Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)=[CH:4][CH:3]=1.[C:18]([O:24][CH3:25])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:20]([C:19](=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7][CH2:6][C:5]1[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:18]([O:24][CH3:25])=[O:23])(=[O:21])[CH3:22]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(COc2ccccc2C=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccccc1OCc1ccc(C)cc1)C(C)=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
25 g (110.6 millimols) of 2-(4-methylbenzyloxy)-benzaldehyde were stirred with 11.9 ml (110.6 millimols) of methyl acetoacetate in 66 ml of isopropanol, and a freshly prepared solution of 0.64 ml of piperidine and 0.38 ml of glacial acetic acid in 5.5 ml of isopropanol was added. The mixture was stirred for 1 hour at 60° C. and for 4 hours at 40° C., and was cooled and concentrated. The residue from evaporation was dissolved in ether, and the solution was washed successively with approx. 100 ml of 1N hydrochloric acid, with two portions of water, with saturated sodium bicarbonate solution and again with two portions of water. The ether phase was dried, filtered and concentrated. 35.3 g (98.51% of theory) of a dark yellow oil were obtained, and the oil was reacted further in the crude form.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:2]1.[Li]CCCC.Cl[CH2:19][O:20][CH3:21]>C1COCC1>[CH:1]1([CH2:4][N:5]([CH2:19][O:20][CH3:21])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1CC1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(CC1CC1)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 90.9 %

Procedure:
Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1N HCl and the organic layer separated. The aquoues layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([CH2:41][CH2:40]2)[CH2:32][NH:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([CH2:41][CH2:40]2)[CH2:32][N:31]1[C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:21]=1)=[O:28]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: c1ccc2c(c1)CNCC21CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5ccccc5C5(CC5)C4)ncn3)CC1)C(=O)N2

Procedure:
50 mg (0.13 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 20 mg (0.13 mmol) 2′,3′-dihydro-1′H-spiro-[cyclopropane-1,4′-isoquinoline], 37 μL (0.26 mmol) TEA and 44.3 mg (0.14 mmol) TBTU were stirred in 1.5 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:8][CH3:9])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)#[N:18]>CN(C=O)C.O>[CH3:1][C:2]1[C:3](=[O:10])[N:4]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:17]#[N:18])[C:5]([S:8][CH3:9])=[N:6][N:7]=1
Reactant: CSc1nnc(C)c(=O)[nH]1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nnc(C)c(=O)n1Cc1ccccc1C#N
Temperature: 0 °C

Procedure:
To a solution of 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5, 1.546 g, 9.85 mmol) in dry DMF (10 mL) at 0° C. was added K2CO3 (1.36 g, 9.85 mmol) and 2-cyanobenzylbromide (2.316 g, 11.82 mmol). The mixture was heated at 0° C. for 16 h. The mixture was diluted with water, and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried over MgSO4, and concentrated. This was purified by column chromatography on silica gel, and eluted with 20% to 50% ethyl acetate in petroleum ether and 1:1:2 petroleum ether-dichloromethane-ethyl acetate to provide 2-((6-methyl-3-(methylthio)-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (6). MS: m/z, 273 (100%, M+1), 295 (60%, M+23).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH3:12])[C:7]=1[C:13](=[O:15])[NH2:14])=[O:4].[OH:16]O>OO.C(O)(=O)C>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH3:12])=[O:16])[C:7]=1[C:13](=[O:15])[NH2:14])=[O:4]
Reactant: CNC(=O)Nc1snc(SC)c1C(N)=O
Reactant: OO
Solvent: CC(=O)O
Product: CNC(=O)Nc1snc(S(C)=O)c1C(N)=O

Procedure:
A mixture of 4.9 g of 1-methyl-3-(4-carbamoyl-3-(methylthio)-5-isothiazolyl)urea and 20 ml of acetic acid was heated to 95° and to the hot mixture was added dropwise 2.2 ml of 30% hydrogen peroxide. The mixture became homogeneous, but solid began to appear again after a few minutes. The mixture was maintained at 95° for two hours and then 9 drops of 30% hydrogen peroxide were added. After heating was continued an additional hour, thin-layer chromatographic analysis indicated that the reaction was completed. The mixture was cooled to -5°; the solid was isolated, washed with cold water and dried to give 4.7 g of 1-methyl-3-(4-carbamoyl-3-(methylsulfinyl)-5-isothiazolyl)urea; m.p. above 355°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:43][C@H:44]1[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]1[OH:50].C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[C:3]([C:13]([NH:43][C@H:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]2[OH:50])=[O:15])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1c(C(=O)O)cc(Br)c2cccnc12
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Br)c2cccnc12
Reaction time: 3 h

