Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[C:17](=[O:19])=[O:18].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:17]([OH:19])=[O:18]
Reactant: CC(C)CCCCCCCCCCCBr
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
Magnesium (1.5 g) was added to a solution of 1-bromo-12-methyltridecane (15.0 g) in tetrahydrofuran (200 ml). The mixture was refluxed for 10 minutes under nitrogen atmosphere and stirred for 1 hour at room temperature. A solid of carbon dioxide (50 g) was added to the mixture. To the mixture was added a mixture of 1% hydrochloric acid (300 ml) and ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with chloroform to give 13-methyltetradecanoic acid as an oil (7.54 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:34])[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[CH3:21][N:22]([CH3:34])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Product: Cc1oc(-c2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2)nc1CCN1CCCC1

Procedure:
Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) and 4-(N,N-dimethylcarbamoyl)phenylboronic acid, follow a procedure significantly analogous to that found in Example 22 to give the titled compound. MS (m/e): 404.3 (M+1)
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[C:23]=3[OH:30])[N:17]=2)[CH:13]=[CH:12][CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:30][C:23]1[C:24]([OH:28])=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[N:17]=[C:16]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=3[OH:1])[N:15]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cccc(-c3cccc(-c4cccc(O)c4O)n3)n2)c1O
Temperature: 0 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To 6,6′-bis(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine (2.03 g, 50.8 mmol) dissolved in DCM (25 ml) was added boron tribromide (1M in DCM, 40.6 ml, 40.6 mmol) and the reaction stirred for 48 hours. The reaction was cooled to 0° C. and quenched by dropwise addition of methanol. The solvent was evaporated under vacuum to give the title compound as a yellow solid (100%); δH [2H6]-DMSO 8.30,(2H, d), 8.22,(2H, t), 8.10,(2H, d), 7.53,(2H, d), 6.88,(2H, d), 6.78,(2H, t).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:21]=[CH:20][C:19]3[C:10](=[C:11]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:12]4[C:17]([C:18]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)=[CH:4][CH:3]=1.[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[NH:51][C:52]4[C:57]([C:58]=3[CH:59]=2)=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].CCCCCC.C1(C)C=CC=CC=1>[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[N:51]([C:2]4[CH:3]=[CH:4][C:5]([C:8]5[CH:21]=[CH:20][C:19]6[C:10](=[C:11]([C:28]7[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=7)[C:12]7[C:17]([C:18]=6[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)=[CH:16][CH:15]=[CH:14][CH:13]=7)[CH:9]=5)=[CH:6][CH:7]=4)[C:52]4[C:57]([C:58]=3[CH:59]=2)=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:36][CH:35]=1
Reactant: Brc1ccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3oc3ccccc34)cc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4ccc(-n5c6ccccc6c6cc(-c7cccc8c7oc7ccccc78)ccc65)cc4)ccc23)cc1
Yield: 70.3 %

Procedure:
In a 50-mL three-neck flask were put 1.3 g (2.7 mmol) of 2-(4-bromophenyl)-9,10-diphenylanthracene, 0.88 g (2.7 mmol) of 3-(dibenzofuran-4-yl)-9H-carbazole, and 0.76 g (8.0 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 76 mg (0.13 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 4 hours under a nitrogen stream. After the stirring, the obtained mixture was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and the filtrate was concentrated to give a solid. This solid was purified by silica gel column chromatography (a developing solvent in which the hexane/toluene ratio was 5:1). This solid was purified by high performance liquid column chromatography (abbreviation: HPLC) (chloroform as the developing solvent). The obtained fraction was concentrated to give 1.4 g of a yellow solid which was the object of the synthesis in 71% yield. The synthesis scheme of Step 2 is illustrated in (b-15).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10]2[CH2:38][N:37]([CH3:39])[CH2:36][CH2:35][C:11]=2[C:12]2[N:13]=[C:14]([O:27]CC3C=CC=CC=3)[C:15]([O:19]CC3C=CC=CC=3)=[N:16][C:17]=2[CH:18]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:6]([O:5][P:4]([C:9]1[C:10]2[CH2:38][N:37]([CH3:39])[CH2:36][CH2:35][C:11]=2[C:12]2[NH:13][C:14](=[O:27])[C:15](=[O:19])[NH:16][C:17]=2[CH:18]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1cc2nc(OCc3ccccc3)c(OCc3ccccc3)nc2c2c1CN(C)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)c1cc2[nH]c(=O)c(=O)[nH]c2c2c1CN(C)CC2
Yield: 83.8 %

Procedure:
A solution of the compound from Example 105 (0.34 g, 0.65 mmol) was dissolved in 60 mL of acetic acid and hydrogenated at 52 psi over 20% Pd/C. The reaction mixture was filtered and concentrated. The residue was dissolved in EtOH (3 mL) and concentrated. This procedure was repeated several times. The residue was then dissolved in EtOH and triturated with ethyl acetate. The solid which formed was collected by suction filtration and dried under vacuum to give the title compound as a yellow solid (0.20 g, 83% yield) mp 310-330° C. (dec).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=O)[CH2:5][CH3:6].CO>O.[OH-].[Na+]>[C:4](=[N:2][OH:3])([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH2:5][CH3:6]
Reactant: NO
Reactant: CCC(=O)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccncc1
Yield: 75.1 %

