Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[IH:18]>ClCCl>[I:18][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: I
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ccnc(I)n2)cc1
Reaction time: 0.67 h
Yield: 94.9 %

Procedure:
2-Chloro-4-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 5) (1.22 g, 4.72 mmol) was added portionwise to HI (57% in water) (4.98 mL, 37.74 mmol) at 0° C. and the dark mixture was stirred for 40 mins. Dichloromethane (5 mL) was added and the resultant light brown mixture was stirred at 0° C. for 18.25 hrs. Additional dichloromethane (5 mL) was added followed by HI (57% in water) (1.87 mL, 14.15 mmol) and vigorous stirring was continued at 0° C. for a further 18 hrs. The mixture was quenched by the addition of satd. aq. K2CO3 (care: gas evolved). After basification, satd. sodium metabisulphite was added and stirring was continued for 5 mins. The mixture was diluted with further DCM and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford the 2-iodo-4-[4-(trifluoromethyl)phenyl]pyrimidine (D6) (1.57 g, 4.48 mmol, 95.1% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](/[N+:11]([O-:13])=[O:12])\[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][NH:36]2)=[CH:32][CH:31]=1>C1COCC1>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34]([CH:8]([C:7]3[C:2]([CH3:1])=[C:3]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[CH:5][CH:6]=3)[CH:9]([N+:11]([O-:13])=[O:12])[CH3:10])=[CH:35][NH:36]2)=[CH:32][CH:31]=1
Reactant: C/C(=C\c1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Reactant: COCCOc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)[N+](=O)[O-])c[nH]c2c1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
(E)-Benzyl 2-methyl-3-(2-nitroprop-1-enyl)phenylcarbamate (0.6849 g, 1.574 mmol) and 6-(2-methoxyethoxy)-1H-indole (0.602 g, 3.15 mmol) were dissolved in THF (50 mL), concentrated in vacuo, and melted at 140° C. for 12 h. After cooling to room temperature, the crude product was purified by flash chromatography using an ISCO 40 g column (solid loading) eluting with 20-75% EtOAc/hexane. Appropriate fractions were collected and concentrated in vacuo to give benzyl 3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate (0.4102 g, 0.793 mmol, 50.4% yield, mixture of 2 isomers) as a yellow oil, LC/MS (M+H)=518.12, 518.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33](SC)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.S(=O)(O)[O-].[Na+].[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOc1nc(SC)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1nc(N2CCOCC2)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of rac-4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (160 mg, 0.261 mmol) in methylene chloride cooled to 0° C. was added 100 mg of m-chloroperoxybenzoic acid (≦77%, Aldrich). After 10 min, sodium bisulfite solution was added to quench the reaction. The product was extracted with methylene chloride. The organic layer was washed with saturated solution of sodium bicarbonate, brine, dried over Na2SO4 and concentrated to give the crude sulphoxide as light yellow foam. The crude sulphoxide/sulphone was taken in 20 mL of tetrahydrofuran, and morpholine (200 uL, 3.34 mmol, Aldrich) was added. The mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50-100% ethyl acetate in hexanes, then with 0-5% methanol in ethyl acetate) gave the tittle compound (94 mg, 55%). HR-MS (ES, m/z) calculated for C32H36N7O4Cl2 [(M+H)+] 652.2201, observed 652.2202.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][NH:12][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=O)(C)(C)C.[ClH:28]>CO>[ClH:28].[ClH:28].[NH2:8][C@H:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:10][CH2:11][NH:12][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1(NCC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)C1(NCC[C@H](N)c2ccccc2)CCCC1

Procedure:
To a cooled (0° C.) solution of methyl 1-({(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylate from Step C (0.920 g, 2.44 mmol) in MeOH (49 mL) was added excess anhydrous hydrogen chloride gas. After 30 min the solution was purged with dry nitrogen for about 40 min. The solvent was then removed in vacuo to provide a solid/oil mix. Additional MeOH (50 mL) was then added and subsequently removed in vacuo to provide the title compound. MS: nm/z=277 (M+1).
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[N:18]1([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]3=[CH:4][CH:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1n[nH]c2nc(N3CCNCC3)ccc12
Yield: 36.1 %

