Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[NH2:14][C:15]([CH:19]([F:21])[F:20])=[CH:16][C:17]#[N:18]>C(O)(=O)C.C1COCC1.CO>[F:20][CH:19]([F:21])[C:15]1[NH:14][C:15]([CH:19]([F:21])[F:20])=[C:16]([C:17]#[N:18])[CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][N:4]=[C:3]3[CH2:1][CH3:2])[C:16]=1[C:17]#[N:18]
Reactant: N#CC=C(N)C(F)F
Reactant: CCc1n[nH]c2ccc(C=O)cc12
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12

Procedure:
A mixture of 80 mg (0.46 mmol) 3-ethyl-1H-indazole-5-carbaldehyde (Example 10A), 119 mg (1.21 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] and a trace amount of powdered 4 Å molecular sieve in acetic acid (0.44 ml) was heated to reflux temperature for 4 h. After cooling, the reaction mixture was diluted with THF/methanol and filtered. The filtrate was purified twice by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 99 mg (57% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.S([Cl:39])(C)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][Cl:39])[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol (22.5 g) was added to 186 ml of dry dichloromethane containing triethylamine (7.8 ml). The stirred solution was cooled to -10° and maintained at that temperature during the dropwise addition of a solution of 5.1 ml of mesyl chloride in 50 ml of dry dichloromethane. The ice bath was then removed and the reaction was stirred overnight at room temperature. The solution was washed with 25 ml of a 5% sodium bicarbonate solution and then dried over anhydrous potassium carbonate. The solvent was removed in vacuo (bath temperature, 25°) to yield 24.2 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4(2-chloroethyl)piperazine 2a as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:29][C@H:28]([CH2:30][O:31]C(C4C(C)=CC=CC=4)=O)[C@@H:17]([O:18]C(C4C(C)=CC=CC=4)=O)[CH2:16]3)[CH:13]=[N:14][C:7]=12>N>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:17]([OH:18])[CH2:16]3)[CH:13]=[N:14][C:7]=12
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To 1.33 g (2.40 mmol) of Compound 5, ammonia-saturated methanol (120 ml) was added at 0° C. The solution was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off and the residue was purified by flash silica gel chromatography using methylene chloride:ethanol (97:3 to 93:7) as an elution solvent to give 717 mg of Compound 6 in a yield of 94%.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH3:31][CH:32]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:33]=O>CCOCC>[CH3:31][CH:32]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:33][CH:2]=[O:3]
Reactant: CC(C)CCC(C)C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: CC(C)CCC(C)CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 21 grams of methoxymethyltriphenylphosphonium chloride in 200 ml. of absolute ether is added under nitrogen at room temperature a solution of 60 mmoles of phenyllithium in ether. After about 10 minutes, the mixture is cooled to -30° and 6 grams of 2,5-dimethylhexan-1-al in ether is added slowly. After about 12 hours at room temperature, the mixture is filtered and the filtrate evaporated. The concentrate is dissolved in aqueous tetrahydrofuran containing a small amount of dilute hydrochloric acid and stirred at room temperature for about 48 hours. The mixture is worked up in ether to yield 3,6-dimethylheptan-1-al which is purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=O)[CH:10]=1)=[O:4].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[N:23][OH:24])[CH:10]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)C1=CC(=NO)CC(c2ccc(Cl)c(OC)c2F)N1
Yield: 83.7 %

