Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[C:14]([CH3:15])=[C:13]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:28])([F:27])[F:29])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reaction time: 15 h
Yield: 89.5 %

Procedure:
To a solution of [6-fluoro-3-methyl-4-(4-trifluoromethanesulfonyl-benzyl)-naphthalen-2-yl]-acetic acid methyl ester (395 mg, 0.87 mmol) in tetrahydrofuran (15 mL) was added a solution of lithium hydroxide monohydrate (208 mg, 8.7 mmol) in water (3 mL) at room temperature. The resulting clear solution was stirred for 15 hours. Then, the tetrahydrofuran was removed under vacuum and the residue was diluted with water (10 mL). The aqueous solution was acidified with 1.0 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided 343 mg (90%) of [6-fluoro-3-methyl-4-(4-trifluoromethanesulfonyl-benzyl)-naphthalen-2-yl]-acetic acid as a white solid. mp=200-201° C.: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1 H), 8.04 (d, J=8.4 Hz, 2 H), 7.96 (dd, J=9.1, 6.0 Hz, 1 H), 7.81 (s, 1 H), 7.69-7.80 (m, 1 H), 7.48 (d, J=8.4 Hz, 2 H), 7.29-7.43 (m, 1 H), 4.71 (s, 2 H), 3.84 (s, 2 H), 2.30 (s, 3 H). ES(+)-HRMS cald. for C21H16F4O4S [(M+Na)+] 463.0597, obsd. 463.0598.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CCCCCCC.[C:17](#[N:20])[CH:18]=[CH2:19]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:19][CH2:18][C:17]#[N:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Solvent: CCCCCCC
Product: COc1ccc(OCCC#N)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
4-Methoxyphenol (263.0 g) was dissolved in acrylonitrile (224.8 g), and then Triton B (18 mL) was added dropwise at room temperature, with stirring at 80° C. for 48 hours. The reaction liquor was returned to room temperature while slowly stirring, and stirred for 12 hours. The reaction liquor was further left to stand at 6° C. to precipitate white prisms. The mother liquor was subjected to decantation, and cold toluene (300 mL) was added to obtain crystals, and then the resulting crude crystals were dried at room temperature under reduced pressure (3 hours) (crude crystals 232.6 g). The crude crystals were dissolved in ethyl acetate (250 mL) at 50° C., n-heptane (250 mL) was slowly added with stirring, and the resulting mixture was recrystallized with slow stirring for 12 hours. The mother liquor was subjected to decantation, n-heptane (300 mL) was added, and crystals were obtained. The crystals were washed with n-heptane (400 mL) and dried at room temperature under reduced pressure (crystal No. 1: white prisms 154.5 g). Since crystals were generated in the mother liquor, pale yellow prisms were obtained as crystal No. 2 (crystal No. 2: pale yellow prisms 56.1 g). All of the filtrate and n-heptane used for washing were recovered and concentrated under reduced pressure. Then, toluene (500 mL) was added to the residue, and the mixture was washed with 1 N aqueous sodium hydroxide solution (100 mL×3 times), water (500 mL), 1 N aqueous hydrochloric acid solution (100 mL×3 times), water (500 mL) and saturated brine (300 mL), then dried over anhydrous sodium sulfate for 30 minutes, and filtered, and subsequently the filtrate was concentrated under reduced. The residue was dissolved in ethyl acetate (150 mL) at 50° C., and n-heptane (150 mL) was slowly added with stirring, and the resulting mixture was recrystallized with slow stirring for 12 hours. The mother liquor was subjected to decantation, and n-heptane (200 mL) was added, and crystals were obtained. The crystals were washed with n-heptane (300 mL) and dried at room temperature under reduced pressure (crystal No. 3: white prisms 59.0 g). Furthermore, pale yellow prisms were obtained as crystal No. 4 (crystal No. 4: 19.0 g). Total amount obtained was 288.6 g, yield was 76.9%+ crude crystals (yellow prisms, 21.8 g, 5.8%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([OH:58])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:61]I>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([O:58][CH3:61])[CH2:40]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(OC)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of (1S,3′R,4′S,5′R,6′R)-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3-ol (26 mg, 0.032 mmol) in dry THF (0.8 mL) was added NaH (1.5 mg, 0.036 mmol, 60%) and CH3I (3.1 μL, 0.049 mmol) at room temperature. The reaction mixture was stirred for 3 h and quenched by addition of 5 mL of water when TLC showed the reaction was complete. Ethyl acetate (10 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted 2× with ethyl acetate (10 mL). The combined organic layers were washed 1× with 10% HCl (10 mL), 2× with water (10 mL), 2× with brine (10 mL) prior to drying over anhydrous Na2SO4. Concentration under reduced pressure and purification of the crude product by prepared TLC provided 22 mg of the pure product.