Procedure:
t-Butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (3.00 g, 0.0126 mole) was dissolved in 100 mL of toluene containing 10.85 g of piperazine (0.126 mole) and refluxed overnight. The resultant precipitate was filtered off and distributed between an aqueous NaHCO3 solution and EtOAc and then the organic phase was dried and concentrated to give a product which was recrystallized from CH3CN to give 1.57 g, mp 190°-191° C. The toluene filtrate was washed with NaHCO3 solution and then concentrated and purified by flash chromatography (EtOAc:MeOH:Et3N/16:2:2) to give an additional 1.38 g of product (total yield 77%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3][NH2:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CO>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH3:24])=[CH:18][CH:17]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: Cc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.05 g) and 4-methylphenylacetone (1.48 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4h. The solvent was removed under reduced pressure, replaced with methanol and sodium borohydride (3 g) added portionwise. The solvent was evaporated under reduced pressure, the residue partitioned between water and ether and the ether layer dried (MgSO4). Removal of the solvent under reduced pressure gave an oil which was dissolved in methanol and treated with an equivalent amount of methanolic fumaric acid. Evaporation of the solvent gave the title compound (fumarate salt) as a 58:42 mixture of diastereoisomers, mp 138°-144° (EtOAc).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N)CC.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.[Cu]I>[OH:12][CH2:9][C:10]#[C:11][C:4]1[CH:3]=[C:2]([C:11]#[C:10][CH2:9][OH:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: OCC#Cc1cccc(C#CCO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
A solution of 1,3-dibromobenzene (0.6 ml, 5.0 mmol) in n-propylamine (15 ml) is admixed successively with Pd(Ph3P)4 (116 mg, 2%), CuI (28 mg, 3%) and propargyl alcohol (0.9 ml, 15 mmol) and stirred at RT for 20 h. More Pd(Ph3P)4 (58 mg, 1%), CuI (14 mg, 1.5%) and propargyl alcohol (0.45 ml, 7.5 mmol) are then added, and the mixture is stirred at reflux for a further 6.5 h. After cooling, the reaction mixture is filtered off with suction over kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [Tol/Ac (8:2)] over a silica gel column. This gives the title compound (0.6 g) as a colorless oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.22.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38]#[N:39]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:37][C:38]#[N:39])[CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCN(CC#N)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 8.8 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DMA (5 ml). Potassium carbonate (138 mg, 1.00 mmol) and chloroacetonitrile (17 μl, 0.25 mmol) were added. The mixture was stirred at 60° C. for 4 hours. Further potassium carbonate (138 mg, 1.00 mmol) and chloroacetortitrile (17 μl, 0.25 mmol) were added, and heating was continued at 60° C. for a further 4 hours. The solvent was evaporated and the residue was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (2×10 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper and evaporated. The residue was purified by chromatography, eluting with 0 to 2% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated. The residue was further purified using reverse phase HPLC, eluting with 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid. The appropriate fractions were combined; the acetonitrile was evaporated from the solution, and the resulting aqueous solution was adjusted to pH 8 using concentrated aqueous ammonia. The resulting suspension was extracted twice with DCM, and the extractions combined, filtered through a silicone-treated filter paper, and evaporated. The residue was triturated with diethyl ether to give the product as a white solid (10 mg, 9%); 1H NMR: 132-1.46 (m, 2H), 1.75-1.92 (m, 3H), 220 (m, 2H), 2.84 (m, 2H), 3.72 (s, 2H), 3.93 (s, 3H), 3.98 (d, 2H), 7.20 (s, 1H), 7.26 (dd, 1H), 7.47 (dd, 1H), 7.50 (dd, 1H), 7.76 (s, 1H), 8.36 (s, 1H), 9.59 (s, 1H); Mass Spectrum; 456.4, 458.4
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].C([Mg]Cl)C(C)C.CN(C)[CH:32]=[O:33].[Cl-].[NH4+]>O1CCCC1>[F:23][C:3]1[C:2]([CH:32]=[O:33])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Br)c2F)CC1
Agent: CC(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2F)CC1
Reaction time: 2 h

Procedure:
194 mg of tert-butyl 4-(3-bromo-2-fluorobenzoyl)piperazine-1-carboxylate was dissolved in 5.0 ml of tetrahydrofuran, and 1.25 ml of a solution of isobutyl magnesium chloride in tetrahydrofuran (2.0 M) was added thereto at −78° C. After stirring at the same temperature for 2 hours, 0.39 ml (5.0 mmol) of N,N-dimethylformamide was added thereto. The resulting mixture was stirred at the same temperature for 30 minutes and further stirred at 0° C. for 30 minutes. To the reaction mixture was added saturated ammonium chloride, and the mixture was extracted with chloroform. The organic layer was washed with brine and then concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M86) (0.35 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 88%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[N+]=[N-].C(#N)C>O.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Agent: [Pd]
Solvent: O
Solvent: CC#N
Product: NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 0.33 h

