Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36]OS(C)(=O)=O)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]>C1COCC1>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CN2CCCC2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
N-Ethyldiisopropylamine (132 mg, 1.02 mmol) and pyrrolidine (145 mg, 2.04 mmol) were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methane-sulphonyloxymethyl-phenyl)-acetate (221 mg, 0.511 mmol) obtained in Example 234.3 in THF (2 ml) and the mixture was stirred for 1 h. at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 99:1). There were obtained 153 mg (73%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-pyrrolidin-1-ylmethyl-phenyl)-acetate as a yellowish foam; MS: 408 ([M+H]+).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]1([N:14]([C:21]2[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1CCCCC1.Cl>N1C=CC=CC=1>[C:21]1([N:14]([C:8]2[CH:9]=[CH:10][C:11]([CH:1]=[CH:2][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:27][CH:28]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
All glassware was dried in a drying oven heated to 140° C. Malonic acid was dried on a high vacuum line over P2O5 and then stored in a nitrogen purged glovebox. Pyridine (Aldrich, anhydrous, 99.8%) and piperidine were used as received and stored in the glovebox. In a 100 mL round bottom flask equipped with a stir bar, condenser and nitrogen inlet-outlet was dissolved malonic acid (2.3 g, 22.0 mmol) in 20 mL pyridine. 4-(N,N-Diphenylamino)benzaldehyde (5.0 g, 18.3 mmol) was added and addition of 20 mL pyridine was necessary to obtain a solution. Piperidine (0.18 mL, 1.8 mmol) was added and the solution was heated to reflux. After heating for 25 hours, malonic acid (0.60 g, 5.8 mmol) was added and heating was resumed for an additional 2.5 h after which time no further reaction was observed. The reaction mixture was allowed to cool to room temperature and then poured into a stirring mixture of 12 N HCl in ice water (1:5). The mixture was filtered and the solids rinsed three times with 20 mL water. The solids were collected and the crude product was purified by recrystallization from 5:3 hexanes:EtOAc at 4° C. The mother liquor was concentrated and recrystallized in a similar fashion from 7:3 hexanes:ethyl acetate. The combined crops give 3.1 g of a light brown powder. The yield was 55%.
Reaction SMILES: [N:1]([C:4]([CH3:24])([CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[C:16]([CH3:21])([N:18]=[N+]=[N-])[CH3:17])=[O:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C:4]([CH3:24])([CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[C:16]([CH3:17])([NH2:18])[CH3:21])=[O:6]
Reactant: CC(C)(N=[N+]=[N-])C(=O)Nc1ccccc1NC(=O)C(C)(C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)C(=O)Nc1ccccc1NC(=O)C(C)(C)N
Yield: 57 %

Procedure:
Wet diazide 18 is then dissolved in ethanol and hydrogenated using palladium on charcoal as the catalyst. The reaction is monitored by IR spectroscopy to verify complete reduction of the azido groups. After hydrogenation is complete, the catalyst is filtered off and the filtrate is dried on a rotary evaporator and under high vacuum to give 1,2-bis(2-amino-2-methylpropanamido)benzene (diamine 20) in 100% crude yield (95% purity by NMR=95% yield) from dibromide 16. This product may be used as is, or may be purified by recrystallization from isopropyl alcohol to obtain an analytical sample. In contrast, Collins et al. report a 57% yield for the comparable sequence of the two steps of azide formation and hydrogenation for their synthesis. As indicated earlier, the substantial increase in yield for this two step sequence may be due to the relatively high purity of the dibromide 16 used, which is a direct result of the use of THF as a precipitate-forcing solvent during formation of the dibromide 16. It will be apparent to those with ordinary skill in the art that methods other than hydrogenation with a platinum group metal, e.g., reduction with ammonium sulfide, might be employed for reduction of the azido groups.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[F:24][CH:25]([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH:25]([F:24])[F:36])=[CH:28][CH:29]=3)[C:34]2=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(OC(F)F)cc3)c(=O)n(C3CCCC3)c12
Yield: 41.9 %

