Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([N:14]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15]2)[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:4][C:3]=1[C:28]#[N:29].C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl>[C:10]([C:9]1[NH:1][C:2]2[C:7]([CH:8]=1)=[C:6]([N:14]1[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15]1)[C:5]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:4][C:3]=2[C:28]#[N:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c(N)c2C#CC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c3[nH]c(C(C)(C)C)cc23)C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(3,3-dimethylbutyn-1-yl)biphenyl-3-carbonitrile (I-246) (54 mg, 0.14 mmol) was dissolved in acetonitrile (3 ml), and at room temperature, bis(acetonitrile)palladium(II) dichloride (7.3 mg, 0.28 mmol) was added, followed by heating under reflux for 3 hours. After cooling to room temperature, the reaction liquid was fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=95:5) to obtain a crude product of the entitled compound (32 mg, 60%) as a pale brown gel. This was recrystallized from hexane/diethyl ether to obtain the entitled compound (15 mg) as a pale brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10]Br>C(O)(=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=Cc1cc(O)ccc1Br
Temperature: 15 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-hydroxybenzaldehyde (10 g, 81.9 mmol) was dissolved in glacial acetic acid (50 mL) and cooled at 15° C. To the stirred solution, bromine (15.7 g, 98.2 mmol) was added dropwise while keeping the temperature below 22° C. After overnight stirring at room temperature, the volatiles were removed under vacuum without heating; the residue was co-evaporated three times with hexane (15 mL) and taken up in warm chloroform. Upon cooling, 9.05 g of 2-bromo-5-hydroxybenzaldehyde 3 were obtained as a white solid in two crops. Yield 55%. 1H NMR (300 MHz, CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.10 (dd, J1=8.7 Hz, J2=3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5BrO2: 199.9472. found: 199.9463; mp: 132-134° C.
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH2:13][OH:14]>O1CCCC1>[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH:13]([OH:14])[C:8]#[C:7][CH:6]([OH:9])[CH3:5]
Reactant: CCC/C=C\CC(C)CCO
Reactant: C#CC(C)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC/C=C\CC(C)CC(O)C#CC(C)O
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A solution of 10.4 g (95.6 mmol) of ethyl bromide in 40 mL of dry tetrahydrofuran was added dropwise over a period of 30 min to a vigorously stirred suspension of 2.32 g (95.6 mmol) of magnesium turnings in 15 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. After stirring the reaction mixture for 90 min under reflux, it was allowed to cool down to room temp., and a solution of 2.95 g (42.1 mmol) of but-3-yn-2-ol in 40 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again refluxed for 3 h, the heating bath removed and a solution of 6.50 g (42.2 mmol) of (5Z)-3-methylnon-5-en-1-ol (vide supra) in 40 mL of dry tetrahydrofuran added at room temp. with stirring over a period of 30 min. The reaction mixture was refluxed with stirring overnight, allowed to cool to room temp., and quenched by pouring into 100 mL of an aqueous satd. NH4Cl solution. The organic layer was separated, and the aqueous one extracted three times with 500 mL of ether each. The combined organic extracts were dried with sodium sulphate, and concentrated to dryness in a rotary evaporator. The resulting residue (8.85 g) was purified by flash chromatography (200 g of silica gel, pentane/ether, 1:1, Rf=0.21) to furnish 7.71 g (82%) of (9Z)-7-methyltridec-9-en-3-yne-2,5-diol as a colourless oil.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH3:14].C(Cl)(=O)CCCCSCCCCCSCC.COCCCCCCCCCCCC(Cl)=O.COCCCCCCCCCCCC([NH2:64])=O>>[C:1]([NH2:64])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH3:14]
Reactant: CCSCCCCCSCCCCC(=O)O
Reactant: COCCCCCCCCCCCC(N)=O
Agent: CCSCCCCCSCCCCC(=O)Cl
Agent: COCCCCCCCCCCCC(=O)Cl
Product: CCSCCCCCSCCCCC(N)=O

