Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NCCc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NCCc2cccs2)c1
Yield: 90.5 %

Procedure:
Reaction of-2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with m-anisoyl chloride (74 μL, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 3-methoxy-N-(2-thiophen-2-yl-ethyl)-benzamide (100 mg, 0.38 mmol, 90% yield) as a yellow wax after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:6]1[SH:7])(=[O:3])[CH3:2].[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:6]1[S:7][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:3])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 29.2 %

Procedure:
A pyridine solution (100 ml) of 35 g (0.096 mole) of 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose [Methods in Carbohydrate Chemistry, Vol. 2, 436 (1963)] and 28 g (0.10 mole) of triphenylmethyl chloride was stirred at room temperature for 12 hours. The solution was filtered and the pyridine removed at reduced pressure. The residue was dissolved in chloroform (350 ml), washed with water (5 × 100 ml) and the chloroform solution dried in magnesium sulfate. The solvent was removed at reduced pressure and the residue dissolved in methanol and cooled to give 17 g (29%) of crystalline 2,3,4,6-tetra-O-acetyl-1-S-trityl-1-thio-β-D-glucopyranose, m.p. 177°-179°; [α]D25 (1% methanol) = -37.8°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OC4CN(C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 87.1 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)pyridine-2(1H)-one 199f (200 mg, 0.55 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (270 mg, 0.56 mmol), PdCl2(dppf) (40 mg, 0.055 mmol), K3PO4 (150 mg), NaOAc (50 mg) in MeCN (8 mL) and water (2 mL) was heated at 110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuo. The residue was purified on reverse phase Combi-flash to give 293a (307 mg, 70%). MS: [M+H]+ 641.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1)[CH3:2].C(N(CC)CC)C.[SH:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44].ClCC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44])[CH:24]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CCl)c1
Reactant: OCC(O)CS
Agent: O=C(O)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CSCC(O)CO)c1
Reaction time: 36 h
Yield: 77 %

Procedure:
Subsequently, 2-(3-chloromethyl-benzoylamino)-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (1.1 g) was dissolved in anhydrous methylene chloride (20 ml). Triethylamine (800 μl) and 3-mercapto-1,2-propanediol (compound B′) (600 μl) were added dropwise to the solution at room temperature, and the mixture was stirred at that temperature for 36 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-[3-(2,3-dihydroxy-propylsulfanylmethyl)-benzoylamino]-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (970 mg, yield 77%).
Reaction SMILES: C12BC(CCC1)CCC2.O1CCCC1.[CH2:15]([OH:19])[CH2:16][CH:17]=[CH2:18].[F:20][C:21]1[CH:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:24]=[C:23]([F:35])[C:22]=1[CH:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[N+]([O-])(C)C>O1CCOCC1.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.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([CH2:18][CH2:17][CH2:16][CH2:15][OH:19])[CH:24]=[C:23]([F:35])[C:22]=1[CH:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: C=CCCO
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: C[N+](C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(CCCCO)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.7 %

Procedure:
To a 0.5 M solution of 9-borabicyclo[3.3.1]nonane (9-BBN) in tetrahydrofuran (95 mL, 47.6 mmol) is added dropwise 3-butene-1-ol (4.1 mL, 47.6 mmol), and the mixture is stirred under nitrogen atmosphere at room temperature for 6 h. The resulting solution is then transferred by a double-ended needle into a mixture of diethyl 2-(2,6-difluoro-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)malonate (10.0 g, 23.8 mmol), potassium phosphate (10.1 g, 47.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (825 mg, 0.714 mmol) in 40 mL of dioxane under nitrogen pressure. The mixture is then heated at 90° C. for 8 h. The reaction is cooled to room temperature, and trimethylamine-N-oxide (3.57 g, 47.6 mmol) is added. The reaction is heated at 80° C. for 1 h and cooled to room temperature. Ethyl acetate is added to dilute the reaction. The organic phase is washed with saturated sodium chloride (x2), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 10% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides diethyl 2-[2,6-difluoro-4-(4-hydroxybutyl)phenyl]malonate as a brown oil (3.5 g). MS: m/z 345.2 (M+H).
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])([O:3][CH3:4])=[O:2].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:11]([CH2:10][CH2:9]/[CH:8]=[CH:7]\[CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCC#CCCC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: COC(=O)CC/C=C\CCC(=O)OC
Yield: 93.1 %

