Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[C:28]1([CH3:36])[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1>C(O)C>[CH3:36][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[CH:34]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Reactant: Cc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4cncnc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
There was suspended, in ethanol (1.0 mL), (7-morpholin-4-yl-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (18 mg, 0.1 mM) prepared in the preceding step 2, then acetic acid (3.0 μL, 0.05 mM) and metatolualdehyde (14 μL, 0.12 mM) were added to the suspension and the mixture was stirred at room temperature for 16 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (4.0 mg, yield: 16.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])/[C:24]#[N:25])=[C:19]([F:35])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:35])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(F)c1F)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 44.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 62a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]2[O:9][C@H:20]2[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC/C=C/c1cccc(Br)c1
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1c1cccc(Br)c1
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A magnetically stirred solution of m-chloroperbenzoic acid (3.57 g, 10.33 mmol) in dichloromethane (60.0 ml) at 25° C. was treated dropwise with a solution of trans-3-(3-bromophenyl)-2-propenol (2.0 g, 9.39 mmol) in dichloromethane (20.0 ml). After stirring for 16 h the mixture was diluted with dichloromethane (200 ml), washed with aqueous 1M NaOH (2×200 ml), brine (2×200 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo returned the crude epoxide as a pale yellow oil (2.06 g). Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 3:7) provided the title compound (1.53 g, 71%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.9 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-Chloro-phenyl)-3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (70 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:29](Cl)=[O:30].C(N(CC)CC)C>O1CCOCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2([CH2:18][NH:19][C:29]([C:21]3[O:20][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:22]=3)=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2(CN)CCCC2)cc(OC)c1OC
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C2(CNC(=O)c3cc4ccccc4o3)CCCC2)cc(OC)c1OC
Reaction time: 15 h
Yield: 11.7 %

Procedure:
C-[1-(3,4,5-Trimethoxy-phenyl)-cyclopentyl]-methylamine (53.1 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (84 μL, 0.60 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (9.59 mg, 0.0234 mmol, 11.7%). ESI-MS m/z calc. 409.2, found 410.4 (M+1)+. Retention time of 3.29 minutes.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:28]1([O:38][C:39](=[O:69])[C@H:40]([CH2:42][CH2:43][CH2:44][N:45]([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:46](=[NH:58])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[NH2:41])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]1([O:38][C:39](=[O:69])[C@H:40]([CH2:42][CH2:43][CH2:44][N:45]([C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:46](=[NH:58])[NH:47][C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[NH:41][C:18](=[O:20])[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](N)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 56.9 %

Procedure:
In 8 ml of DMF were dissolved 808 mg of benzoyl-L-phenylalanine and 2.05 g of Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester trifluoroacetate, after which 681 mg of DCC, 405 mg of HOBt and 304 mg of TEA were added thereto with ice-cooling, and the mixture was stirred for 3 hrs, and then at room temperature for a further 24 hrs. After the reaction, the DCU thus precipitated was removed by filtration, and ethyl acetate was added to the filtrate, after which the mixture was washed with 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue thus obtained was recrystallized from chloroform-diethyl ether to obtain 1.4 g (yield 57%) of benzoyl-L-phenylalanyl-Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester, m.p. 177°-185° C.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)C(C)O3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)C(C)O3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 24hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes. was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give crystals, which were recrystallized from ethanol-ethyl acetate to give N-[4-[hydroxy(1-oxidopyridin-2-yl)-methyl]phenyl]-6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (Compound 203) (129 mg) as pale yellow crystals.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=O)=[CH:12][CH:11]=2)[N:3]=1.P(Cl)(Cl)([Cl:21])=O>C(OCC)(=O)C>[Cl:21][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]#[N:16])=[CH:12][CH:11]=2)[N:3]=1
Reactant: NC(=O)c1ccc(Nc2ncc(I)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2ncc(I)c(Cl)n2)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 4-((4-hydroxy-5-iodopyrimidin-2-yl)amino)benzamide (J11, 1.35 g), phosphorus oxychloride (14 mL) was added at room temperature, and the mixture was stirred at 90° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then poured into ice, and then ethyl acetate was added to the mixture. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with a mixed solvent of diisopropyl ether and chloroform, and then dried under reduced pressure to obtain 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 764 mg) as pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:29][C:2]([F:28])([F:1])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:30](=[O:32])[CH3:31])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CO)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(CC(F)(F)F)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 486, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: ClC1N=C(F)N=C2C=1NC=N2.C(N)[C:13]1[CH:18]=[CH:17]C=CC=1.N[CH2:21][C:22]1[CH:27]=C[CH:25]=[CH:24][N:23]=1.NCC1C=NC=CC=1.NCC1C=CN=CC=1>CCCCO>[CH3:25][CH2:24][N:23]([CH:18]([CH3:17])[CH3:13])[CH:22]([CH3:27])[CH3:21]
Reactant: NCc1ccccn1
Reactant: NCc1ccccc1
Agent: Fc1nc(Cl)c2[nH]cnc2n1
Agent: NCc1cccnc1
Agent: NCc1ccncc1
Solvent: CCCCO
Product: CCN(C(C)C)C(C)C

