Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)[O:5][C:6]=1[CH3:7].[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]3[C:11]=2[C:19](=[O:21])[N:29]([CH:28]2[CH2:27][CH2:26][C:25](=[O:45])[NH:24][C:23]2=[O:22])[C:13]3=[O:15])[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(CNc2cccc(C(=O)O)c2C(=O)O)oc1C
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: Cc1cc(CNc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)oc1C
Yield: 22 %

Procedure:
3-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-phthalic acid (3 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by preparative HPLC (Symmetry C18, isocratic, 40% acetonitrile/water) to give 0.25 g (22%) of product as a yellow solid: mp 127-129° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (dd, J=7.4 Hz and 8.4 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.91 (t, J=6.1 Hz, 1H), 5.11 (s, 1H), 5.06 (dd, J=5.4 and 12.5 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 2.97-2.82 (m, 1H), 2.63-2.44 (m, 2H), 2.13 (s, 3H), 2.08-1.99 (m, 1H), 1.85 (s, 3H); 13C NMR (DMSO-d6) δ 172.75, 170.02, 168.77, 167.21, 148.75, 146.18, 145.82, 136.05, 132.07, 117.57, 114.16, 110.94, 110.55, 109.61, 48.56, 38.94, 30.95, 22.10, 11.08, 9.50; Anal. Calcd. For C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found: C, 62.75; H, 4.97; N, 10.72.
Reaction SMILES: S1CCS[C:2]21[C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH:8]([NH:14][CH:15]=[O:16])[CH2:7][CH2:6]2.O.C(=O)([O-])[O-:19].[Ca+2]>C(#N)C>[O:19]=[C:2]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]([NH:14][CH:15]=[O:16])[CH2:7][CH2:6]1
Reactant: O=CNC1CCC2(SCCS2)c2sccc21
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Product: O=CNC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirred mixture of N-(5,6-dihydrospiro[benzo-[b]thiophen-7(4H), 2'-[1,3]dithiolan]-4-yl)formamide (1.5 g), acetonitrile (20 ml) and water is added calcium carbonate (1.65 g) and mercuric chloride (3.0 g). The mixture is stirred at room temperature for 35 minutes and acetonitrile is added. The solid is filtered and washed with acetonitrile. The filtrate (100 ml) is evaporated to dryness to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=c1occc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1occc2cc(OC[C@@H]3CCCO3)ccc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a solution of 6-hydroxyisochromen-1-one (2 g) in DMF (50 ml) were added methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (2.7 g) and cesium carbonate (12 g), and the mixture was stirred at 80° C. for 7 hours. After water had been added, the mixture was extracted with dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 246.27 (C14H14O4); MS (ESI): 247 (M+H+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:12])([CH3:11])[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:22][C:23]([O:26][C:27]([N:29]1C(C2C=CC(C#N)=CC=2)O1)=[O:28])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:26][C:27](=[O:28])[NH:29][N:9]1[CH2:10][CH:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:12])[CH3:11])[CH2:8]1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-azetidine (300 mg, 1.6 mmol) was combined with dichloromethane (16 mL) to give a brown solution. N,N-Diisopropylethylamine (455 mg, 615 μl, 3.52 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (355 mg, 1.44 mmol) in dichloromethane (10 mL) was added during 25 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 12 g, ethyl acetate/n-heptane 1/1) to give the title compound (320 mg, 67%) as white waxy solid; GC-MS (EI) 302.0 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][CH2:24][OH:25])[C:15]=2[F:26])[C:11]([NH2:13])=[S:12])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.[CH3:32][O+](C)C.C1(C)C=CC=CC=1>C(#N)C.[O-2].[O-2].[Mn+4]>[CH3:32][S:12][C:11](=[NH:13])[C:10](=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][CH2:24][OH:25])[C:15]=1[F:26]
Reactant: C[O+](C)C
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Agent: [Mn+4]
Agent: F[B-](F)(F)F
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1cc(OCCO)c(F)c(C(=Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(4-cyanophenylamino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxypheny l]thioacetamide (100 g, 267 mmol) in acetonitrile (600 mL), under water cooling, trimethyloxonium tetrafluoroborate (39.5 g, 267 mmol) was added over 20 minutes, and the resulting mixture was stirred at room temperature for 0.5 hours. To the solution, under water cooling, manganese dioxide (139 g, 1.602 mmol) was added over 10 minutes, and the resulting mixture was stirred at room temperature for 1 hour. Toluene (500 mL) was added to the reaction mixture, and the resulting mixture was filtered, after which the resulting filter cake was washed with ethyl acetate. The filtrate obtained and a washing solution were combined, and the resulting mixture was sequentially washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate obtained was concentrated under reduced pressure to obtain a crude product of the captioned compound as an oily product.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>C(OCC)C>[Br:14][CH2:11][C:3]1[C:4]([CH:8]([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: Cn1nc(C(F)F)c(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cn1nc(C(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 286.3 %

