Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:4]1)=O.Cl.[CH2:32]([N:35]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH:33]=[CH2:34].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[CH2:32]([N:35]([CH:42]1[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]3[CH2:20][C:21]([OH:23])=[O:22])[CH2:4]2)[CH2:44][CH2:43]1)[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:33][CH3:34]
Reactant: O=C[C@H]1CN([C@@H]2CCCCC2CC(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Reactant: C=CCN(c1ncccn1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The title compound was prepared using 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, benzyl ester using (75 mg, 0.185 mmol; prepared above as Aldehyde 4), 4-(N-allyl-N-(pyrimid-2-yl)amino)piperidine hydrochloride (61 mg, 0.24 mmol) from Example 2, Step A, NaHB(OAc)3, (97 mg, 0.46 mmol) and triethylamine (0.026 ml, 0.24 mmol) in 3 ml dichloromethane. The mixture was stirred overnight at room temperature. The reaction was diluted with 100 ml EtOAc and washed with 1M NaOH and saturated NaCl. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The material was purified using flash chromatography (5% EtOAc in hexane) to provide 80 mg (71%) of the title compound. HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 4.4 minutes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[S:12][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][C:16]=4[NH:22][S:23]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:10][CH2:9]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:37][CH:38]([F:40])I>CN(C)C=O.C(OCC)(=O)C>[F:37][CH:38]([F:40])[N:22]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[NH:14][C:13]([C:11]1[S:12][CH:8]([CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH2:9][N:10]=1)=[CH:21]2)[S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Nc1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)c1cccs1
Reactant: FC(F)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccs1)N(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (200 mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (90.0 mg) and difluoroiodomethane (77.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (60 mg, yield 27%) as white crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 513 (MH+). melting point 185-186° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.2 %

Procedure:
To (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7B) (6.70 g, 20.2 mmol) in CH2Cl2 (100 mL) at 0° C. was added Dess-Martin periodinane. The ice bath was removed and the reaction was warmed to rt. After 2 h, saturated aqueous Na2S2O3 and NaHCO3 (ca. 100 mL each) were added and the reaction mixture was stirred vigorously for 0.5 h. The layers were separated, the organic layer was washed with a mixture of saturated aqueous Na2S2O3 and NaHCO3 followed by brine, dried (MgSO4), and was then filtered and concentrated to obtain compound 7C (7.20 g) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:58][N:57]=[C:56]([CH3:59])N=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:58][N:57]=[C:56]([CH3:59])[N:16]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1noc(CCl)n1
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Product: Cc1noc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as brown gum. MS (m/e): 359.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH2:13]([N:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19][NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH2:13][N:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19][NH:20][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CC(C)CN(CCN)CC(C)C
Product: CC(C)CN(CCNC(=O)CN1CCCC1=O)CC(C)C

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 12.9 g. of 2-(diisobutylamino)ethylamine (British Pat. No. 614,164), following the procedure of Example 1, there is obtained N-[2-[bis(2-methylpropyl)amino]ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 155°-160° C./0.1 mm.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([CH2:7]P(=O)(OC)OC)[CH2:4][O:3]1.[N:14]1([CH2:19][CH2:20][O:21][CH:22]2[CH2:34][CH2:33][C:25]3([CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]3)[CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.[H-].[Na+]>[N:14]1([CH2:19][CH2:20][O:21][CH:22]2[CH2:34][CH2:33][C:25]3([CH2:30][CH2:29][CH:28]([CH:31]=[CH:7][C:5]4[CH2:4][O:3][C:2](=[O:1])[CH:6]=4)[CH2:27][CH2:26]3)[CH2:24][CH2:23]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=CC1CCC2(CC1)CCC(OCCN1CCCC1)CC2
Reactant: COP(=O)(CC1=CC(=O)OC1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(C=CC2CCC3(CC2)CCC(OCCN2CCCC2)CC3)CO1
Yield: 108 %

Procedure:
Sodium hydride (0.045 mg, 60% dispersion in mineral oil) was added under nitrogen atmosphere and at room temperature, to a mixture of 0.740 g of dimethyl (2-oxo-[5H]-4-furyl)methylphosphonate and 0.080 g of 9-(2-(N-pyrrolidinyl)ethoxy)-3-formyl-spiro[5.5]-undecane (I-af, Ex. 30) in 5 ml of anhydrous tetrahydrofuran. After 2 hrs the reaction was quenched with sodium dihydrogenophosphate (5% water solution) and diluted with ethyl acetate; the organic layer was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure The residue was purified by flash chromatography (SiO2 ; chloroform/methanol 80/20) to give 0.110 g of (EZ)-9-(2-(N-pyrrolidinyl)ethoxy)-3-(2-(2-oxo-[5H]-4-furyl)vinyl)-spiro[5.5]-undecane (I-b) as amorphous solid. TLC: Rf=0.32 (SiO2 plates, chloroform/methanol 80/20). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 6.50-5.70 (2H, m); 6.30 (1H, bs); 4.81 (2H, bs); 3.68 (2H, t), 3.45(1H, m), 2.75 (2H, t), 2.70-2.00 (5H, m); 1.97-0.99 (22H, m).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10]>ClCCl>[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:4])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCC(C)(C)C(=O)O
Solvent: ClCCl
Product: C=CCC(C)(C)C(=O)Cl
Reaction time: 3 h

