Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[CH2:23]2)=[C:15]([S:30][NH2:31])[N:14]=1>C(O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[CH2:23]2)=[C:15]([S:30]([NH2:31])=[O:6])[N:14]=1
Reactant: NSc1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
A solution of m-chloroperoxybenzoic acid (0.50 g, 2.5 mmol) in ethanol (50 mL) was added dropwise to an ice-cooled (0°-5° C.), stirred solution of 45 (0.75 g, 2.5 mmol) in ethanol (150 mL), during 15 min. The reaction mixture was allowed to stand at room temperature overnight and the crystalline product that deposited was collected by filtration. The product was washed with ethanol (2×15 mL) and air-dried to yield 0.24 g (31%) of 46. mp 178° C. (dec.). IR (KBr): 1040, 1300 (s, S=O), 3100-3600 (NH2, OH)cm-1 ; UV: λmax (pH 1) 329 nm (ε 3,800): λmax (pH 7) 323 nm (ε 5,800): λmax (pH 11) 323 nm (ε 3,700): 1H NMR (DMSO-d6): δ 6.27 (dd, 1, J=5.5 Hz, C1'H), 6.50 (s, 2, SONH2, exchanged with D2O), 6.94 (s, 2, NH2, exchanged with D2O), 8.43 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C10H14N6O4S (314.32): C, 38.21; H, 4.49; N, 26.74; S, 10.20. Found: C, 38.34; H, 4.59; N, 26.47; S, 10.17.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(CC)CC.[NH2:37][CH2:38][CH2:39][OH:40].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:38][CH2:39][OH:40])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: NCCO
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and 2-amino ethanol (40 mg, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (72%) of the title compound as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:8]([CH:10]([CH2:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:9])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:8]([CH:10]([CH2:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:5])[CH3:2]
Reactant: CCCCCN(CC(=O)OCC)C(=O)C(CCC(=O)OCc1ccccc1)CS(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCN(CC(=O)OCC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 60 h
Yield: 100.6 %

Procedure:
To a solution of benzyl 4-(N-ethoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate (200 mg) in ethanol (10 ml) was added 10% Pd-C (20 mg), and the mixture was hydrogenolyzed at atmospheric pressure for 60 hours. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (10:1), and recrystallized from isopropyl ether-hexane to give 170 mg of 4-(N-ethoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoic acid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[O:13]([CH2:20][CH2:21]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>>[O:13]([CH2:20][CH2:21][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[C:1]([OH:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: OCCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cccc(CCOc2ccccc2)c1C(=O)O
Temperature: 90 °C

Procedure:
148.1 g of anhydrous phthalic acid and roughly the molar equivalent 139.3 g of 2-phenoxyethanol were added to a 500 ml glass round-bottomed flask equipped with stirring blades, thermometer and Dimroth condenser, heated while slowly stirring, and after the generated heat at about 90° C. wore off, raised to a temperature of 130° C., which was maintained for 1 hour. The mixture was subsequently cooled to 60° C. The acid value (number of mg of KOH necessary to neutralize 1 g of a sample) of the reaction solution was 212.6. Since the acid value for the case where the reaction is 100% complete is 202.2, the reaction rate was computed to be 95%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.Cl.[OH:14][C:15]1[CH:26]=[C:25]2[C:18]([NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C(Cl)CCl.C(OCC)(=O)C>CCCCCC>[OH:14][C:15]1[CH:26]=[C:25]2[C:18](=[CH:17][CH:16]=1)[NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH:24][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)NCCc1c[nH]c2ccc(O)cc12

