Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([C:13]([C:9]3[NH:10][C:11]4[CH:12]=[C:4]5[O:3][C:2](=[O:1])[NH:16][C:5]5=[CH:6][C:7]=4[CH:8]=3)=[O:15])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Solvent: CCOCC
Product: O=C(c1cc2cc3[nH]c(=O)oc3cc2[nH]1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903, (1992)] according to the method described in Example 1/c. Mp.: 244-247° C. (diethyl ether).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2:36].[Ca+2:37]>CC(CC(C)C)=O.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:36].[OH2:5].[Ca+2:37]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: [O-2]
Agent: [Ca+2]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Pseudomonic acid (10 g) was dissolved in isobutyl methyl ketone (120 ml). Calcium oxide (0.57 g) was suspended in water (68 ml), and added to the solution of pseudomonic acid. The mixture was stirred for one hour, and the phases were separated. The volume of the aqueous phase was reduced to 40 ml by vacuum distillation. The mixture was cooled to 5° C., and after standing for 15 hours, the crystalline product was filtered and washed with cooled water (10 ml). The product was then dried in an air circulated oven at RT. Mupirocin calcium dihydrate (3.7 g, 35%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[Cl:45].C1(C)C=CC=CC=1>C(O)C.[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.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[C:42]1[CH:41]=[CH:40][C:39]([Cl:38])=[C:44]([Cl:45])[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccccc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(-c1ccc(Cl)c(Cl)c1)n2Cc1ccccc1
Temperature: 85 °C
Yield: 86.7 %

Procedure:
Step 1 7-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.985 mmol, intermediate 83), potassium carbonate (0.326 g, 2.36 mmol), tetrakis(triphenylphosphine) palladium(0) (0.032 g, 0.028 mmol) and 3,4-dichlorophenyl boronic acid (0.206 g, 1.08 mmol) were combined in ethanol (12.0 mL), toluene (2.0 mL) and water (2.0 mL) in a sealed vial. The reaction was heated at 85° C. for 18 h. The reaction was cooled and filtered through Celite. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a golden solid. The solid was purified using a 25 g silica gel CombiFlash column eluted with 20% ethyl acetate/hexanes to give 7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(3,4-dichlorophenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.49 g, 86% yield) as a golden oil. LCMS retention time=5.489 min and 97% purity, LCMS MH+=573.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[O:11].[CH:12]#[C:13][CH3:14]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH:10]([OH:11])[C:12]#[C:13][CH3:14]
Reactant: CC1=C(C=O)C(C)(C)CC=C1
Reactant: C#CC
Product: CC#CC(O)C1=C(C)C=CCC1(C)C

Procedure:
Safranal, prepared according to Compt. rend. 262, 1725 (1966), was reacted with propyne to give 2,6,6-trimethyl-1-[1-hydroxy-2-butynyl]-1,3-cyclohexadiene, following the procedure outlined in Example 18, paragraph b), for the reaction of citral with propyne. The above carbinol was oxidised with MnO2 to 2,6,6-trimethyl-1-tetrolyl-1,3-cyclohexadiene, following the procedure described in Example 18, paragraph c), for the oxidation of the dihydro analogue. The above acetylenic ketone was then partially reduced to the title compound following the method described in Example 18, paragraph a). Cis-2,6,6-trimethyl-1-crotonoyl-1,3-cyclohexadiene gave the following NMR data (CCl4): 1.06 (6 H, s), 1.69 (3 H, s), 2.09 (2 H, d, J = 2.3 cps), 2.14 (3 H, d, J = 5.5 cps), 5.81 (2 H, t + s, J = 2.3 cps), 6.2 (2 H, complex band) ppm (δ).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:13]([O-])=O)[N:3]=1>CO.O1CCOCC1>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(O)c(O)nc12