Procedure:
A solution of 2.0 g (10.0 mmoles) of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol dissolved in 50 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g (3.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 2.6 g (yield: 100.0%) of 4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole.
Reaction SMILES: [S:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:17])([F:16])[F:15])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:18][S:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:15])([F:16])[F:17])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=[O:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(S(=O)O)ccc1OC(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 5-Sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) was added 1.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (0.66 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time the reaction mixture was concentrated in vacuo, and the residue was treated with 1N NaOH (10 mL) and THF (4 mL). The reaction mixture was stirred for a further 2 hours at room temperature. After such time the solution was acidified with concentrated HCl solution. THF was then removed in vacuo) and the precipitate was isolated by filtration and washed several times with water to yield the title compound. MS (m/e): 283.0 (M−H, 100%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16].Cl[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:19]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])[C:27](=[O:28])[O:29][CH3:30]
Reactant: COC(=O)Cl
Reactant: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-fluorobenzyl)amine from Step A (0.14 g) in methylene chloride at room temperature, excess methyl chloroformate (0.1 ml) and triethyl amine (0.1 ml) were added. The solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (1:9) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.48 (m, 1H), 6.88 (m, 2H), 4.60 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([O:37][C:38]([N:40]1[CH2:46][CH2:45][CH:44]([OH:47])[CH:43]([NH2:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH2:42][CH:43]([NH:48][C:12]([C:10]2[S:11][C:7]3[C:6]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])[CH:44]([OH:47])[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)CC1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3O)nc12
Reaction time: 16 h
Yield: 79 %

Procedure:
0.50 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.31 g 1,1′-carbonyl-diimidazole in 25 ml dimethylformamide were stirred at room temperature for 16 hours. 0.43 g 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester were added and stirring was continued for 16 hours at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with dichloromethane/methanol 98:2 yielded 0.68 g (79%) 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester as a yellow solid; M.p.: 71–73° C.; MS (ISP): m/e=507 (M+H+).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[NH:15]1[CH:19]=[C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[N:16]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 417.2 g, 2.15 mol, 1.05 equiv) and 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 645 g, 2.04 mol) in acetonitrile (4.9 L) was added DBU (30.5 mL, 0.204 mol, 0.1 equiv) drop wise at room temperature. The resulting reaction mixture was then stirred at room temperature for 3 h. After about 1 h, a clear, brown solution was obtained. When LCMS showed that no starting material remained, silica gel (SiO2, 1 Kg) was added and the mixture was concentrated to dryness under reduced pressure. This material, which contains the crude desired product (15), was then loaded onto a pre-packed silica column (SiO2, 2.5 Kg) and the column was eluted with 60-80% of ethyl acetate/heptane. The fractions containing the pure desired product (15) were combined and concentrated under reduced pressure to give the desired product as thick oil which was then stirred in heptane at room temperature until crystallization occurred. The solids were collected by filtration and washed with heptane to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 1014.9 g, 1039.7 g theoretical, 97.6% yield) as white solids. For 15: 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.80 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.50 (d, 2H, J=9.3 Hz), 4.21 (d, 2H, J=9.3 Hz), 3.66 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 1.40 (s, 9H), 0.82 (t, 2H, J=8.1 Hz), −0.12 (s, 9H) ppm; C25H35N7O3Si (MW, 509.68), LCMS (EI) m/e 510 (M−+H) and 532 (M++Na).
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:11]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1>C(O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:11]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reaction time: 2 h

