Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12.[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[C:15]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(=O)Cl
Reactant: Cc1cc(NCCO)c2[nH]ncc2n1
Product: CCCCC(=O)OCCNc1cc(C)nc2cn[nH]c12
Yield: 41 %

Procedure:
The title compound was prepared from 7-(2-hydroxyethylamino)-5-methyl-1H-pyrazolo[4,3-b]pyridine* (2.5 g) and valeryl chloride by the general method of Example 4. The product obtained was purified by column chromatography as described for Example 4 and then partitioned between ethyl acetate and water, the aqueous layer being brought to pH 9 with 10% sodium hydroxide. The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (×3). The combined organic layers were dried (anhydrous sodium sulphate) and evaporated to dryness to give a pale yellow gum which on trituration with ether and washing the resulting solid with ethyl acetate/ether gave the title compound as a pale yellow solid (1.48 g, 41%), m.p. 117°-119°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].IC1C=CC=CC=1.[OH-].[NH4+]>CS(C)=O.[Cu]I.CC(=O)OCC>[C:11]1([N:1]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:20]=1
Reactant: Oc1cccc2cccnc12
Reactant: c1cnc2cc[nH]c2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Solvent: CS(C)=O
Product: c1ccc(-n2ccc3ncccc32)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 188.4 %

Procedure:
To a mixture of 4-azaindole (1.20 g, 10.2 mmol), copper(I) iodide (290 mg, 1.53 mmol), 8-hydroxyquinoline (221 mg, 1.53 mmol) and potassium carbonate (1.55 g, 11.2 mmol) in DMSO (24 ml) was added iodobenzene (1.25 ml, 11.2 mmol). The reaction mixture was stirred at 130° C. for 3 h. The mixture was then cooled to room temperature and a solution of ammonium hydroxide (10% in water) and EA were added. The organic layer was separated, washed twice with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography on silica gel (EA/HEP) gave 560 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:34][CH2:33]4)=[N:21][N:22]3[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH2:25]([N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:24]=2)[C:20]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]2)=[N:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccccc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(c2nn(Cc3ccccc3)c3cc(/C=C/C4CCNCC4)ccc23)CC1
Reaction time: 18 h