Procedure:
A mixture of 1,6-dicarbomethoxy-3-hexyne [II-1] (5 g), a Lindlar catalyst (5% Pd-CaCO3 -PbO) (50 mg), quinoline (25 mg) and methanol (15 ml) is charged in an atmospheric hydrogenation apparatus and subjected to reduction at room temperature under atmospheric pressure. After completion of the reaction, the catalyst is removed by filtration and the filtrate is concentrated to give 1,6-dicarbomethoxy-cis-3-hexene [II-2] (4.70 g, yield; 93.0%), b.p. 92°-95° C./0.3 mmHg.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].BrC1N(COCC[Si](C)(C)C)C(COC)=C(C(OCC)=O)C=1>C1(C)C=CC=CC=1>[CH:3]([C:4]1[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:2]
Reactant: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c1COC
Agent: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1COC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Reaction was carried out in the same manner as in Reference example 15-(f) except for using 42.1 g (0.134 mol) of ethyl 2-methoxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 15-(d) in place of ethyl 5-bromo-2-methoxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate. After completion of the reaction, 45 g of Celite and 200 ml of toluene were added to the reaction suspension, the mixture was stirred at room temperature for 30 minutes, and insoluble material was removed by filtration. The organic layer obtained by separating the filtrate was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 37.7 g of the title compound as a colorless oil. (Yield: 95%)
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.Cl[C:51]1[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]2[CH:74]=[CH:73][C:65]([CH2:66][CH2:67][PH:68](=[O:72])[O:69][CH2:70][CH3:71])=[CH:64][C:63]=2[O:75][CH3:76])[N:52]=1.[NH2:77][C:78]1[C:79]([C:85]([NH:87][CH3:88])=[O:86])=[N:80][C:81]([Br:84])=[CH:82][CH:83]=1>>[Br:84][C:81]1[N:80]=[C:79]([C:85](=[O:86])[NH:87][CH3:88])[C:78]([NH:77][C:51]2[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]3[CH:74]=[CH:73][C:65]([CH2:66][CH2:67][PH:68](=[O:72])[O:69][CH2:70][CH3:71])=[CH:64][C:63]=3[O:75][CH3:76])[N:52]=2)=[CH:83][CH:82]=1
Reactant: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Reactant: CNC(=O)c1nc(Br)ccc1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Yield: 75.4 %

Procedure:
Prepared analogously to Compound 1B using ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)methylphosphinate (Compound 61 D, 270 mg, 0.64 mmol) and 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 154 mg, 0.669 mmol) to afford 298 mg of the title compound (76%). 1H NMR (400 MHz, CD-3OD) δ 9.00 (br. s., 1H), 8.36 (s, 1H), 7.63-7.73 (m, 1H), 7.51-7.61 (m, 1H), 7.07 (t, J=1.9 Hz, 1H), 6.93 (td, J=2.2, 8.1 Hz, 1H), 4.04-4.16 (m, 2H), 3.89 (s, 3H), 3.33 (s, 1H), 3.29 (s, 1H), 2.93 (s, 3H), 1.51 (s, 3H), 1.33 (t, J=7.1 Hz, 3H). MS (ESI): m/z=617.06/619.06 [M+H]+. HPLC: tR=1.01 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1C[O:28]CC1.[OH-].[Na+].OO>C1COCC1.C(Cl)(Cl)Cl.O>[NH:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:14]([CH:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[OH:28]
Reactant: C1CCOC1
Reactant: C(=C1CCC(Cc2ccccc2)CC1)c1nc2ccccc2[nH]1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: OC(c1nc2ccccc2[nH]1)C1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Example 3 was prepared by the following procedure. To a stirred solution of 20 mg of 2-(4benzyl-cyclohexylidenemethyl)-1H-benzimidazole in 10 mL of THF cooled in an ice bath was added 1 mL of 1M borane•THF. After stirring for 24 h warming to room temperature, 0.5 mL of water was added followed by 0.5 mL of 6N sodium hydroxide and 0.5 mL of 30% hydrogen peroxide. After 30 min, the solution was diluted with 100 mL of chloroform, washed 2×10 mL of water, dried over magnesium sulfate and concentrated to dryness.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:23])[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:23])[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:13](=[O:12])[CH2:14][C:10]([CH3:23])([CH3:11])[CH3:7])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(C)(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(C)(c1ccc(C(C)C)cc1)CO2
Yield: 37 %