Procedure:
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16, 5.19 g, 16.5 mmol) was slurried in methanol (160 mL). Hydroxylamine hydrochloride (3.35 g, 48.3 mmol) was added, followed by pyridine (10.0 mL, 123 mmol). The reaction mixture was stirred at reflux for 120 min. Methanol was evaporated under vacuum. H2O (200 mL) was added, and the residue was extracted into ether (4×150 mL). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (18; 4.54 g, 80%) as a white solid: mp 136-138° C. A 1:1 mixture of syn and anti isomers was observed by NMR spectroscopy and HPLC. 1H NMR (400 MHz, C6D6) δ 8.34 (br, 1H, NOH), 8.25 (br, 1H, NOH), 7.00 (s, 1H, H3), 6.71 (dd, JF-H=1.5 Hz, JH-H=9 Hz, 1H, aromatic), 6.69 (dd, JF-H=1.8 Hz, JH-H=9 Hz, 1H, aromatic), 6.57 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 6.53 (s, 1H, H3), 6.50 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 4.72 (s, 1H, NH), 4.52 (s, 1H, NH), 4.38 (dd, JH-H=3.6, 10.2 Hz, 1H, H6, isomer A), 4.23 (dd, JH-H=3.9, 11.4 Hz, 1H, H6, isomer B), 3.53 (s, 6H, CO2Me), 3.24 (s, 3H, OMe), 3.23 (s, 3H, OMe), 3.30 (dd, JH-H=4.2, 16.8 Hz, 1H, H5, isomer B), 2.63 (dd, JH-H=4.2, 15.3 Hz, 1H, H5, isomer A), 2.44 (dd, JH-H=10.5, 15.3 Hz, 1H, H5, isomer A), 2.33 (dd, JH-H=11.1, 16.8 Hz, 1H, H5, isomer B); 13C{1H} NMR (CDCl3) δ 164.2 (CO2Me), 163.9 (CO2Me), 153.7 (d, JF-C=250 Hz, C2′), 153.6 (d, JF-C=251 Hz, C2′), 152.6 (C4), 149.6 (C4), 144.3 (d, JF-C=3 Hz, C3′), 144.1 (d, JF-C=3 Hz, C3′), 139.2, 138.3, 128.6 (d, JF-C=12 Hz), 127.9 (d, JF-C=11 Hz), 127.8 (d, JF-C=3 Hz), 127.7 (d, JF-C=3 Hz), 125.3, 121.7, 101.7 (C3), 92.6 (C3), 61.42, 61.38, 52.7, 52.6, 49.3, 48.3, 33.6 (C5), 28.7 (C5). HRMS-ESI (m/z) calcd for C14H14ClFN2O4, 328.0621. found, 328.0620. Anal. Calcd for C14H14ClFN2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 51.31; H, 4.34; N, 8.40.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1>CO.[Zn]>[NH2:16][C:13]1[CH:12]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119 %

Procedure:
Ammonium chloride (11.5 g, 214 mmol) and zinc (14.0 g, 214 mmol) were added to a solution of methyl 4′-bromo-4-nitrobiphenyl-2-carboxylate (7.2 g, 21.42 mmol) in MeOH (110 mL) and stirred at room temperature for 1 hour. The solid was filtered, and the filtrate was evaporated. The residue was dissolved in diethyl ether, filtered and concentrated to give methyl 4-amino-4′-bromobiphenyl-2-carboxylate (7.8 g, 25.5 mmol, 119% yield). LCMS: rt=1.54 min, [M+H]+=305 and 307; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@:7]1([CH2:40][CH:41]=[O:42])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C@@H:27]([CH2:37][CH3:38])[CH2:28][N:29]([CH3:36])[S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:32])=[O:31])[C:8]1=[O:39])(=[O:4])=[O:3].OOS([O-])=O.[K+].[CH3:49][OH:50]>C(Cl)Cl.O>[Cl:19][C:15]1[CH:14]=[C:13]([C@@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C@@H:27]([CH2:37][CH3:38])[CH2:28][N:29]([CH3:36])[S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[C:8](=[O:39])[C@:7]([CH2:40][C:41]([O:50][CH3:49])=[O:42])([CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CO
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CC=O)(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](COS(C)(=O)=O)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of ((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)methyl methanesulfonate (Example 414, Step F, 1.0 g, 1.516 mmol) in MeOH was treated with Oxone (0.932 g, 1.516 mmol) over a weekend. The reaction mixture was diluted with DCM and water. The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([F:18])=[CH:16][C:15](Cl)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([F:18])=[CH:16][C:15]([CH:20]3[CH2:22][CH2:21]3)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2F)c1C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ncc(C3CC3)cc2F)c1C
Temperature: 0 °C
Yield: 92.2 %