Procedure:
4-{2-[1-Benzyl-3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl]-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1carboxylic acid tert-butyl ester (95 mg, 0.154 mmol) was treated with trifluoroacetic acid (2 ml) and the mixture stirred under nitrogen for 18 h. The solution was concentrated in vacuo and the residue dried in vacuo for 1 h. The resulting yellow gum was saturated with dry diethyl ether (5 ml); the supernatant was decanted off and the solid was washed with ether (5 ml) and dried in vacuo at 60° for 18 h to give the title compound (94 mg) as a pale yellow solid (94 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[N:35]=[C:34](CN)[CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[N:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CN1CCC(Oc2cccc(CN)n2)CC1
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CN1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (1.39 g, 4.29 mmol) and 1-{6-[(1-methylpiperidin-4-yl)oxy]pyridin-2-yl}methanamine (0.950 g, 4.29 mmol, from step b above) were mixed with 4 g of phenol and heated to 130° C. on an oil bath for 1 h. When the mixture had cooled down it was diluted with 150 mL of diethyl ether. The mixture became opaque and left overnight. Very little had precipitated but when evaporation of ether was commenced much precipitate was formed and filtered off. The material was recrystallized from ethanol, filtered, washed with ethanol and dried to give 0.675 g (32%) of the desired compound. Mp 202-203° C. 1H NMR (600 MHz, CD3OD) δ 8.43 (s, 1H), 7.75 (m, 2H), 7.65 (s, 1H), 7.60 (t, 1H), 7.45 (m, 2H), 6.95 (d, 1H), 6.55 (d, 1H), 5.30 (s, 2H), 4.55 (br, 1H), 2.52 (m, 2H), 2.05 (s, 3H), 1.84 (m, 2H), 1.70 (m, 2H), 1.51 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 162.7, 157.9, 157.0, 151.9, 151.6, 149.1, 140.1, 135.9, 131.7, 129.7, 127.9, 123.0, 121.1, 115.7, 111.2, 51.4, 50.3, 44.6, 28.7, 22.1. MS (ESI+) 467/469 (M+1H+).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][C@@H:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:18]1([NH:17][C:11]([C@@H:10]2[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]2)=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of N-Boc-(R)-nipecotic acid 25 (4.00 g, 17.5 mmol) and aniline (1.67 mL, 1.05 eq.) in 30 mL of dry CH2Cl2 was added DCC (4.88 g, 1.05 eq.) in one portion at 0° C. The mixture was stirred at room temperature for 4 hours. Filtration and removal of the solvent gave an oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford (R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 as a colorless oil (5.26 g, 99%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])/[C:11](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Cl.C(N(CC)CCCN=C=NCC)C.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH2:61]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])/[C:11](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:61][O:60][CH:55]2[CH2:56][CH2:57][CH2:58][CH2:59][O:54]2)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
(E)-8-(3-(1H-imidazol-1-yl)propylamino)-7-((naphthalen-1-yloxy)-methyl)-8-oxo-6-octenoic acid (286 mg, 0.65 mM) obtained in Example (2-1-2) was dissolved in dimethylformamide (3 ml), and triethylamine (136 μl, 0.98 mM) was added thereto. Then, the resulting mixture was cooled to 0° C., and to the mixture, N-hydroxy-6-trifluorobenzotriazole (144 mg, 0.72 mM), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (162 mg, 0.85 mM) and tetrahydropyranyloxyamine (114 mg, 0.98 mM) were added and stirred at room temperature for 18 hrs. After the completion of reaction, ice water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 220 mg of the title compound (yield 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:6])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCN2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(=O)N(Cc1ccccc1)c1c([N+](=O)[O-])ccc2c1CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of the product from Example 87 (0.58 g, 2 mmol), benzylbromide (0.41 g, 2.4 mmol) and cesium carbonate (0.78 g, 2.4 mmol) in 10 mL of acetonitrile was stirred at room temperature for 2 hours. The triethylamine hydrobromide was removed by filtration and the filtrate evaporated. The residue was purified by silica gel chromatography (2:1 heptane:ethyl acetate as eluant) to give the title compound as a yellow solid (0.7 g, 91% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.C(O[C:38](=[O:40])[CH3:39])(=O)C>ClCCl.C1COCC1>[OH:40][CH2:38][CH2:39][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (30 mg, 0.07 mmol, Example 26a) was dissolved in dichloromethane (1 mL) and THF (1 mL). Acetic anhydride (6.61 μL, 0.07 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated under reduced pressure, the crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (5.9 mg, 17.91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a solution of methyl 4-[(3,4-dichlorobenzyl)oxy]benzoate (Preparation 8, 750 mg; 2.41 mmol) in tetrahydrofuran (12 mL) was added an aqueous solution of lithium hydroxide (2 M, 6 mL, 12 mmol) and the reaction stirred at reflux for 4 hours. Upon consumption of starting material the reaction mixture cooled to room temperature and solvent removed in vacuo. The resulting residue was dissolved in water (15 mL) and acidified with 2M hydrochloric acid solution. The aqueous phase was then extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound (620 mg, 87%) as a white solid.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1>[OH:14][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COP([O-])OC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)[C@H](O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The solution of the Al--Li--(R)-binaphthol complex (hereinafter abbreviated as ALB) obtained in Example 1 in tetrahydrofuran (0.1M, 0.36 ml) was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C. After it was maintained at this temperature for 15 minutes, benzaldehyde (0.48 mmol) was added thereto. After reacting for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2 SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxyphenylmethylphosphonate as a final product in a yield of 95%. The chemical reaction in this Example is shown in chemical formula 26.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[O:24])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:35][S-:36].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[O:24])=[C:4]([S:36][CH3:35])[N:3]=1
Reactant: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a round bottom flask is added 2-(2-amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (80.0 mg, 0.21 mmol, 1.0 eq.), THF (5.0 mL), and DIEA (0.036 mL, 0.21 mmol, 1.0 eq.). The flask was then cooled to 0° C. before adding sodium thiomethoxide (16.0 mg, 0.23 mmol, 1.1 eq.). The reaction was warmed to RT and stirred for 3 hrs before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give pure 2-(2-amino-5-formyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (75.0 mg, 92%). LC/MSD (HP Series 1100 MSD): Expected MW: 385, Observed M+H, 386.1, Retention time: 1.58 min. ANALYTICAL HPLC: >95%, Retention time: 4.30 min (8 minute run). 1H-NMR (d6-DMSO): 10.48 (s, 1H), 9.98 (s, 1H), 9.35 (t, 1H), 8.10 (s, 1H), 7.80 (d, 1H), 7.59 (t, 1H), 7.41 (m, 2H), 7.25 (br s, 1H), 4.25 (d, 2H), (3 thiomethyl protons are buried under DMSO peak) ppm. 1H-NMR (d-MeOH): 10.0 (s, 1H), 8.00 (s, 1H), 7.78 (d, 1H), 7.50 (t, 1H), 7.39 (d, 1H), 4.33 (s, 2H), 2.51 (s, 3H) ppm.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:16]1[CH:15]=[C:14]([C:13]2[O:26][C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccccn3)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Yield: 20 %

