Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2)=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2sccc21
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a solution of 15.0 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 150 ml of dichloromethane cooled to 0° C. is added 27.2 ml of triethylamine. After stirring 5 minutes, a solution of 28.0 g of 2-chloro-4-nitrobenzoyl chloride in 140 ml of dichloromethane is added slowly. The solution is stirred at room temperature overnight, diluted with 450 ml of dichloromethane and the solution washed with 200 ml each of water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried over N2SO4, filtered through a thin pad of hydrated magnesium silicate and the filtrate concentrated under vacuum. The residue is crystallized from ethyl acetate to give 24.3 g of off-white crystals, m.p. 131°-134° C.
Reaction SMILES: CN1CCN(C2C=CC3C(C=2)=CC=C2C=3OC(C(NC3C=CC([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=CC=3)=O)=CC2=O)CC1.N1(C([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]([C:55]3[O:56][C:57]4[C:62]([C:63](=[O:65])[CH:64]=3)=[CH:61][CH:60]=[CH:59][C:58]=4[N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)=[O:54])=[CH:48][CH:47]=2)=O)CCOCC1>>[N:30]1([C:51]2[CH:50]=[C:49]([NH:52][C:53]([C:55]3[O:56][C:57]4[C:62]([C:63](=[O:65])[CH:64]=3)=[CH:61][CH:60]=[CH:59][C:58]=4[N:66]3[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]3)=[O:54])[CH:48]=[CH:47][CH:46]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(C(=O)N5CCOCC5)cc4)oc23)CC1
Reactant: CN1CCN(c2ccc3c(ccc4c(=O)cc(C(=O)Nc5ccc(N6CCOCC6)cc5)oc43)c2)CC1
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4cccc(N5CCOCC5)c4)oc23)CC1

Procedure:
This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (120 mg=86%), LCMS-m/z=449.5.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>O.C(O)C>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:3][OH:2])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(Cc2ccccc2)=NO)cc1
Yield: 70.9 %

Procedure:
Hydroxylammonium chloride (4.19 g, 60.2 mmol) and sodium acetate (7.42 g, 90.4 mmol) are dissolved in 20 ml of water. To this solution 9.72 g (40.1 mmol) of 1-(4-methylsulfanyl-phenyl)-2-phenyl-ethanone in 60 ml of ethanol are added. The reaction mixture is heated to reflux for 18.5 hr. The reaction mixture was concentrated by rotary evaporation and poured into water. The resulting white solid is filterd and washed with water. After drying under reduced pressure, recrystallization from hexane-CH2Cl2 affords 7.32 g of a white solid (71%). 1H NMR (CDCl3), δ[ppm]: d 2.45 (s, 3H), 4.20 (s, 2H), 7.16-7.20 (m, 3H), 7.24-7.27 (m, 4H), 7.54 (d, 2H), 9.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30]1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][NH:29]2)=[CH:33][CH:34]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Yield: 10.5 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (1H-indol-6-yl)boronic acid (23 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.43 mol) according to the method described in Example 3 to give 7 mg (14% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([C:16]1[NH:17][C:18]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([Cl:28])=[C:25]([OH:27])[CH:26]=2)[N:20]=1)([CH3:15])[CH3:14]>ClCCl.CO>[Cl:28][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:16]([C:13]([CH3:14])([CH3:15])[CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[NH:17][C:18]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:26][C:25]=1[OH:27]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CNC(=O)Nc1ccc(Cl)cc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A solution of 4-chlorophenylisocyanate (46 mg, 0.3 mmol) in dichloromethane (5 ml) was treated with a solution of Example 3 (103 mg, 0.3 mmol) in methanol (1 ml). After stirring at room temperature for 30 min the solution was concentrated under reduced pressure and the residue chromatographed on silica gel eluting with dichloromethane/methanol (10:1) to the give the title compound (72 mg, 48%) as a pale yellow solid; MS(ES+) m/e 496/498/500 [M+H]+.
Reaction SMILES: S([O:11][C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:39](O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45].O1CCOCC1>CCCCCC>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:11][C@@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Reactant: OCCCCCCO
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 52 %