Procedure:
1-Cyclopentyl-3-(4-difluoromethoxy-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-difluoromethoxy-4-isocyanato-benzene (0.5 mmol) following general procedure C. LCMS: m/z 454 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]1.[OH-].[Na+].C(O)C>[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)N1CCN(CCCCCO)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Ethyl 4-(5-hydroxypentyl)piperazinecarboxylate (10.87 g, 65.09 mmol), 10% aqueous sodium hydroxide solution (150 mL) and ethanol (150 mL) were placed in a 500 mL round-bottomed flask, and heated under reflux with stirring overnight; the reaction system was cooled down to room temperature, and the solvent was distilled off under reduced pressure, to obtain a pale yellow oil; to the oil, 200 ml of saturated brine was added, followed by extraction with dichloromethane (5×200 mL); the resulting extract was dried with Na2SO4, filtered, and concentrated to obtain a pale yellow oil 9.69 g, yield 86.5% (which was directly used in the next step reaction).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(C)([O-])C.[K+].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[CH2:40]Br>C1COCC1>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:40][C:31]1[CH:32]=[C:33]([C:36]([F:37])([F:39])[F:38])[CH:34]=[CH:35][C:30]=1[Br:29])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (3.9 g, 12 mmol) in THF (50 mL) at room temperature was added potassium tert-butoxide (KOtBu) (13.2 ml of 1M solution, 13.2 mmol) followed by 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (4 g, 12.6 mmol). The mixture was stirred at room temperature for 16 hours. Additional KOtBu in THF (13.2 mL of 1M solution, 13.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexane-ethyl acetate) to yield the title compound (4.72 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3 H) 4.8 (s, 2 H) 4.9 (s, 2 H) 7.4 (dd, J=8.2, 1.7 Hz, 1 H) 7.5 (d, J=1.7 Hz, 1 H) 7.7 (m, 3 H) 7.8 (s, 1 H). MS (ES+) Calc: 561.02, Found: 561.7 (M+1).
Reaction SMILES: CC(OC([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([B:19]([OH:21])[OH:20])[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)C.[ClH:22]>O1CCOCC1.C(OCC)C>[ClH:22].[O:11]1[C:12]2[CH:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: OB(O)c1ccc2c(c1)CNCCO2
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 95 %

Procedure:
(4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (Example 1, step 2) (1.07 g, 3.64 mmol) was dissolved into 4M hydrogen chloride in dioxane and the resulting solution was allowed to stir at room temperature for 1.3 h. The heterogeneous mixture was then diluted with ethyl ether (100 mL) and the solid collected by filtration to give 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (791 mg, 95%). 1H NMR (400 MHz, D2O): 7.79 (dd, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.47 (s, 2H), 4.36 (m, 2H), 3.69 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:6]#[N:7])=[C:4]([S:15][CH3:16])[N:3]=1.C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:6]#[N:7])=[C:4]([S:15]([CH3:16])=[O:25])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(N)cc(-c2ccco2)c1C#N
Solvent: ClCCl
Product: CS(=O)c1nc(N)cc(-c2ccco2)c1C#N
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a stirred suspension of 600 mg (2.59 mmol) 6-amino-4-furan-2-yl-2-methylsulfanyl-nicotinonitrile in 10 ml dichloromethane was added 1,36 g (5.19 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The resulting crystals were collected by filtration and washed with dichloromethane to afford 500 mg (78%) 6-amino-4-furan-2-yl-2-methanesulfinyl-nicotinonitrile as a white crystalline solid. EI-MS m/e (%): 247 (M+, 26), 230 (12), 201 (100), 184 (24), 172 (27), 156 (28), 129 (24), 102 (13).
Reaction SMILES: BrC1C=C[C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[N:37]1C=C[N:40]=[CH:39][C:38]=1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[N:40][CH:39]=[CH:38][N:37]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)c1cnccn1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cnccn4)ccc3c1)n2C1CCCCC1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-pyrazin-2-yl-ethanone (32 mg, 0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (15 mg, 10% yield).
Reaction SMILES: [OH:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][O:14][CH3:15])[C:11](=[O:16])[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:15][O:14][CH2:13][N:12]1[C:6]2[CH:5]=[CH:4][C:3]([N:2]=[O:1])=[CH:23][C:7]=2[C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:9][CH2:10][C:11]1=[O:16]
Reactant: COCN1C(=O)CN=C(c2ccccc2)c2cc(NO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCN1C(=O)CN=C(c2ccccc2)c2cc(N=O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
30 g. of Manganese dioxide was added to a solution of 3.1 g. (0.01 mole) of 1,3-dihydro-7-hydroxyamino-1-methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one in 200 ml. of methylene chloride. After stirring for 10 minutes at room temperature the inorganic material was filtered off and the filtrate was evaporated to leave an oil with a greenish tint. Since crystallization attempts were unsuccessful the material was purified by chromatography over 50 g. of silica gel using 5% ethylacetate in methylene chloride. The thin layer chromatographically pure fractions still did not crystallize.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[NH2:8].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[N:8]=[C:1]=[S:2]
Reactant: Cc1ccc(N)c(F)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N=C=S)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophosgen (4.0 mL) (supplied from Aldrich) was added dropwise to a solution of 2-fluoro-4-methylaniline (6.31 g) (supplied from Aldrich) in 70 mL of chloroform under ice cooling, and subsequently 15 mL of triethylamine was added dropwise thereto at the same temperature. The reaction solution was stirred at room temperature overnight. Then 70 mL of 1 N hydrochloric acid was added thereto, and the mixture was separated into two liquid phases. The organic layer was washed with 70 mL of water, dried on sodium sulfate anhydrate and subsequently concentrated The residue was applied onto the silica gel column and eluted with hexane, to yield 7.72 g of the title compound.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH:17]([CH3:30])[C:18](=[O:29])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=O.[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)(Cl)Cl>[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[N:35]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:19][C:18](=[O:29])[C:17]([CH3:30])=[C:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1Cl
Reactant: Nc1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2Cl)c(-c2ccccc2Cl)cc1=O
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To 200 ml of xylene were added 6.9 g (0.020 mole) of 1,5-bis(2-chlorophenyl)-2-methyl-1,3,5-pentanetrione, 25.5 g (0.20 mole) of 2-chloroaniline and 20.0 g of Molecular Sieves 5A. After heating the reaction mixture under reflux for 2 hours, the reaction mixture was poured into ice water, followed by addition of 200 ml of chloroform thereto and vigorous stirring of the resultant mixture. One hour later, the reaction mixture was filtered to remove solid matter. The organic layer was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) and then recrystallization from acetone to give 1.4 g of 1,2,6-tris(2-chlorophenyl)-3-methyl-4(1H)-pyridinone having a melting point of 205°-207° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8]1=[O:21])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8]1=[O:21])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCC(C)=O)C1=O