Procedure:
Using 3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 34, the title compound was synthesized in the same manner as in Example 1. Yield: 37%. Melting point: 194-195° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.N[C@@H]1CC[C@H](OC2C=C3C(=CC=2C)C(=O)NC=C3)CC1.C(=O)C(C)C.C(N[C@@H]1CC[C@H](OC2C=C3C(=CC=2C)C(=O)NC=C3)CC1)C.[CH2:49]([NH:53][CH:54]1[CH2:59][CH2:58][CH:57]([O:60][C:61]2[CH:62]=[C:63]3[C:68](=[CH:69][C:70]=2[CH3:71])[C:67](=[O:72])[NH:66][CH:65]=[CH:64]3)[CH2:56][CH2:55]1)[CH:50]([CH3:52])[CH3:51]>>[CH2:49]([NH:53][C@@H:54]1[CH2:55][CH2:56][C@H:57]([O:60][C:61]2[CH:62]=[C:63]3[C:68](=[CH:69][C:70]=2[CH3:71])[C:67](=[O:72])[NH:66][CH:65]=[CH:64]3)[CH2:58][CH2:59]1)[CH:50]([CH3:52])[CH3:51]
Reactant: Cc1cc2c(=O)[nH]ccc2cc1OC1CCC(NCC(C)C)CC1
Agent: CC(C)C=O
Agent: CCN[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2C)CC1
Agent: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CC[C@@H](N)CC1
Product: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CC[C@@H](NCC(C)C)CC1

Procedure:
From 0.2 (0.65 mmol) of 6-(cis-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride (138) and isobutyraldehyde were obtained analogous to example 139 151 mg of 6-(4-isobutylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one. Rt=1.10 min (Method A). Detected mass: 329.20 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(Cl)Cl>[CH2:38]([O:37][C:35]([NH:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 3-[3-(1-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate (4.1 g, 9.7 mmol) and DIPEA (3.4 mL, 20 mmol) in methylene chloride (49 mL) at 0° C. was treated with benzyl chloroformate (1.8 mL, 13 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was diluted with dichloromethane (300 mL), washed with saturated sodium bicarbonate solution, water, and brine, dried with sodium sulfate, filtered and concentrated to a crude residue that was purified by flash column chromatography using EtOAc in hexanes (5%-40%) to give the desired racemic product (4 g, 81%). This racemic material was separated by chiral HPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, eluting with 30% ethanol in hexanes at 12 mL/min, column loading ˜135 mg/injection) to give the desired peak 2 isomer (1.9 g, 38%). Peak 2 isomer: LCMS for C25H30Cl2N2O5Na (M+Na)+: m/z=531.2. Found: 531.2.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C:12]1[CH:13]=[C:14]([S:22]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([N:32]3[CH:36]=[N:35][N:34]=[CH:33]3)[CH2:27]2)(=[O:24])=[O:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]>CCO>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:10]/[C:9]([C:12]1[CH:13]=[C:14]([S:22]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([N:32]3[CH:33]=[N:34][N:35]=[CH:36]3)[CH2:27]2)(=[O:23])=[O:24])[CH:15]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:17]=1)=[O:11]
Reactant: CC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Temperature: 100 °C