Procedure:
To a solution of hydroxylamine hydrochloride (7 g, 0.1 mol) in H2O (40 mL) and 2N NaOH solution (50 mL) was added the compound 1 (9.46 g, 70 mmol). The reaction mixture was heated to reflux and made homogeneous by the addition of methanol (MeOH) (30 mL). After heating at reflux for 2 hours, the reaction mixture upon cooling gave the compound 2 as a white solid (7.90 g, 75%): mp 141°-144° C.; NMR (DMSO-d6) δ 1.03 (t, 3H, J=8 Hz), 2.72 (q, 2H, J=8 Hz), 3.34 (bs, 1H), 7.56 (d of d, 2H), and 8.56 (df d, 2H); IR (KBr) 1600 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O.[NH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CNC
Reactant: OCc1cc(Cl)nc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)c1cc(CO)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of crude (2,6-dichloropyridin-4-yl)methanol in 7 mL of (CH3)2NH (40 wt % solution in H2O) was stirred at r.t. for 45 min. The temperature was increased to 50° C., and the solution was stirred at 50° C. for about 24 h. Ethyl acetate and H2O (15 mL) were added, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) provided 1.01 g of (2-chloro-6-(dimethylamino)pyridin-4-yl)methanol with some impurity (unreacted starting material).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH3:10]I>>[NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Nc1ccc(C(=O)O)s1
Product: COC(=O)c1ccc(N)s1
Yield: 114.5 %

Procedure:
5-Aminothiophene-2-carboxylic acid (1.00 g, 5.78 mmol) instead of 2-formylbenzoic acid and methyl iodide (1.44 mL, 23.1 mmol) instead of benzyl bromide were used to give the title compound (1.04 g; yield, 97%) as a dark brown solid according to the method described in Example 3a.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:32]([N:34]1[CH2:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:22])([F:24])[F:23])[CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:38][CH2:39]1)([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (1.0 g, 2.2 mmol) prepared in Step 1 of Preparation 6, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (820.0 mg, 2.6 mmol), Pd(dppf)Cl2 (181.0 mg, cat.) and potassium carbonate (915.0 mg, 6.6 mmol) were added to a mixed solvent of 1,4-dioxane (32.0 mL) and distilled water (8.0 mL). The reaction mixture was stirred at 90° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 1.1 g of the titled compound as a yellow liquid.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[C:10]([NH:17][CH3:18])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26](Cl)(Cl)=[O:27].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([N:7]2[CH2:8][C:9]3[C:10](=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=3)[N:17]([CH3:18])[C:26]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(C1CCCCC1)C2
Temperature: 0 °C
Yield: 51.9 %