Procedure:
Using the procedure of Davis, J. Chem. Soc. 178-181 (1962), cholesterol tosylate and 1,6-hexanediol were condensed in refluxing dioxane to provide 52% yield of the title ether as colorless plates from hexane, m.p. 79.5°-81° C.; [α]D25 -28.1°±0.5° C.; IR 3500-3200 (OH), 1100 and 1080 cm-1 (ether); NMR (CDCL3): δ2.8-3.3 (br, 1H, H-1), 3.3-3.75 (2t,4H), 5.4 m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].C[CH2:16][N:17](C(C)C)[CH:18](C)C.CNC.C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][N:17]([CH3:18])[C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C(=O)N(C)C)cc1C
Yield: 5.6 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added a 2M solution of dimethylamine in THF (0.10 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-[(dimethylamino)carbonyl]-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.45 (br. s., 1H) 6.37 (d, 1H) 4.22 (q, 2H) 3.10 (br. s., 3H) 2.97 (br. s., 3H) 2.26 (s, 3H) 1.28 (t, 3H). MS: m/z 225.5 (M+1).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:35])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)Cl.[CH2:39]([O:41][C:42]([C:44]1[CH:45]=[C:46]([N:50]2[C:54]([SH:55])=[N:53][N:52]=[N:51]2)[CH:47]=[CH:48][CH:49]=1)=[O:43])[CH3:40].S(Cl)(Cl)(=O)=O>ClCCl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:55][C:54]2[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[CH:45]=3)[N:51]=[N:52][N:53]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:35])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)c1cccc(-n2nnnc2S)c1
Agent: ClSCl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)OCC)c2)c2ccccc2c1O
Yield: 77.5 %

Procedure:
2-(2-Tetradecyloxyphenyl)carbamoyl-1-naphthol (22.8 g) was dissolved in 100 ml of dichloromethane, and a dichloromethane solution of sulphenyl chloride prepared from 25 g of 1-(3-ethoxycarbonylphenyl)-5-mercaptotetrazole and 13.5 g of sulfuryl chloride was added dropwise thereto at room temperature. The resulting dichloromethane solution was stirred for an additional 5 hours, and washed with an aqueous sodium bicarbonate solution and further with water. The dichloromethane was distilled away under reduced pressure and the residue was crystallized from methanol to obtain 26.9 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-ethoxycarbonylphenyl)-5-tetrazolylthio]-1-naphthol, m.p., 88°-90° C. Yield was 74.3%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C=O)C.CCOCC>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCc1cc(O)cc(C(=O)OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCOc1cc(CCOC)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-hydroxy-5-(2-methoxyethyl)benzoate (1 eq.) from the previous step in DMF (0.2 M) was added Cs2CO3 (2 eq.) and 1-bromo-2-methoxy-ethane (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether and washed extensively with water and brine. The organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 25% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc4ccccc4c3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc3ccccc3c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-2-yl)pyrazin-2-amine (7e) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11e (460 mg, 681 μmol, 58.2%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 6H), 0.21 (s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 3.46 (s, 2H), 6.55-6.65 (AA′BB′, 2H), 6.91-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.47-7.58 (m, 2H), 7.75-8.00 (m, 4H), 8.08-8.14 (AA′BB′, 2H), 8.23 (s, 1H), 9.00 (s, 1H), 10.63 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.8, 17.9, 25.5 (6C), 119.4 (2C), 120.3 (2C), 125.5, 126.1, 126.6, 127.1, 127.2, 127.3, 127.5, 127.9, 128.2 (2C), 128.5, 130.2 (2C), 132.6, 132.8, 135.3, 137.6, 143.0, 147.5, 148.0, 153.7, 156.7, 169.4 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 478, 527, 687, 718, 746, 781, 804, 839, 914, 1009, 1082, 1103, 1128, 1169, 1261, 1362, 1415, 1445, 1472, 1508, 1605, 1670, 2857, 2886, 2928, 2955, 3057, 3221; HRMS (ESI+) m/z 698.3194 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: [Li].O(CC)CC.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](OCC)=O)[CH2:18][CH2:17]1>O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1NC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
To a stirred and refluxing suspension of 2 parts of lithium aluminumhydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-[N-(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 40 parts of 1,1'-oxybisethane. After the addition is complete, stirring and refluxing is continued for 20 hours. The reaction mixture is cooled to 5° C. and 7 parts of water are added. The formed precipitate is filtered off, washed on the filter with 1,1'-oxybisethane and the filtrate is evaporated. The oily residue is distilled, yielding 5.8 parts of N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine; bp. 90°-93° C. at 0.003 mm. pressure. On standing the distillate solidifies, to yield solid N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a melting point of 45° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[C:11]([C:32]2[C:40]3[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=3)[N:34]([S:45]([C:48]3[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[CH:33]=2)=[N:12][C:13]([NH:16][C@@H:17]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH3:18])=[N:14][CH:15]=1)#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:22]1[CH2:21][CH2:20][CH:19]([C@H:17]([NH:16][C:13]2[N:12]=[C:11]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=4)(=[O:46])=[O:47])[CH:33]=3)[C:10]([C:8]#[N:9])=[CH:15][N:14]=2)[CH3:18])[CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)OC(C)(C)C)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCNCC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Trifluoroacetic acid (2 mL, 25.96 mmol) was added to a solution of tert-butyl 4-((1R)-1-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)piperidine-1-carboxylate (1.2 g, 1.79 mmol) in dichloromethane (25 mL) and the reaction mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated to dryness to give the title compound as a white solid (1.021 g, 98% yield).
Reaction SMILES: [CH:1]([C:4]1([CH3:30])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:31]([N:7]1[C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:30])[N:5]=[C:6]1[C:10]1[N:19]=[CH:18][C:17]([CH2:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc(CS(=O)(=O)c2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(CS(=O)(=O)c2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 5.9 g of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5 -[(phenylsulfonyl)methyl]nicotinic acid, methyl ester, and 0.3 g p-dimethylaminopyridine in 50 mL pyridine is stirred at room temperature and 1.75 mL benzoyl chloride is added in one portion. After stirring overnight, the reaction is concentrated in vacuo and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The aqueous phase is further extracted with methylene chloride, and the combined organic phases are dried and concentrated in vacuo. Chromatography of the residue on silica gel using hexane-ethyl acetate mixtures affords the desired product, mp 162°-166°.
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:15][CH3:16])[C:10]=2[Cl:14])[C:5]1=[O:18])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:29])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:19]([C:4]1([CH2:1][C:2](=[O:29])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:15][CH3:16])[C:10]=2[Cl:14])[C:5]1=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CCCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CCCCC1(CC(C)=O)CCc2c(cc(F)c(OC)c2Cl)C1=O
Reaction time: 16.5 h