Procedure:
To a solution of 8-amino-5-bromoquinoline-7-carboxylic acid (1.00 g, 3.74 mmol) in 20 mL of dichloromethane was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.99 g, 4.49 mmol), (1S,2S)-2-aminocyclohexanol (0.517 g, 4.49 mmol), and triethylamine (1.04 mL, 7.49 mmol). After 3 h, a brown solid was collected and washed with dichloromethane and water to provide 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-7-carboxamide that gave a mass ion (ES+) of 365.9 (81Br) for [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][CH:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH2:19][CH2:18][NH:17]2)=[CH:13][CH:12]=1.C(Cl)Cl.[CH:31]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32]1>O>[CH:31]1([C:35]([N:17]2[CH2:18][CH2:19][C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=3[CH:16]2[CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(CC2NCCC3=C2CCCC3)cc1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CC2C3=C(CCCC3)CCN2C(=O)C2CCC2)cc1

Procedure:
Triethylamine (22.2 g., 0.22 mole) is slowly added to 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride Ia (29.4 g., 0.1 mole) dissolved in 200 ml. of methylene chloride with stirring and ice-bath cooling. Cyclobutylcarbonyl chloride (13 g., 0.107 mole) in 30 ml. of methylene chloride is then added dropwise with stirring to the mixture while maintaining a temperature of 0° to 5° C. After stirring the reaction mixture for 1 hr. at room temperature, 100 ml. of water is added, the mixture acidified by adding 50 ml. of 10% sulfuric acid, and the methylene chloride layer separated. If desired, the methylene chloride solution containing IIa can be used for the next step directly or concentrated to give an oil which solidifies upon standing. Recrystallization of a sample of the solidified material from acetone provides crystalline product IIa, m.p. 89°-91°.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10].S(Cl)(Cl)=O>C(Cl)Cl>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: COC(=O)c1cc(C=NO)ccc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) was dissolved in methylene chloride (25 mL) and cooled to 0° C. The reaction was treated with thionyl chloride (0.59 mL, 8.1 mmol) and stirred at 0° C. for 2 h. After warming to room temperature, the reaction was diluted with methylene chloride, washed with saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 0.87 g (92%) which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 8.09 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H). Mass spec.: 192.02 (MH)+.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:77][N:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:53][C:52]=2[N:66]([CH3:76])[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:76][N:66]([C:52]1[CH:53]=[C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:77][N:78]3[CH2:79][CH2:80][O:81][CH2:82][CH2:83]3)[CH2:45][N:46]=1)=[CH:57]2)[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68]
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a solution of triphenylphosphine oxide (1.0 g) in dichloromethane (4 mL) was slowly added trifluoromethanesulfonic anhydride (0.46 mL) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[2-(benzylthio)-3-morpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.88 g) and thioanisole (0.61 mL) in dichloromethane (25 mL) was added dropwise, and the mixture was stirred for 90 min under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=50:50-85:15), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (174 mg, yield: 23%) as colorless prism crystals. MS: 608 (MH+). melting point 168-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH2:13][C:14]([NH2:16])=O)[N:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:11]([CH2:13][C:14]#[N:16])[N:12]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Agent: N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Yield: 96.5 %

Procedure:
To a solution of 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetamide (3.4 g) and phosphorus oxychloride (3 ml) in chloroform (50 ml) was added one drop of pyridine, and the mixture was refluxed for 8 hours. Cold diluted aqueous ammonia was poured into the mixture and the organic layer was collected. After removing the solvent under reduced pressure, ethanol was added to the residue and crystal was collected by filtration to obtain 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetonitrile (3.1 g).
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])SC.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS.O.[NH2:27][NH2:28].C>C(#N)C>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)[NH:28][N:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NN
Agent: CS
Solvent: CC#N
Solvent: O
Product: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Temperature: -10 °C
Yield: 39.7 %