Procedure:
The saponification was performed by the addition of 1.14 mL of 2.0 M LiOH solution to a solution of 0.27 g (0.76 mmole) of ethyl α-[bis(4-fluorophenyl)methylene]-1 H-tetrazole-1-acetate in 5 mL of 95% ethanol at room temperature. After two hours, the crude reaction mixture was diluted with water and washed with diethyl ether (20 mL×2). The free acid in the aqueous layer was regenerated by the addition of aqueous HCl then extracted with diethyl ether, dried and evaporated. The crude acid was dried under high vacuum for 48 hours before it was used in the next step.
Reaction SMILES: FC(F)(S(O[C:17]1[CH:18]=[C:19]2[C:36](=[CH:37][CH:38]=1)[C:23]1=[N:24][O:25][C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][CH:28]=3)=[C:22]1[CH2:21][CH2:20]2)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl-].[Li+].[CH2:42]([Sn](CCCC)(CCCC)C=C)[CH2:43]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:33]([C:30]1[CH:31]=[CH:32][C:27]([C:26]2[O:25][N:24]=[C:23]3[C:36]4[C:19]([CH2:20][CH2:21][C:22]=23)=[CH:18][C:17]([CH:42]=[CH2:43])=[CH:38][CH:37]=4)=[CH:28][CH:29]=1)[CH2:34][CH3:35]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2-3)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a mixture of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Preparation 11A, 160 mg, 0.272 mmol), anhydrous lithium chloride (34.6 mg, 0.817 mmol), tributyl(vinyl)tin (0.120 mL, 0.409 mmol), and anhydrous dioxane (1 mL) was bubbled nitrogen gas for 3 min before Pd(Ph3P)4 (62.9 mg, 0.054 mmol) was added. The reaction mixture was purged with nitrogen gas for an additional 3 min, stirred for 1 h at room temperature, and then at 110° C. for 4 h. The reaction mixture was cooled and treated with saturated aqueous sodium bicarbonate solution (1.5 mL). The biphasic mixture was extracted with ethyl acetate (2×2 mL). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered through a pad of silica gel and rinsed with dichloromethane. The filtrate was concentrated to give 3-(4-propylphenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (74 mg, 0.235 mmol, 86% yield) LC/MS M+1=316.17.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: [Ru]
Solvent: ClCCl
Solvent: CO
Product: CCCCC[C@H](O)CC(=O)OC
Yield: 95.9 %

Procedure:
Into a 100-ml autoclave (made of Hastelloy) were introduced 20 g of methyl 3-oxooctanoate (manufactured by Inoue Perfumery Mfg. Co., Ltd.) and 50 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 140 mg of Ru2Cl4 ((-)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 1.0 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 6 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 19.4 g of methyl (S)-3-hydroxyoctanoate. Yield, 96%.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: Cc1ncc(CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ncc(CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Reaction time: 4 h

Procedure:
To a solution of the benzyl ether from Step B (419 mg, 0.75 mmol) in 6 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (250 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 4 hours, another portion of Pd/C was added (250 mg). After 16 hours, the solution was filtered through celite. Concentration in vacuo provided the titled product which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.Cl[C:29]1[CH:34]=[C:33]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[N:32]2[N:40]=[C:41]([NH2:43])[N:42]=[C:31]2[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:43][C:41]1[N:42]=[C:31]2[CH:30]=[C:29]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:4][CH2:3][C:2]([CH3:1])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6]4)=[N:9][CH:10]=3)[CH:34]=[C:33]([N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)[N:32]2[N:40]=1
Reactant: Nc1nc2cc(Cl)cc(-n3cccn3)n2n1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(-n4cccn4)n4nc(N)nc4c3)cn2)CC1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
A suspension of ethyl 4-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-4-carboxylate (360 mg, 0.97 mmol), 7-chloro-5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (190 mg, 0.81 mmol), cesium carbonate (400 mg, 1.2 mmol) and Pd(dppf)2C12 (60 mg, 0.08 mmol) in 1,4-dioxane (4.5 mL) and water (0.5 mL) was added to a microwave vial and degassed with N2. The vessel was then heated at 110° C. in a microwave reactor for 60 mins. The resultant solution was concentrated in vacuo and the residue purified by flash column chromatography (Biotage SP4, 40 g 0-10% MeOH/DCM) and (Biotage SP4, 12 g 2% MeOH/DCM, then flush with 10% MeOH/DCM) to give the desired product as a cream solid (200 mg, 55%) MS: 448.27 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51]>C(OCC)(=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51])=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Reactant: CCCCOC(=O)COCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)COCCCNC(=O)c1sc(NC(=N)N)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
175 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 2.6 ml of DMF, 0.29 ml of N-MM and 332 mg of HBTU are stirred at room temperature (RT) for one hour, treated with 197 mg of butyl (3-amino-propoxy)-acetate hydrochloride and stirred at RT for a further 18 hrs. For the working up, the mixture is diluted with ethyl acetate, washed with dilute sodium carbonate solution, dilute sodium chloride solution and saturated sodium chloride solution, dried and evaporated in a vacuum. Chromatography on silica gel with methylene chloride-alcohol gives 162 mg of butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy}-acetate, mass spectroscopy (MS): 372 (M+H)+.