Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Oc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Yield: 96.6 %

Procedure:
2-Chlorobenzenesulfonic acid 3-benzyloxyphenyl ester (3.75 g, 10 mmol), as prepared in the preceding step, Pd/C (10%) (350 mg) in tetrahydrofuran (80 mL) was hydrogenated (balloon) for 3 h. The catalyst was filtered through Celite and washed with tetrahydrofuiran. The combined tetrahydrofuran solution was evaporated in vacuo and the residue was then purified by flash column chromatography (methylene chloride) to give the title compound as a colorless oil (2.75 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 6.68 (m, 3 H), 7.12 (t, 1H, J=6.5 Hz), 7.37 (t, 1 H, J=7.1 Hz), 7.60 (m, 2 H), 7.94 (dd, 1 H, J=0.6, 4.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[CH2:17](N(CC)CC)C.O1CCCC1.[P:29]([S:35][CH2:36][CH3:37])(=[S:34])(Cl)[O:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:29]([S:35][CH2:36][CH3:37])(=[S:34])([O:16][C:14]1[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([CH3:17])=[CH:8][CH:7]=3)[CH:3]=[C:2]([Br:1])[CH:15]=1)[O:30][CH2:31][CH3:32]
Reactant: Oc1cc(Br)cc2cc3ccccc3nc12
Reactant: CCOP(=S)(Cl)SCC
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=S)(Oc1cc(Br)cc2cc3ccc(C)cc3nc12)SCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-4-hydroxyacridine (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O,S-diethyl phosphorochloridodithioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O,S-diethyl O-(2-bromo-6-methylacridin-4-yl) phosphorodithioate.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1.CN(C=O)C.[C:19](O)(=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)(C)C>[C:19]([O:13][CH2:12][C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)(=[O:21])[CH3:20]
Reactant: Cc1nc2nc(CO)cc(O)n2n1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 33.06 g of 7-hydroxy-5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidine, 500 ml of DMF, 86 ml of anhydrous acetic acid and 1.5 g of p-toluenesulfonic acid was stirred in a bath at 50 ° C. for 6 hours. To an oily isopropanol to dissolve therein, and the solution was dropwise in 4 liters of ether. Precipitates were collected by filtration and dried to obtain 38.08 g of the compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:18](=O)[CH3:19])[C:16]#[N:17])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)C.C(O[CH:27](OCC)[CH2:28][NH:29][NH2:30])C.[ClH:34]>O1CCOCC1.C(OCC)(=O)C>[ClH:34].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:18]([CH3:19])=[N:30][N:29]3[CH:28]=[CH:27][NH:17][C:16]=23)=[CH:13][CH:14]=1
Reactant: CC(=O)C(C#N)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(CNN)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nn2cc[nH]c2c1-c1ccc(N)cc1

Procedure:
A mixture of 2.5 g of 2-(4-t-butoxycarbonylamino-phenyl)-3-oxobutyronitrile, 20 ml of ethanol and 1.4 g of 2,2-diethoxyethylhydrazine was heated under reflux for 2 hours. 20 ml of 4N hydrogen chloride in dioxane were added, and then the whole mixture was heated under reflux for a further 30 minutes. After the mixture had been cooled, ethyl acetate was added to precipitate crystals. These crystals were collected by filtration and recrystallized from ethanol to give 1.4 g of the title compound as pale brown plates melting at 180°-190° C.
Reaction SMILES: C([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][C:9](=[O:34])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=O)C.[CH3:35][Mg]Cl>O1CCCC1>[Si:18]([O:17][CH:15]([C@@H:14]1[C@:25]2([CH3:33])[C@H:11]([C@H:10]3[C@H:28]([CH2:27][CH2:26]2)[C@:29]2([CH3:32])[C:7]([CH2:6][CH:5]([OH:4])[CH2:31][CH2:30]2)=[CH:8][C:9]3([CH3:35])[OH:34])[CH2:12][CH2:13]1)[CH3:16])([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CCC(O)CC1=CC3(C)O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of 3-acetoxy-20-tert-butyldimethylsilyloxy-pregn-5-ene-7-one (279 gm, 0.57 mol) in tetrahydrofuran (5.6 L) was cooled to 4° C. A 3M solution of methyl magnesium chloride in tetrahydrofuran (1.037 L, 3.1 mol) was added at such a rate as to keep the temperature <0° C. The ice bath was removed and the reaction allowed to warm to room temperature overnight. The reaction was cooled in an ice bath and quenched with a 20% solution of ammonium chloride (3 L). The organic layer was removed and the aqueous layer extracted with ethyl acetate. The organic layers were combined, washed with saturated salt solution, and dried over anhydrous magnesium sulfate. The solution was filtered through a pad of anhydrous sodium sulfate and the solvent removed by rotoevaporation to yield the title compound (265.7 gm, 92.3% yield).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].C(O)[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O.[C:26]([OH:34])(=[O:33])[CH:27]([CH2:29][C:30]([OH:32])=[O:31])[OH:28].C(=O)(O)[O-].[Na+:39]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Na+:39].[C:26]([O-:34])(=[O:33])[CH:27]([CH2:29][C:30]([O-:32])=[O:31])[OH:28]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=C([O-])O
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Product: O=C([O-])CC(O)(CC(=O)O)C(=O)O
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
Process: Apply crystallized citric acid, then heat to 60° C. and wet with 36 ml of gluconic acid delta-lactone solution (10 parts of gluconic acid delta-lactone to 5 parts of water); apply malic acid, then allow sodium bicarbonate I to react to give monosodium citrate and malate and then allow sodium bicarbonate II, calcium carbonate and potassium bicarbonate to undergo partial reaction (partial conversion to the citrate). Then cover the surface with citric acid powder. Finally allow sodium carbonate to undergo partial reaction, and dry in vacuo. This effervescent base is mixed with 500 parts of aspirin and with corresponding additives.