Procedure:
A mixture of 210 mg (0.79 mmol) of 5-cyclohexylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml of triethylamine in 10 ml of tetrahydrofuran was added dropwise to an ice-cooled solution of 0.5 ml (0.96 mmol) of phosgene (20% solution in toluene) in 5 ml of tetrahydrofuran. After 1 hour 15 ml of aqueous ammonium chloride solution and 10 ml of tetrahydrofuran were added to the resulting mixture. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and then evaporated. The residue was chromatographed on silica gel using diethyl ether/hexane (3:2) for the elution. Product-containing fractions were combined and evaporated to give 120 mg (52%) of 3-cyclohexyl-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7](S(C)(=O)=O)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3].[N:24]1([CH2:29][CH2:30][O:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([N:36]2[CH2:37][CH2:38][CH:33]([CH2:32][O:31][CH2:30][CH2:29][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:34][CH2:35]2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1nc(S(C)(=O)=O)c2c(-c3ccccc3)coc2n1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)coc2n1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
2,4-Bis(methylsulphonyl)-5-phenyl-furo[2,3-d]-pyrimidine (400 mg, 1.14 mmol) in acetonitrile (10.0 mL) was treated with 4-(2-pyrrolidine-1-ylethyloxymethyl)piperidine (360 mg, 1.7 mmol) and potassium carbonate (219 mg, 1.71 mmol) and heated in a microwave at 120° C. for 30 min. The reaction was concentrated in vacuum to a gum and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was purified by preparative HPLC (basic method 6) to yield methylsulfonyl-5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]furo[2,3-d]pyrimidine (96 mg, 0.198 mmol, 17%). 1H NMR (CDCl3) δ: 1.07 (2H, m), 1.52 (2H, br d, J=8 Hz), 1.75 (5H, br s), 2.5 (4H, b s), 2.6 (2H, t, J=5 Hz), 2.8 (2H, t, J=8 Hz), 3.18 (2H, d, J=4 Hz), 3.35 (3H, s), 3.5 (2H, t, J=4 Hz), 4.05 (2H, d, J=8 Hz), 7.4 (5H, m), 7.6 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:30][C:31](=[NH:35])[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:13][N:35]=[C:31]([CH2:32][CH2:33][CH3:34])[N:30]=2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Reactant: CCCC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCc1noc(C=Cc2ccc(OC)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(4-Methoxy-3-nitro-phenyl)-acrylic acid (compound of Example 6; 0.95 g, 4.25 mmol) was dissolved in DMF (15 mL) to which CDI (0.82 g, 5.10 mmol) was added and the reaction mixture was stirred at room temperature. After 45 min, N-hydroxy-butyramidine (0.52 g, 5.10 mmol) was added. The reaction mixture was stirred at room temperature for about 16-18 h. After completion of the reaction, additional CDI (0.82 g, 5.10 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 6 h to effect cyclodehydration. DMF was evaporated and the reaction mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture followed by extraction with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 0.25% ethyl acetate in petroleum ether) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]1)(=[O:11])=[O:10].[NH2:20][C:21]1([C:24]#[N:25])[CH2:23][CH2:22]1>>[C:24]([C:21]1([NH:20][C:17]([C@@H:14]2[CH2:15][CH2:16][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:11])[CH2:13]2)=[O:19])[CH2:23][CH2:22]1)#[N:25]
Reactant: O=C(O)C1CCC(S(=O)(=O)c2ccc(F)cc2Cl)C1
Reactant: N#CC1(N)CC1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from rac-(1S,3S)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid and 1-amino-cyclopropanecarbonitrile to afford the desired product as a light yellow oil. MS (EI): 371.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33]C)=O)[C:19]([C:35]([F:38])([F:37])[F:36])=[CH:18][N:17]=1.O[Li].O.C1C=CC2N(O)N=[N:48]C=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])[O-].[NH4+].[NH4+].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:48])=[O:33])[C:19]([C:35]([F:36])([F:37])[F:38])=[CH:18][N:17]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)cc2C)ncc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
Methyl 2-(2-(2-(2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I55) (476 mg, 0.906 mmol) and LiOH.H2O (113 mg, 2.71 mmol) in a mixture of THF (20 mL), water (4 mL) and MeOH (2 mL) were stirred at room temperature for 24 hours. The volatiles were evaporated under reduced pressure to give a light yellow solid which was dissolved in dry DMF (10 mL) and dry THF (10 mL). HOBT (171 mg, 1.26 mmol), EDCl (196 mg, 1.26 mmol), ammonium carbonate (458 mg, 4.87 mmol) and DIPEA (829 μL, 4.87 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure and the residue taken up in ethyl acetate. The resulting solution was washed with 10% NaHCO3, the layers separated and the organic layer was dried (MgSO4). The volatiles were evaporated under reduced pressure and the residue chromatographed (SiO2, 0-100% MeOH/DCM) to give the title compound (12) (358 mg, 52%) as a cream solid; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 7.28-7.19 (m, 4H), 7.14-7.09 (m, 2H), 5.66 (s, 1H), 5.49 (s, 1H), 3.65 (s, 2H), 3.13-3.04 (m, 4H), 3.04-2.97 (m, 2H), 2.54-2.41 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.08 (td, J=11.3, 3.8 Hz, 2H), 1.88-1.80 (m, 4H). LCMS Method C: rt 4.91 min; m/z 512.2 [M+1]+, 510.2 [M−1]−.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[OH:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#C[C@@H](O)CCCCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (S)-(−)-1-octyn-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (S)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(COc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3,5-dimethylpyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [F:1][CH:2]([F:17])[CH:3]1[CH2:8][CH:7]([C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][N:4]1[C:13]([O:15][CH3:16])=[O:14].[OH-].[Li+].Cl.C(Cl)Cl>C1COCC1.O>[F:17][CH:2]([F:1])[CH:3]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1CCN(C(=O)OC)C(C(F)F)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Dimethyl 2-(difluoromethyl)piperidine-1,4-dicarboxylate (2.35 g, 9.35 mmol) was dissolved in THF (35 mL) and 1 M lithium hydroxide (12.16 mL, 12.16 mmol) in water was added. The mixture was stirred at room temperature for 3 h, then 1 M HCl and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were dried by filtration through a phase separator and evaporated. 2-(Difluoromethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.2 g, 99%) was isolated. MS m/z 275 (M−H)−
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCCCCC>[C:1]([N:5]([C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (2 g) was stirred in toluene (35 ml) and 50% aqueous sodium hydroxide (1 g) at 5° C. Phenylacetylchloride (1.5 g) was added slowly, dropwise to the reaction mixture, warmed to room temperature and stirred 1 hour. The reaction mixture was diluted with hexane (50 ml) and filtered off to yield a solid product. The filter cake was washed with hexane and water and allowed to air dry. The white solid product obtained in 90% yield melted at 167°-169° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1>>[OH:1][C:2]1[C:11]([O:12][C:15]2[CH:14]=[C:13]([CH3:22])[CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: Cc1cccc(B(O)O)c1
Product: COC(=O)c1cccc(Oc2cccc(C)c2)c1O
Yield: 36.5 %

Procedure:
According to the method of (Example 99) <Step 1>, from methyl 2,3-dihydroxybenzoate (1 g) and m-tolyl boronic acid (0.97 g) that are commercially available, the subject compound (0.56 g) was obtained as pale yellow oil.