Procedure:
2-allyl-2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (40 mg, 0.12 mmol) was dissolved in acetonitrile (0.36 mL) and treated with benzoquinone (20 mg, 0.18 mmol), Pd(OAc)2 (5 mg. 0.02 mmol), water (0.018 mL) and perchloric acid (70%, 0.005 mL) to give an orange solution. This solution was stirred under an air atmosphere for 16.5 hours, then purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 4:1 hexane-EtOAc. The band at Rf 0.53-0.59 was eluted with 5% MeOH in CH2Cl2 to give 2-butyl-5-chloro-7-fluoro-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-2H-naphthalen-1-one as a slightly yellow oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)(O)[O-].[Na+].[Br:25]Br>CO.C(Cl)Cl>[Br:25][C:9]1[CH:8]=[C:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:19]=[CH:18][C:10]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Yield: 29.7 %

Procedure:
To a chilled suspension of 4-methylaminosulfonylmethyl-N-trifluoroacetylaniline (10.9 g) in methanol (100 mL) was added sodium bicarbonate (28 g), followed by bromine (18.3 g) in methylene chloride (30 mL). The reaction mixture was then diluted with methylene chloride (70 mL) and quenched by the addition of sodium sulfite (20 g), filtered through CELITE and concentrated in vacuo to a yellow residual solid. This solid was twice reslurried in methylene chloride (300 mL) then refiltered and the filtrates evaporated in vacuo. The residual materials were combined in 10% acetone/methylene chloride solution and concentrated then purified by column chromatography (eluting with 4% acetone in methylene chloride) to give the title compound (4.10 g) mp 170° C.; TLC (methylene chloride/acetone 15:1) Rf=0.36, and the corresponding dibromide (5.56 g) TLC (methylene chloride/acetone 15:1) Rf=0.31.
Reaction SMILES: [CH3:1][C@H:2]([C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:1][C@H:2]([C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:33]([C:32]2[CH:36]=[CH:37][C:29]([O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:30][CH:31]=2)=[O:34])=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC[C@H](C)C(=O)Oc1ccc(O)cc1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC[C@H](C)C(=O)Oc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
{circle around (3)}: A mixture comprising 1.66 g of (S)-4-(1′-methylnonylcarbonyloxy)phenol, 1.37 g of 4-benzyloxybenzoic acid, 1.24 g of DCC and 10 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate under reduced pressure. The resultant residue was purified by means of silica gel column chromatography, whereby 2.0 g of (S)-4-[4′-(1″-methylnonylcarbonyloxy)phenyloxycarbonyl]-1-benzyloxybenzene was obtained in the form of a colorless crystal.