Procedure:
A suspension of 1-(5-chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2 g) in Reference Example 124 (1), cyclopropylboronic acid (911 mg), 1,1′-bis(di-tert-butylphosphino)ferrocene (167 mg), palladium acetate (79 mg) and tripotassium phosphate (4.49 g) in 1,4-dioxane (16 ml) was stirred under reflux. After completion of the reaction, the mixture was allowed to cool, ice water and a saturated aqueous solution of ammonium chloride were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(5-cyclopropyl-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.88 g) as a light brown oil. MS (ESI) m/z: 290 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 2-amino-5-bromo-3-methylbenzoic acid (3.0 g, 13 mmol) from Step A above in DMF was added cesium carbonate (6.4 g, 20 mmol) followed by iodomethane (0.8 ml, 13 mmol). The reaction was stirred at ambient temperature overnight. The mixture was washed with water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo to afford methyl 2-amino-5-bromo-3-methylbenzoate (3.2 g, 100%) as a grey solid: 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=2.4 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 5.84 (brs, 2H), 3.87 (s, 3H), 2.15 (s, 3H); MS (ESI+) m/z 245 (M+H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH:19]([CH3:35])[C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=2[Cl:32])[CH:23]=1)=[O:21].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[ClH:32].[ClH:1].[CH2:3]([N:12]1[CH2:17][CH2:16][N:15]([CH:19]([C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=3[Cl:32])[CH:23]=2)=[O:21])[CH3:35])[CH2:14][CH2:13]1)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(C(=O)C(C)N3CCN(CC=Cc4ccccc4)CC3)ccc2c1Cl
Yield: 437.1 %

Procedure:
A mixture of N-cinnamyl piperazine dihydrochloride (2.75 g, 10 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.05 g, 3.2 mmol) and K2CO3 (1.3 g, 9.5 mmol) in 50 ml of CHCl3 was treated according to general preparation 2 to give 3.65 g of compound (IV-35), yield 70%. M+ 449.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:84])[CH2:59][C:60]2[N:61]([C:65]([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH:84][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:50])[CH2:59][C:60]2[N:61]([C:65]([C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([C:72]3[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1
Reactant: NC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added portionwise to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (150 mg, 0.42 mmol), 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanamine (Intermediate 88) (193 mg, 0.42 mmol) and N-ethyldiisopropylamine (0.087 mL, 0.50 mmol) in DMF (2.0 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours then quenched in water (10 mL) to give a pale yellow ppt. The precipitate was collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (320 mg, 95%) as a cream solid, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]([CH3:12])(C)[CH:4]([CH3:10])[CH2:5][C:6]([O:8]C)=[O:7])=O.O=O>>[CH3:10][CH:4]1[C:3]([CH3:12])([CH3:1])[O:8][C:6](=[O:7])[CH2:5]1
Reactant: COC(=O)CC(C)C(C)(C)C=O
Agent: O=O
Product: CC1CC(=O)OC1(C)C
Yield: 71 %

Procedure:
Using a method similar to Example 1, 172 parts of methyl 4-formyl-3,4-dimethyl-valerate are reacted with 80 parts of oxygen in the course of 4 hours. 91 parts (71% of theory) of β,γ,γ-trimethyl-γ-butyrolactone (boiling point 94°-96° C./16 mbar) are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([O:9]CC)=O.[OH-].[NH4+:13]>>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([NH2:13])=[O:9]
Reactant: CCOC(=O)c1ocnc1C
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1ncoc1C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 4-methyloxazole-5-carboxylate (7.8 g, 50 mmoles) and ammonium hydroxide in a seal tube was stirred at rt for 12 hours. After completion of the reaction, solid was filtered and washed with water. The aqueous was extracted with ethyl acetate. The organic extract was dried and concentrated and combined with the filtered solid. Yield: 4.1 g (47%) 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H), 7.92 (s, 1H). LCMS: (ES+) m/z=126.7 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][N:16](CC4C=CC=CC=4)[CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.Cl>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2c[nH]c(C3CNCCO3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 168.6 %

Procedure:
Palladium on carbon (10 wt %, 0.609 g, 0.572 mmol) was added to a solution of 2-{-4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-(phenylmethyl)morpholine (2.0 g, 5.72 mmol) and hydrochloric acid (4.76 mL, 57.2 mmol) in CH3OH (80 mL) under nitrogen, and the resulting mixture was stirred under hydrogen overnight at room temperature. The mixture was filtered, washing with CH2Cl2 (50 mL) and CH3OH (3×50 mL), and then concentrated. Water (80 mL) was added, and the resulting mixture was lyophilized to afford an HCL salt of the title compound (2.5 g) as a brown oil. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:23]B1OB(C)OB(C)O1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH3:23][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2c1oc1ccccc12
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1oc1ccccc12
Temperature: 25 °C
Yield: 554.3 %