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc2nc(O)c(O)nc12
Reaction time: 20 h

Procedure:
2.00 g of 2,3-dihydroxy-5-nitroquinoxaline was dissolved in 1:1 mixed solvent of methanol/dioxane, then the reaction system was sufficiently flushed with argon, and 1.00 g of Pd/C (anhydrous) was added to the reaction mixture. Thereafter, the reaction system was flushed with hydrogen, and reaction was allowed at room temperature for 20 hr. After the reaction was over, the reaction mixture was dispersed in a solution of 6.00 g of potassium carbonate in 130 ml of water, thereby dissolving the reaction product. Filtration was conducted, and 35% hydrochloric acid was gradually added to the solution obtained upon the filtration, to obtain precipitates.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH:15]=[C:14]([O:17][Si](C)(C)C)[CH2:13][CH2:12]1.C(=O)(OC)OCC=C.O>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH2:16]1
Reactant: C[Si](C)(C)OC1=CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd+2]
Agent: C=CCOC(=O)OC
Agent: CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1C=CN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirring solution of the enol silyl ether from step 2 (100.0 g, 322 mmol) and allyl methyl carbonate (43.6 g, 386 mmol) in DMSO (625 ml) at ambient temperature is added Pd(OAc)2 (7.20 g, 32 mmol). The resulting solution is stirred under N2 at ambient temperature overnight. H2O (1 liter) is added and solvent allowed to cool to ambient temperature. The aqueous layer is extracted with EtOAc (2×800 ml) and the organic layers combined, washed with brine (800 ml) and organics dried over MgSO4. The solvent is removed and residue recrystallized from EtOAc/MTBE to afford 53.6 g (70%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 2.71 (m, 2 H), 4.06 (m, 2 H), 5.41 (d, J=8 Hz, 1 H), 7.25 (m, 1 H), 7.35 (d, J=8 Hz, 1 H), 8.08 (m, 2 H); Anal. Calcd for C11H9FN2O3: C, 55.94; H, 3.84; N, 11.86; F, 8.04. Found: C, 55.82; H, 3.81; N, 11.67.
Reaction SMILES: C(=O)=O.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2I)=[CH:7][CH:6]=1.C([Li])CCC.[CH3:28][O:29][C:30](Cl)=[O:31]>C1COCC1.CC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2[C:30]([O:29][CH3:28])=[O:31])=[CH:7][CH:6]=1
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(I)c2c1
Reactant: COC(=O)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 15 h

Procedure:
To a cooled solution (−78° C., dry ice, acetone) containing 2-(4-fluorophenyl)-3-iodo-5-methoxybenzo[b]thiophene (1.0 g, 2.6 mmol,) and THF (26 mL) was added n-butyllithium (2.0 mL, 1.0 M THF) over 5 min. The solution was maintained at −78° C. for 1 h. Methylchloroformate (0.80 mL, 10.4 mmol) was then added quickly in a steady stream via syringe. The solution was removed from cooling and allowed to stand at ambient temperature for 15 h. The solution was concentrated and purified on silica gel (0-10% ethyl acetate/hexanes, 40 min. gradient) to afford methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate as a yellow residue. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.88 (d, J=2.44 Hz, 1H), 7.66 (d, J=8.85 Hz, 1H), 7.47 (dd, J=8.85, 5.19 Hz, 2H), 7.12 (t, J=8.70 Hz, 2H), 7.05 (dd, J=8.70, 2.59 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LCMS: retention time: 3.355 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 317 (MH−).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccccc1
Reactant: c1ccc2ocnc2c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 10 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), chlorobenzene (450 mg, 4.0 mmol), t-BuOK (336 mg, 3.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 78 mg (40%) of 2-phenylbenzoxazole is obtained. Table I, entry 1.