Procedure:
A mixture of 4.25 g (0.025 moles) of [bis(methylthio)methylene]malononitrile [K. A. Jensen and L. Hendriksen, Acta Chem. Scand., 22(4), 1107 (1968)] and 4.7 g (0.025 moles) of 1-benzylpiperazine in 100 ml of acetonitrile was stirred at reflux for 5 hours with evolution of methanethiol. Then 1.31 g (0.025 moles) of hydrazine hydrate was added and the solution was stirred at reflux for 16 hours, again with evolution of methanethiol. The reaction mixture was clarified while hot with activated charcoal and filtered through diatomaceous earth. The filtrate was cooled at -10° C. and a white precipitate developed. The precipitate was collected by filtration, washed with 50 ml of cold acetonitrile, air dried, then dried in vacuo at 60° C. and gave 4.5 g of crude product. The material was recrystallized from 150 ml of 2-propanol, cooled at -10° C. and gave 2.8 g of the desired product as a white solid, mp 157°-158° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[O:18])=[C:14]([NH:27][C:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)=[O:29])[C:13]=2[CH:39]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[ClH:26].[CH3:37][N:36]([CH3:38])[C@H:33]1[CH2:32][CH2:31][C@H:30]([C:28]([NH:27][C:14]2[C:13]3[CH:39]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[CH:10]=[CH:11][C:12]=3[O:16][C:15]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:18])=[O:29])[CH2:35][CH2:34]1
Reactant: CC(=O)OCC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(NC(=O)CO)cc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trans-5-acetoxyacetylamino-3-[4-(dimethylamino)-cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (70 mg) obtained in Example 189 is dissolved in tetrahydrofuran/methanol (1:1, 8 ml), and thereto is added potassium carbonate (5 mg), and the mixture is stirred at room temperature for 48 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol=30/1). The resulting trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-hydroxyacetylamino-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide is dissolved in ethanol, and treated with 4N hydrogen chloride in ethyl acetate to give the title compound (46 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)CC.N(OS(=O)(=O)O)=O.[CH:24]([O:26][C:27](=[O:39])[CH2:28][CH2:29][N:30]([CH2:37][CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH2:25].S(=O)(=O)(O)[NH2:41]>CO.C(O)(=O)C>[CH:24]([O:26][C:27](=[O:39])[CH2:28][CH2:29][N:30]([C:31]1[CH:36]=[CH:35][C:34]([N:41]=[N:4][C:3]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=2[Cl:1])=[CH:33][CH:32]=1)[CH2:37][CH3:38])=[CH2:25]
Reactant: NS(=O)(=O)O
Reactant: C=COC(=O)CCN(CC)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: O=NOS(=O)(=O)O
Solvent: CCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: C=COC(=O)CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
5.2 parts of 2-chloro-4-nitroaniline, 20 parts of propionic acid and 30 parts of acetic acid were charged and cooled to 5° C. 11.4 parts of 40% (w/w) nitrosyl sulfuric acid were added, whilst the temperature was held below 10° C. The diazotization mixture was stirred for a further 2 hrs at 5-10° C. To a separate vessel were charged 6.5 parts of 3-(ethyl-phenyl-amino)-propionic acid vinyl ester, 100 parts of methanol, 1 part sulfamic acid and 100 parts of ice. With stirring, the diazotization mixture was slowly added followed by a further 300 parts of ice. The reaction mixture was stirred over night and the product was isolated by filtration, washed with water and dried to yield 9.9 parts of 3-{[4-(2-chloro-4-nitrophenylazo)-phenyl]-ethyl-amino}-propionic acid vinyl ester. λmax=510 nm (DMF).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[CH:37][C:38]([F:45])=[C:39]([CH2:41][C:42]([OH:44])=[O:43])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:45][C:38]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:40][C:39]=1[CH2:41][C:42]([OH:44])=[O:43]
Reactant: O=C(O)Cc1cc(Br)ccc1F
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1ccc(F)c(CC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
(4S,5R)-4-Methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one (0.080 g, 0.17 mmol), 5-bromo-2-fluorophenylacetic acid (0.061 g, 0.26 mmol), potassium carbonate (0.084 g, 0.61 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.021 g, 0.02 mmol) were combined in DME:H2O (2:1; 3 mL), and the mixture was purged with N2 for 5 minutes. The reaction was stirred under N2 at 90° C. overnight. After work-up with EtOAc and brine, the crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound. M+H is 488.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=O)=[CH:4][NH:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][NH:3][CH:4]=1)=[S:29])[CH3:19]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=S)C1=CNCCc2c1[nH]c1ccccc21
Yield: 5 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.51g, 2 mmol) in toluene (20 mL) was added Lawesson's reagent (1.45 g, 3.6 mmol). The resulting suspension was heated to reflux under nitrogen for 24 hours. Solvent was evaporated to give the crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to give 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carbothioic acid O-ethyl ester (27 mg); MS (ES): 273 (MH+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 66.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (158 mg) in dry methylene chloride (3.5 ml) was added an excess of diisopropylethyl amine (82 μl) and o-nitrophenylsulfonyl chloride (87 mg) followed by addition of 4-dimethylaminopyridine (58 mg). The mixture was stirred at room temperature for 23 hours at which time it was diluted with ethyl acetate, extracted from saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate: hexane (1:1)+1% methanol to give the title compound (130 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH3:10])[CH3:9])[CH2:4][CH3:5])[CH3:2].[NH4+:27].[OH-]>O>[NH2:27][C:22]1[N:21]=[C:20]([CH2:19][N:11]([CH:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:8]([CH3:10])[CH3:9])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:25]=[CH:24][CH:23]=1
Reactant: [NH4+]
Reactant: CCN(CC)CC(C(C)C)N(Cc1cccc(Br)n1)C(=O)OC(C)(C)C
Agent: [OH-]
Solvent: O
Product: CCN(CC)CC(C(C)C)N(Cc1cccc(N)n1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a stirred solution of N-{1-[(diethylamino)-methyl]-2-methylpropyl}(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]carboxamide (5 mg, 0.012 mmol) in IpOH (5 ML) in a sealed tube, was added NH4OH (28–30% 6 mL) followed by excess Cu. The resulting solution was heated under pressure at 90° C. for 24 h. The mixture was brought to RT, diluted with H2O (10 mL) and extracted with CHCl3 (3×20 mL) The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a green oil. No purification was required. EI-MS m/z 365 (M+H).