Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:21][CH2:20]3)=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:27]([N:29]1CCN2C(C3CC3)=C(C#N)C=C2C1)=O)(C)(C)C.ClS(N=C=O)(=O)=O.CN(C)C=O>C(#N)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:20][CH2:21]3)=[C:15]([C:27]#[N:29])[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C3CC3)cc(C#N)c2C1
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc(C#N)c2C2CC2)C1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCn2c(c(C#N)c(C#N)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of a mixture of 8-cyano-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester and 7-cyano-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (6.67 g, Reference Example 9) in dry acetonitrile (370 mL) under a blanket of nitrogen at 0° C. was treated with chlorosulfonyl isocyanate (2.75 mL) dropwise whilst maintaining the temperature below 5° C. After stirring below 5° C. for a further 2.5 hours the reaction mixture was treated with dimethylformamide (18.5 mL), allowed to warm to room temperature and then stirred for a further 1 hour. The reaction mixture was then treated with triethylamine (21.7 mL), stirred for a further 1 hour and then left to stand overnight. The reaction mixture was evaporated and the residue treated with dichloromethane (200 mL) and water (80 mL). The organic phase was separated, further washed with water (80 mL), then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:3, v/v) to give the title compound (4.97 g) as a yellow oil, Rf 0.29 (ethyl acetate:pentane, 2:3). 1H NMR [(CDCl3]: δ 4.70 (s, 2H), 4.03 (t, 2H), 3.87 (t, 2H) 1.73–1.65 (m, 1H), 1.51 (s, 9H), 1.14–1.07 (m, 2H) and 0.99–0.93 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[N:4]=[C:3]([CH2:2][NH:1][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:13])=[O:24])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: Cc1ccc(S(=O)(=O)NCc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 42 and 4-methylbenzene-1-sulfonyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.53-11.64 (bs, 1H), 8.19-8.33 (bs, 1H), 8.23 (ddd, J=7.8, 1.5, 0.6 Hz, 1H), 8.06 (ddd, J=8.1, 1.4, 0.7 Hz, 1H), 7.95 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.87 (ddd, J=7.9, 7.2, 1.3 Hz, 1H), 7.57-7.61 (m, 2H), 7.33-7.49 (m, 4H), 7.21-7.25 (m, 2H), 4.22-4.24 (m, 2H), 3.69 (s, 2H), 2.31 (s, 3H); MS (ESI+) M/Z 497 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2)[S:3][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C(C)c1ccc(NC(N)=S)cc1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C(=O)O)c1ccc(Nc2nc(C(C)(C)C)cs2)cc1
Yield: 57 %

Procedure:
Following the same procedure described for 1 and starting from methyl 2-[4-(carbamothioylamino)phenyl]propanoate (2.49 g, 10 mmol) and 1-bromopinacolone (1.75 ml, 13 mmol), after workup and methyl ester hydrolysis, pure compound 6 (1.75 g, 5.7 mmol) was isolated by filtration (38% overall yield from methyl 2-[4-(carbamothioylamino)phenyl]propanoate).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][C@H:21](O)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:2]1([O:1][C@@H:23]2[CH2:22][CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2nccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-hydroxyisoquinoline (1.00 g, 6.9 mmol), (S)-1-BOC-3-hydroxypiperidine (4.17 g, 20.7 mmol), Ph3P (7.23 g, 27.6 mmol) in THF (40 mL) was stirred at RT into a clear solution. DIAD (5.43 mL, 27.6 mmol) was added dropwise. The mixture was stirred at RT for 1 h and then at 50° C. for overnight. The mixture was diluted with EtOAc, washed with water ×3, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0% to 15% EtOAc in DCM to afford (R)-tert-butyl 3-(isoquinolin-1-yloxy)piperidine-1-carboxylate (53).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)Cl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluorodiphenyl ether 1b (1.00 g, 5.31 mmol) in dry CH2Cl2 (30 mL) under an argon atmosphere at 0° C., was added chlorosulphonic acid (0.35 mL, 5.31 mmol). The reaction mixture was stirred for 2 h at 0° C. The solvent was evaporated at room temperature and the residue dried overnight under vacuum to give the corresponding 4-(4-fluorophenoxy)benzenesulphonic acid (2b) as a pale-pink hygroscopic solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.Cl.[NH2:22][OH:23].[OH-].[Na+].Cl>CCO.O>[CH3:1][CH:2]([CH3:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[N:22][OH:23]
Reactant: CC(C)C(=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1c(-c2ccccc2)nn2ccccc12
Temperature: 0 °C
Yield: 28.3 %