Procedure:
(E)-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-3-(4-hydroxyphenyl)acrylamide (2b) was synthesized according to by the condensation of 4-hydroxy cinnamic acid (150 mg, 0.914 mmol) and 5-hydroxy tryptamine hydrochloride (232 mg, 1.09 mmol) using standard EDC coupling method. 2b was isolated as reddish semi solid (182 mg 62%) by elution with 55% ethyl acetate in hexane. Rf: 0.58 (ethyl acetate);
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)=[CH:11][C:10]=1[C:22]([OH:24])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:49][NH2:50])=[N:45][C:46]=1[O:47][CH3:48].CN1CCOCC1>CN(C)C=O>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:49][NH:50][C:22]([C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=3)[CH:13]=[N:14][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])=[O:24])=[N:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ccc(CN)nc1OC
Reactant: Cc1cncc(-c2cnc(-c3ccccc3F)c(C(=O)O)c2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)cnc2-c2ccccc2F)nc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylic acid hydrochloride (3-4, 3.0 g, 8.70 mmol) in dimethylformamide (43 mL) cooled to 0° C., was added EDC (2.67 g, 13.92 mmol) and HOBt (2.13 g, 13.92 mmol) followed by 1-(5,6-dimethoxypyridin-2-yl)methanamine (11-6, 1.90 g, 11.31 mmol) and N-methylmorpholine (5.74 mL, 52.2 mmol). The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organics were washed with water and brine, then stripped to dryness. The crude product was taken up in DMF/DMSO (30 mL, 1:1), filtered and purified via reverse phase chromatography (5→65% acetonitrile in water with 0.1% TFA buffer). The clean fractions were pooled, partitioned between ethyl acetate and 2M sodium carbonate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (3-5) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=2.5 Hz, 1H), 8.74 (d, J=2 Hz, 1H) 8.53 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 1H), 7.31 (m, 1H), 7.21 (t, J=14.6 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.92 (t, J=18.3 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.46 (m, 1H), 4.44 (d, J=5 Hz, 2H), 3.87 (s, 3H), 3.81(s, 3H), 2.45 (s, 3H). HRMS [M+H] C26H23FN4O3 calc'd 459.1827, found 459.1830.
Reaction SMILES: [N:1]([C@@H:4]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[C:5]([OH:7])=[O:6])=[N+]=[N-].C(O)(=O)C>[Pd].O>[NH2:1][C@@H:4]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CCC(CC)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)[C@H](N)C(=O)O
Temperature: 70 °C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
A mixture of the product from Example 4 (31.7 g, 0.185 mol), 10% palladium on carbon (7.9 g), glacial acetic acid (370 mL), and water (926 mL) was placed under an atmosphere of hydrogen (40 psi) and shaken on a Parr hydrogenator. After 20 h, the reaction mixture was filtered through a pad of Celite (½″), which was rinsed well with water (200 mL). The filtrate was concentrated under reduced pressure in a bath heated to 70° C. to produce a white solid. The solid was triturated with ethyl acetate (500 mL), filtered, and washed once more with ethyl acetate (500 mL), and then air dried. This gave the title compound as a white solid (21.2 g, 79%): Opt. Rot. [α]D25=+12.01° (1% solution, H2O); 1H NMR (D2O, 500 MHz): δ4.65 (s, 3H), 3.69 (d, J=3.4 Hz, 1H), 1.69 (m, 1H), 1.44 (m, 1H), 1.03-1.10 (m, 3H), 0.83 and 0.81 (two overlapping triplets, J=7.5 Hz, 6H); MS(−ESI): [M−H]−, 144 (100%); Anal. Calc. for C7H15NO2: C, 57.90; H, 10.41; N, 9.65. Found: C, 57.75; H, 10.89; N, 9.40. Chiral HPLC (Symmetry C18 column, eluant: solvent A=50 mM triethylamine pH adjusted to 3.0 with phosphoric acid, solvent B=AcCN, gradient 80% A/20%B to 50% A/50%B over 20 min, flow rate 1.0 mL/min, detection at 340 nm, S isomer has a retention time of 12.26 min and R isomer has a retention time of 15.46 min) of the amino acid derivatized by Marfey's reagent (N-α-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) gave an enantiomeric ratio of 99.5:0.5 (2S:2R).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: Cc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Acrylic acid (16.5 mL, 240.6 mmol) was added to a solution of 5-methyl-1H-indole (10.5 g, 80.2 mmol) in acetic acid (20 mL) and acetic anhydride (20 mL) and the mixture was stirred at room temperature for 1 week. Aqueous sodium hydroxide (4N, 100 mL) was added and the mixture was washed with ethyl acetate. The aqueous fraction was acidified to pH 1 with hydrochloric acid (5M) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (7 g, 43%). 1H NMR (360MHz, CDCl3) δ7.85 (1H, br s), 7.38 (1H, s), 7.24 (1H, d, J 8.3 Hz), 7.02 (1H, dd, J 8.3, 2.3 Hz), 6.97 (1H, d, J 2.3 Hz), 3.09 (2H, t, J 7.6 Hz), 2.76 (2H, t, J 7.6 Hz), and 2.46 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.[NH:37]1[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]1>ClCCl>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:42]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[O:43])[CH2:22][CH2:23]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCNCC3)ccc21
Reactant: O=C(O)c1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCN(C(=O)c4cn[nH]c4)CC3)ccc21
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of N,N-dimethyl-2-(2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazol-1-yl) ethanamine (STEP C, 687 mg, 1.63 mmol) in dichloromethane (8 mL) were added triethylamine (230 microL, 1.63 mmol), 1H-pyrazole-4-carboxylic acid (201 mg, 1.80 mmol) and O-benzo-triazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (638 mg, 1,68 mmol) at room temperature. After 2 h, the mixture was diluted with dichloromethane (80 mL) and washed with sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by amine gel column chromatography (ethyl acetate-methanol, gradient) to give the title compound (757 mg, 90%) as a pale yellow grease.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:35]=[CH:36][C:37]3[N:38]([CH:40]=[C:41]([C:43]4[CH:51]=[C:50]5[C:46]([CH:47]=[CH:48][NH:49]5)=[CH:45][CH:44]=4)[N:42]=3)[CH:39]=2)[CH:31]=[CH:32][CH:33]=1)(C(C)(C)C)(C)C>O1CCCC1>[NH:49]1[C:50]2[C:46](=[CH:45][CH:44]=[C:43]([C:41]3[N:42]=[C:37]4[CH:36]=[CH:35][C:34]([C:30]5[CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=[CH:32][CH:31]=5)=[CH:39][N:38]4[CH:40]=3)[CH:51]=2)[CH:47]=[CH:48]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc3nc(-c4ccc5cc[nH]c5c4)cn3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc3nc(-c4ccc5cc[nH]c5c4)cn3c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
210 mg of tetrabutylammonium fluoride are introduced into a round-bottomed flask containing 180 mg of 6-[3-[(tert-butyldimethylsilanyloxy)methyl]phenyl]-2-(1H-indol-6-yl)imidazo[1,2-a]pyridine in 4 ml of tetrahydrofuran. The reaction mixture is stirred at ambient temperature for 48 h and is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 117 mg of compound are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C:13]3[CH:14]=[C:15]([CH:19]=[C:20](OC)[CH:21]=3)[C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:35]=[N:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:42]1([S:39]([NH:38][C:34]2[CH:33]=[C:32]([C:2]3[CH:11]=[C:10]4[C:5]([N:6]=[CH:7][C:8]([NH:12][C:13]5[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=5)[C:16]([OH:18])=[O:17])=[N:9]4)=[CH:4][CH:3]=3)[CH:37]=[N:36][CH:35]=2)(=[O:41])=[O:40])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: COc1cc(Nc2cnc3ccc(Br)cc3n2)cc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Nc2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)c1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
A slurry of 3-[(7-bromo-2-quinoxalinyl)amino]-5-(methyloxy)benzoic acid (0.73 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.80 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.06 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 18 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (100% ethyl acetate). The desired fractions were combined and concentrated to give the title compound (60 mg, 16%) as a yellow solid. MS(ES)+ m/e 497.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.[F:33][C:34]([F:45])([F:44])[CH2:35]OS(C(F)(F)F)(=O)=O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:35][C:34]([F:45])([F:44])[F:33])[CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(C2CCNCC2)sc1COc1ccc(C#N)c(Cl)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C2CCN(CC(F)(F)F)CC2)sc1COc1ccc(C#N)c(Cl)c1
Yield: 114 %

