Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:15][CH2:14][CH2:12][OH:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1ccc2ncc(Br)n2n1
Product: OCCNc1ccc2ncc(Br)n2n1
Yield: 63.8 %

Procedure:
400 mg (1.72 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2.0 ml (33.4 mmol) of ethanolamine were stirred at 90° C. for 16 h. After cooling, the mixture was concentrated. The resulting residue was purified by chromatography (DCM/EtOH 9:1). 282 mg of the product were obtained.
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:23][C:24]([Cl:34])([O:26][C:27](=[O:33])[O:28][C:29]([Cl:32])([Cl:31])[Cl:30])[Cl:25]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[Cl:23][C:24]([Cl:25])([O:26][C:27](=[O:33])[O:28][C:29]([Cl:32])([Cl:30])[Cl:31])[Cl:34].[C:1]1([C@@:7]2([C:24]([Cl:23])=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)[C@@]1(c2ccccc2)NCCc2ccccc21
Temperature: 60 °C
Reaction time: 12 h

Procedure:
In a three-neck flask the solution of triphosgene (10.87 g, 36.63 mmol) in toluene (60 mL) is prepared at room temperature (23° C.), then the reactor is placed in an ice-water cooling bath. In a separate flask (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (20.0 g, 95.55 mmol, purity 99% (HPLC)) and pyridine (3.26 mL, 40.30 mmol) are placed in toluene (80 mL), while heating at 50-70° C. until the whole amount of solid is dissolved. After cooling down to room temperature, the clear toluene solution is transferred into a dropping funnel. The solution is added dropwise within ca. 10 min. to triphosgene in toluene solution. When the addition is complete, the cooling bath is removed and the reactor is submerged in an oil bath. Reaction mixture is heated at 70-80° C., in a mean time thick yellow solid slowly dissolves. Since reaction temperature reaches 50° C., heating and stirring is continued for 45 min., until disappearance of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline signal (TLC control in CH2Cl2—MeOH 95:5, v/v against substrate sample) is observed. After completion of the reaction the mixture is cooled down to room temperature (20-24° C.), filtered through celit to remove precipitated pyridinium hydrochloride. Celit layer is washed with toluene (20 mL). Toluene (145 mL) is removed under reduced pressure (0.1-0.15 mmHg) from the post-reaction mixture, while heating the condensing flask in a water bath at 60-65° C. The oily residue is dissolved in heptan (200 mL) at reflux and the hot solution is filtered through celit (20 g), washed with heptan before filtration. The celit layer is washed with hot heptan (2×50 mL) after filtration. The excess of solvent (170 mL) is removed under reduced pressure; the condensed solution to ca. ½ volume is left at 5° C. for 12 h. Crystalline, colorless solid is filtered off and washed with heptan (2×15 mL). (S)-1-Phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride is obtained in 23.3 g, 90% yield; purity (HPLC) 98.4%; T(onset)=62.7° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[C:7](=O)[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][C:4]=2[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:10]([C:8]1[CH2:7][C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:9]=1)([CH3:12])[CH3:11]
Reactant: Cc1sc2c(c1-c1ccccc1)CC(C(C)C)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1sc2c(c1-c1ccccc1)C=C(C(C)C)C2
Temperature: 80 °C
Reaction time: 12 h
Yield: 104.6 %

Procedure:
A solution of 2-methyl-5-(isopropyl)-3-phenyl-4,5-dihydrocyclopenta[2,1-b]thiophen-6-one (18.5 g, 0.068 mol) in 80 mL of ether was treated with 40 mL of an ether solution of LiAlH4 (1 M, 0.04 mol). After sting for 12 h, water (˜20 mL) was added cautiously and the mixture was filtered through celite. The filter pad was washed with dichloromethane (3×100 mL) and the combined organic fractions were dried (MgSO4). Solvents were evaporated and the residue was dissolved in 150 mL of toluene. p-TSA (1.0 g) was added and the mixture was stirred at 80° C. for 2 h. After cooling, the mixture was washed with a saturated aqueous solution of NaHCO3, brine solution, and dried (MgSO4). Evaporation of solvent gave 18.1 g of product (93% purity by GC/MS). 1H-NMR δ (CD2Cl2): (major isomer) 7.3–7.5 (m, 5H), 6.48 (s, 1H), 3.2 (s, 2H), 2.8 (m, 1H), 2.5 (s, 3H), 1.22 (d, 6H). EIMS: m/z (%) 254 (M+, 55), 239 (100), 224 (25), 211 (5), 191 (5), 178 (9), 165 (7).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:11](C)=[CH:10]C(C)=[N:8][N:7]([CH3:14])[C:6]=2[N:15]=1.Cl>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:11]([CH3:10])=[N:8][N:7]([CH3:14])[C:6]=2[N:15]=1
Reactant: CC1=CC(C)=NN(C)c2nc(N)[nH]c(=O)c21
Agent: Cl
Solvent: CO
Product: Cc1nn(C)c2nc(N)[nH]c(=O)c12
Reaction time: 8 h

