Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]2=[O:8])=[CH:19][CH:18]=1
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cn2cc(I)c(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (2.90 g, 10.4 mmol) and sodium hydride (60% in oil, 0.44 g, 11 mmol) was stirred at rt for 2.5 hours. 4-Methoxybenzyl chloride (1.50 mL) was added, and the mixture was stirred at rt for 18 h. Water was added, and the l s mixture and extracted with ethyl acetate. The organic phase was washed, dried and evaporated. Chromatography of the residue over silica gel (35% ethyl acetate/petroleum ether) followed by crystallization from water gave 1-(4-methoxybenzyl)-5-iodo-4-methyl-3-nitro-2-pyridone (3.11 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: NCCCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 4-phenylbutylamine in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:25])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[BH4-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[C:3]([CH3:25])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(CO)c1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A solution of 3′-fluoro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.77 g, 8.00 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.336 g, 8.00 mmol) was added, and the mixture was stirred for 8 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.75 g, yield 94%) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=O)=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.Cl.[NH2:22][OH:23].[OH-].[Na+].Cl>O.C(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH:14]=[N:22][OH:23])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C=NO)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
To a solution of 0.288 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal in 4 ml. of ethanol is added a solution of 0.12 g. of hydroxylamine hydrochloride and 0.11 g. of sodium hydroxide in 0.4 ml. of water. The mixture is refluxed briefly, then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated to yield a crude product which is chromatographed on silica gel, eluting with chloroform:methanol (19:1) to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal oxime.
Reaction SMILES: S(O[CH:12]1[CH2:30][CH2:29][N:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]2[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:31][NH:32][CH3:33].O>CS(C)=O>[CH3:31][N:32]([CH3:33])[CH:12]1[CH2:30][CH2:29][N:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]2[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN3c4ccccc4Cc4ccccc4C3C2)cc1
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-tosyloxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a] -dibenzo[ c,f]-azepine (eg.) are dissolved in 50 ml of dimethylsulphoxide. After that 15 ml of dimethylamine are added to the solution. This solution is now heated in a sealed ampoule on a vapour-bath for 2 hours. After cooling the solution, it is poured into 300 ml of water after which the mixture is extracted with 3×200 ml of ether. The ether layers are washed and then dried, whereupon the solvent is evaporated and the residue is recrystallized. Yield: 1.3 g.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][CH2:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>ClCCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[S:13][CH2:14][CH3:15])=[O:25])=[CH:19][CH:18]=1
Reactant: CCSc1nc2ccccc2c(=O)n1N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCCl
Product: CCSc1nc2ccccc2c(=O)n1NC(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 3-amino-2-ethylthio-4-quinazolone (0.60 g, 2.71 mmol) and 4-chlorophenyl isocyanate (0.48 g, 3.13 mmol) in 1,2-dichloroethane is heated at reflux for 63 hours, cooled to 0° C. and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 0.84 g (83%) mp 234°-235° C.
Reaction SMILES: C[Al](C)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][NH2:12].[CH2:13]([O:20][C@H:21]([C:39](OC)=[O:40])[C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:13]([O:20][C@H:21]([C:39](=[O:40])[NH:12][O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)[C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:33])[CH3:34])[S:27]([CH3:30])(=[O:28])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](OCc1ccccc1)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](OCc1ccccc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
0.530 ml of a 2M solution of trimethylaluminium in toluene was added to a solution of 0.124 g of O-(tetrahydro-2H-pyran-2(RS)-yl)-hydroxylamine in 5 ml of dry toluene at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 0.5 hours and then 0.335 g of 2(R)-[(S)-(benzyloxy)(methoxycarbonyl)methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide was added in one portion. The mixture was then left to warm to room temperature overnight. The mixture was diluted with ethyl acetate and washed in succession with 2M aqueous hydrochloric acid and 5% aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue was triturated with hexane/diethyl ether (2:1) to give 0.119 g of 2(R)-[(S)-(benzyloxy)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:5].O.[NH2:19][NH2:20]>CO>[NH:19]([C:3](=[O:2])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:5])[NH2:20]
