using a Biotage SP4), eluting with 0-10% gradient of ethyl acetate in hexane (10 column volumes), to give ethyl 2-[1-bromo-2-(ethyloxy)-2-oxoethyl]benzoate (2.77 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][C:17]#[N:18])[CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[N:21]=2)=[CH:4][CH:3]=1.C(O)C.[H][H]>O=[Pt]=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[N:21]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cc(CC#N)ccn23)n1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cc(CCN)ccn23)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 300 mL pressure bottle containing nitrile 22 (980 mg, 2.41 mmol) was charged with ethanol (18 mL), chloroform (2 mL), and then PtO2 (200 mg, 0.881 mmol). The pressure bottle was then sealed, then charged with 50 psi hydrogen, and the reaction mixture was allowed to stir at room temperature for 12 hours, after which additional PtO2 (500 mg, 1.14 mmol) was added, and an the pressure bottle was charged with an additional 50 psi hydrogen then sealed, and the reaction mixture was stirred at room temperature for 3 hours. At this point, TLC analysis showed the reaction to be complete. The reaction mixture was then filtered through successive 0.45 □m Gelman nylon acrodiscs. The filtrate was then concentrated under reduced pressure and carried onto the next step without further purification. Crude yield of 23: 1.20 g (121%). MS (ESI+) 412.2.
Reaction SMILES: N#N.C[O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1.O.[OH-].[Li+]>C1COCC1.O>[CH3:15][C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:16])=[O:4])[O:14][CH2:13][CH2:12][O:11]1
Reactant: COC(=O)CCCCC1(C)OCCO1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CCCCC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoic acid methyl ester (5.43 g, 26.85 mmol) in a mixture of THF (70 mL) and water (70 mL) was treated at rt with lithium hydroxide monohydrate (1.45 g, 34.55 mmol) and the mixture was stirred for 3 h at rt. The THF was removed under reduced pressure and the aqueous phase was washed with EA, concentrated under reduced pressure and poured in cold sat. aq. NH4Cl. The pH was adjusted to 4-5 using 1N HCl and the aqueous phase was extracted with EA (3×). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1→1:2 hept-EA) gave the title compound as a white solid. LC-MS-conditions 02: tR=0.68 min [M+H]+=189.52.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][N:34]=1.[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51]O)=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1>[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51][O:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][N:34]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccccc12
Temperature: 5 °C
Yield: 68.9 %

Procedure:
To a solution of triphenylphosphine (0.95 g) in tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.63 g) with stirring at 5° C., then stirred at the same temperature for 15 minutes. To a reaction mixture, 3-hydroxy-1,2-benzisoxazole (0.45 g) was added and stirred for 15 minutes, then N-t-butoxycarbonyl ethanolamine (0.53 g) was added and the mixture stirred at room temperature for 24 hour. The solvent was evaporated under reduced pressure and residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.63 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>CN(C)C=O.C(OCC)(=O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Temperature: 115 °C

Procedure:
To a solution of 4-fluoroaniline (2.40 mL, 24.5 mmol) in N,N-dimethylformamide (30 mL) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give 2-amino-N-(4-fluoro-phenyl)-benzamide as white solid. Yield: 2.00 g (35%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:18]([N:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[NH:28][CH:27]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26]1=[O:42])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]1([S:14]([N:32]2[CH2:33][CH2:34][C:29]3([N:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26](=[O:42])[CH:27]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]3)[CH2:30][CH2:31]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cc2ccccc2)NC2(CCN(S(=O)(=O)c3ccccc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently benzenesulfonyl chloride (0.19 ml, 0.26 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro-[4,5]decan-2-one (250 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml), and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent, and column chromatography, the desired product 8-benzenesulfonyl-1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 259 mg (73% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[CH3:23][C@H:24]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[O:35])[NH:25]1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:25]2[C@@H:24]([CH3:23])[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][C:26]2=[O:35])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-Bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [Cl-].[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH3+:22])[CH:17]=2)[O:12][CH2:11][CH:10]1[NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC1C=CN=C(N)C=1C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[N:40]1>C(Cl)Cl>[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:22][S:44]([C:42]3[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH:17]=2)[O:12][CH2:11][CH:10]1[NH:23][C:24](=[O:25])[O:26][CH2:27][CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CCOC(=O)NC1COc2ccc(OCC[NH3+])cc2C1Cc1ccccc1
Agent: Cc1ccnc(N)c1C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)NC1COc2ccc(OCCNS(=O)(=O)c3cnn(C)c3)cc2C1Cc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
100 mg (0.25 mmol) of 2-(4-benzyl-3-(ethoxycarbonylamino)chroman-6-yloxy)ethanaminium chloride were dissolved in 5 ml methylene dichloride. Then, 95 mg (0.79 mmol) dimethyl aminopyridine and 54 mg (0.30 mmol) 1-methyl-1H-pyrazole-4-sulfonyl chloride were added. The reaction mixture was stirred at room temperature over night. The mixture was concentrated in vacuo and the residue was dissolved in ethylacetate and water. The phases were separated. The organic phase was washed with saturated ammonium chloride solution (2×), dried over MgSO4 and concentrated (127 mg crude). The crude material was purified by column chromatography to give 118 mg (0.23 mmol, 93%) of the desired product.