Procedure:
Methyl 2-hydroxy-3-(3-(pyridin-2-yl)benzamido)benzoate (1.4 g, 4 mmol) and 4-methylbenzenesulfonic acid (1.9 g, 10 mmol) were added to toluene (30 mL) and the mixture was stirred under reflux for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 10:1). 264 mg of methyl 2-(3-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate as a solid was obtained, yield: 20%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Br[CH:31]([CH3:34])[C:32]#[N:33]>>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:31]([CH3:34])[C:32]#[N:33])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(Br)C#N
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3C(C)C#N)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2) and 2-bromopropionitrile. The desired product was obtained in a yield of 20% as a light yellow foam. MS (m/e): 473.6 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]([OH:24])([CH2:11][C:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13])[C:7]([F:10])([F:9])[F:8].B1([C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.[OH-].[NH4+]>[F:10][C:7]([F:8])([F:9])[C:6]([CH2:5][C:4]1[CH:25]=[CH:26][CH:27]=[C:2]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:3]=1)([OH:24])[CH2:11][C:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:13])[CH3:14]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(Br)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(-c2cccnc2)c1)C(F)(F)F
Yield: 73.1 %

Procedure:
A mixture of 50 mg (0.11 mmol) of 2-(3-bromobenzyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol, 98 mg (0.60 mmol) of pyridine-3-boronic acid 1,3-propanediol cyclic ester, and 28 mg (0.02 mmol) of Pd[P(Ph)3]4 in 4 mL of toluene, 2 mL of EtOH, and 1 mL of 2 M aqueous sodium carbonate was warmed to reflux for 20 hours. The reaction mixture was then cooled and diluted with 5 mL of 12% aqueous ammonium hydroxide and extracted with three 5 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using hexanes with a few drops of dichloromethane to load the sample and then eluted with EtOAc-hexanes (1:99, then 3:97, then 1:9) to afford 36 mg (72%) of a white solid. Recrystallization from ether/hexanes gave 28 mg of the title compound as a crystalline material, m.p. 148° C.-150° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1.C1([C@@H](N)C)C=CC=CC=1>>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: CCCCCC(C(=O)O)c1cccc2c1OCO2
Agent: C[C@H](N)c1ccccc1
Product: CCCCC[C@@H](C(=O)O)c1cccc2c1OCO2

Procedure:
A salt obtianed from (±)-2-(2, 3-methylenedioxyphenyl) heptanoic acid and (S) -1phenylethylamine was three times recrystallized from a mixed solvent of ethyl acetate-heptane (1:9). This salt was treated with hydrochloric acid and extracted with ethylene chloride. The organic layer was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and the solvent evaporated to give (R )-(2, 3-methylenedioxyphenyl) heptanoic acid. Yield, 39%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1c(-c2cccnc2)[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.50 ml) is added dropwise to a solution of 7.5 g 3-(2-hydroxyethyl)-2-(3-pyridyl)-indole and 10.0 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride and the extract is washed with saturated sodium bicarbonate solution, dried over MgSO4 and evaporated in vacuo to give 3-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-indole.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[S:6](=[O:9])([OH:8])[O-:7].[Na+:10]>>[Na+:10].[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:6]([O-:9])(=[O:8])=[O:7]
Reactant: O=S([O-])O
Reactant: ClCC1CO1
Agent: [Na+]
Product: O=S(=O)([O-])CC(O)CCl
Temperature: 80 °C

Procedure:
Epichlorohydrin (one mole, 93 g) is slowly added to an aqueous solution of one mole sodium bisulfite (104 g in about 120 ml water) while maintaining the temperature at about 80° C. The epichlorohydrin is added dropwise over about three hours, and after addition is complete, the mixture is stirred for an additional hour. After the mixture cools to about 20° C., the solids of 3-chloro-2hydroxypropylsulfonic acid sodium salt formed from the reaction are filtered and analyzed by Nuclear Magnetic Resonance (NMR). The ISC spectra shows peaks at 69.99 ppm, 56.97 ppm, and 51.18 ppm from TMS (tetramethyl silane) and the proton spectrum shows, three groups of peaks centering at 2.95, 3.58 and 4.17 ppm (from TMS), in a 2:2:1 ratio respectively, consistent with the structure of CHPS.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:33][S:30]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:22]=1[CH:4]1[N:3]([S:37]([CH3:36])(=[O:39])=[O:38])[C:2](=[O:1])[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]1=2)[C:26]#[N:27])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2ccnc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.6, 150 mg, 0.32 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 35 mg, 0.88 mmol) in tetrahydrofuran (8.0 mL). After 10 min methanesulfonyl chloride (49 μL, 0.63 mmol) is added and the mixture is heated at 50° C. for 1.5 h. The mixture is cooled at room temperature and treated with water (1 mL). The mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (first purification: Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]+=555; Retention time HPLC: 0.90 min (Z011_S03).