Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[NH:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:28](Cl)(=[O:30])[CH3:29].C(OCC)(=O)C>CN(C)C=O.O>[C:16]1([CH:8]([NH:7][C:3]2[N:4]([C:28](=[O:30])[CH3:29])[CH2:5][CH2:6][N:2]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(CC(NC2=NCCN2)c2ccccc2)cc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN=C1NC(Cc1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 21.7 %

Procedure:
A mixture of 457 mg (4,5-dihydro-1H-imidazol-2-yl)-(1,2-diphenylethyl)-amine hydroiodide (1.16 mmol) and 400 mg potassium carbonate (2.9 mmol) in 20 ml dimethylformamid was treated with 83 mg acetyl chloride (1.06 mmol) and heated up to 50° C. for 6 hours. Aqueous work-up with ethyl acetate and water yielded a crude that was purified by column chromatography on silica gel to give 70 mg product (0.23 mmol, 22%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:29])=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:21][CH2:20]4)=[C:13]3[C:12]([CH3:30])=[CH:11]2)=[C:5]([CH3:31])[CH:4]=1.Cl.[CH2:33]([O:35][C:36](=[O:46])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:38])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O.C(N(CC)CC)C>[CH2:33]([O:35][C:36](=[O:46])[C@@H:37]([NH:38][C:26](=[O:27])[CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:18]2[CH:17]=[C:16]([CH3:29])[N:15]=[C:14]3[N:10]([C:6]4[C:5]([CH3:31])=[CH:4][C:3]([Br:2])=[CH:8][C:7]=4[CH3:9])[CH:11]=[C:12]([CH3:30])[C:13]=23)[CH2:20][CH2:21]1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:34]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid hydrochloride (300 mg), L-phenylalanine ethyl ester hydrochloride (204 mg), 1-hydroxybenzotriazole (108 mg) and triethylamine (90 mg) in DMF (3 mL) in an ice cooling bath was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg), and the mixture was stirred at room temperature for 4 hours. Water was added into the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaHCO3 solution and brine, and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1) to obtain (S)-2-(2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetylamino)-3-phenyl-propionic acid ethyl ester (222 mg) as a colorless oil.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Br:4][C:5]1[S:19][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][NH:15][C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1>>[Br:4][C:5]1[S:19][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([CH2:1][CH3:2])[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1
Reactant: CCBr
Reactant: O=c1cc2c(n[nH]1)-c1cc(Br)sc1SCC2
Product: CCn1nc2c(cc1=O)CCSc1sc(Br)cc1-2