Procedure:
When 6,12-dithiatetradecanoic acid is substituted for an equivalent amount of 12-methoxydoecanoic acid in Example 11 and then the resulting 6,12-dithiatetradecanoyl chloride is substituted for an equivalent amount of the 12-methoxydodecanoyl chloride in Example 12, the compound 6,12-dithiatetradecanamide is prepared and can be used in place of the 12-methoxy-dodecanamide with substantially similar antiviral results.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH:4]1[C:12]([NH:14][NH:15][C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1)=O)[CH3:2].O1CCOCC1.CCN(C(C)C)C(C)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH:4]1[C:12]1[N:17]2[C:18]3[CH:24]=[CH:23][N:22]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:27])=[O:26])[C:19]=3[N:20]=[CH:21][C:16]2=[N:15][N:14]=1)[CH3:2]
Reactant: CCC1CC2(CC1C(=O)NNc1cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n1)OCCO2
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CC2(CC1c1nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n13)OCCO2
Temperature: 75 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A round bottom flask was charged with 8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide (4.90 g, 10.1 mmol) and 1,4-dioxane (50 mL). To the flask was added DIEA (8.81 mL, 50.5 mmol) followed by the addition of thionyl chloride (0.770 mL, 10.6 mmol). The mixture was heated to about 75° C. for about 90 min. Additional thionyl chloride (0.074 mL, 1.0 mmol) was added and heating was continued for about 1 h. The reaction was cooled to rt and stirred overnight. The solution was diluted with DCM (75 mL) and washed with water (50 mL). The layers were separated and the organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a dark brown oil. The crude product was purified via flash silica gel chromatography eluting with a gradient of 0-60% acetone in heptane. The product containing fractions were combined and concd to give material that was loaded onto a second column eluting with a gradient of 0-60% acetone in heptane. The product containing fractions were combined and concd under reduced pressure to give 1-(8-ethyl-1,4-dioxaspiro[4.4]nonan-7-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a tan powder (3.0 g, 64%): LC/MS (Table 1, Method c) Rt=1.44 min; MS m/z: 468 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH2:20][C:21]([O:23]C)=[O:22].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1CC(=O)O)CCC3
Temperature: 65 °C
Yield: 53 %

Procedure:
To a solution of methyl [2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.061 g; 0.181 mmol) in dioxane (4 mL) and water (1 mL) was added a 1N lithium oxide solution (1 mL; 1 mmol). The reaction mixture was heated at 65° C. for 2.5 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.031 g (54%) of the title compound as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)(=[O:28])=[O:29])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 18 h
Yield: 103.1 %

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.0 g) was dissolved in DCM (50 mL) and 3-nitrobenzenesulfonyl chloride (4.8 g) was added. This solution was cooled to 5° C. and the TEA (8.52 mL) was carefully added. The reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was then extracted with 0.1 N aqueous HCl (50 mL) and aqueous Na2CO3 (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtrated and evaporated to dryness to yield a light brown amorphous solid (9.05 g). MS: m/z=431.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2cccc(F)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(F)c3)CC2)cc1
Yield: 81.8 %

Procedure:
0.5 g (0.00239 mol) of 1-(3-fluoro-benzyl)-piperidin-4-ol and 0.67 ml (0.00478 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.632 ml (0.00478 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.64 g (82%) of 1-(3-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C20H23FNO2+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH2:18])[CH:24]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(N)ncn1
Yield: 58.3 %

Procedure:
To a solution of 2-methoxyphenyl boronic acid (X) (10.3 g, 68.2 mmol) in 300 ml of 1,4-dioxane was added 100 ml of saturated aqueous sodium carbonate solution. Argon gas was purged for 30 min at room temperature. Then 4-amino-6-chloropyrimidine (I) (8.8 g, 68.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.9 g, 3.4 mmol) were added simultaneously and argon gas was bubbled through the mixture for another 20 min. The reaction mixture was heated to reflux for 12 hours (TLC confirmed completion of the reaction) and was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The obtained crude residue was purified by silica gel column chromatography eluting with 15% ethyl acetate in dichloromethane to provide 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (8.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:22][CH2:21][CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCCOCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCCOCc1ccccc1)c1ccc(Br)cc1
Yield: 94.3 %

Procedure:
A solution of 4-bromobenzenesulfonyl chloride (5.5 g, 21.7 mmol) dissolved in dichloromethane (15 ml) was added dropwise to a solution of 2-benzyloxyethanol (3.0 g, 19.7 mmol) in triethylamine (3 g, 29.6 mmol) at 0° C. under nitrogen. The resultant mixture was stirred for 16 h at room temperature. To the reaction mixture was added water (3 ml) and then the combined mixture was poured onto water (100 ml) and the product was extracted with dichloromethane. The organic layer was washed repeatedly with water and then saturated aqueous sodium hydrogen carbonate solution, before drying (Na2SO4) and concentrating in vacuo to give the title compound as a white solid (6.9 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH:12]([CH3:14])[CH2:11][C:8]4[C:7]5[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=4)[CH2:31][CH2:32]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2occ(CC(C)N3CCN(c4cc(C)cc5cccnc45)CC3)c2c1

