Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1.C1C(=O)N([Br:22])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[C:9]=1[Br:22]
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(OC)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
3,5-Dimethoxy-benzoic acid methyl ester (4.0 g) was dissolved in MeCN (28 mL), and NBS (4.4 g) was added at 0° C. After stirring at room temperature for 3 hours, saturated Na2SO3 (15 mL) was added. The mixture was evaporated under vacuum and extracted with ether (1×, 500 mL). After the solvent was removed, the crude material was subjected to silica gel chromatography using effluent of 10-40% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-bromo-3,5-dimethoxy-benzoic acid methyl ester (5.2 g, 93%) as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[CH:14][N:13]=2)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[CH:14][N:13]=2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4[N+](=O)[O-])nc3c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Yield: 81.5 %

Procedure:
A mixture of tert-butyl 4-((2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate (2.13 g, 4.7 mmol), NH4Cl (2.00 g, 37 mmol), iron powder (1.31 g, 23.5 mmol), H2O (40 mL) and methanol (160 mL) was refluxed for 3 h under N2. The reaction mixture was filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography (petroleum ether: ethyl acetate: Et3N=800:200:1) to afford tert-butyl 4-((2-(2-aminophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate as a yellow solid (1.63 g, yield: 81%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[N:7]([CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:32])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:32])[N:7]([CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][O:24]2)/[C:8](=[N:10]/[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)nn1C[C@H]1CCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Yield: 54.9 %

Procedure:
A mixture of Example 45C (392 mg, 1.0 mmol) and dimethyl sulfate (0.38 mL, 4.0 mmol) in toluene (2 mL) was heated in a microwave at 130° C. for 1 hour. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, MeOH/Et3N (90:10) in EtOAc in 10-60% gradient) to yield 223 mg (55%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.51-1.68 (m, 1H), 1.79-1.97 (m, 2H), 2.01-2.18 (m, 1H), 3.62-3.84 (m, 2H), 3.92 (s, 3H), 4.07-4.12 (s, 3H), 4.14-4.26 (m, 1H), 4.50-4.63 (m, 1H), 4.65-4.79 (m, 1H), 6.92-7.02 (m, 1H), 7.31 (d, J=8.82 Hz, 1H), 7.63-7.75 (m, 2H); MS (ESI) m/z 406 [M+H]+, 404 [M−H].
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[OH-].[K+:34].CO>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([O-:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[K+:34]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid (0.20 g) was added to a mixture of a 1N aqueous potassium hydroxide solution (0.46 mL), methanol (5 mL) and tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give crystals (0.19 g, yield 86%) of potassium 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate. Recrystallization from methanol-diethyl ether gave colorless prism crystals. melting point: 157-159° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([S:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[CH3:28][C:29]1[CH:30]=[CH:31][N:32]2[C:37]=1[C:36](=[O:38])[N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([C@@H:45]([NH3+:47])[CH3:46])=[N:33]2.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([S:11][C:10]2[C:3]3[C:2]([NH:47][C@H:45]([C:34]4[N:35]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:36](=[O:38])[C:37]5=[C:29]([CH3:28])[CH:30]=[CH:31][N:32]5[N:33]=4)[CH3:46])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccn2nc([C@H](C)[NH3+])n(-c3ccccc3)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1cc(Sc2ccc(N)cc2)c2c(Cl)ncnc21
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3ccc(N)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 42.9 %

Procedure:
4-((4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)aniline (350 mg, 0.73 mmol) was treated with (S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethanaminium chloride (215 mg, 0.80 mmol), cesium fluoride (11 mg, 0.07 mmol), N,N-diisopropylethylamine (318 μl, 1.83 mmol) and tert-butanol (4 ml) as a solvent according to Preparation 163. The residue was purified by reverse phase using SP1® Purification System to obtain 200 mg (40% yield) of the title compound. Yield 98%.
Reaction SMILES: C(O)(=O)[C@H:2]([C:4]1C=CC=C[CH:5]=1)[OH:3].[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:5][CH2:4][CH2:2][OH:3])[CH2:14]1
Reactant: C[C@H]1CCCNC1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H]1CCCN(CCCO)C1
Yield: 77.2 %

Procedure:
(3S)-3-methylpiperidin(S)-(+)-mandelate (19.9 g, 79.1 mmol), 3-bromo-1-propanol (10 g, 71.9 mmol) and potassium carbonate (14.9 g, 108 mmol) were mixed in THF (200 mL), and heated under reflux for 30 hours. The insoluble matter was separated by filtration, the filtrate was concentrated, and ethyl acetate and hexane were added to the residue. The resulting insoluble matter was separated by filtration, the filtrate was concentrated and evaporated under reduced pressure to obtain the intended product (9.6 g, 85%) as a colorless oil. (3S)-3-methylpiperidin (S)-(+)-mandelate was synthesized according to the method described in a reference (J. Org. Chem., 1987, Vol. 52, p. 5466).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]2[CH3:48])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[CH3:48][C:40]1[N:39]([CH:36]2[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[O:16])[CH2:4]3)[CH2:38][CH2:37]2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=1
Reactant: Cc1nc2ccccc2n1C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4c(C)nc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 69.8 %