Procedure:
The reaction and procedure are conducted in the same manner as in Example 36 using ethyl bromide in place of methyl iodide and using 9-bromo-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in place of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as used in Example 36 to give 9-bromo-2-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 149°-151° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.CCCCCC>[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]1[CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of dry diisopropylamine (7.7 ml, 5.5 ×10-2 mol) and dry THF (25 ml) under argon at 0° C. is added dropwise a hexane solution of n-butyl-lithium (21.1 ml, 5.5 ×10-2 mol). After stirring 1/2 hour at 0° C. a solution of t-boc-piperazinone (2) (5.0 g, 2.5 ×10-2 mol) and dry THF (125 ml) is added dropwise. The resultant mixture is stirred at 0° C. for 3 hours before a solution of p-benzyloxybenzyl chloride (6.40 g, 0.75 ×10-2 mol) and dry THF (20 ml) is added dropwise via syringe. This mixture is stirred an additional hour at 0° C. before the cooling bath is removed and the reaction allowed to warm to room temperature. After stirring overnight the mixture is quenched into saturated aqueous NH4Cl. The aqueous phase is extracted with Et2O (3 times) and CH2Cl2 (2 times). The ethereal extracts are combined and subsequently washed with saturated aqueous NaCl as are the CH2Cl2 extracts. The ethereal and CH2Cl2 extracts are then combined and dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives 3a as an almost colorless solid which crystallizes from ethyl acetate as colorless prisms 5.2 g (53%), m.p. 145°-147° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:24]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:24]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COCCCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 309c (120 mg, 0.30 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate monohydrate (82 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), and acetonitrile/water (8/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The water layer was extracted with dichloromethane (2×10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 309d (150 mg, 74%) as yellow solid. MS-ESI: [M+H]+ 668.9
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([S:39]([NH:42][CH3:43])(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:31][C:32]1[CH:33]=[C:34]([S:39]([NH:42][CH3:43])(=[O:40])=[O:41])[CH:35]=[CH:36][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: CNS(=O)(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(-c4nccs4)[nH]3)c2)c(F)c1
Temperature: 100 °C
Reaction time: 19 h
Yield: 29.3 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60.0 mg, 0.139 mmol) synthesized in Example (38d) and 3,4-difluoro-N-methylbenzenesulfonamide (47.4 mg, 0.229 mmol) synthesized in Example (58a) were dissolved in N,N-dimethylformamide (5.0 mL), and potassium carbonate (77.0 mg, 0.557 mmol) was added, followed by stirring at 100° C. for 19 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-25%) to afford the desired compound (21.1 mg, yield 30%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]([NH2:27])=[O:26]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:19]=[CH:20][CH:21]=3)[NH:24][C:25](=[O:26])[N:27]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(C(=O)/C=C/c2cccc(OCC(=O)O)c2)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
(E)-2-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid (15.0 g, 48.0 mmol) and urea (14.4 g, 0.24 mol) were suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 150 mL of 2-propanol and heated in a 90° C. oil bath for 10 minutes, then cooled down to room temperature. The suspension was filtered and washed with 50 mL of 2-propanol and dried in the air. 9.2 g (54%) of the desired ({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}oxy)acetic acid were obtained. 1H NMR (400 MHz, DMSO-d6): 10.39 (s, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.65 (s, 1H), 7.40-7.55 (m, 2H), 7.16 (m, 1H), 6.95 (m, 1H), 4.80 (s, 2H), 2.20 (s, 3H). MS (EI) for C19H16N2O5: 353 (MH+).
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([Br:42])=[C:27]([C:29]2[CH2:33][C:32]([CH2:38]C(O)=O)([CH2:34][C:35]([OH:37])=[O:36])[O:31][N:30]=2)[CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([Br:42])=[C:27]([C:29]2[CH2:33][C:32]([CH2:38][C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])([CH2:34][C:35]([O:37][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:36])[O:31][N:30]=2)[CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CC1(CC(=O)O)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
1,1-Di-tert-butoxy-N,N-dimethylmethanamine (22.11 g) was added dropwise to a mixture of 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetic acid (9.75 g) and toluene (100 mL) at 100 C, and the obtained mixture was stirred at 100 C for 30 minutes. Further, 1,1-di-tert-butoxy-N,N-dimethylmethanamine (5.53 g) was added thereto, and the obtained mixture was stirred at 100 C for 30 minutes. Further, 1,1-di-tert-butoxy-N,N-dimethylmethanamine (2.211 g) was added thereto, and the obtained mixture was stirred at 100 C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then, the residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was washed with hexane to obtain the title compound (5.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: Cc1ccc(N)c(C#N)c1
Reactant: NS(=O)(=O)Cl
Product: Cc1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from 2-amino-5-methylbenzonitrile (Example 14b) and sulfamoyl chloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(OS(C)(=O)=O)c1ccc(C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (341 mg, 2.97 mmol) was added dropwise to a solution of ethyl 4-(1-hydroxybutyl)benzoate (504 mg, 2.27 mmol) and triethylamine (477 mg, 4.58 mmol) in dichloromethane (5 mL) at 0° C. The reaction was stirred at 0° C. for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride, saturated sodium bicarbonate, and brine. The organics were dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-(methylsulfonyloxy)butyl)benzoate. 1H NMR (400 MHz, CDCl3, δ): 8.02-8.10 (d, J=8.19 Hz, 2H), 7.44 (d, J=8.19 Hz, 2H), 5.50-5.61 (m, 1H), 4.37 (q, J=7.22 Hz, 2H), 1.97-2.11 (m, 1H), 1.78-1.88 (m, 1H), 1.39 (t, J=7.22 Hz, 3H), 1.28-1.52 (m, 2H), 0.94 (t, J=7.41 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[N:25](C(OC(C)(C)C)=O)[CH:26]=[CH:27][CH:28]=1)[CH:15]=2)=[O:10].[OH-].[Na+].O>ClCCl>[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1)[CH:15]=2)=[O:10]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)Nc1[nH]c2cc(-c3ccc[nH]3)ccc2c1C(N)=O
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Trifluoroacetic acid (0.50 mL, 6.7 mmol) was added to a solution of 2-aminocarbonylamino-6-(1-tert-butoxycarbonylpyrrol-2-yl)indole-3-carboxamide (Compound 4-20, 28 mg, 0.073 mmol) in dichloromethane (0.5 mL) under ice-cooling, and the mixture was stirred for 30 minutes. 2 N Sodium hydroxide aqueous solution (3.5 mL) and water (10 mL) were added to the reaction mixture, and the whole was extracted with ethyl acetate (15 mL). The organic layer was washed with water (5 mL), brine (5 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.0 mg) as an off-white solid (yield 29%).
Reaction SMILES: [CH:1]1([CH2:6][C:7](=O)[CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[N+:16]=[N-:17].[O-]CC.[Na+].O>C(O)C>[CH:1]1([CH2:6][C:7]2[N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)[N:16]=[N:17][C:8]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CC1CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
Ethyl 4-cyclopentyl-3-oxobutyrate (0.781 g, 3.94 mmol, 1.25 eq.) obtained in Example 103a) and 4-azido-N-ethylbenzamide (0.60 g, 3.15 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (298 mg, 3.94 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 12 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate (35 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-yellow powder (971 mg, 2.84 mmol, 90.0%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:21][C:20]4[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Reactant: ClCc1ccc(Cl)cc1
Product: Clc1ccc(CSc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 89 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-chlorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[O:12]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C([O-])(=O)C.[Na+]>C(O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([O:12][C:4]3=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]3[CH2:13]2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cn1cc([N+](=O)[O-])nc1O2
Yield: 28.7 %

