Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:10][O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:13][CH2:12]1>C(O)(C)C>[OH:9][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:25]=[N:24][NH:23][CH:22]=2)=[O:20])[CH2:13][CH2:12]1
Reactant: c1ccc(CC2CO2)cc1
Reactant: O=C(NCC1CCNCC1)c1cn[nH]c1
Solvent: CC(C)O
Product: O=C(NCC1CCN(CC(O)Cc2ccccc2)CC1)c1cn[nH]c1
Temperature: 60 °C

Procedure:
To a solution of 2-benzyloxirane (0.01 mL, 0.07 mmol) in iso-propyl alcohol (5 mL) was added 1H-pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (EXAMPLE 137, Step 1) (15 mg, 0.07 mmol). The resulting reaction mixture was heated to 60° C. for 24 h. The reaction mixture was concentrated, partitioned between EtOAc and aqueous sodium bicarbonate. The organic phase was dried, the solvent evaporated, and the crude product purified by reverse phase HPLC to give 1H-Pyrazole-4-carboxylic acid [1-(2-hydroxy-3-phenyl-propyl)-piperidin-4-ylmethyl]-amide.
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[CH:14]([C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][N:5]1[C:4](=[O:13])[C:3]2[N:2]=[C:14]([C:16]3[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:9][C:8]=2[N:7]([CH3:10])[C:6]1=[O:11]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(C)c1=O

Procedure:
5,6-Diamino-1,3-dimethyluracil hydrate (5.11 g, 30.0 mmol) and 4-formylcinnamic acid (5.29 g, 30.0 mmol) were refluxed in nitrobenzene (500 mL). The nitrobenzene was allowed to distill slowly with water formed. Fresh nitrobenzene was added to keep the volume constant. After 5 hours of reflux, the mixture was cooled and the precipitate collected (8.07 g). Recrystallization from N,N-dimethylformamide-water gave the monohydrate of the title compound as a pale yellow powder, identical with that of Example 1 by 1H-NMR and elemental analysis.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[N:12][C:11]=1[C:22]#[N:23]>O1CCCC1>[NH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([Br:1])=[N:12][C:11]=1[C:22]#[N:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ncn(Cc2ccccc2)c1N
Solvent: C1CCOC1
Product: N#Cc1nc(Br)n(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
N-bromosuccinimide (3.55 g, 19.9 mmol) was added portionwise to a suspension of 5-amino-1-benzyl-1H-imidazole-4-carbonitrile (3.59 g, 18.1 mmol) in tetrahydrofuran (50 ml) and the reaction mixture stirred at room temperature for 10 minutes. The solvent was evaporated in vacuo and the residue extracted from a saturated aqueous solution of sodium hydrogen carbonate (50 ml) into ethyl acetate (300 ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography over silica gel eluting with 2-3% dichloromethane:methanol. The material was recrystalised from ethyl acetate, then triturated with diethyl ether to yield the title compound as a pink solid (2.7 g, 9.7 mmol, 53%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CSc1ccc(C=O)s1
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 189.9 mg of the 5-methylmercaptothiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 246.6 mg (90%) of the title compound as a orange solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][NH2:31])=[O:29])[N:27]=1)(=[O:21])=[O:20]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][N:31]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:29])[N:27]=1)(=[O:20])=[O:21]
Reactant: NNC(=O)c1csc(CS(=O)(=O)Cc2ccco2)n1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1csc(CS(=O)(=O)Cc2ccco2)n1
Temperature: 100 °C
Yield: 63 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-{[(2-furylmethyl)sulfonyl]methyl}-1,3-thiazole-4-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 32 mg of the title compound (63%) as a yellow solid in 99.3% purity by HPLC (Rt: 4.8, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: O.[CH:2](=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH2:7]([OH:11])[CH:8]=[CH:9][CH3:10]>CCCCCC>[CH2:2]([O:6][CH:7]([O:11][CH2:2][CH:3]=[CH:4][CH3:5])/[CH:8]=[CH:9]/[CH3:10])[CH:3]=[CH:4][CH3:5]
Reactant: CC=CCO
Reactant: C/C=C/C=O
Solvent: CCCCCC
Solvent: O
Product: CC=CCOC(/C=C/C)OCC=CC
Temperature: 70 °C
Yield: 185.6 %

