Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.C(N(CC)CC)C.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]1([C:6]2[CH:7]=[C:2]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:3]=[C:4]([NH2:14])[N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(C#Cc2ccccc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chloro-6-phenylpyrimidin-2-ylamine (2.0 g, 9.7 mmol), (PPh3)2PdCl2 (204 mg, 0.29 mmol), triethylamine (4.9 g, 48.5 mmol) in DMF (10 mL) was stirred at 25° C. for 0.5 hour under a nitrogen atmosphere. Then phenylacetylene (1.29 g, 12.70 mmol) was added to it and the mixture was stirred at 100° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C., diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layers were collected, combined, washed with water (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography using EtOAc-petroleum ether to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[NH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CCCCCC>[C:22]1([S:28]([N:10]2[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc(-c2c[nH]c3ccncc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccc(F)cc2)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
106 mg (0.5mM) of the product of Step 3, above, in 5 ml of absolute THF is cooled to -78°. 0.328 ml (0.525mM) of 1.6M n-butyllithium in hexane is added and the mixture stirred for 1 hour whilst allowing the temperature to rise to 0°. The mixture is then re-cooled to -60° and 97mg (0.55mM) of benzenesulfonyl chloride is added. After allowing to warm to RT overnight, the mixture is quenched with aqueous NaHCO3 and extracted with ethyl acetate. After washing with NaHCO3 the mixture is dried over Na2SO4 and evaporated to dryness. The residue is triturated with ether and the solids produced precipitated and dried to produce the title product of this step.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[I:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.CON(C)[C:18](=[O:21])[CH2:19][CH3:20]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[I:9][C:10]1[S:11][C:12]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:13][CH:14]=1
Reactant: Ic1cccs1
Reactant: CCC(=O)N(C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCC(=O)c1ccc(I)s1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
38.4 ml of a 2M solution of lithium diisopropylamide (8.2 g, 76.8 mmol) in THF-heptane-ethylbenzene was added to THF (50 ml) taken in a 500 three neck RB flask equipped with a nitrogen inlet. The mixture was cooled to −40° C. and then 2-iodothiophene (16.1 g, 76.8 mmol) taken in 50 ml of THF was added with vigorous stirring. After 10 minutes the mixture was warmed to −10° C. and stirred for 30 min. The reaction mixture was re-cooled to −40° C. and N-methoxy-N-methylpropionamide (9 g, 76.8 mmol) taken in 50 ml of THF was added in one portion. The reaction mixture was allowed to warm slowly to 0° C. and then the reaction was quenched with saturated 50 ml of NH4Cl solution. The contents were extracted with 3×100 ml of DCM, dried over MgSO4 and concentrated to give an oily residue. This was purified by flash chromatography to give the title compound (10 g, 49%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:37][CH:36]=[C:35]([O:34][CH3:38])[CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: COc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.093 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 4.17 (s, 2 H) 6.84 (m, 1 H) 6.98 (m, 3 H) 7.22 (d, J=8.09 Hz, 1 H) 7.26 (d, J=5.15 Hz, 1 H) 7.56 (t, J=7.17 Hz, 1 H) 7.67 (d, J=8.09 Hz, 1 H) 7.79 (t, J=8.46 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.22 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.84 (s, 1 H). MS (ESI−) m/z 481 (M−H)−.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[O:48][C:47]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[N:46][C:45]=1[C:57]#[N:58].[NH2:59][C:60]1[CH:82]=[CH:81][C:63]([C:64]([NH:66][CH2:67][CH:68]2[CH2:73][CH2:72][N:71]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][CH2:69]2)=[O:65])=[CH:62][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)CCC.O1CCOCC1.CCOC(C)=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]>[C:57]([C:45]1[N:46]=[C:47]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])[O:48][C:44]=1[NH:59][C:60]1[CH:82]=[CH:81][C:63]([C:64]([NH:66][CH2:67][CH:68]2[CH2:69][CH2:70][N:71]([C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[CH2:72][CH2:73]2)=[O:65])=[CH:62][CH:61]=1)#[N:58]
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Nc3oc(-c4c(F)cccc4F)nc3C#N)cc2)CC1
Temperature: 140 °C
Yield: 32 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.021 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.011 g, 0.021 mmol) in nBuOH:dioxane (1:1) (5 mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.080 g, 0.281 mmol), tert-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate (0.250 g, 1.40 mmol) and cesium carbonate (0.108 g, 0.561 mmol) were added and the mixture heated in the microwave for 3 minutes at 140° C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through a thiol resin cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford tert-butyl 4-((4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzamido)methyl)piperidine-1-carboxylate (0.035 g, 0.09 mmol, 26%) as a light yellow solid. LCMS (2) Rt: 3.09 min; m/z (ES+) 538.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:30])[C:19]([C:28]#[N:29])=[C:20]4[C:26]=3[O:25][CH:24]([CH3:27])[CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.C(N(CC)CC)C.Br.Br[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>CN(C)C=O>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:30])[C:19]([C:28]#[N:29])=[C:20]4[C:26]=3[O:25][CH:24]([CH3:27])[CH2:23][N:22]([CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CNC3)c2ncnc(N)c12
Reactant: BrCc1cccnc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(Cc2cccnc2)C3)c2ncnc(N)c12
Temperature: 85 °C