Reactant: NN
Reactant: COC(=O)C(=O)Nc1cccc(C(=O)OC)c1
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(NC(=O)C(=O)NN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of methyl 3-{[methoxy(oxo)acetyl]amino}benzoate (100 mg, 0.42 mmol) in MeOH (8 mL) was added hydrazine hydrate (0.2 mL). After stirring for 0.5 h at rt, the reaction mixture was filtered. Washing with MeOH (2×1 mL) and water (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave 82 mg of the title compound (82%) as a white solid in 97.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O=S(Cl)[Cl:14]>C(Cl)(Cl)Cl>[Cl:14][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1
Reactant: OCc1ccc2c(c1)OCC2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc2c(c1)OCC2
Yield: 80 %

Procedure:
To a solution of (2,3-dihydrobenzofuran-6-yl)methanol (13.8 g, 92 mmol) in CHCl3 (200 mL) was slowly added SOCl2 at 0□. The reaction mixture was stirred at reflux for 4 h. After the solvent was removed, saturated NaHCO3 and ethyl acetate were added to the mixture. The organic layer was extracted with ethyl acetate. The combined organic layer was then washed with brine and dried over Na2SO4, filtered and concentrated to afford 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 80.0% yield). 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J=7.5, 1H), 6.87 (d, J=7.5, 1H), 6.83 (s, 1H), 4.58 (t, J=8.7, 2H), 4.49 (s, 2H), 3.20 (t, J=8.7, 2H).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH2:37][C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCC>C(Cl)Cl.[Zn]>[Br:1][C:2]([Br:5])=[CH:42][C:41]1[CH:44]=[CH:45][C:38]([CH2:37][CH2:36][C@H:33]2[CH2:32][CH2:31][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)=[CH:39][CH:40]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=O)cc2)CC1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 13.27 g of tetrabromomethane, 10.49 g of triphenylphosphine and 2.62 g of zinc dust in 100 ml of methylene chloride was stirred at room temperature for 24 hours in a sulphonation flask under argon gasification. In so doing, the heterogeneous mixture changed in colour via yellow-green to dark violet and pale violet. A solution of 2.86 g of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzaldehyde in 10 ml of methylene chloride was subsequently added dropwise, the mixture was stirred at room temperature for 4 hours and then poured into 700 ml of pentane. The voluminous precipitate which separated was filtered off (rinsing with pentane), the concentrated filtrate (5.25 g) was digested with 300 ml of pentane, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (4.8 g) on silica gel with 3% ethyl acetate/petroleum ether gave 3.13 g (71%) of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene as colourless crystals (purity 99.8%); m.p. 47.3° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=3)=[N:4][CH:5]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)cc2F)cc1

Procedure:
0.29 g (0.91 mmol) of 3-fluoro-5-hydroxy-2-(4-octyloxyphenyl)pyridine, 0.19 g (0.91 mmol) of dicyclohexylcarbodiimide, 0.16 g (0.91 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.01 g of 4-(N,N-dimethylamino)pyridine are stirred at room temperature for 18 hours in 10 ml of dichloromethane. Filtration, evaporation to dryness, chromatographic purification (silica gel/hexane: ethyl acetate 8:2) and recrystallization from acetonitrile give 0.19 g of 3-fluoro-2-(4-octyloxyphenyl)pyridin-5-yl trans-4-pentylcyclohexanecarboxylate. ##STR28## The compound has the phase sequence: X 65.2 (40.2) Sc 63 SA 129 N 173 I.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]3[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=3[CH3:35])=[O:28])[CH2:19][CH2:18]2)[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:6][CH:5]=1.[Cl-].[NH4+:40]>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]3[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=3[CH3:35])=[O:28])[CH2:19][CH2:18]2)=[CH:6][CH:5]=1)(=[O:2])[NH2:40]
Reactant: COC(=O)c1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: [NH4+]
Agent: [Cl-]
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(C(N)=O)cc2)CC1
Yield: 36.7 %

Procedure:
Using general procedure K with COMPOUND 299 (61 mg, 0.11 mmol) followed by general procedure E with the resulting acid and ammonium chloride (10 mg, 0.18 mmol) afforded COMPOUND 300 as a pale yellow foam (21 mg, 35%, over 2 steps). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.0 Hz), 1.15-1.25 (m, 1H), 1.54-1.58 (m, 2H), 1.78 (d, 3H, J=9.0 Hz), 2.20-2.23 (m, 1H), 2.53 (s, 6H), 2.60 (td, 1H, J=9.0, 3.0 Hz), 2.86-2.96 (m, 3H), 3.33 (td, 1H, J=9.0, 3.0 Hz), 3.69 (td, 1H, J=9.0, 3.0 Hz), 3.84-3.86 (m, 1H), 3.94 (s, 2H), 6.62 (d, 2H, J=9.0 Hz), 6.99-7.02 (m, 2H), 7.31 (dd, 1H, J=6.0, 3.0 Hz), 7.63 (d, 2H, J=9.0 Hz), 8.68 (d, 1H, J=3.0 Hz), 8.91 (s, 1H). ES-MS m/z 521 [M+H]+.