Procedure:
The title compound was prepared from 60 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 50 mg of 1-1-piperidin-4-yl-2-methyl-1-H-benzoimidazole (from Step B) and 80 mg of sodium triacetoxyborohydride in 4 mL THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 61 mg of the title compound as an oil.
Reaction SMILES: F[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1.[CH2:22](OC1C=C2C(CCC2=O)=CC=1)C(C)C.C(OC)(=O)C=C>>[CH2:4]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1)[CH:3]([CH3:22])[CH3:2]
Reactant: CC(C)COc1ccc2c(c1)C(=O)CC2
Reactant: O=C1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Solvent: C=CC(=O)OC
Product: CC(C)COc1ccc2c(c1)C(=O)C1(CCC(=O)CC1)C2
Yield: 72 %

Procedure:
The title compound (3.02 g, 72% yield) was prepared using the method described for Intermediate 63 starting from 6-isobutoxy-2,3-dihydro-1H-inden-1-one (Intermediate 66, 3.0 g, 14.7 mmol) and methyl acrylate (2.92 mL, 32.3 mmol): 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (m, 8H) 1.86 (m, 2H) 2.11 (dt, 1H) 2.21 (m, 2H) 2.47 (m, 3H) 2.70 (m, 2H) 3.15 (s, 2H) 3.76 (m, 3H) 7.20 (m, 1H) 7.25 (m, 1H) 7.38 (d, 1H); MS (ES+) m/z 287 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]12[CH2:23][CH2:22][CH2:21][CH2:20][C:7]1([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1)[NH:8][C:9](=[O:19])[N:10]2[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)C.[Li+].[OH-].Cl>CO.O>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:7]23[CH2:20][CH2:21][CH2:22][CH2:23][C:6]2([CH2:5][C:4]([OH:33])=[O:3])[N:10]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:9](=[O:19])[NH:8]3)=[CH:26][CH:27]=1)#[N:32]
Reactant: CCOC(=O)CC12CCCCC1(Cc1ccc(C#N)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CC23CCCCC2(CC(=O)O)N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Reaction time: 96 h
Yield: 12.2 %

Procedure:
[7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid ethyl ester (34 mg) (0.07 mmol) and LiOH (3.0 mg) (1.1 eq) in a 1:1 mixture of MeOH/H2O (4 ml) (5 ml) were stirred 4 days. The reaction mixture was acidified with an aqueous solution of HCl 1N, then concentrated. The residue was purified on HPLC to give [7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid (3.9 mg) as a white solid. 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 7.15 (1H, m), 6.75 (2H, m), 5.0 (1H, m), 4.45 (1H, d), 3.83 (1H, d), 3.05 (1H, d), 2.9 (1H, d), 2.5-2.1 (2H, m), 2.1-1.8 (4H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:7]/[CH:8]=[N:9]/[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH2:7][CH2:8][NH:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:2]
Reactant: CCOC(=O)CN(C/C=N/N1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CN(CCNN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Reaction time: 5.5 h
Yield: 81.2 %

Procedure:
A solution of (benzyloxycarbonyl-{2-[(E)-1,3-dioxo-1,3-dihydro-isoindol-2-ylimino]ethyl}-amino)-acetic acid ethyl ester (7.7 mmol) in CH3CN (65 mL) is treated with sodium cyanoborohydride (1.92 g, 30.5 mmol), and acetic acid (6.8 mL, 118.8 mmol) is added with stirring under N2. After 5.5 h, the reaction solution is diluted with EtOAc (150 mL) and washed with saturated aqueous KHCO3 (3×50 mL) and saturated aqueous NaCl (50 mL). The organic phase is dried (MgSO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography (75:25 to 50:50 heptane:ethyl acetate gradient elution) to afford {benzyloxycarbonyl-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylamino)-ethyl]-amino}-acetic acid ethyl ester as an oil (2.66 g, 81%). MS: 426 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.79-7.91 (m, 2H), 7.69-7.79 (m, 2H), 7.17-7.39 (m, 5H), 5.04-5.21 (m, 2H), 4.87-5.04 (m, 1H), 4.04-4.23 (m, 4H), 3.48-3.59 (m, 2H), 3.18-3.38 (m, 2H), 1.10-1.30 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38]([O:40]CC)=[O:39])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O.O.[OH-].[Li+]>O1CCCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38]([OH:40])=[O:39])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(C)Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(CC(C)C(=O)O)c2ccc(C(=O)NCC3CCCC3)cc21
Reaction time: 6 h
Yield: 95.3 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-ethoxycarbonylpropyl)indol-1-ylmethyl]-3-methoxybenzoate (0.75 g) in a mixture of tetrahydrofuran (3.5 ml), methanol (3.5 ml), and water (1.3 ml) was treated with lithium hydroxide monohydrate (0.33 g). The mixture was stirred at 30° for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 10% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-carboxypropyl)indol-1-ylmethyl]-3-methoxybenzoate (0.68 g, 95%) as a white powder; mp 195°-197°; partial NMR (80 MHz, CDCl3): 2.55-3.24(m, 3H, CH2CHCH3), 3.38(t, 2H, NHCH2), 3.91(s, 3H, OCH3), 5.24(s, 2H, NCH2), 6.17(br t, 1H, NH), 6.61(d, 1H, Ar), 7.04(s, 1H, H2 -indole), 7.85(br s, 1H, H7 -indole).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: COc1ccccc1C=O
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and 2-methoxybenzaldehyde (0.08 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (119 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: c1coc(C2CCCN2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccco2)cc1