Procedure:
A solution of 6-1 (380 mg, 1.0 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 6-2 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)=[CH:4][C:3]=1[Br:28].[OH:29]O>>[NH2:1][C:2]1[C:3]([Br:28])=[CH:4][C:5]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])=[CH:6][C:7]=1[Br:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3cc(Br)c(N)c(Br)c3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3cc(Br)c(N)c(Br)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-amino-3,5-dibromo-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16]>CC#N>[C:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C2CNCCO2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 4-morpholin-2-yl-phenol (3.95 g; 22.0 mmol), and tert-butyl acrylate (9.60 mL; 66.1 mmol) in CH3CN (100 mL) was heated under reflux overnight. After cooling to RT, the mixture was concentrated and purified by column chromatography (SiO2, Et2O) to afford 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (5.22 g).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2].Br[CH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1>>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: Cc1cc(CBr)no1
Reactant: COc1ccc2c(C=O)c(C(C)C)[nH]c2c1
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3cc(C)on3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and 3-(bromomethyl)-5-methylisoxazole by General Procedure J.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])/[CH:55]=[C:50]1\[S:51][C:52]([CH3:54])=[N:53][N:49]\1[CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1ccccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.88 (t, 3 H) 1.26-1.37 (m, 2 H) 1.67-1.76 (m, 2 H) 2.47 (s, 3 H) 4.15 (t, 2 H) 6.16 (s, 1 H) 7.26-7.36 (m, 1 H) 7.39-7.51 (m, 2 H) 7.59-7.68 (m, 1 H); MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([N:8]=[N+:9]=[N-:10])[CH2:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C@H:3]1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:1][C@@H:2]1[C@@H:7]([N:8]=[N+:9]=[N-:10])[CH2:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C@H:3]1[O:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])(=[O:31])[CH3:30]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
Ethyl (3R,4R,5S)-4-Amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (14 gm) was added to triethyl amine (10 gm) and methylene chloride (110 ml) and then the contents were cooled to 20° C. To the contents added acetic anhydride (5.6 gm) at 20-25° C. for 1 hour and then stirred for 3 hours at 20-25° C. The reaction mass was quenched into water (140 ml) and then separated the layers. The organic layer was washed with 8% sodium bicarbonate solution (140 ml) and then washed with 30% sodium chloride solution (140 ml). The organic layer was distilled and recrystallized from n-hexane (70 ml) to give 8.5 gm of Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH3:5][C:6]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)([C@@H:8]1[CH2:10][O:9]1)[CH3:7]>CO>[CH3:5][C:6]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)([CH:8]1[O:9][C:2]([NH2:3])=[N:1][CH2:10]1)[CH3:7]
Reactant: N#CN
Reactant: CC(C)(Oc1ccc2c(c1)CCC2)[C@@H]1CO1
Agent: [Na]
Solvent: CO
Product: CC(C)(Oc1ccc2c(c1)CCC2)C1CN=C(N)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.21 g, 3.21 mmol) in methanol (10 mL) was added slowly (S)-2-(1,1-dimethyl-indan-5-yloxymethyl)-oxirane (0.57 g, 3.21 mmol). The reaction mixture was stirred at room temperature overnight after which the reaction mixture was concentrated. Anhydrous diethyl ether (50 mL) was added. The resulting white precipitate was filtered through Celite and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 0.41 g (49%) of 5-(1,1-dimethyl-indan-5-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])=[CH:3]1.[C:20](=S)=[S:21]>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]=[C:20]2[SH:21])=[CH:3]1
Reactant: S=C=S
Reactant: Cn1cc(CNc2ccccc2N)c2ccccc21
Solvent: c1ccncc1
Product: Cn1cc(Cn2c(S)nc3ccccc32)c2ccccc21
Yield: 38.7 %

Procedure:
212 mg (0.845 mmol) of ((1-methylindole-3-yl)methyl)(2-aminophenyl)amine were dissolved in 1 ml of pyridine followed by the addition of 1 ml (16.9 mmol) of carbon disulfide and refluxing for 1 hour in a nitrogen atmosphere. The solvent was distilled off followed by purification by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 96 mg of 1-((1-methylindole-3-yl)methyl)benzimidazole-2-thiol (yield: 39%).