Procedure:
Oxalyl chloride (5.1 mL, 58 mmol) was added to a 0-5° C. solution of 2,2-dimethyl-4-pentenoic acid (5.00 g, 39.0 mmol) in 25 mL of dichloromethane. The mixture was stirred for 3 h, then concentrated to afford crude 2,2-dimethyl-4-pentenoyl chloride, which was dissolved in 10 mL of dichloromethane for use in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:32]([OH:35])(=[S:34])[CH3:33].[Na].C(O)(=S)C.[H-].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][S:34][C:32](=[O:35])[CH3:33])[CH2:16][CH2:17]2)=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: CC(O)=S
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of N-p-nitrobenzyloxycarbonyl-4-p-toluenesulfonyloxymethylpiperidine (3.72 g) in dry dimethylformamide (10 ml) was added to a solution of sodium thioacetic acid (1 g) prepared from thioacetic acid and sodium hydride in dry dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue which was then purified by silica gel column chromatography to give N-p-nitrobenzyloxycarbonyl-4-acetylthiomethylpiperidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[OH:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23][C:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23][C:24]1([C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]2[OH:15])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
To the solution of tert-butyl 4-amino-3-hydroxypiperidin-1-carboxylate (20 g, 92 mmol) obtained in step 4 of Preparation Example 1 and 1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarboxylic acid (5.0 g) obtained in Step 2 in 70 ml of dimethylformamide, were added hydroxybenzotriazole(HOBt; 3.1 g, 23.1 mmol) and diisopropylethylamine (DIEA; 9.0 ml, 53.4 mmol). The reaction mixture was cooled to 0° C. and was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl; 5.1 g, 26.7 mmol) thereto. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with 200 ml of ethyl acetate, washed with 10% citric acid solution, a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 4.3 g of the titled compound.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]=[C:4]1[C:10](OCC)=[O:11])[CH3:2].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:4]([CH2:10][OH:11])=[CH:5][CH:6]=[CH:7][C:8]1=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cccc(=O)n1CC
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCn1c(CO)cccc1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Ethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (2.25 g, 11.5 mmol) obtained in Step 1 was dissolved in ethanol (50 mL), and at 0° C., calcium chloride (2.56 g, 23.1 mmol) and sodium borohydride (2.18 g, 57.6 mmol) were added thereto, followed by stirring at 0° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of ammonium chloride was added to the resulting residue, followed by stirring at room temperature for 30 minutes. The reaction mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=49:1) to afford 1-ethyl-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine (1.51 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C2(CO)CCN(C(OC(C)(C)C)=O)CC2)[CH:5]=[CH:6][CH:7]=1.[OH:23][CH2:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]1>>[CH2:31]([N:28]1[CH2:29][CH2:30][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:45])[F:47])[CH:39]=2)([CH:24]=[O:23])[CH2:26][CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2cccc(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2cccc(C(F)(F)F)c2)CC1
Product: O=CC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1

Procedure:
Using standard Swern oxidation reaction conditions (see step (v)/Example 80 or step (iii)/Example 81), tert-butyl 4-(hydroxymethyl)-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.2 mmol, 0.43 g) was oxidized to give 1-benzyl-4-(3-(trifluoromethyl)phenyl)piperidine-4-carbaldehyde which was used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[Cl:20])=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][CH2:2][CH2:3][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:16])([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[Cl:20]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CBr)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CCBr)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of ethyl 2-[4-(2-bromoacetyl)-3-chlorophenoxy]-2-methylpropionate (209 mg) in trifluoroacetic acid (445 μl) was added triethylsilane (300 μl), and the mixture was stirred for 1 hour at 60° C. After the reaction mixture was concentrated under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent:hexane/ethyl acetate=30/1) gave ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]-2-methylpropionate (171 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.CO.Cl.C(=O)([O-])[O-].[K+].[K+]>[Fe].ClCCl.O.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:4][C:3]=1[NH2:19]
Reactant: CCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCOc1ccc(N)c(C)c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 74.8 %