Procedure:
710 mg 2-Chloro-4-(4-methyl-2-piperidin-4-yl-thiazol-5-ylmethoxy)-benzonitrile were dissolved in 20 ml tetrahydrofuran. 0.55 ml N,N-Diisopropylethylamine and 710 mg 2,2,2-Trifluoroethyl-trifluoromethanesulfonate were added and the reaction mixture heated under reflux for two hours. The cooled reaction mixture was diluted by addition of 100 ml ethyl acetate, washed with 20 ml water and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 1.0 g crude 2-Chloro-4-{4-methyl-2-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-thiazol-5-ylmethoxy}-benzonitrile.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:20][C:8]=2[N:7]=1)(=O)C.[OH-].[Li+].Cl>CO>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:19]1[CH:18]=[CH:17][C:9]2[N:10]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:6]([CH2:5][OH:4])=[N:7][C:8]=2[CH:20]=1
Reactant: CC(=O)OCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: OCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A 4-neck flask (1 L) was charged with 2-acetoxymethyl-5-(benzothiazol-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 7-2) (5.00 g, 12.27 mmol), and methanol (253 mL), and an aqueous lithium hydroxide solution (1.0 M, 61 mL) was added at room temperature. After stirring under these conditions for 2 h, this was cooled in ice (0 to 10° C.) and dilute hydrochloric acid was added to the liquid to give an approximate pH of 5. The precipitated crystals were filtered off, washed with distilled water, and then dried under reduced pressure with heating to yield the title compound (4.28 g, 95.4% yield) as a greenish-white powder.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[NH2:5][N:6]1[C:11](=[O:12])[CH:10]([F:13])[N:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=[C:7]1[SH:18]>[OH-].[Na+].C(Cl)(Cl)Cl>[CH2:1]([S:18][C:7]1[N:6]([NH2:5])[C:11](=[O:12])[CH:10]([F:13])[N:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)N1N=C(S)N(N)C(=O)C1F
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCSC1=NN(C(C)(C)C)C(F)C(=O)N1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.9 %