Procedure:
6-methyl-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 62 mg (14%); (M+H): 416; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H): 8.02˜8.00 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.99˜6.58 (m, 7H); 3.87 (s, 3H); 3.46˜2.62(m, 11H); 2.5 (s, 3H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:3]1=[O:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccccc1C1C(=O)N(C)c2ccccc21
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1C1(Cc2ccccc2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
20.24 g (0.08 mol) of 1-methyl-3-(2-methoxyphenyl)indolin-2-one are dissolved in 200 ml of dry THF. Then 9.2 g (0.08 mol) of potassium tertiary-butylate are added, and the mixture is stirred at room temperature for 15 minutes. At 10°, a solution of 12.1 ml of benzyl bromide in 20 ml of dry THF is added dropwise, and the mixture is then stirred at room temperature for 3 hours. It is then concentrated in vacuo, the residue is partitioned between water and ethyl acetate, and the organic phase is washed twice with water, dried and concentrated. 26.1 g of product of melting point 174°-176° C. are obtained.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=4[CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1cccc(C)c1N1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(C)c1N1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2,6-dimethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 50% overall yield. FDMS m/e=379 (M+ of free base). α[D]589=−11.89 (c=0.47, methanol).
Reaction SMILES: [I-].[C:2]([O:6][C:7]([NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])[CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[N:27][C:28]2CCNC[C:33]=2[CH:34]=1.CCN(CC)CC>C(Cl)Cl>[C:2]([O:6][C:7](=[O:8])[NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:18][CH2:33][C:28]3[N:27]=[CH:26][C:25]([C:24]([F:36])([F:35])[F:23])=[CH:34][C:20]=3[CH2:21]2)=[O:16])[CH2:11]1)([CH3:3])([CH3:4])[CH3:5]
Reactant: C[n+]1ccn(C(=O)N2CCC(NC(=O)OC(C)(C)C)C2)c1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 3-(3-tert-butoxycarbonylamino-pyrrolidine-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (preparation #4) (7.81 g, 18.5 mmol) in DCM (70 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine (3.74 g, 18.5 mmol) and Et3N (2.6 mL, 18.5 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. Additional Et3N (1.5 mL, 10.7 mmol) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 5% MeOH/DCM as the mobile phase to give [1-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (4.91 g, 64%). RP-HPLC (Table 1, Method a) Rt 2.37 min; m/z: (M+H)+ 415.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH:6]([OH:9])[CH2:7][OH:8])(=[O:4])=[O:3].[S:10](Cl)(Cl)=[O:11]>C(Cl)Cl>[CH3:1][S:2]([CH2:5][CH:6]1[CH2:7][O:8][S:10](=[O:11])[O:9]1)(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)CC(O)CO
Solvent: ClCCl
Product: CS(=O)(=O)CC1COS(=O)O1
Temperature: 35 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
9.00 g (58.4 mmol) of 3-(methylsulfonyl)propane-1,2-diol was dissolved in 100 mL of methylene chloride. 7.64 g (64.2 mmol) of thionyl chloride was dropwise added to the solution at an inner temperature of from 20 to 25° C. After this was stirred at 35° C. for 2 hours, the solvent and the remaining thionyl chloride were evaporated away under reduced pressure to give 11.40 g of a crude crystal. The obtained crude crystal was recrystallized from dimethyl carbonate/2-propanol to give 6.60 g of the intended 4-(methylsulfonylmethyl)-1,3,2-dioxathiolane-2-oxide as a diastereomeric mixture (mixture ratio 9/1) (yield 56%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CO)=CC=CC=1.C(O)C.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 80 °C
Yield: 82.7 %

Procedure:
A mixture of 7-chloro-imidazo[1,2-a]pyridine (15.0 g, 98.6 mmol), 4-fluorophenylboronic acid (16.55 g, 118.3 mmol), potassium carbonate (81.5 g, 590 mmol) in toluene-methanol-ethanol-water (1:1:1:1, 800 mL) was degassed with N2 and then bis(tri-tert-butylphosphine)palladium(0) (400 mg) added. The mixture was degassed and then heated to 80° C. for 18 h. The mixture was cooled to ambient, transferred to a separating funnel and the layers separated. The organic portion was reduced under reduced pressure and the residue extracted with dichloromethane. The dichloromethane extracts were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to afford 17.3 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.22 (1H, d), 7.87 (1H, s), 7.71 (1H, s), 7.69-7.58 (3H, m), 7.20 (2H, t), 7.11 (1H, d).
Reaction SMILES: [OH:1][C:2]1([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>CO.[Pd]>[OH:1][C:2]1([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3][NH:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCCC1C1(O)CNC1
Reaction time: 15 h
Yield: 98.7 %

Procedure:
To a solution of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (595 mg, 1.52 mmol), prepared using procedures similar to those described in Reference 5, in methanol (5 mL) was added catalytic palladium on carbon (5% wt). The heterogeneous mixture was stirred under a hydrogen gas atmosphere for 15 hours at ambient pressure and then was filtered. The filtrate was concentrated in vacuo to afford 385 mg, 1.50 mmol (98%) of 1,1-dimethylethyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate as a colorless film without further purification.