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.C(O)C.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:23]=1
Reactant: Cc1ccnc(Oc2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccnc(Oc2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yloxy)phenyl)guanidine (0.2 g) in dichloromethane (2 ml) and ethanol (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 7 hours. The solvent was evaporated under reduced pressure. To the residue was added 20% ethanol in ethyl acetate (20 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (3-(4-methylpyridin-2-yloxy)-phenyl)guanidine dihydrochloride (125 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:19][CH:18]=1.O>CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:25]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[O:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][CH:5]=1
Reactant: Clc1ccc(CCCCCBr)cc1
Reactant: CCOC(=O)CS(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)S(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
First 1.64 g (37.6 mmol) of sodium hydride in 55% mineral oil suspension, and then 9.8 g (37.6 mmol) of 5-(4-chlorophenyl)pentyl bromide, are added to a solution of 8.5 g (37.6 mmol) of ethyl 4-methylphenylsulfinylacetate in 75 ml of dimethylsulfoxide. Then the mixture is stirred at room temperature for another 4 hours. Then it is poured into water, extracted with ether, the extracts are washed with water, dried and concentrated. The concentrate is chromatographed with a mixture of n-heptane and butanone (2:1) on silica gel. Yield: 8.0 g (52% of theory) of ethyl 7-(4-chlorophenyl)-2-[(4-methylphenyl)sulfinyl]heptanoate, a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18](N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl.CO.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1.28 Grams of 6-{(tert-butoxycarbonyl)amino}hexanoic acid was dissolved in a liquid mixture of 9 ml of chloroform and 3 ml of methanol. To the solution 1.27 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 7 mg of 4-dimethylaminopyridine were successively added at room temperature, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 1.03 g of the title compound was obtained.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]1[NH:13][C:14]1[C:19]([CH:20]2[CH2:22][CH2:21]2)=[N:18][C:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:16]([CH:31]2[CH2:33][CH2:32]2)[N:15]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH:20]1([C:19]2[C:14]([NH:13][C@@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C@H:4]3[NH2:1])=[N:15][C:16]([CH:31]3[CH2:32][CH2:33]3)=[C:17]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:18]=2)[CH2:21][CH2:22]1
Reactant: [N-]=[N+]=N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of N-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine (0.55 g, 1.15 mmol) in anhydrous THF (30 mL) was added PPh3 (0.396 g, 1.51 mmol). The resulting mixture was stirred at rt for 3 hr. To the solution was added water (0.25 mL, 13.9 mmol). The reaction is then allowed to stir overnight at rt. The mixture is concentrated, and the resulting solid is dissolved in MeOH. Purify by passage over Biorad acidic resin by applying the MeOH solution onto the resin and rinsing the resin with MeOH. The resin was then rinsed with 5% triethylamine/MeOH solution to afford 0.52 g (75%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.85-1.12, 1.64-1.76, 1.89, 2.68-2.82, 3.31-3.39, 3.66-3.72, 5.16, 5.33, 7.28-7.53; MS (ESI+) for C25H24Cl2N4 m/z 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1cc(I)cnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CNc2cnc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
An oil bath was preheated to 130° C. A mixture of 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (47 g, 152.8 mmol), (4-methoxyphenyl)methanamine (23.8 mL, 183.4 mmol), Xantphos (2.6 g, 4.58 mmol) and NaOtBu (22 g, 229.2 mmol) in toluene (500 mL) was stirred at room temperature while bubbling nitrogen for 5 min. Pd2(dba)3 (2.8 g, 3.05 mmol) was then added and the reaction mixture was refluxed for 2 h. The mixture was cooled to room temperature and it was filtered through a pad of celite. The pad of celite was washed with toluene and the filtrate was concentrated. The residue obtained was dissolved in EtOAc, the organic layer was washed with water (4×), and it was then evaporated to dryness. The dark oil obtained was dissolved in DCM and hexanes was added with swirling until a brown solid precipitated. The brown solid was filtered, washed with hexanes, and dried to afford 38.8 g (80%) of 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 7.96 (d, 1H), 7.38 (d, 1H), 7.29 (d, 2H), 7.07 (t, 1H), 6.92 (d, 2H), 4.29 (d, 2H), 3.73 (s, 3H). The filtrate was purified by column chromatography on Silica Gel eluting with 0 to 50% EtOAc/Hexanes to afford an additional 4 g of 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine as an orange solid (Total yield: 42.8 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=O)=[CH:18][CH:17]=1.O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21]/[C:22]/2=[CH:5]\[C:3]#[N:4])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)/C(=C/C#N)CC2
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a suspension of 60% sodium hydride (2.71 g, 67.9 mmol.) in tetrahydrofuran (150 ml) was added dropwise, under ice-cooling, diethyl cyanomethylphosphonate (11.5 g, 64.8 mmol.). The mixture was stirred for 15 minutes. To the reaction mixture was added dropwise a solution of 6-methoxy-1-indanone (10.0 g, 61.7 mmol.) in tetrahydrofuran (30 ml). The reaction mixture was stirred for 30 minutes at room temperature, which was poured into water, and then the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue thus obtained was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8), followed by recrystallization from ethyl acetate/hexane to afford the titled compound (6.00 g, yield 53%), m.p.95-96° C. (recrystallized from ethyl acetate/hexane).
