Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccn3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
Diisopropylethylamine (0.4 mL, 2.3 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 100 mg, 0.24 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 min and then a solution of pyridine-2-sulfonyl chloride (which may be prepared as described above; 213 mg, 1.2 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 25% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (32 mg, 30%) as a white solid. MS cald. for C23H24FN2O4S [(M+H)+]: 443, obsd. 443.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10]CC=C)=[CH:6][CH:5]=1.C(N(CC)[C:18]1[CH:23]=CC=C[CH:19]=1)C>C(OCC)C>[CH2:23]([C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:10])[C:3]([O:2][CH3:1])=[O:14])[CH:18]=[CH2:19]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Solvent: CCOCC
Product: C=CCc1cc(C(=O)OC)ccc1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of methyl-4-allyloxy-benzoate (4.74 g, 24.7 mmol) in N,N-diethylaniline (10 mL) was heated at reflux for 48 hours and cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), washed with aqueous HCl (10% v/v, 3×20 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (10:1→5:1, hexanes:EtOAc) to afford 5 (3.55 g, 75%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.86-7.84 (m, 2H), 6.85 (dd, J=2.8, 7.7 Hz, 1H), 6.07-5.95 (m, 1H), 5.68 (s, 1H), 5.21-5.15 (m, 2H), 3.88 (s, 3H), 3.45 (d, J=6.3 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]3[CH2:32][CH2:31]3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7]C[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:51])CC2)CC1>>[OH:51][CH:4]1[CH2:5][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]3[CH2:31][CH2:32]3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CC3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCC3CC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (preparation see Example 4) and amine 21.
Reaction SMILES: [O:1]=O.[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[OH-].[Na+]>[Cl-].[NH4+].[NH4+].[NH4+].[NH4+].[Cl-].[Cl-].[Cl-].C1(C)C=CC=CC=1>[Br:3][C:4]1[C:5](=[O:1])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=1)[CH:7]=2
Reactant: O=O
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Yield: 87.4 %

Procedure:
Into a three-necked, 300-mL flask equipped with a stirrer, a molecular-oxygen-containing gas (air) inlet tube and a gas outlet tube (fitted with a condenser), 2,7-dibromofluorene (9.30 g, 0.029 mol) was charged, followed by its dissolution with toluene (100 g). Subsequent to addition of tetraammonium chloride (0.21 g) and a 48% aqueous solution of sodium hydroxide (2.66 g), the resulting mixture was vigorously stirred at 60° C. for 2 hours while introducing air at a flow rate of 0.1 L/min. After completion of the stirring, the reaction mixture was allowed to stand, and the resulting toluene layer was collected. The toluene layer was then subjected to acid washing, followed by water washing until its pH arose to 7. Toluene was then distilled off to recover crude crystals of 2,7-dibromofluorenone. The content of 2,7-dibromofluorene in the crude crystals at that time was 0%. Those crude crystals were recrystallized from N,N′-dimethylformamide (15 g) to afford 2,7-dibromofluorenone as yellow crystals (8.06 g).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>C(O)C>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=4[NH:19][C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccc(C)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.6 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 24 parts of a hydrochloric acid solution, 50 parts of water and 96 parts of ethanol is stirred first for a while at about 50° C. and further for 30 minutes at room temperature. The reaction mixture is evaporated and the oily residue is triturated in 2-propanone. The hydrochloride salt is filtered off and the free base is liberated in the conventional manner with ammonium hydroxide in water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The semi-solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one; mp. 178.3° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([S:21]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]([CH:13]=[O:14])=[C:4]2[Cl:3])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
The title compound is prepared in accordance with the procedure of O. Olton et al., Tetrahedron, 54 (1998), 13915-13928 as follows. Sodium hydroxide is added to a stirred solution of 2-chloro-1H-indole-3-carboxaldehyde (239 mg, 1.33 mmol) in ethanol (10 mL). After 2 hr, the solvent is removed and the solid residue is dissolved in acetone and treated with benzenesulfonyl chloride (0.25 mL, 1.96 mmol). Soon a solid precipitated. After stirring for 1.5 hr at room temperature, the reaction mixture is heated to reflux for 1.5 hr. After cooling, water is added and the reaction is extracted with dichloromethane. The combined dichloromethane layer is washed with brine, dried over sodium sulfate and concentrated to an oil that is purified by chromatography eluting with heptane-0 to 10% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-benzenesulfonyl-2-chloro-1H-indole-3-carboxaldehyde (70 mg, 17% yield) as a yellow solid. MS 320 (M+H); NMR 10.09 (1H, s); 8.26 (1H, d, J=9 Hz); 8.15 (3H, m); 7.85 (3H, m); 7.56 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:12]([O:11][CH3:10])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(N)cc1OC
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(OC)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted to yield N2,N4-bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=1.8 Hz), 7.13 (d, 2H, J=4.8 Hz), 7.08 (d, 1H, J=8.7 Hz), 6.94 (d, 2H, J=10.5 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.76 (d, 1H, J=8.7 Hz), 6.70 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H); 19F NMR (CDCl3): δ −47433; LCMS: ret. time: 19.64 min.; purity: 95%; MS (m/e): 401 (MH+).
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:25]([C:27]1[C:28](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:29][C:30]([CH3:34])([CH3:33])[C:31]=1[CH3:32])#[N:26].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:32][C:31]3[C:30]([CH3:33])([CH3:34])[O:29][C:28](=[C:35]([C:36]#[N:37])[C:38]#[N:39])[C:27]=3[C:25]#[N:26])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
In an ethanol/tetrahydrofuran mixed solvent were dissolved 170 mg (0.50 mmol) of 5-[2-[4-(dibutylamino)phenyl]vinyl]thiophene-2-carboaldehyde and 110 mg (0.55 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture, 42 mg of ammonium acetate was added, and the mixture was stirred at room temperature. The solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 198 mg of a black crystal having amp of 208-209° C. (yield: 76.1%).
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl>CN(C)C=O>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[C:2]=1[C:21]#[N:22])(=[O:10])=[O:9]
Reactant: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2C#N)CC1