Procedure:
4-Iododibenzo[b,d]furan (10 g, 34.0 mmol) and potassium phosphate (23.49 g, 102 mmol) were dissolved in 200 mL of toluene and 20 mL of water. The reaction was purged with nitrogen for 20 minutes and then 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5.34 mL, 5.94 mmol), Pd2(dba)3 (0.311 g, 0.34 mmol) and S-Phos (0.558 g, 1.36 mmol) were added. The reaction was refluxed for 18 hours. After allowing the reaction to cool to room temperature, 100 mL of water was added, the organic and aqueous layers were separated, and the aqueous layer extracted twice with 100 mL of toluene. The organic layers were passed through a plug of silica gel, eluting with DCM. After evaporation of the solvent, the crude product was subjected to column chromatography (SiO2, 3% ethyl acetate in hexane to 5% ethyl acetate in hexane, v/v) to yield 6 g (96.7%) pure product which was confirmed GC.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([N:16]([CH3:26])[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:3]1.[C:27]([C:32]1[CH:42]=[C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:33]=1[O:34][CH2:35][C:36](Cl)=[O:37])([CH2:30][CH3:31])([CH3:29])[CH3:28].Cl.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1.O>[O:1]=[C:2]1[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([N:16]([CH3:26])[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:42][C:32]=3[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:19]=2)[CH2:3]1
Reactant: CN(C(=O)c1cccc(N)c1)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)N(C)C3=NN(c4c(Cl)cc(Cl)cc4Cl)C(=O)C3)c2)c(C(C)(C)CC)c1
Reaction time: 1 h

Procedure:
N-[4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl]-N-methyl-3-aminobenzamide (8.2 g, 19.9 mmole) was dissolved in a mixture of tetrahydrofuran (100 ml) and pyridine (20 ml) and cooled in an ice bath. 2,4-Di-t-pentylphenoxyacetyl chloride (20.5 mmole) was dissolved in tetrahydrofuran (20 ml) and added dropwise to the stirred mixture. Stirring was continued for 1 hr and the mixture was then poured into stirred dilute hydrochloric acid (1.51), the oil extracted into ethyl acetate and the extract washed and dried. The solvent was removed by evaporation and replaced with ethanol (100 ml). A solution of sodium hydroxide (0.8 g, 20 mmole) in water (5 ml) was added dropwise and the mixture stirred for 15 min. The oil gradually dissolved and a solid gradually formed. The mixture was poured into dilute hydrochloric acid (11) and the pale orange solid filtered off washed and dried. The solid was chromatographed on silica gel using 1:1 60-80 petroleum ether: ethyl acetate as eluent to give the product as a white glass, 6.9 g, 50%.
Reaction SMILES: [SH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:26][C:27]([F:31])([F:30])[CH2:28]I>>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:14][C:10]1[CH:9]=[C:8]([C:2]2([S:1][CH2:28][C:27]([F:31])([F:30])[F:26])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)CI
Reactant: SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Product: FC(F)(F)CSC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 61 %

Procedure:
Using a similar procedure to that described in Example 1, 4-mercapto-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran was reacted with 2,2,2-trifluoroethyl iodide to give 4-[3-(naphth-2-ylmethoxy)phenyl]-4-(2,2,2-trifluoroethylthio)tetrahydropyran in 61% yield, m.p. 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].O.C(O)[CH2:25][OH:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:25][OH:26])=[N:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)cn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCCOc1ccc(Cc2ccc(Br)cc2)cn1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
(4-Bromophenyl)(6-methoxypyridin-3-yl)methanone (0.88 g, 3.0 mmol), hydrazine monohydrate (1.5 mL, 30 mmol) and potassium hydroxide (0.60 g, 12 mmol) were dissolved in ethylene glycol (10 mL), followed by stirring at 140° C. for 20 minutes. After the reaction solution was cooled to room temperature, water was added, followed by extraction with diethyl ether. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.30 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.38 g, 1.2 mmol) as a colorless oil (yield 41%).