Procedure:
A mixture of 8-amino-1,3,5-trimethyl-1H-pyrimido{4,5-c}-1,2-diazepin-6(7H)-one (219 mg) and N hydrochloric acid (3 ml) was heated using a hot water bath (>85° C.) for 2 hours. During that period a solution formed before crystals gradually began to separate. The mixture stood at room temperature overnight before the straw-coloured crystals were collected, washed with water and dried under vacuum (70° C.) to yield 140 mg (78%) of analytically pure product: mp>300°; nmr (DMSO-d6) δ2.28 (s, 3H), 3.60 (s, 3H), 6.52 (br s, 2H), 10.30 (br s, 1H); uv λmax (CH3OH) 217 nm (ε26,800), 254 (13,000). Mass spectrum (120° C., 70 ev): M, m/e 179, 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[N:10]([CH3:20])[C:9]2=[O:18])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2cc(F)ccc2n1-c1cc(Cl)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(=O)n(-c2cc(Cl)ccc2O)c2ccc(F)cc21

Procedure:
A mixture of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-fluoro-2H-benzimidazol-2-one (300 mg, 1.1 mmol), anhydrous potassium carbonate (415 mg) and Iodomethane (68 μl) in 10 ml absolute acetone was refluxed for 5 hours. The mixture was filtered, concentrated in vacuo and the crude product was subjected to column chromatography using methylene chloride:acetone (20:1) as eluent. The fraction containing the product was concentrated in vacuo and the title compound was obtained as white crystals, M.p. 247°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[F:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:39]([C:36]2([C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:35])[CH2:38][CH2:37]2)=[O:40])=[CH:20][C:19]=1[F:25]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine (0.22 g, 0.61 mmol) and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2×). The combined extracts were washed with 5% LiCl(aq.) (3×), water, (1×) and brine (1×), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. 1H NMR (DMSO-4) δ 10.34 (s, 1H), 9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14](O)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C1C=CC=CC=1>[C:2]1([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([Cl:27])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a suspension of 12 g of the sodium salt of α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid in 200 ml of absolute benzene are added with stirring at 5°C 25 g of oxalyl chloride. The mixture is continuously stirred overnight at room temperature, then evaporated to dryness in vacuo. The residue is dissolved in 200 ml of absolute benzene are added with stirring at 5° C 25 g of oxalyl chloride. The mixture is continuously stirred overnight at room temperature, then evaporated to dryness in vacuo. The residue is dissolved in 200 ml of absolute benzene and filtered under anhydrous conditions. The filtrate is evaporated to dryness in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid chloride, which is used directly for further processing.
Reaction SMILES: BrBr.[CH2:3]=[CH:4][CH:5]=[CH2:6].[C:7]([O-:10])(=[O:9])[CH3:8].[K+].[C:12]([O-:15])(=[O:14])[CH3:13]>C(O)(=O)C>[C:7]([O:10][C:4]([CH3:3])=[C:5]([O:15][C:12](=[O:14])[CH3:13])[CH3:6])(=[O:9])[CH3:8]
Reactant: C=CC=C
Reactant: CC(=O)[O-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC(C)=C(C)OC(C)=O