Procedure:
Preparation according to Example 7: 4-[2-fluoro-3-(methylsulfonyl)phenyl]-1-propylpiperidine (0.2 g, 0.67 mmol), N,N-dimethylformamide (30 ml), sodium cyanide (0.82 g, 1.67 mmol) and 18-crown-6-ether (5 mg). Yield: 0.06 g (29%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: MS m/z (relative intensity, 70 eV) 306 (M+, 3), 279 (6), 278 (16), 277 (bp), 198 (5).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].C(N(CC)CC)C.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.O>ClCCl.C([O-])(O)=O.[Na+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1OC
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)[C@H](Nc2cccnc2)C[C@H](C)N3C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.56 %

Procedure:
To a stirred solution of (2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 94) (50.1 mg, 0.147 mmol) in dichloromethane (DCM) (2 mL) was added triethylamine (0.061 mL, 0.442 mmol) and copper (II) acetate (41.0 mg, 0.226 mmol) followed after 10 min by 3-pyridinylboronic acid (36.4 mg, 0.296 mmol). The resulting mixture was stirred at room temperature for 3 h. Further 3-pyridinylboronic acid (9.1 mg, 0.074 mmol) was added and the mixture was stirred at room temperature for a further 6 days after which time the solvent had evaporated in vacuo. After standing for 19 days, further dichloromethane (DCM) (2 mL) was added followed by further 3-pyridinylboronic acid (18.6 mg, 0.151 mmol) and copper (II) acetate (42.3 mg, 0.233 mmol). The mixture was stirred at room temperature for a further 24 h, then left to stand for 36 h before further triethyalamine (0.061 mL, 0.443 mmol) and 3-pyridinylboronic acid (19.8 mg, 0.161 mmol) were added. Stirring at room temperature continued for a further 6 h before additional 3-pyridinylboronic acid (19.5 mg, 0.159 mmol) was added. After stirring for a further 65 h a 3:1 mixture of water/0.880 ammonia (1 mL) was added and the mixture was stirred for 15 min then was diluted with a saturated NaHCO3 aqueous solution (6 mL). The aqueous phase was extracted with dichloromethane (3×6 mL) and the combined organic phases were dried using a phase separator then concentrated using a stream of nitrogen. The residue was dissolved in methanol (1 mL) and was purified by MDAP (modifier: formic acid) to give (2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-N-3-pyridinyl-1,2,3,4-tetrahydro-4-quinolinamine (2.8 mg, 6.71 μmol, 4.56% yield) as a light brown oil.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:9]=[CH:10][CH:11]=1.C>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:3][CH2:2][C:1]#[N:4])[C:13]2=[O:21])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(Cl)c1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1C(=O)C(O)(c2cccc(Cl)c2)c2ccccc21

Procedure:
Acrylonitrile (1.06 g.) was added to a solution of 3-(m-chlorophenyl)-3-hydroxyindolin-2-one (2.6 g.) in ethanol (50 ml.) containing Triton B (40% aqueous solution, 3 drops) and the resulting mixture stirred and heated under reflux for 6 hours. Charcoal was added and the mixture filtered and evaporated to about 15 ml. The product crystallised as colourless prisms 1.57 g., m.p. 149°-50°. (Analysis: Found C, 65.5; H, 4.4; N, 8.8%. C17H13ClN2O2 requires C, 65.3; H, 4.2; N, 8.9%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:25])=[CH:21][C:22]=4[F:24])[N:17]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:15]=3[CH3:32])=[CH:11][C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.I[CH2:40][CH3:41].[H-].[Na+].O>CN(C)C=O>[N:4]1([C:7]2[C:12]([N:13]([CH2:40][CH3:41])[C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:25])=[CH:21][C:22]=4[F:24])[N:17]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:15]=3[CH3:32])=[CH:11][C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCI
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1cc(N2CCOCC2)cnc1N1CCOCC1)c1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 60 °C
Reaction time: 41 h