Procedure:
The title compound, white solid, m.p. 58° C. and MS: m/e=291 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-furan-2-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+]>CN(C)C=O.Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]2[CH2:11][CH:5]([CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[C:4]([OH:21])=[C:37]([C:32]3[NH:31][C:30]4[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=4[S:34](=[O:35])(=[O:36])[N:33]=3)[C:38]2=[O:39])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(CC=C(C)C)CNCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [H-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)=CCC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A solution of 2-[(4-fluoro-benzylamino)-methyl]-5-methyl-hex-4-enoic acid ethyl ester (102 mg, 0.35 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (115 mg, 0.345 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) in anhydrous N,N-dimethylformamide (5 mL) was treated with N-methylmorpholine. The reaction was stirred for 1 h at 25° C., diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (41 mg, 1.74 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 10 to 80% ethyl acetate in hexanes) to give N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-(3-methyl-but-2-enyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (90 mg, 46%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.54 (s, 3H), 1.69 (s, 3H), 2.15-2.23 (m, 1H), 2.39-2.44 (m, 1H), 2.60-2.66 (m, 1H), 3.06 (s, 3H), 3.19 (dd, 1H, J1=13.1 Hz, J2=4.3 Hz), 3.45 (dd, 1H, J1=12.4 Hz, J2=5.4 Hz), 4.61 (s, 2H), 4.89 (t, 3H, J=6.6 Hz), 7.05 (t, 2H, J=8.5 Hz), 7.23-7.28 (m, 3H), 7.63-7.66 (m, 1H), 7.69 (d, 1H, J=2.2 Hz). LC-MS (ESI) calculated for C25H27FN4O6S2: 562.6, found 563.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:8]2([F:11])[F:10])=[CH:4][C:3]=1[N+:21]([O-])=O.[Sn](Cl)Cl.[F-].[K+]>O1CCOCC1.Cl>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[Cl:1])[CH2:6][C:7]1([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:9][C:8]1([F:11])[F:10]
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [F-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1(F)F
Temperature: 70 °C

Procedure:
1.60 g (4.60 mmol) of (+/−)-tert-butyl 1-(4-chloro-3-nitrobenzyl)-2,2-difluorocyclopropanecarboxylate were dissolved in 20 ml of dioxane, and 4.36 g (23.0 mmol) of tin(II) chloride and a few drops of 1 N hydrochloric acid were added at RT. The reaction mixture was heated at 70° C. for 1 h. After cooling to RT, 10 ml of 10% strength aqueous potassium fluoride solution were added. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→10:1). This gave 1.16 g of the target product (79.3% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN1C(=O)CCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 50 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroanisole (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (2.0 eq) in NMP at 100° C. for 16 hours yielding tert-butyl 4-(4-methoxy-2-nitro phenyl)piperazine-1-carboxylate (50%). LCMS (m/z): 338.2 (MH+); LC Rt=3.37 min.
Reaction SMILES: O[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20].CCN(CC)CC>>[CH3:18][S:19]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:21])=[O:20]
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2ccccc2)c1S(C)(=O)=O

Procedure:
An ethereal solution (1 liter) containing 50.0 g (0.22 mol) of methyl 2-hydroxy-3-phenylbenzoate, 0.25 mole of methanesulfonyl chloride and 0.25 mole of Et3N was allowed to react at room temperature for 18 hours. The reaction mixture was washed with 1 N NaOH (1 × 1 liter) and H2O (1 × 500 ml). After drying with MgSO4 the ether solution was evaporated to give a yellow solid; yield 61.9 g (91.7%), mp. 101°-115°. Recrystallization of the crude product from benzene-hexane gave the analytical sample, mp. 120°-124°.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1COCC1>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of benzylamine (60.3 mL) and triethylamine (96.3 mL) in THF (800 mL) was added chloroacetyl chloride (45.8 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over night. Additional chloroacetyl chloride (4.6 mL) was added and stirring was continued until no starting material could be detected. The reaction mixture was filtered, washed with ethyl acetate and concentrated. The crude product was crystallized from dichloromethane to yield N-benzyl-2-chloro-acetamide (71.6 g) as off-white solid.