Reaction SMILES: [C:1]([CH2:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH2:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH:25][C:9](=[O:11])[C@@H:8]([CH2:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
A suspension of 3.0 g (12 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0.184.550) and 2.66 g (11 mmol) of L-histidine methyl ester dihydrochloride in 40 ml of dimethylformamide is treated at room temperature under a nitrogen atmosphere with 3.45 g (34 mmol) of triethylamine and 4.58 g (12 mmol) of HBTU. The reaction mixture is stirred at room temperature for 5 hours and subsequently evaporated in a high vacuum. The residue is dissolved in 500 ml of ethyl acetate and washed in succession with 100 ml of water, three times with 100 ml of saturated sodium bicarbonate solution each time and 100 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate, evaporated under reduced pressure and the yellowish crude product obtained is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol which contains 0.1% ammonia. In this manner there are obtained 3.6 g of N-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine methyl ester as a colourless foam, MS: 399 (M)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].Br[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[C:7]1([CH:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][CH2:3][CH2:2][Br:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCBr
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: BrCCOC(c1ccccc1)c1ccccc1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
37.5 g (0.3 mole) of 2-bromoethanol was added to a mixture of 61.8 g (0.25 mole) of bromodiphenylmethane and 31.8 g (0.3 mole) of sodium carbonate. The reactive medium was slowly heated to 130° C., held at this temperature for 5 hours and then left overnight at room temperature. The mixture was taken up with ether and washed with water. The ethereal extract was dried on sodium sulfate. The evaporation of the ether yielded an oil, which was purified by distillation.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[NH:25][C:24]2=[O:31]>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[NH:25][C:24]3=[O:31])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)C(=O)NC3=O)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 5-amino-1H-isoindole-1,3(2H)-dione in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.44-1.54 (m, 2H), 1.78-1.86 (m, 2H), 3.77 (t, 2H), 7.06-7.31 (m, 6H), 7.36-7.52 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[CH3:31])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([N:5]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=1[CH3:31])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C(F)(F)F)ccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1N(CC(C)C)S(=O)(=O)c1ccc(CCC(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 3-(4-(N-isobutyl-N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)phenyl)propanoate (15 mg, 0.033 mmol) in tetrahydrofuran (THF) (1.5 mL) at room temperature, was added a solution of lithium hydroxide (approximately 0.785 mg, 0.033 mmol—tip of spatula used) in water (1.5 mL). The reaction mixture was stirred at 20° C. for 4 hours and then stood overnight. The mixture was concentrated in vacuo then partitioned between water (2 mL) and ethyl acetate (2×5 mL). The aqueous layer was separated (hydrophilic frit) and acidified, then extracted with ethyl acetate (5 mL). The organic layer was separated (hydrophobic frit) and concentrated in vacuo to give required product, 2.4 mg. LCMS (M+1) 444, RT 1.25 mins.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17](O)=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C(Cl)CCl.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:28][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][C:11]([C:17]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])=[CH:12][CH:13]=4)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)O)cc4c3c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)NS(C)(=O)=O)cc4c3c2)cc1F
Yield: 54.9 %

Procedure:
To a solution of 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-3-carboxylic acid (53 mg, 0.070 mmol, Example 187) in DMF (1 ml) was added DMAP (63 mg, 0.516 mmol), then EDC (128 mg, 0.668 mmol) and methanesulfonamide (92 mg, 0.967 mmol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC (water/CH3CN/NH4OAc eluent system). Product containing fractions were evaporated to give 17.5 mg 3-(3-fluoro-4-methoxyphenyl)-N6-(methylsulfonyl)-9H-carbazole-1,6-dicarboxamide as an off-white solid. HPLC retention time 11.10 min (HPLC conditions as in Table 9 and Table 10). MS (ESI) m/z [M−H]− 454; [M+H]+ 456. 1H NMR (CD3OD) δ ppm 8.88 (s, 1H), 8.53 (d, 1H, J=1.3), 8.16 (m, 2H), 7.63-7.55 (m, 3H), 7.22 (t, 1H, 8.5), 3.96 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([Li])CCC.[Si:40]([O:47][C:48]1[CH:59]=[CH:58][C:51]([C:52](N(OC)C)=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC>[Si:40]([O:47][C:48]1[CH:59]=[CH:58][C:51]([C:52]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([O:27][Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:29])[CH3:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][CH:7]=2)=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CON(C)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl N-[2-(4-bromophenyl)-ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (880 mg) in tetrahydrofuran (13 ml) was added a solution of butyllithium in hexane (1.59M, 1.07 ml) dropwise at −70° C. under nitrogen and the mixture was stirred at −70° C. for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-N-methylbenzamide (480 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give tert-butyl N-[2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]benzoyl]phenyl]ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (710 mg).