Procedure:
To a stirred solution of N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.050 g, 0.096 mmol), in N,N-dimethylformamide (1.0 mL) was added iodoethane (0.030 g, 0.193 mmol) followed by 60% sodium hydride (7.71 mg, 0.193 mmol). The reaction was heated to 60° C. and stirring continued for 41 h. Water was added to quench the reaction and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0-50% EtOAc/hexane) to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-N-ethyl-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (1H, d, J=4.3 Hz), 8.02 (1H, s), 7.83-7.90 (1H, m), 7.77-7.83 (1H, m), 7.61-7.69 (2H, m), 7.35 (1H, ddd, J=7.4, 4.9, 1.4 Hz), 6.86-7.00 (2H, m), 3.77-3.98 (6H, m), 3.21 (4H, br. s.), 2.95 (4H, s), 2.88 (3H, s), 2.48 (4H, br. s.), 2.12 (3H, s). Mass Spectrum (ESI) m/e=547.3 (M+1).
Reaction SMILES: CCCCCCCC(OOC(C)(C)C)=[O:9].C(OCCCC)(=O)[C:17]1[C:18](=[CH:26]C=CC=1)[C:19]([O:21][CH2:22][CH2:23]CC)=[O:20]>>[C:19]([O:21][CH2:22][CH2:23][OH:9])(=[O:20])[C:18]([CH3:17])=[CH2:26]
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Reactant: CCCCCCCC(=O)OOC(C)(C)C
Product: C=C(C)C(=O)OCCO
Reaction time: 8 h

Procedure:
2 h after the end of the addition, 1 g of tert-butyl peroctoate is fed in. The total polymerization time is 8 h. After the end of polymerization, the mixture is diluted with 590.0 g of dibutyl phthalate. An almost clear, viscous solution is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33].CCOC(C)=O.CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:32]([F:35])([F:33])[F:34])[CH:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 eq) in anhydrous DMF is added NaH (1.1 eq) at room temperature. After 5 minutes, 1-chloro-4-chloromethyl-2-trifluoromethyl-benzene (1.1 eq) in DMF is added. The resulting mixture is stirred for 30 minutes. After aqueous work up, flash column chromatography (10% EtOAc/hexane) gave 4-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester. [MS: (ES+) 490.3 (M+1)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][NH:5][C:6]=1[CH2:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH2:33][N:5]3[C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[C:3]([C:9]([F:10])([F:12])[F:11])=[N:4]3)[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Reactant: CCc1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-ethyl-3-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.53) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.18–7.22 (d, 2H), 6.38–6.48 (m, 2H), 4.98 (s, 2H), 3.86 (s, 3H), 3.66–3.76 (m, 4H), 3.1–3.2 (m, 4H), 2.66–2.74 (q, 2H), 1.18–1.28 (m, 3H). MS (ES) M+H) expected=464.82, found 465.
Reaction SMILES: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O.[C:14]([NH:17][C@@H:18]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@H:19]1[O:20][CH3:21])(=[O:16])[CH3:15].[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.N1C=CN=C1>[C:14]([NH:17][C@@H:18]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[O:22][C@H:19]1[O:20][CH3:21])(=[O:16])[CH3:15]
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1NC(C)=O

Procedure:
This compound was prepared from the corresponding methyl glucoside, Methyl 2-acetamido-2-deoxy-β-D-glucopyranoside (Carbohydrates, Ed. Collins, P. M., Chapman and Hall, New York, 1987, p. 414) by treatment with t-butyldimethylchlorosilane in DMF and imidazole. 1H NMR δ0.00 (2Xs, 6H), 0.80 (2Xs, 9H), 1.98 (s, br, 3H), 3.20-3.32 (m, 1H), 3.32-3.50 (s superimposed on m 5H), 3.59 (dd, J=12, 8, 1H), 3.76, 3.84 (ABX, JAB=18, 2H), 4.28 (d, J=8, 1H), 6.42 (d br J=4, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH3:30][C:31]1([CH2:35]O)[CH2:34][O:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:30][C:31]3([CH3:35])[CH2:34][O:33][CH2:32]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC1(CO)COC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(C)COC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.6 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (3-methyloxetan-3-yl)methanol (0.6 g) and tributylphosphine (1.9 mL) in THF (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.03 g, 16%).