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1COCC1>[CH3:15][S:16]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:1])[CH3:6])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(F)(F)CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(F)(F)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-difluorobutan-1-ol (2.60 g) and triethylamine (6.58 mL) in THF (50 mL) was added dropwise methanesulfonyl chloride (2.74 mL) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow oil (2.69 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH2:13][CH2:14]Br.O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:8]#[N:9])[CH2:14][CH2:13]2)=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: N#CCc1ccncc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CC1(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g of 4-pyridylacetonitrile are added to a mixture of 2.5 g of sodium amide in 80 ml of DCM, followed by 2.6 ml of 1,2-dibromoethane, and the mixture is stirred overnight at RT. The reaction mixture is poured into water and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvents are evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a DCM/MeOH mixture from (99/1; v/v) to (95/5; v/v). 2.5 g of the expected product are obtained.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]([CH3:16])[S:6]([N:9]1[CH:13]=[C:12](C=O)[N:11]=[CH:10]1)(=[O:8])=[O:7].[BH4-].[Na+].O.[CH3:20]O>>[CH3:16][N:5]([CH3:4])[S:6]([N:9]1[C:13]([CH2:20][NH:3][CH2:1][CH3:2])=[CH:12][N:11]=[CH:10]1)(=[O:7])=[O:8]
Reactant: CO
Reactant: CN(C)S(=O)(=O)n1cnc(C=O)c1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCNCc1cncn1S(=O)(=O)N(C)C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a saturated solution of ethylamine in methanol (40 ml) was added 4-formyl-imidazole-1-sulfonic acid dimethylamide (2.5 g, 12.3 mmol) and the mixture was stirred overnight. Sodium borohydride (0.70 g, 18.5 mmol) was added and the mixture was stirred at room temperature for 3 h. Water was added and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (SiO2: dichloromethane/methanol=9:1) to yield a light yellow oil (0.785 g, 27%); MS (ISP): 233.1 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17]>>[ClH:1].[ClH:1].[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-cyanophenyl)pyrimidine and 1-isopropylpiperazine.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1([CH3:13])[C:9]([O:11][CH3:12])=[O:10].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:2][C@@H:3]2[CH2:8][CH2:7][O:6][CH2:5][C@:4]2([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:2][C@@H:3]2[CH2:8][CH2:7][O:6][CH2:5][C@@:4]2([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C1(C)COCCC1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Product: COC(=O)[C@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude methyl 4-amino-3-methyl-tetrahydro-2H-pyran-3-carboxylate hydrochloride (8.65 mmol), 4-benzyloxy-benzenesulfonyl chloride (1.2 eq), CH2Cl2 (175 mL) and saturated NaHCO3 (90 mL) were combined and stirred at room temperature overnight. The organic phase was then washed with water (100 mL) and brine (100 mL), dried over MgSO4, and concentrated. The residue was purified by chromatography with 20-35% ethyl acetate/hexane to provide two diastereomers, (3R,4R)-methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylate and (3S,4R)-methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylate. MS: (M+H)+=420.0.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH:14]([C:44]1[N:45]=[CH:46][O:47][CH:48]=1)[CH2:15][CH:16]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:17]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH3:19])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH:49]([C:51]1[O:55][CH:54]=[N:53][CH:52]=1)=[O:50].Cl>CCCCCC.C1COCC1.O>[O:55]1[C:51]([CH:49]([C:46]2[O:47][CH:48]=[C:44]([CH:14]([O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:7])[CH3:8])[CH2:15][CH:16]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH:17]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:18]([O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[CH3:19])[N:45]=2)[OH:50])=[CH:52][N:53]=[CH:54]1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)C(CC(O[Si](C)(C)C(C)(C)C)c1cocn1)O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cnco1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)C(CC(O[Si](C)(C)C(C)(C)C)c1coc(C(O)c2cnco2)n1)O[Si](C)(C)C(C)(C)C
Temperature: -50 °C
Reaction time: 3 h

Procedure:
Butyllithium (n-Buli, 0.32 g, 5 mmol) in hexane is added to a -50° C. Solution of 4-[1,3,4,5-tetra(t-butyldimethylsilyloxy)hexyl]oxazole (6, 3.4 g, 5 mmol) in THF (50 mL). The resulting solution stirred at -50° C. for three hours. A solution of 5-formyloxazole (0.53 g, 5.5 mmol - Preparation 20) in THF (7 mL) is added, and the mixture allowed to warm to room temperature while stirring for 12 hours. The resulting mixture is added to water, acidified with HCl and extracted three times with ether. The organic layer is washed with aqueous Na2SO3 and brine, dried over Na2SO4, and evaporated to yield 2-[1-(oxazol-5-yl)-1-hydroxymethyl]-4-[1,3,4,5-tetra(t-butyldimethylsilyloxy)hexyl]oxazole (7).