Procedure:
A solution of 17-azido-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid (8.36 g, 25.0 mmol) in water (100 ml) was reduced using H2(g) —Pd/C (10%). The reaction was run until LC-MS analysis showed complete conversion of starting material (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm, ES ionisation giving M+H at 335 for starting material and 309 for the product). The solution was filtered and used directly in the next step.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:16].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:15]#[N:16])=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ccc(CC#N)cc2)s1
Temperature: 80 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
5-Bromo-thiophene-2-sulfonic acid tert.-butylamide (0.6 g) was suspended in toluene (5 mL) under an Ar-atmosphere. To the suspension (4-cyanomethylphenyl)boronic acid (486 mg), Na2CO3 (533 mg), water (2.5 ml) and EtOH (2.5 mL) was added. To this suspension 2′-(dimethylamino)-2-biphenyl-palladium (II) chloride dinorbornylphosphine complex (23 mg) was added and the mixture was stirred for 18 h at 80° C. After that the suspension was cooled to 25° C., evaporated to ⅓ of the original volume and treated with EtOAc (30 mL). The organic layer was washed with aqueous HCl (1N, 10 mL) and brine. The organic layer was dried over Na2SO4, filtrated and evaporated to dryness. The crude material was purified by flash chromatography (eluent CH2Cl2, 2N NH3 in methanol) to yield 5-(4-cyanomethyl-phenyl)-thiophene-2-sulfonic acid tert-butylamide (268 mg, 40%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]#[CH:11])[CH:3]=1.Br[C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C(=O)C(F)(F)F.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]2[NH:20][C:14]3[C:13]([CH:11]=2)=[C:18]([F:19])[CH:17]=[CH:16][CH:15]=3)[CH:3]=1
Reactant: O=C(Nc1cccc(F)c1Br)C(F)(F)F
Reactant: C#Cc1cc(Cl)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.9 %

Procedure:
A mixture of 4-chloro-2-ethynyl-1-methoxybenzene (255 mg, 1.5 mmol), N-(2-bromo-3-fluorophenyl)-2,2,2-trifluoroacetamide (400 mg, 1.4 mmol), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was stirred in TBAF.3H2O (1.43 g, 7 mmol) at 110° C. for 12 hours. The reaction mixture was cooled to 25° C. and added to water, then extracted with ethyl acetate and washed with brine, dried over Na2SO4. After concentrated, the crude product of 2-(5-chloro-2-methoxyphenyl)-4-fluoro-1H-indole (100 mg, yield: 20%) was obtained. MS (M+H)+: 276/278.
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])[C:17]([F:30])([F:29])[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[C:11]([F:32])[C:10]=1[CH2:33][CH2:34][OH:35].[ClH:36]>C(#N)C.[Cu](Cl)Cl>[Cl:36][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:31])[C:17]([F:30])([F:29])[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[C:11]([F:32])[C:10]=1[CH2:33][CH2:34][OH:35]
Reactant: Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c(F)c1CCO
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccc(F)c2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
To a flask charged with copper(II) chloride (1.84 g, 13.7 mmol) was added a solution of tert-butylnitrite (1.46 g, 12.8 mmol, 90%, Aldrich) in acetonitrile (35 mL) under argon atmosphere. The resulting green reaction mixture was cooled in an ice-bath to 0° C., and a solution of N-[4-amino-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl) acetamide (3.58 g, 9.13 mmol), as prepared according to the procedure of the preceding step, in acetonitrile (60 mL) was added over a period of 45 minutes. After stirring for an additional 6 hours at 0° C., the resulting brown mixture was allowed to warm up to ambient temperature, then poured into 20% aqueous HCl (160 mL), and extracted with DCM (3 times). The extracts were combined, washed with 20% HCl, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0 and 2.5%) to deliver the title compound (2.1 g, 56% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.31 (br s, 1H), 8.24-8.12 (m, 3H), 7.84 (dd, J=8.2, 5.3 Hz, 1H). 7.68-7.60 (m, 2H), 7.22-7.20 (m, 2H), 3.87 (dd, J=12.6, 6.5 Hz, 2H), 3.09 (dt, J=6.7, 2.2 Hz, 2H), 1.47 (t, J=5.6 Hz, 2H). Mass spectrum (LCMS, ESI) calc'd for C20H15ClF4NO2 (M+H): 412.1. Found: 412.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][S:7](=[O:9])(=[O:8])[NH2:10]
Reactant: COCCCN
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Product: COCCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and 3-methoxypropylamine (0.42 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1) was performed to give N-(3-methoxypropyl)sulfuric diamide (Compound GG) (165 mg, yield: 24%).
Reaction SMILES: I[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:19][C:11](=[O:18])[C:12]([CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ICCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)OCC
Temperature: 52 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A mixture of 2-iodoethylphenyl sulfide (19.81 g, 75 mmol), diethyl malonate (4.80 g, 30 mmol), potassium carbonate (10.35 g, 75 mmol) and DMF (40 mL) was heated at 52° C. for 18 hours. More potassium carbonate (10 g) was added and the reaction was continued at 52° C. for another 8 hours. The reaction mixture was cooled, diluted with ice water and the product extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid diethyl ester (5.648 g).