Procedure:
In a 300-ml three-necked flask equipped with a water separator, 70 g (1 mole) of crotonaldehyde, 144 g (2 mole) of crotyl alcohol, 3 mg of stannous chloride dihydrate and 40 g of hexane were charged. The resulting mixture was heated at 70° C. under atmospheric pressure and for 4 hours in a nitrogen atmosphere while removing the water formed from the reaction mixture by azeotropic distillation. When water was no longer distilled, the solvent (hexane) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 182.2 g of crotonaldehyde dicrotyl acetal [R1 =a 1-propenyl group, R2 =a hydrogen atom and R3 =a crotyl group) (boiling point: 120° C./25 mmHg) (yield: 91.9%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:5](=[C:7]([Cl:12])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[OH:6].[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>C1COCC1>[Cl:12][C:7]1[C:5]([OH:6])=[C:4]([C:3](=[O:13])[CH:14]([CH3:16])[CH3:15])[CH:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cc(Cl)cc(Cl)c1O
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20](O)=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([NH2:24])=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(N)=O)[nH]n1
Yield: 29 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of 2-hydroxy-2-methylpropylamine, to the title compound (17 mg, 29%) which was obtained as an off white solid. MS: m/e=316.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:22][O:21][C:20](=[O:23])[O:19]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])[CH:25]=[CH2:26].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([N:10]([CH2:17][CH:18]1[CH2:22][O:21][C:20](=[O:23])[O:19]1)[C:3]1[C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1)=[O:16]
Reactant: C=CC(=O)OCCCC
Reactant: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(=O)/C=C/c1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A mixture of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-2,2-dimethyl-N-[(2-oxo-1,3-dioxolan-4-yl)methyl]propanamide (5.722 g, 14.722 mmol), Pd(PtBu3)2 (151 mg, 0.296 mmol), Pd2(dba)3 (135 mg, 0.149 mmol), in 1,4-dioxane (40 ml) was treated with N,N′-dicyclohexylmethylamine (3.48 ml, 16.265 mmol) and n-butyl acrylate (2.54 ml, 17.743 mmol) and the mixture was then heated at 80° C. for 1 h. The reaction was then cooled, treated with water (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a yellow oil (6.156 g, 96%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]3[C:31](=[O:52])[CH2:32][C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28]([O:30][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:27][N:26]3[C:31](=[O:52])[CH2:32][C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC[C@H]1CCCN(CC2CCCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 30 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.6 ml of chloroform, 0.018 ml of triethylamine and 0.004 ml of methanesulfonyl chloride were added under cooling with ice, followed by 50 minutes' stirring at room temperature. The reaction liquid was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 33 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[N:9](OC(C)C)=[O:10].C(OCC)C.[ClH:20]>C(O)(C)C>[ClH:20].[OH:10][N:9]=[C:4]([C:5](=[O:7])[CH3:6])[CH2:3][N:2]([CH3:8])[CH3:1]
Reactant: CC(C)ON=O
Reactant: CC(=O)CCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)C(CN(C)C)=NO
Reaction time: 0.5 h

Procedure:
To a solution of 4-dimethylamino-2-butanone[34.5 g, 0.3 moles, described by E. C. du Feu et al., J. Chem. Soc., 56 (1937)] in dry isopropanol (120 ml), gaseous hydrogen chloride is introduced at 0° C. until the solution is acidic to congo red (ca. pH=4). Isopropanol saturated with hydrogen chloride (2 ml) is added. Isopropyl nitrite (29.4 g, 0.33 moles) is added dropwise with stirring while maintaining the reaction temperature at 30° to 35° C. After 30 min, diethyl ether (100 ml) is added and the mixture is stirred for 30 min. The precipitate is collected to obtain 47 g of the title compound, mp 188°-199° C. The latter precipitate is crystallized from ethanol-diethyl ether to obtain 32 g of title compound; mp 205°-206° C., nmr(DMSO-d6) δ 2.4(s), 2.75(s), 4.07(s) and 12.35(broad singlet).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.[N:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[F:27])=[N+:15]=[N-:16]>CO>[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[N:16]=[N:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:18]=3[F:27])[C:10]=2[NH2:11])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Reactant: N#CCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(Cl)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.296 g, 5.4848 mmol) in methanol (25 ml), commercial 4-chlorobenzyl cyanide (0.610 g, 4.0222 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (0.750 g, 3.6565 mmol) are added portion wise. The reaction mixture is allowed to reach room temperature spontaneously overnight, concentrated in vacuo, added water, and extracted with ethylacetate (3×80 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a red solid residue (1.200 g, 92% mass balance). This crude material is purified by column chromatography over silica gel (230-400 mesh) eluting with 10% ethylacetate in petroleum ether, to obtain the title compound as an off-white solid (0.350 g, 26% yield). M.p. 169.9-170.2° C. LC-ESI-HRMS of [M+H]+ shows 357.0516 Da. Calc. 357.053011 Da, dev. −4 ppm.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=3)[C:35]([O:37][CH3:38])=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Reaction time: 72 h
Yield: 83.3 %