Procedure:
Halogen, e.g., bromine, and a conjugated diene, e.g., butadiene, are reacted in vapor phase, the reacted mass condensed and contacted with alkali metal acetate dissolved or dispersed in an acid, e.g., potassium acetate in glacial acetic acid, thus causing a reaction of formed dibromobutene-2 with the acetate to form diacetoxy-2-butene. The latter is hydrogenated to the corresponding diacetoxylated alkane. The diacetoxy alkane is hydrolyzed to the dihydroxy alkane, e.g., 1,4-butanediol. Alternately, the diacetoxy alkene can be hydrolyzed and the hydrogenation then conducted.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][C:34](F)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>CS(C)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=3)=[CH:35][CH:36]=2)=[O:38])=[CH:39][CH:40]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
Tert-butyl 2-(4-hydroxyphenyl)acetate (200 mg, 0.960 mmol) was diluted with DMSO (4 mL) followed by the addition of K2CO3 (133 mg, 0.960 mmol) and N-(4-chlorophenethyl)-4-fluorobenzamide (267 mg, 0.960 mmol). The reaction was stirred at 85° C. overnight, and then stirred at 138° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (4:1) to yield tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetate (20 mg, 4.47% yield) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Brc1cccc2c1CCN2
Reaction time: 4 h
Yield: 52 %

Procedure:
A solution of 4-bromoindole (881 mg) in acetonitrile (18 ml) was cooled to 0° C. under argon atmosphere, and thereto were added dropwise successively triethylsilane (2.15 ml), and boron trifluoride diethyl ether complex (1.71 ml). The mixture was stirred at the same temperature for 4 hours, and then further stirred at room temperature for 1.5 hours. To the resultant mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the organic solvent was evaporated under reduced pressure. The residual mixture was extracted with ethyl acetate (60 ml) twice, and the combined organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=100:0-90:10) to give the titled compound (463 mg) as a yellow oil. APCI-Mass m/Z 198/200 (M+H). 1H-NMR (DMSO-d6) δ 2.90 (t, J=8.6 Hz, 2H), 3.45 (td, J=8.7, 1.4 Hz, 2H), 5.86 (br-s, 1H), 6.43 (d, J=7.7 Hz, 1H), 6.63 (d, J=7.9 Hz, 1H), 6.83 (t, J=7.9 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:24]>>[ClH:24].[N+:1]([C:4]1[C:5]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Agent: Cl
Product: O=[N+]([O-])c1cccnc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (8.5 g, 26.4 mmol) in hydrogen chloride (4 M solution in methanol, 50 mL) was stirred at room temperature for 3 hours. It was concentrated under reduced pressure to give crude 3-nitro-N-(piperidin-4-yl)pyridin-2-amine hydrochloride (6 g, 23.2 mmol, 88% yield) which was used without further purification.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[N:9]=[C:8]2[N:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:17]([F:29])[CH:16]=3)[C:7]2=[N:6][CH:5]=1>>[F:29][C:17]1[CH:16]=[C:15]([O:14][C:13]2[C:7]3[C:8](=[N:9][C:4]([NH:2][CH3:1])=[CH:5][N:6]=3)[N:10]=[CH:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CN
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Product: CNc1cnc2c(Oc3ccc(NC(=O)OC(C)(C)C)c(F)c3)ccnc2n1

Procedure:
Method D6 was used with methylamine and Tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate to give the title compound as a white solid. Yield: 80 mg (90%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.C1([Se](O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Agent: O=[Se](O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Temperature: 85 °C