Procedure:
To a solution of 5.32 g (20 mmol) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one in 32 ml of anhydrous EtOH was added 3 g of hydroxylamine hydrochloride, followed by dropwise addition of a solution of 4.0 g NaOH in 12 ml water. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 11 ml of 6N HCl and 200 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 4.6 g of crude compound, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to furnish 1.58 g (30.1%) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime. Compound 1016.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(OCC)([O:19][CH2:20][CH3:21])[CH2:17][CH3:18]>CCCCCC>[CH2:20]([O:19][C:16](=[N:15][S:12]([C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)(=[O:14])=[O:13])[CH2:17][CH3:18])[CH3:21]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Solvent: CCCCCC
Product: CCOC(CC)=NS(=O)(=O)c1nc(-c2ccccc2)ns1
Temperature: 25 °C

Procedure:
A mixture of 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide and 11 ml of triethyl orthopropionate was warmed in an oil bath at 80° for 4 hours. The mixture was cooled to room temperature and diluted with hexane (35 ml) and the precipitated solid was collected, washed with hexane and dried to give 3.3 g of solid, m.p. 98°-100°.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]2)=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[O:17]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH2:6][C:5]2[CH:23]=[CH:24][C:2]([C:35]3[N:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[N:32]=[CH:33][CH:34]=3)=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CCOC(=O)c1cn(Cc2ccc(Br)cc2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccnn3C3CCCCO3)cc2)c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a suspension of ethyl 1-(4-bromobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.8 g) known from a document (Journal of Medicinal Chemistry, 2007, 50, 5471), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.86 g) and potassium phosphate (1.1 g) in DME-water (4:1, 20 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.08 g), and the mixture was stirred at 100° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (0.37 g) as a pale-yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][OH:19])=[O:17])=[O:9])=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(Cl)Cl>[C:4]1([NH:7][C:8](=[O:9])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][O:19][C:30](=[O:32])[CH3:31])=[O:17])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCCCCCC(=O)Nc1ccccc1)NO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)ONC(=O)CCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of SAHA (0.43 g, 16.3 mmol) in pyridine/CH2Cl2 (5/5 mL) was added acetic anhydride 1-hydroxybenzotriazole (153 μL, 16.3 mmol). After stirring for 18 h at RT, the solvent was removed, and the material was without further purification. 1H NMR (DMSO-d6) δ 11.71 (br s, 1H), 10.01 (br s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.44 (dd, J=7.6, 7.4 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 2.43 (t, J=7.2 Hz, 2H), 2.35-2.20 (m, 2H), 2.30 (s, 3H), 1.82-1.58 (m, 4H), 1.58-1.36 (m, 4H). MS (EI): cal'd (MH+) 307.1, exp (MH+) 307.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1.O[N:28]1[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2N=N1.N1CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([N:28]3[CH2:34][CH2:35][CH2:36][CH2:31][CH2:32]3)=[O:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1nnc2n1-c1sc(CC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1nnc2n1-c1sc(CC(=O)N3CCCCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of 1.1 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.3 g of piperidine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 21 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 100 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogen-carbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 0.9 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4 ]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid piperidide as colorless crystals, melting at 182°-183° C.
Reaction SMILES: [N:1]1([CH:6]=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][C:10]#N)CCCC1.[ClH:14]>>[Cl:14][C:10]1[CH:9]=[CH:8][C:7]([C:6]#[N:1])=[CH:12][N:13]=1
Reactant: Cl
Reactant: N#CC=CC(C#N)=CN1CCCC1
Product: N#Cc1ccc(Cl)nc1