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (0.020 g, 0.05 mmol) was taken up in N,N-dimethylformamide (2.0 mL) and triethylamine (0.034 mL, 0.24 mmol), and the 3-(bromomethyl)pyridine hydrobromide was added. The reaction was heated to 85° C. for 2 h and was allowed to cool. The product was purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers: Peak #1 (Example 59): LCMS calculated for C25H26ClN8O (M+H)+: m/z=489.2; found: 489.2; Peak #2 (Example 60): LCMS calculated for C25H26ClN8O (M+H)+: m/z=489.2; found: 489.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[C:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cc(F)cc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(C#CC=C2CCNCC2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of Compound 228a (0.090 g, 0.27 mmol) in CHCl3 (1 mL) was added trifluoroacetic acid (0.42 mL, 5.4 mmol) and the reaction mixture was then stirred at 70° C. for 15 min. until the complete conversion of the reagent was observed by LC-MS. After cooling to r.t., water was added and the solution was alkalinized by addition of 2 N NaOH. The solution was extracted with CH2Cl2, the organic layer washed with brine and dried over Na2SO4 affording the title compound (0.051 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.Cl>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:16][CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[N:4][CH:3]=1
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of N,N-dimethylformamide, 770 mg of 7-bromo-1,5-naphthyridin-2(1H)-one was dissolved, 278 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 1.1 mL of 2-bromomethyl-1,3-dioxolan at 110° C. for 4 days. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added. The organic layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane 2:1 to obtain 467 mg of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: F[C:2]1[N:11]=[C:10]([F:12])[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([I:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[N:11]=[C:10]([F:12])[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[C:20]([I:25])[CH:19]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: COC(=O)c1cc([Si](C)(C)C)c(F)nc1F
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1cc([Si](C)(C)C)c(F)nc1Oc1ccc(Br)cc1I
Temperature: 60 °C

Procedure:
Methyl 2,6-difluoro-5-(trimethylsilyl)nicotinate (1.19 g, 4.85 mmol), 4-bromo-2-iodophenol (1.450 g, 4.85 mmol), and silver trifluoromethanesulfonate (1.496 g, 5.82 mmol) were dissolved in dry THF (40 mL) and treated with potassium carbonate (1.006 g, 7.28 mmol). The mixture was heated to 60° C. for 10 hours before being cooled to rt and filtered through a pad of celite. Water (100 mL) and diethyl ether (100 mL) were added to the filtrate and the phases were separated. The organics were dried with magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to DCM gradient) gave the desired methyl 2-(4-bromo-2-iodophenoxy)-6-fluoro-5-(trimethylsilyl)nicotinate.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[CH:30][C:31]=1[CH3:32]>CCCCO.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:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH3:25])[CH:27]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(S)cc1C
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: Cc1ccc(Sc2ccc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc1C
Temperature: 110 °C
Yield: 44.5 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dimethyl-thiophenol (175 uL, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.5:0.5→8:2) to give 260 mg of the title compound as colorless oil (yield 44%). 1H NMR (CDCl3) δ 8.00-8.10 (m, 2H), 7.55-7.65 (m, 3H), 7.40-7.50 (m, 1H), 7.10-7.30 (m, 2H), 3.30-3.40 (m, 4H), 3.10-3.20 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=3)[CH:5]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Yield: 81.1 %