Procedure:
2,4-Dinitro-1H-imidazole (1.0 g, 6.3 mmol), tert-butyl 1-oxa-6-azaspiro[2,5]octane-6-carboxylate (2.0 g, 9.5 mmol) and sodium acetate (612 mg, 7.5 mmol) in ethanol (7 ml) were stirred under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution and methylene chloride were added followed by stirring vigorously, and then the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was crystallized from methylene chloride-diisopropyl ether to afford 1′-tert-butoxycarbonyl-2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine] (586 mg, yield 29%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:10].[CH3:11]O>>[ClH:10].[NH2:1][C:2]1([C:7]([O:9][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1(C(=O)O)CCCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(N)CCCC1
Reaction time: 2 h

Procedure:
A solution of 1-aminocyclopentanecarboxylic acid (2.00 g, 15.5 mmol) in MeOH (30 mL) was saturated with HCl (g). The resulting mixture was aged at ambient temperature for 2 h and concentrated in vacuo to provide the title compound. MS: m/z=144 (M+1).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:32])[C:12]2[O:18][C:17]3[C:19]([Cl:28])=[CH:20][C:21]([NH:23][C:24](=[O:27])[CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:29])[C:13]=2[CH:31]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:32])[C:12]2[O:18][C:17]3[C:19]([Cl:28])=[CH:20][C:21]([NH:23][C:24](=[O:27])[CH2:25][NH:4][CH:1]4[CH2:3][CH2:2]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:29])[C:13]=2[CH:31]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CC3)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Cyclopropyl amine (0.285 ml, 4.067 mmol) was added to a solution of Example 133 (0.6 g, 1.35 mmol) in DMF (15 mL) and the reaction mixture was stirred at 80° C. for 2 h. It was concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.58 g (92%); 1H NMR (CDCl3): δ 0.6 (s, 4H, 2CH2), 2.4 (m, 1H, CH), 2.67 (s, 3H, CH3), 3.6 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 4.7 (s, 2H, CH2), 7.6 (s, 1H, Ar), 7.65 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar), 9.35 (bs, 1H, NH); MS: m/e (ES+) 465 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:6]2.Br[CH2:19][C:20]([OH:22])=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:7]1([CH2:12][CH2:11][N:10]([CH2:19][C:20]([OH:22])=[O:21])[CH2:9][CH2:8]1)[CH2:6]2
Reactant: O=C(O)CBr
Reactant: COc1ccc2c(c1)CC1(CCNCC1)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC1(CCN(CC(=O)O)CC1)C2=O
Yield: 65.9 %

Procedure:
A stirred solution of 5-methoxyspiro[indene-2,4′-piperidin]-1(3H)-one (511 mg, 1.93 mmol), bromoacetic acid (349 mg, 2.51 mmol) and DIPEA (1.013 mL, 5.80 mmol) in DMF (5 mL) was heated at 100° C. for 20 min via microwave. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with 5 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 100:0 to 85:15 CH2Cl2/MeOH with 5% NH4OH over 20 min) to give the title compound (368 mg, 1.272 mmol). MS calculated for C16H19NO4 290.3. found (ESI) m/z 290.1 (M+H)+, retention time 1.10 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].CO>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][OH:6])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COc1ncccc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncccc1CO
Temperature: 70 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a 100-mL round-bottomed flask was added 2-methoxynicotinic acid (1.52 g, 9.93 mmol, Aldrich, St. Louis, Mo.) and borane methyl sulfide complex (3.77 mL, 39.7 mmol, Aldrich, St. Louis, Mo.) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 70° C. for 16 h. The mixture was cooled to 0° C. and MeOH (10 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred for further 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give (2-methoxy-3-pyridinyl)methanol (1.15 g) as a white solid.