Procedure:
26.6 g (0.22 mol) of allyl bromide were added to a solution of 43.6 g (0.2 mol) of 4-amino-6-fluoro-tert.-butyl-3-mercapto-1,2,4-triazin-5-one in 200 ml of 1 N sodium hydroxide solution at room temperature. The reaction mixture was stirred for approximately 20 hours at room temperature, the organic phase was then taken up in chloroform, and the solution was washed with three times 150 ml of 0.1 N sodium hydroxide solution, dried over sodium sulphate, filtered and concentrated. The oily residue was degassed at 50° C./0.05 mbar, and recrystallized from ethyl acetate/petroleum ether. 20.8 g (40% of theory) of 3-allylthio-4-amino-6-fluoro-tert.-butyl-1,2,4-triazin-5-one of melting point 75° to 74° C. were obtained.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]([C:18](=[O:38])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]2[C:35]([C:36]#[N:37])=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH:20]=1)[CH3:17])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:16]([CH3:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[O:38])=[CH:20][C:21]=1[C:26]1[C:35]([C:36]#[N:37])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2nc3ccccc3cc2C#N)c1)c1ccccc1CCCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc(Cl)c(-c2nc3ccccc3cc2C#N)c1)c1ccccc1CCCC(=O)O

Procedure:
4-(2-{[4-Chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid tert-butyl ester (20 mg, 0.037 mmol) was stirred in a mixture of DCM (0.2 mL) and TFA (0.2 mL) for 1 hr. The mixture was concentrated, dissolved in MeOH and purified by prep LCMS to yield 4-(2-{[4-chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid 15-1. MS [M+H]+: 483.9; tR=7.05 min, (method 2)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([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:5]=[CH:6][CH:7]=1.[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[S: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[S:39][C:38]=2[C:37]([C:47]2[CH:48]=[CH:49][C:50]3[N:51]([C:6]4[CH:7]=[CH:2][CH:3]=[C:4]([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:5]=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: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3sc3ccccc34)cc12
Reactant: Brc1cccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4cccc(-n5c6ccccc6c6cc(-c7cccc8c7sc7ccccc78)ccc65)c4)ccc23)cc1
Yield: 69.5 %

Procedure:
In a 100-mL three-neck flask were put 1.0 g (2.1 mmol) of 2-(3-bromophenyl)-9,10-diphenylanthracene, 0.72 g (2.1 mmol) of 3-(dibenzothiophen-4-yl)-9H-carbazole, and 0.59 g (6.2 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, 59 mg (0.10 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 5 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). The filtrate was concentrated to give a yellow solid. This solid was purified by silica gel column chromatography (developing solvent, hexane:toluene=5:1). The obtained solid was recrystallized from toluene/hexane to give 1.1 g of a yellow solid in 70% yield. The synthesis scheme of Step 2 is illustrated in (b-14).