Procedure:
For the synthesis of the 6-benzylamino-, 6-(pyridin-2-ylmethyl), 6-(pyridin-3-ylmethyl) and 6-(pyridin-2-ylmethyl)-intermediates, the initial step involved reaction of 6-chloro-2-fluoro-purine 29 [Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett., 1997, 38 (7), 1161-1164] with either benzylamine, 2-(aminomethyl)pyridine, 3-(aminomethyl)pyridine or 4-(aminomethyl)pyridine, in n-BuOH the presence of DIPEA, to afford the corresponding 6-substituted intermediates 30. These compounds then underwent reaction with 2-bromopropane and K2CO3 in DMA [Havlicek, L.; Hunus, J.; Vesely, J.; Leclerc, S.; Meijer; L.; Shaw, G.; Strnad, M.; J Med Chem., 1997, 40 (4), 408412], to afford their corresponding N9-isopropyl substituted intermediates 31. These purine intermediates were finally reacted with the aminoalcohols (1-2, 15-22, and 27-28) in DMSO/n-BuOH/DIEA at 140° C. over 72 h to give their corresponding C2-substituted aminoalkyl analogues 32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:17]([NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.Cl.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][CH2:17][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)cc1
Yield: 57.7 %

Procedure:
A mixture of ethyl 4-[2-benzyloxy-5-bromophenylacetamido]-benzoate (2.5 g) and BH3. THF (10 mM) in THF (60 ml) was stirred at 50° C. for 2 hours, cooled (ice bath) and diluted with 2N HCl solution (10 ml) and diethyl ether (50 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel eluting with dichloromethane to give ethyl 4-[N-(2-benzyloxy-5-bromophenethyl)amino]benzoate (1.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].[CH3:21][Sn](C)(C)C>CN(C=O)C.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:21])[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2nc(C(C)(C)C)sc2c1O
Yield: 89.2 %

Procedure:
A solution of 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (145 mg, 0.40 mmol), tetramethyl tin (220 μL, 1.6 mmol), dichlorobis(triphenylphosphine)-palladium II (30 mg, 0.04 mmol) in 2.5 mL anhydrous DMF was heated to 130° C. for 1 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 10-50% ethyl acetate in hexanes) to give 105 mg of a white solid. MS (ESI−): m/z 293.4 (M−1).
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO>[CH2:24]([O:23][C:21]([CH:20]([O:6][C:7]1[N:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=1)[CH3:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nc(O)nn1-c1ccccc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1nc(C)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A 3.2 g portion of sodium was dissolved in 50 ml of methanol, and the solution was added to 100 ml of dimethylsulfoxide. To it was added 24.6 g of 3-hydroxy-5-methyl-1-phenyl-1,2,4-1H-triazole, and the solution was heated on the steam bath for 2 hours, adding 100 ml of additional dimethylsulfoxide. To the solution was then added 25.4 g of ethyl 2-bromopropionate, and heating was continued for 2 hours more. The reaction mixture was then cooled, poured over ice-water, and extracted with 300 ml of chloroform. The extract was washed with water and with saturated brine, and was dried with sodium sulfate and phase separation paper. The solvent was removed under vacuum, and the product was distilled at 1.2 mm of mercury and 192° to obtain 20 g of the desired product, an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:41])[O:36][CH2:37][CH2:38][O:39][CH3:40]>ClCCl>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:35](=[O:41])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (150 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and 2-methoxyethyl carbonochloridate (68 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 to afford the title compound as a solid
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OC
Temperature: 75 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 510 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-iodopyridine, 200 mg of (3R)-3-ethynyl-3-quinuclidinol, 139 mg of tetrakis (triphenylphosphine) palladium (0), 11 mg of cuprous iodide, 0.50 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 281 mg of the target compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)[CH2:14][CH3:15].[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>C1COCC1>[CH2:29]([O:28][C:25](=[O:27])[CH2:26][C:22](=[O:23])[C@H:19]1[CH2:20][CH2:21][C@H:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1)[CH3:30]
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C(=O)CC(=O)OCC)CC1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
THF (1,000 ml) was added to diisopropylamine (162.9 g) in a reaction vessel under an atmosphere of nitrogen. n-Butyllithium was added dropwise, while the solution was kept at −40° C. or lower, and the stirring was continued for 30 minutes. The solution was cooled at −65° C. or lower, and ethyl acetate (141.9 g) and then a THF (200 ml) solution of trans-4-propylcyclohexanecarboxylic acid chloride (2) (189.9 g) prepared in the first step were added dropwise. After the reaction mixture had been slowly warmed up to room temperature with stirring, it was quenched with a saturated aqueous solution of ammonium chloride. Water (1,000 ml) was then added to give two layers. The water layer was extracted with toluene (500 ml) three times, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 300 g, eluent: toluene) to give 3-oxo-3-(trans-4-propyl-cyclohexyl)-propionic acid ethyl ester (3) (220 g) in 90% yield.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[Cl:16].[CH3:18][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[O:17])[CH3:18])=[C:10]([Cl:16])[CH:11]=1
Reactant: O=C(Sc1ccccn1)c1ccc(Br)cc1Cl
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 80 %

Procedure:
4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (1.86 g, 5.66 mmol) from Step 1 above was dissolved in dry THF (30 mL) and cooled to −78° C. A solution of methyl magnesium bromide in 75:25 toluene/THF (1.4 M, 4.45 mL, 6.23 mmol) was added dropwise. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (1.05 g, 80%) as a colorless oil.