Procedure:
To a solution of 1-(3-biphenylyl)-5hydroxymethylbenzimidazole (61a) (0.2 g, 0.7 mmol) in toluene (3 ml) was added benzeneseleninic acid (0.19 g, 1 mmol). The reaction mixture was heated to 85° C. for 2 hours. After cooling, the product was filtered off and washed thoroughly with warm water. Yield: 80 mg, 0.27 mmol, 38%. mp 170°-172° C.
Reaction SMILES: C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1.Cl[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:59]3[C:54](=[CH:55][C:56]([S:60]([NH:63][C:64]4[CH:69]=[CH:68][N:67]=[CH:66][N:65]=4)(=[O:62])=[O:61])=[CH:57][CH:58]=3)[CH:53]=[CH:52][N:51]=2)=[C:46]([O:70][CH3:71])[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:59]4[C:54](=[CH:55][C:56]([S:60]([NH:63][C:64]5[CH:69]=[CH:68][N:67]=[CH:66][N:65]=5)(=[O:61])=[O:62])=[CH:57][CH:58]=4)[CH:53]=[CH:52][N:51]=3)=[C:46]([O:70][CH3:71])[CH:45]=2)=[CH:38][CH:37]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: Oc1ccc(F)cc1
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Oc2ccc(F)cc2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 135 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
A microwave vial charged with di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (0.017 g, 0.035 mmol), 4-fluorophenol (0.039 g, 0.351 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.075 g, 0.176 mmol), potassium phosphate (0.149 g, 0.703 mmol), 1.5 mL dioxane was heated to 135° C. in the microwave for 30 minutes. LC/MS showed mostly product, so the reaction mixture was filtered through a 0.45 μm syringe filter and was treated with HCl (4N in dioxane) (0.176 ml, 0.703 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-(4-fluorophenoxy)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.020 g, 0.040 mmol, 22.65% yield). 1H NMR (MeCN-d3) δ: 8.68 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.88-7.98 (m, 2H), 7.83 (d, J=9.0 Hz, 1H), 7.25-7.33 (m, 1H), 7.13-7.21 (m, 4H), 7.08 (d, J=5.4 Hz, 1H), 6.83 (s, 1H), 6.62-6.69 (m, 1H), 3.60 (s, 3H); (M+H)+=503.0.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].OC1C=CC=CC=1C=O>CN(C=O)C>[CH2:25]([NH:27][C:28]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Solvent: O=Cc1ccccc1O
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DMF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% of the title compound as a light buff solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=O)OC(C)(C)C)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)[CH3:2].C=O>C(O)=O>[CH2:1]([O:3][CH2:4][CH2:5][CH:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]([CH3:33])[CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[CH3:2]
Reactant: CCOCCC1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Agent: C=O
Solvent: O=CO
Product: CCOCCC1CCc2sc3ncnc(OC4CCC(N(C)C)CC4)c3c21
Temperature: 100 °C
Reaction time: 0.27 h

Procedure:
A 25-mL round-bottom flask containing 19.1 (19 mg, 0.04 mmol, 1.00 equiv), formic acid (1 mL) and formaldehyde (37%, 5 mL) was heated at 100° C. for 12 h in an oil bath under nitrogen. The mixture was concentrated under reduced pressure and the residue (45 mg) purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18, 19*150 mm 5 um; mobile phase: water (0.05% NH4HCO3) and CH3CN (5.0% CH3CN up to 53.0% in 16 min); UV detection at 254 and 220 nm. The product-containing fractions were collected and evaporated under reduced pressure to afford compound I-31 (5.7 mg, 37%) as an off-white oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (m, 3H), 1.54 (m, 4H), 1.61 (m, 1H), 2.02-2.80 (m, 14H), 2.28-3.10 (m, 2H), 3.48 (m, 5H), 5.24 (m, 1H), 8.50 (s, 1H). MS: m/z 390 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH2:5][CH3:6].[CH3:21][O:22]N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC>>[CH3:21][O:22][C:19]1[CH:20]=[C:15]([C:2](=[O:1])[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])[CH2:4][CH2:5][CH3:6])[CH:16]=[CH:17][CH:18]=1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as (91c) from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96 mmol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=[C:16]([N+:18]([O-])=O)[CH3:17].O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][CH:16]([NH2:18])[CH3:17]
Reactant: CC(=Cc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a suspension of lithium aluminum hydride (0.33 g, 8.9 mmol) in tetrahydrofuran (20 ml) was added dropwise a solution of 2,4-dichloro-1-(2-nitro-1-propenyl)benzene (1.0 g, 4.3 mmol) in tetrahydrofuran (5 ml) at room temperature. Refluxing started slowly and the mixture was heated under reflux for 1 hr thereafter. The mixture was allowed to cool to room temperature and water (2 ml) was added under cooling in an ice bath. A 1N aqueous sodium hydroxide solution (5 ml) was added, and the insoluble material was removed by filtration through celite. Water was added to the filtrate, and the mixture was extracted with methyl t-butyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crude [2-(2,4-dichlorophenyl)-1-methylethyl]amine (yield; 0.8 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:15])[CH:3]=1.[H][H]>[Pt].C(O)C.O1CCCC1>[NH2:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([F:15])=[C:5]([CH:10]=1)[NH:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(N)c(Cl)cc1F

Procedure:
A mixture of 4'-chloro-2'-fluoro-5'-nitroacetanilide (35.2 g, 151 mmol), and 5% platinum on carbon (7.0 g, 20 wt/wt %) in an ethanol/tetrahydrofuran (2:1) solution is hydrogenated until 28 psi of hydrogen is taken up. The reaction mixture is then filtered, and concentrated in vacuo to give the title product as a tan solid which is identified by 1H NMR spectral analysis.