Procedure:
Analogously to Example 5, pyrrolidinomethylene-glutacononitrile was cyclized with HCl gas. 2-Chloro-5-cyanopyridine was obtained in 83.3% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:17]=[CH:16][NH:15][C:14](=O)[C:13]1=[O:19].CN(C)C=O.C(Br)(=O)C([Br:28])=O>C(Cl)Cl>[Br:28][C:14]1[C:13](=[O:19])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[Cl:1])[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][N:15]=1
Reactant: O=C(Br)C(=O)Br
Reactant: COC(=O)c1ccc(Cl)c(-n2cc[nH]c(=O)c2=O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(-n2ccnc(Br)c2=O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)benzoate (Example 330d, 8 g) in DCM (80 mL) was treated with N,N-dimethylformamide (0.220 mL) and oxalyl bromide (2.94 mL) dropwise over 5 min at room temperature under nitrogen. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture turned black and was evaporated to afford crude product. Purification (SiO2 chromatography eluting with 30% diethyl ether in dichloromethane) gave the subtitle compound (6.33 g).
Reaction SMILES: Cl[CH2:2][CH2:3][Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[N:14]([CH2:2][CH2:3][Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[Si](CCCl)(OCC)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[Si](CCN=[N+]=[N-])(OCC)OCC

Procedure:
1.0 mole of 2-chloroethyltriethoxysilane and 1.1 moles of sodium azide in 500 ml of acetone were heated in the presence of 3 mole percent of the catalyst described in Example 1 (a) for ten hours under intensive stirring and under reflux. After separation of the salt the subsequent distillation under reduced pressure gave the 2-azidoethyltriethoxysilane in a yield of 69 weight percent with the following characteristics:
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[CH:3]=1.[CH3:27][C:28]([N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:15][C@@:7]1([C:16]([F:18])([F:19])[F:17])[C:6]2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])[CH:3]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([C:28]([CH3:27])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:39]=3)[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)CCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)n1cc(-c2cc(OCCC(C)(C)O)cc3c2-c2ccccc2[C@]3(O)C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 100.4 %

Procedure:
Under an argon atmosphere, (9R)-4-chloro-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-9-ol (49.5 g) was dissolved in toluene (445 ml), ethyl 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate (59.2 g), water (149 ml), tripotassium phosphate (54.3 g), palladium acetate (2.9 g) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) (10.5 g) were added, and the mixture was stirred at an oil bath temperature of 100° C. for 3.5 hr. The reaction mixture was cooled to room temperature, and water (300 ml) was added. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (150 ml) and water (50 ml). The obtained filtrates were combined to allow for layer separation. The obtained organic layer was washed successively with water (500 ml) and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture of (hexane:ethyl acetate) at a mixing ratio 2:1, and then with the mixture at a mixing ratio 1:1, and further with the mixture at a mixing ratio 1:2), and further purified by silica gel column chromatography (a mixture of hexane and acetone was used as an elution solvent, first eluted with a mixture of (hexane:acetone) at a mixing ratio 2:1, and then with the mixture at mixing ratios 4:1, 3:1, 2:1, 1:1, 2:3, and further with the mixture at a mixing ratio 1:2) to give the title compound (68.4 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:10].N([O-])=O.[Na+].C(OC(C)C)(=O)C.[I-:30].[K+]>O.C(O)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([I:30])=[C:3]([C:9]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Temperature: 2.5 °C
Yield: 79.7 %