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:43])[CH:41]=O)=[CH:35][CH:34]=1.CC(O)=O>C1COCC1>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:43])[CH:41]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:35][CH:34]=1
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(CC(C)C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CC(C)C=Cc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
Potassium t-pentylat (1.7 M in toluene, 6.5 mL, 11.0 mmol, 1.1 equiv.) was added to a solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 15 min, 3-(4-methoxyphenyl)-2-methylpropanal (1.78 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 70° C. for 1.5 h. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was extracted with MTBE, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 19:1) to yield 2.20 g (74%) of the title compound as a yellow oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[Cl:45][C:46]1[N:51]=[CH:50][C:49]([CH:52]([NH2:54])[CH3:53])=[CH:48][CH:47]=1>O1CCCC1>[Cl:45][C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:54][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=4)[N:22]([S:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=4)(=[O:35])=[O:34])[CH:21]=3)[C:17]([C:43]#[N:44])=[CH:16][N:15]=2)[CH3:53])=[CH:48][CH:47]=1
Reactant: CC(N)c1ccc(Cl)nc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)c4ccc(Cl)nc4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
Diisopropylethylamine (730 μl, 4.2 mmol) was added to a mixture of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (330 mg, 2.1 mmol) and 1-(6-chloropyridin-3-yl)ethanamine (described in the literature: EP 375907 (B1)) (500 mg, 1 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 15 minutes. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a wax (345 mg, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](Cl)=[O:52])[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](=[O:52])[NH:25][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A CH2Cl2 solution (111.0 mL) of C-(3-chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (1.9 g, 5.5 mmol) and PS-DIPEA (2.8 g, 11.1 mmol) in a round bottom flask under N2 atmosphere was charged with 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (1.4 g, 5.0 mmol) and stirred at rt for 1.5 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 100% CH2Cl2 to 10% CH3CN/CH2Cl2) to afford 4-{[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylic acid benzyl ester as a pale yellow solid; MS (ES+): m/z 592/594 (100/50) [MH+]; HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([OH:6])[CH3:5].CCN(C(C)C)C(C)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[Cl:13][C:9]1[CH:8]=[C:7]([C:4]2([CH3:5])[O:6][C:24](=[O:26])[NH:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)(CCN)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2cccc(Cl)c2)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A stirred solution of crude 4-amino-2-(3-chlorophenyl)butan-2-ol (550 mg) and i-Pr2NEt (1 mL, 5.5 mmol) in CH2Cl2 was cooled in an ice bath and solid triphosgene (286 mg, 0.96 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (50 mL) and satd aq NaHCO3 (50 mL) and dried over MgSO4. Removal of the solvent left a brown oil (590 mg) which was purified by chromatography on a 12-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford 6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one (57 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8]([OH:10])=[O:9])=O.[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:10]1)[CH3:39]
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1
Yield: 1.5 %

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)3,4,5,6-tetrachlorobenzoic acid (44.9 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (29.7 g.) and acetic anhydride (50 ml.) was heated (at 85°- 90° C.) during three hours. The resulting crystalline product was washed with methanol, slurried in hot ethanol and washed again with methanol, affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= Y4 = (CH3CH2)2N, Y2 = CH3, Z4 = Z5 = Z6 = Z7 = Cl) (34. 1 g., m.p. 162°- 164° C.).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][CH2:27][CH3:28])[CH:20]=1.C(OCC)(=O)C>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:20][C:21]=1[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1cc(I)ccc1O
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 4-iodo-2-propylphenol under the conditions described in Example 1. The product was isolated by chromatography over the 40 fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. It was crystallized from ether/hexane to give off-white crystals with m.p. 154°-156°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:28])[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[C@H:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:28])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:22][CH:21]=3)=[O:27])[C@H:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Br)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(-c4ccccc4)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 100 °C
Reaction time: 14 h
Yield: 70.3 %

Procedure:
To a mixture of the compound obtained in Example 18 (0.20 g) in toluene (10 mL) and water (0.5 mL) were added phenylboronic acid (0.083 g), tetrakis(triphenylphosphine)palladium(0) (0.039 g) and potassium carbonate (0.047 g), and the mixture was stirred under an argon atmosphere at 100° C. for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.14 g, 69%) as a white powder.