Procedure:
A mixture of 55.0 g (123 mmol) of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide, 36.7 g (184 mmol) of methyl 5-fluoro-2-nitrobenzoate, and 39.1 g (369 mmol) of sodium carbonate in 400 mL of DMF was heated to 70° C. with vigorous stirring. After 72 hours LCMS indicated nearly complete reaction. The mixture was cooled to RT, diluted with 300 mL of EtOAc, and filtered through a bed of celite to remove solids. The filter cake was washed with EtOAc until the filtrate ran colorless which gave a total filtrate volume of 1.2 L. The filtrate was transferred to a separatory funnel, partitioned with 1.4 L of 5% aqueous NaCl, and the phases separated. The aqueous solution was extracted with two additional 300 mL portions of EtOAc. The combined EtOAc solutions were washed with 95% aqueous NaCl (2×), saturated aqueous NaCl (1×), dried over sodium sulfate and concentrated to approximately 200 mL by rotary evaporation. At this point a solid began to crystallize. The suspension was diluted with 200 mL of DCM and the suspension stirred overnight. The suspension was then cooled in an ice water bath for 2 hours and the solid collected by vacuum filtration. The filter cake was washed twice with cold 1:1 EtOAc/DCM, suction air dried for 30 minutes and then dried in vacuo overnight to afford 59.6 g (83%) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (q, J=4.42 Hz, 1H) 8.13 (d, J=9.07 Hz, 1H) 8.08 (s, 1H) 7.93-8.01 (m, 2H) 7.57 (d, J=2.63 Hz, 1H) 7.53 (dd, J=9.07, 2.73 Hz, 1H) 7.38-7.46 (m, 2H) 7.29 (s, 1H) 3.83 (s, 3H) 3.60 (s, 3H) 2.85 (d, J=4.59 Hz, 3H) 1.87-2.04 (m, 1H) 0.87 (m, 2H) 0.73 (m, 1H) 0.46 (m, 1H). LCMS (ESI): 582 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-Methoxy-3,4-dihydro-2H-naphthalen-1-one (25.6 g, 145.28 mmol) in THF (300 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (300 ml; prepared from 22.6 ml of diisopropylamine (160 mmol) and 100 ml of 1.6 M n-BuLi in hexane (160 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (30.5 g, 159.8 mmol) in THF (300 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 3:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.32-2.52 (m, 2H), 2.82-2.90 (m, 2H), 3.10-3.18 (m, 2H), 3.78 (s, 1H), 4.52-4.58 (m, 1H), 7.01-7.05 (m, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.47-7.48 (m, 1H). ES+-MS: 211.3, 213.3 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2([CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)[CH2:7][CH2:8][OH:9])=[CH:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:9][CH2:8][CH2:7][C:6]1([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1(c2ccsc2)C=CC=CC1
Solvent: c1ccncc1
Product: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
1-(3-Thienyl)phenethyl alcohol (10 g, 49 mmol) was dissolved in a 2:1 pyridine and acetic anhydride mixture (50 ml). This was stirred at 80° C. for 4 h. Excess of pyridine and acetic anhydride mixture was removed under reduced pressure and the residue was dissolved in water (100 ml). This was extracted with methylene chloride (3×75 ml) and the combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave 1-(3-thienyl)phenethyl acetate (10.2 g, 84% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][C:44](OC(C)=O)=[O:45]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26]([O:31][C:44](=[O:45])[CH3:43])([CH2:27][CH3:28])[CH2:29][CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(CC)(COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C)OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A reaction mixture containing 3-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol (3.92 g, 8.27 mmol), Et3N (11.5 mL, 82.7 mmol) and Ac2O (3.9 mL, 41.3 mmol), is stirred at rt for 3 h. It is diluted with EtOAc (100 mL), washed with 0.1 M HCl (2×60 mL) and brine (60 mL); MgSO4 dried and concentrated to give the title compound (2.82 g, 5.47 mmol, 66%).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:55]([O:57][CH3:58])=[O:56])[CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][CH:61]=1>>[CH3:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:55]([O:57][CH3:58])=[O:56])[CH2:52][CH2:53][CH2:54]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][CH:61]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C)cc5)cc4)cc3C2=O)CCC1
Yield: 96 %

Procedure:
The compound of example 581 was prepared analogous to compound of example 97 by reaction of compound of example 574 with 4-methyl benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH2:5]2.CN[C@@H]1CCCC[C@H]1NC.[I-:27].[Na+]>C(O)CCC.C(OCC)(=O)C.[Cu]I>[CH:14]1([CH2:13][N:6]2[CH2:5][C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([I:27])[CH:3]=3)[C:7]2=[O:12])[CH2:16][CH2:15]1
Reactant: Cc1cc(Br)cc2c1C(=O)N(CC1CC1)C2
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1cc(I)cc2c1C(=O)N(CC1CC1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 5-Bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (1.0 g, 3.56 mmol) in butanol (10 ml), (1R,2R)-N,N′-dimethylcyclohexane-1,2-diamine (204 mg, 1.42 mmol), copper(I) iodide (140 mg, 0.714 mmol) and sodium iodide (1.08 g, 14.3 mmol) were added. The resulting mixture was stirred at 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate, filtered, concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound (1.07 g, 92%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 7.65 (s, 1H), 7.59 (s, 1H), 4.42 (s, 2H), 3.46-3.44 (d, 2H), 2.70 (s, 3H), 1.04-1.02 (m, 1H), 0.61-0.57 (m, 2H), 0.34-0.31 (m, 2H)