Procedure:
4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.291 g, 1.43 mmol) was treated with 4-chlorophenyl isocyanate (0.247 g, 1.57 mmol, 1.1 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 75 (0.415 g, 1.16 mmol, 81%) as a white solid. LCMS m/z (%)=357 (M+H). 1H NMR (400 MHz, acetone-d6) δ: 8.21 (s, 1H), 8.07 (s, 1H), 7.58 (dd, J=2.8, 8.9 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.9 Hz, 1H), 6.20 (d, J=1.8Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[N:9]O)[S:6][CH:7]=1)#[N:2].C(C1C=C(C=O)SC=1)#N.C(=O)([O-])[O-].[Na+].[Na+].Cl.NO>CO.O>[NH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1csc(C=NO)c1
Agent: Cl
Agent: N#Cc1csc(C=O)c1
Agent: NO
Solvent: O
Solvent: CO
Product: N#Cc1csc(CN)c1
Temperature: 15 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
4-Cyanothiophene-2-carbaldehyde oxime 11.6 g (84.6 mmol) of 4-cyanothiophene-2-carbaldehyde were dissolved in 140 ml of methanol, and 12.3 g (116.1 mmol) of sodium carbonate were added. Then 6.5 [lacuna] (93.5 mmol) of hydroxylamine hydrochloride were added in portions while cooling at 15° C., and the mixture was stirred at 10° C. for 2 h. After addition of 80 ml of water, the reaction mixture was extracted five times with 50 ml of diethyl ether each time, the organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure to result in 12.5 g of the required product as yellow crystalline powder (96% of theory).
Reaction SMILES: [C:1]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC2C=CC(OC)=CC=2)=[O:25])[CH:13]=1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C1C2C(=CC=CC=2)N(CCCC(OCC2C=CC(OC)=CC=2)=O)C=1)(=O)/C=C/CCCCCC>>[C:1]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12
Agent: CCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12
Product: CCCCCCC/C=C/C(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 45 was repeated except that (E)-4-methoxybenzyl 4-[3-(2-decenoyl)-1-indolyl]butyrate obtained in Ex. 46 was used in place of (E)-4-methoxybenzyl 4-[3-(2-none-noyl)-1-indolyl]butyrate to give (E)-4-[3-(2-decenoyl)-1-indolyl]butyric acid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([S:13](Cl)(=[O:15])=[O:14])=[C:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][S:13]([C:7]2[S:6][C:5]3[CH:17]=[CH:18][C:2]([F:1])=[CH:3][C:4]=3[C:8]=2[CH2:9][CH:10]([CH3:12])[CH3:11])(=[O:15])=[O:14])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Solvent: c1ccncc1
Product: CC(C)Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12

Procedure:
This compound was prepared in analogy to Example 1 starting from 5-fluoro-3-isobutyl-benzo[b]thiophene-2-sulfonyl chloride (044 g), 2-amino-5-bromobenzotrifluoride (3.44 g) in pyridine (5 ml) for 18 h at rt to obtain the desired compound (0.24 g) as a colorless solid. MS (ISN): 508.2, 510.3 (M−H)−
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7])[CH3:2].[ClH:13]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7])[CH3:2].[ClH:13]
Reactant: CCc1cc(C#N)ccc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCc1cc(CN)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of 3-ethyl-4-methoxybenzonitrile (8-2, 0.12 g, 0.71 mmol) in MeOH (3.5 mL) was added Pearlman's Catalyst (0.020 g, 0.036 mmol) and concentrated HCl (0.47 mL, 5.71 mmol). The system was then stirred under an atmosphere of hydrogen via a balloon overnight. The reaction contents were filtered through a pad of celite and solvents were removed in vacuo to yield the desired product (8-3) as a salmon colored crystalline solid in the form of a mono HCl salt. ESI+ MS [M+H]+ C8H12N2O2: M-16 (—NH2), 149.07 found, 149.2 required.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6](C(F)(F)F)=[C:7]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:8]=1.CC(O)=O>CCOC(C)=O.CO.O=[Pt]=O>[ClH:1].[Cl:1][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][C:7]=1[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: Fc1ccc(C(F)(F)F)c(C2=CCNCC2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(Cl)c(C2CCNCC2)c1
Temperature: 25 °C
Yield: 131.2 %

Procedure:
A mixture of 4-(5-fluoro-2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (16, 0.310 g, 1.31 mmol) PtO2 (0.085 g, 0.37 mmol), and HOAc (71 μL, 1.31 mmol) in EtOAc (12 mL) stirred at ambient temperature for 18 under an atmosphere of H2 (1 atm). The reaction mixture was diluted with EtOAc (50 mL) and CH3OH (5 mL) and filtered over Celite and the filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (5 mL). To this solution was added HCl (2.0 N solution in Et2O, 2.0 mL) and the mixture stirred at ambient temperature for 5 min. The resulting suspension was diluted with Et2O (20 mL) and the solids collected by filtration to give 4-(2-chloro-5 fluorophenyl)piperidine hydrochloride (17) as an off-white solid (215 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 8.93-8.20 (m, 2H), 7.58-7.48 (m, 1H), 7.22-7.12 (m, 1H), 7.11-7.01 (m, 1H), 3.43-3.30 (m, 2H), 3.29-3.16 (m, 1H), 3.14-2.89 (m, 2H), 2.01-1.68 (m, 4H); ESI MS m/z 214 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.O.[K].CN(C)C=O.[F:18][C:19]([F:26])([F:25])[C:20]([F:24])=[C:21]([F:23])[F:22]>O.C(OCC)(=O)C>[F:22][C:21]([F:23])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH:20]([F:24])[C:19]([F:26])([F:25])[F:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 4.63 g of p-nitrophenol and 0.56 g of potassium hydrate added to 100 ml of N,N-dimethylformamide blowed hexafluoropropene at room temperature, and then the solution was stirred at 50° C. for 1 hour. Next, ethyl acetate and water were introduced in the reaction solution for separating the organic phase. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under a reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:EtOAc=20:1) to obtain 3.81 g of the desired product (Yield: 42%) as a yellow oil.