Procedure:
The mixture of crude 2-methyl-4-decyloxynitrobenzene (90 g, 0.294 mol), methanol (246 mL), concentrated hydrochloric acid (159 mL) and dioxane (70 mL) was heated to 75° C. Iron powder (49.9 g, 0.89 mol) was added in small portions with vigorous stirring. After the addition was complete the reaction mixture was stirred at 75° C. for another 20 minutes and poured warm into water (3 L), stirred for 30 minutes and the pH adjusted to 11.0 by addition of aqueous potassium carbonate solution. Dichloromethane (3 L) was added and the mixture was stirred intensively for 1 hour. The layers were separated and the organic layer dried over sodium sulfate and passed through a thin pad of silica gel. The solvent was evaporated to dryness to give a brown oil (58.5 g, 0.22 mol, 76% yield).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[H-].[Na+].[C:10]([C:12](=[C:17](SC)[S:18][CH3:19])[C:13](OC)=[O:14])#[N:11].O>CN(C)C=O>[CH3:2][CH:3]([C:4]1[NH:6][C:17]([S:18][CH3:19])=[C:12]([C:10]#[N:11])[C:13](=[O:14])[N:5]=1)[CH3:7]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1[nH]c(C(C)C)nc(=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 2-methylpropanimidamide hydrochloride (7.0 g, described in Example 7) in dimethylformamide (15 mL) was added dropwise to a suspension of sodium hydride (3.0 g, 50% in mineral oil, prewashed with hexane) in dimethylformamide (15 mL) and the whole mixture was left at 25° C. for 1 hr. 2-Cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (6.5 g) in dimethylformamide (15 mL) was then added dropwise, and the reaction mixture was stirred for an additional 4 hr at 25° C. Water (25 mL) was then added, and acidification with concentrated hydrochloric acid (10 mL) precipitated the product. The precipitate was collected and air dried to give the title compound (6.0 g): mp>260° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:26]([C:27]([N:29]=[C:30]=[O:31])=O)=[C:25]([F:32])[C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:25]([F:32])[C:26]=1[C:27]1[NH:29][C:30](=[O:31])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g of pure product. 1H NMR (300 MHz, CDCl3): δ 1.19 (s, 9H), 4.40 (m, 2H), 6.22 (m, 1H), 7.26 (m, 1H), 7.35 (m, 1H), 7.62 (d, J=8.1 Hz, 2H), 8.12 (d, J=7.8 Hz, 2H); MS (m/z): 471.18 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:31])=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[C:5]([F:31])=[CH:4][N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)cc1
Product: COc1cc(Cl)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
Example 217 was synthesized in a similar manner to Example 212, except that 1-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate QQQ) and (4-chloro-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 1-(4-chloro-2-methoxyphenyl)-4-fluoro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.70 (s, 1H), 8.58 (d, J=10.4 Hz, 2H), 8.21 (s, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.40-7.30 (m, 2H), 7.19 (dd, J=2.0, 8.0 Hz, 1H), 7.10-6.80 (m, 1H), 3.67 (s, 3H). m/z (ESI) 445.2 (M+H)+.
Reaction SMILES: [CH:1](OCC)=[O:2].C[O-].[Na+].[CH2:9]([C:16]1([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.C(Cl)Cl.C(OCC)C>[CH2:9]([C:16]1([C:23]#[C:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH2:21][C:20](=[CH:1][OH:2])[C:19](=[O:22])[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC=O
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)C(=CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
Under an argon atmosphere, ethyl formate (110.6 μL, 1.33 mmol, 5 eq) then sodium methoxide (71.7 mg, 1.33 mmol, 3 eq) were successively added to a solution of 31 (75 mg, 0.265 mmol) in dry benzene (3.07 mL). This mixture was stirred at room temperature for 1 hour, during which time a color change from orange to red-brown occurred. The mixture was then diluted with a mixture of methylene chloride/ethyl ether (1:2, 20 mL) and washed with saturated aqueous ammonium chloride solution (2×8 mL). The aqueous washings were combined and extracted with methylene chloride/ethyl ether (1:2, 3×10 mL). The organic layers were then combined and washed with brine (1×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 4-benzyl-6-hydroxymethylene-4-((trimethyl-silyl)ethynyl)cyclohex-2-enone (83 mg, 100%) as a yellow-brown oil. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 13.67 (1H, bs), 7.45 (1H, bs), 7.23-7.16 (5H, m), 6.51 (1H, dd, J=1, 10.5 Hz), 5.98 (1H, d, J=10 Hz), 2.84 (1H, d, J=13 Hz), 2.68 (1H, d, J=13 Hz), 2.57 (1H, dd, J=1, 14.5 Hz), 2.40 (1H, d, J=15 Hz); 13C NMR (CDCl3) δ 187.5, 168.7, 151.4, 136.0, 130.8, 128.5, 128.1, 127.2, 127.1, 109.9, 108.0, 44.4, 38.9, 34.6, 0.10.