Procedure:
N,N,-Dimethylformamide dimethyl acetal (200 μL, 1.49 mmol) was added to a stirred solution of 9a (100 mg, 0.240 mmol) in EtOH (1.50 mL). The mixture was placed in a sealed tube and heated in a microwave reactor at 100° C. for 2 h. After cooling to rt, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 9b. m/z (ES) 472 (MH)+
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([C:15](=[O:17])[CH3:16])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([O:19][CH3:18])=[O:29])=[CH:22][CH:23]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(C)=O)c2cccc(Cl)c2)cc1
Temperature: -78 °C

Procedure:
Sodium t-butoxide (0.60 g, 6.34 mmol) was added all at once to a THF solution (10 mL) of 1-(3-chloro-phenyl)-propan-2-one (1.08 g, 6.40 mmol) stirred at −78° C. After 3 minutes 4-bromomethyl-benzoic acid methyl ester (1.54 g, 6.72 mmol) was added all at once and the reaction solution was allowed to warm to room temperature. After stirring for 1 hour the reaction solution was partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.2 Hz, 2H); 7.29-7.25 (m, 2H); 7.20 (s, 1H); 7.13 (d, J=8.2 Hz, 2H); 7.07-7.03 (m, 1H); 3.91 (broad s, 4H); 3.47 (dd, J=7.2, 13.8 Hz, 1H); 2.96 (dd, J=7.6, 13.8 Hz, 1H); 2.07 (s, 3H). LCMS1 3.66 min. (M+H)=317.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[C:15]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>CCO.C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: O=C(O)c1ccc(Br)c2cccnc12
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(-c2ccc(C(=O)O)c3ncccc23)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 3,5-dimethoxyphenylboronic acid (217 mg, 1.19 mmol, 1.2 equiv) (Step 1.8) in EtOH (0.5 mL) was added dropwise to a mixture of 5-bromo-quinoline-8-carboxylic acid (Step 159.3) (250 mg, 0.99 mmol), PdCl2(dppf) (22 mg, 0.03 mmol, 0.03 equiv), Na2CO3 (2M solution in H2O, 1 mL, 3.97 mmol, 4 equiv) in toluene (5 mL) at 105° C., under an argon atmosphere. The reaction mixture was stirred at 105° C. for 1 h, allowed to cool to rt, diluted with EtOAc and H2O, basified by addition of a 2N aqueous solution of NaOH (2 mL), filtered through a pad of celite and the filtrate was extracted with EtOAc. The aqueous layer was separated and acidified to pH 5. The resulting precipitate was collected by vacuum filtration to provide 248 mg of the title compound as a white solid: ESI-MS:310.1 [M+H]+; tR=4.06 min (System 1).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10].C([Li])CCC.[CH2:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[CH2:16]([OH:17])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCCCCC#C
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCCCCCCC#CCO
Temperature: 0 °C
Yield: 50.4 %

Procedure:
To a solution of 13.42 g of deca-1,9-diyne in 300 ml of absolute tetrahydrofuran were added dropwise over one hour while stirring at -40° C. in an atmosphere of dry nitrogen, 59.4 ml of n-butyllithium solution. After stirring for another hour, during which time the mixture was allowed to warm to 0° C., 6.0 g of paraformaldehyde were added and then the mixture was heated to boil under reflux (TLC:petroleum ether/ether--3:2). When the reaction was finished, a saturated solution of ammonium chloride was added at room temperature. The mixture was extracted several times with ether, the combined extracts were dried over sodium sulfate and then evaporated under vacuum. The oily residue was purified by column chromatography with petroleum ether/ether (3:2) to give 8.27 g of the title compound in the form of a liquid which slowly solidified on storing in a refrigerator.