Procedure:
Into a reactor at room temperature was added (2-amino-5-chlorophenyl)(2,6-difluorophenyl)methanone (1, 60.0 kg, 224 mol) and acetic acid (427 L). The mixture was stirred until all solids fully dissolved, filtered and washed with acetic acid (9.47 L). Concentrated HCl (156 L) was added over a minimum of 30 minutes at 20 to 25° C. and the resulting mixture was cooled to 0 to 5° C. A solution of sodium nitrite (18.6 kg, 269 mol) in water (88.0 L) was added while maintaining the reaction temperature between 0 and 5° C. The mixture was stirred for 1 h at 0 to 5° C. Water (270 L) and isopropyl acetate (717 L) were then added at 0 to 5° C. A solution of potassium iodide (50.2 kg, 303 mol) in water (133 L) was added over 1 h at 0 to 5° C. The reaction mixture was stirred for 30 min and warmed to 20 to 25° C. over 1.5 h. The layers were separated and the organic phase was washed with a dilute brine solution (22 kg NaCl in 200 L water) and a sodium carbonate solution (175 kg Na2CO3 in 523 L water). The resulting organic layer was washed twice with a sodium ascorbate solution (15.8 kg in 188 L water for each wash) followed by water (200 L). The organic phase was concentrated using a maximum 50° C. jacket temperature until 430 L of solvent was removed. Heptane (400 L) was added and the mixture was concentrated using a 50° C. jacket temperature until 395 L of solvent were removed. 2-Butanol (398 L) was added and the mixture was concentrated using a maximum 60° C. jacket temperature until 322 L of solvent were removed. An additional portion of 2-butanol (398 L) was added and the mixture was concentrated using a 70° C. jacket temperature until 390 L of solvent were removed. The reaction mixture was cooled to −5 to −8° C., stirred for 2 h, filtered and washed with 2-butanol (2×84.2 L) at −5 to 0° C. The resulting wet cake was dried at 40 to 50° C. under vacuum to provide 67.6 kg (80% yield) of 2. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=8.2 Hz, 1H), 7.51 (m, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.18 (dd, J=2.3, 8.2 Hz, 1H), 7.00 (m, 2H); Elemental Anal. Calcd. for C13H6ClF2IO: C, 41.25; H, 1.60; Cl, 9.37; F, 10.04; I, 33.52; O, 4.23. Found: C, 41.36; H, 1.65; Cl, 9.51; F, 10.03; I, 33.41; O, 4.04.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=2)=[O:6])[CH2:2][CH3:3]>CCO.[Pd]>[CH2:1]([NH:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([NH2:16])=[CH:11][CH:10]=2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCNC(=O)c1cc2cc(N)ccc2[nH]1
Yield: 0.1 %

Procedure:
To a solution of 5-nitro-1H-indole-2-carboxylic acid propylamide (2.94 g, 11.9 mmol) in EtOH (150 ml) a suspension of palladium on charcoal (10%, 1 g) in EtOH was added. The mixture was hydrogenated at atmospheric pressure. After filtration and removal of the solvents in vacuo the product was obtained as a yellow powder (2.46 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12]C(O)=O)=[CH:8][C:7]=1[CH3:16])=[O:5].O>C(O)(=O)CC>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[CH:8][C:7]=1[CH3:16])=[O:5]
Reactant: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: CCC(=O)O
Solvent: O
Product: Cc1cc(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
A solution of 62.69 g (0.18 mole) 5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (4) in 550 mL of propionic acid was heated under reflux overnight then poured into water. The solution was extracted three times with diethyl ether. The ether solution was washed successively with NaHCO3, water and brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a tan solid which was recrystallized from methylcyclohexane: mp 96-98° C.; mass spectrum (Cl—CH4) m/z=282 (M+1); NMR 300 MHz (CDCl3) d 7.5 (s, 1H); 7.35-7.2 (m, 2 H); 5.8 (s, 1H ); 3.9 (s, 3 H); 2.25 (s, 3 H); 1.6 (s, 3 H). Anal Calcd for C14H13Cl2NO: C, 59.59; H, 4.64; N, 4.96. Found: C, 59.79; H, 4.39; N, 4.92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]([CH3:26])[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=O)[NH2:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]([CH3:26])[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[S:36])[NH2:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(C(C)C(=O)Oc3ccc(C(N)=O)cc3)ccc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(C(N)=S)cc3)ccc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
4-Carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)-propanoate, 5 (1.80 g, 4.34 mmol) and Lawesson reagent (1.75 g, 4.34 mmol) were dissolved in 130 ml of anhydrous benzene. The reaction was warmed to 60° C. and stirred for 4 h. The solvent was removed under reduced pressure; the crude residue was purified by silica gel column (dichloromethane/methyl alcohol 9.75:0.25) to furnish 2.9 g of crude compound 6. The obtained compound was purified by a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5)) giving the pure compound 6 (970 mg, 61% yield).