Reaction SMILES: C[O:2][CH:3]([O:11]C)[CH2:4][O:5][CH:6]([CH3:10])[CH:7](O)[CH3:8]>S(=O)(=O)(O)O.O>[CH3:10][CH:6]1[CH:7]([CH3:8])[O:11][CH:3]([OH:2])[CH2:4][O:5]1
Reactant: COC(COC(C)C(C)O)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1OCC(O)OC1C
Temperature: 60 °C
Reaction time: 11 h
Yield: 55.5 %

Procedure:
Next, a four neck flask having a content volume of 200 mL equipped with a thermometer, a distilling head and a stirring device was charged with 137.4 g of water, 42.2 mg of sulfuric acid and 24.2 g (130 mmol) of 3-(2,2-dimethoxyethyloxy)-2-butanol. The mixture was stirred for 11 hours on the conditions of a pressure of 18.0 kPa and a vessel inside temperature of 60° C. while removing water and resulting methanol by distillation. In this regard, the reaction solution was analyzed by gas chromatography to find that a conversion rate of 3-(2,2-dimethoxyethyloxy)-2-butanol was 99.6%. After the vessel inside temperature was lowered down to room temperature, the pH was adjusted to 8.0 by a 10.0 mass % sodium hydroxide aqueous solution, and the reaction solution was extracted three times with 300 g of ethyl acetate. The extracts of three extractions thus obtained were put together and concentrated under reduced pressure, and the concentrate obtained was refined by silica gel chromatography to obtain 9.66 g (72.2 mmol) of 5,6-dimethyl-1,4-dioxane-2-ol in the form of a colorless and transparent oil (purity: 98.8%, yield: 55.5% based on 3-(2,2-dimethoxyethyloxy)-2-butanol).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].Cl.Br[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(OCC)C.O>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Brc1cccs1
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: c1csc(-c2ccncc2)c1
Temperature: 25 °C

Procedure:
2-Bromothiophene (7.6 mL, 78.5 mmol) is added dropwise to a flame and vacuum dried three-necked round-bottomed flask fitted with a condenser, stopper and magnesium (2 g, 82.3 mmol) in diethyl ether (70 mL). The resulting grey solution is stirred at reflux for 1.5 hours. Meanwhile 4-bromopyridine hydrochloride is converted to the free base in the following manner: 4-Bromopyridine hydrochloride (15.3 g, 78.7 mmol) is dissolved in water (100 mL), and cooled in an ice bath. One equivalent of 1 N NaOH (ca. 100 mL) is added dropwise until pH is ˜5.6. The ice-cooled aqueous solution is extracted with hexane (3×150 mL) and the combined organic layers are dried over MgSO4 and filtered. Hexane is removed under vacuum (11 mm Hg) while cooling in an ice-bath to a volume of ca. 30 mL. The resulting colorless clear solution is diluted with THF (150 mL) under N2. The Grignard reagent is then cooled to room temperature and added via cannula to the solution of NiCl2dppp (0.54 g, 1 mmol) and 4-bromopyridine in THF. The resulting dark solution is refluxed overnight. The reaction mixture is then poured over saturated NH4Cl solution and extracted with diethyl ether (3×200 mL). The combined ethereal layers are acidified with 2 N HCl (300 mL) and the aqueous layer is washed with diethyl ether. The aqueous layer is then cooled in an ice-bath and neutralized with sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3×200 mL) and the combined organic layers are dried over MgSO4, filtered and concentrated to give a brown solid. The crude solid is taken up in hot hexanes and the yellow solution is separated from the insoluble black solid. The hexane solution is concentrated and the above procedure is repeated. Upon cooling the hexane solution, yellow solid precipitates form. The yellow solid is collected to give the title compound (8.99 g, 55.8 mmol).