Reaction SMILES: [PH2:1](=[O:3])[OH:2].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:16]=[C:17]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([CH:17]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH2:16][PH:1](=[O:2])[OH:3])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=[PH2]O
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 mL of chloroform and treated with triethylamine (155 g, 1.52 mol). The mixture was evaporated and transferred to a three liter flask containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsilyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g or 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28 (3:1 Hexane/EtOAc 5% TFA).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]([CH3:13])[CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:14]([Sn:18]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]I)[CH2:15][CH2:16][CH3:17].O>O1CCCC1.C(OCC)(=O)C>[CH3:13][N:9]([CH2:10][CH2:11][O:12][CH2:19][Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(CCO)C1CCCCC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCN(C)C1CCCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a mixture of sodium hydride (50%, 241 mg, 5.0 mmol) and tetrahydrofuran (20 ml) was added 2-[cyclohexyl(methyl)amino]ethanol (791 mg, 5.0 mmol) at 0° C. (external temperature). Then, the reaction mixture was stirred at 60° C. for 30 minutes. After the reaction mixture was cooled at 0° C. (external temperature), to the reaction mixture was added dropwise a solution of tributyl-iodomethyl-tin (2.2 g, 5.0 mmol) in tetrahydrofuran (5 ml), and the reaction mixture was stirred at 60° C. for 1 hour. After the reaction mixture was cooled at room temperature (external temperature), water was added to stop the reaction. Ethyl acetate was added to the reaction mixture, and the organic layer was separated. After the organic layer was washed with water, an aqueous saturated sodium chloride solution, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=20:1, NH silica gel) to obtain the title compound (790.7 mg, 4.3 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([N:20]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH2:20])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)s2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)cc1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of Example 48E (1.06 g, 2.4 mmol) in ethanol (15 mL) was added hydrazine monohydrate (0.698 mL, 144 mmol). The reaction was heated at 60° C. for 45 minutes and then filtered. The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 90:8:2 dichloromethane/methanol/concentrated ammonium hydroxide to provide 746 mg of title compound (98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.62 Hz, 3H) 3.80 (s, 3H) 3.99-4.16 (m, 1H) 6.66-6.74 (m, 2H) 6.81-6.85 (m, 1H) 6.99-7.11 (m, 2H) 7.33-7.41 (m, 2H) 7.92 (s, 1H); MS (ESI) m/z 318.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:39]([N:16]1[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]2[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:18]=2[CH2:17]1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)c1ccccc1)CC2(C)C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a stirred turbid mixture of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (0.0105 g, 0.025 mmol) and Et3N (0.017 ml, 0.123 mmol) in CH2Cl2 (2 mL) was added benzoyl chloride (8.53 μl, 0.074 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-(6-benzoyl-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (0.0102 g, 77% yield) as a white powder. 1H NMR (500 MHz, CD3OD) δ ppm 6.94-7.58 (9H, m), 4.79 (1H, br. s.), 4.59 (0.5H, d, J=17.4 Hz), 4.40 (0.5H, d, J=17.7 Hz), 4.30 (0.5H, d, J=16.5Hz), 4.00 (0.5H, d, J=12.5 Hz), 3.92 (0.5H, d, J=16.5Hz), 3.77 (0.5H, d, J=12.8 Hz), 3.54-3.64 (2H, m), 1.43 (3H, d, J=19.2 Hz), 1.12-1.35 (9H, m), 0.98 (4H, br. s.), 0.94 (5H, br. s.). LCMS (M+H) calcd for C32H38FN2O4: 533.28. found: 533.4.
Reaction SMILES: [Br:1][CH:2]([C:5]1[N:6]=[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:8]2[C:9](=[O:11])[CH:10]=1)[CH2:3][CH3:4].[I:17]N1C(=O)CCC1=O>C(#N)C>[Br:1][CH:2]([C:5]1[N:6]=[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:8]2[C:9](=[O:11])[C:10]=1[I:17])[CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(Br)c1cc(=O)n2c(C)cccc2n1
Solvent: CC#N
Product: CCC(Br)c1nc2cccc(C)n2c(=O)c1I
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 2-(1-bromopropyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.46 g, 12.3 mmol) and N-iodosuccinimide (4.15 g, 18.4 mmol) in acetonitrile (100 mL) was stirred at 80° C., under nitrogen, overnight. After removal of acetonitrile in vacuum, the resulting solid was dissolved in methylene chloride, washed with water, saturated Na2S2O3, saturated sodium bicarbonate, and brine; and then the organic layers dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to provide the desired product (4.53 g, 90.4%). LCMS calculated for C12H13BrIN2O (M+H)+: m/z=406.9. Found: 407.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]1[S:10][C:9]2[S:11][C:12](=[C:14]3[S:18][C:17]([C:19]([O:21]C)=[O:20])=[CH:16][S:15]3)[S:13][C:8]=2[S:7]1.O1CCOCC1.[Li+].[OH-].Cl>CO.C1COCC1>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]1[S:7][C:8]2[S:13][C:12](=[C:14]3[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][S:15]3)[S:11][C:9]=2[S:10]1
Reactant: COC(=O)C1=CSC(=C2SC3=C(SC(=C4SC=CS4)S3)S2)S1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)C1=CSC(=C2SC3=C(SC(=C4SC=CS4)S3)S2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
10 (125 mg, 0.285 mmol) was suspended in a mixed solvent of 1,4-dioxane (50 ml), THF (50 ml), and MeOH (50 ml). The resultant mixture was charged with 2 N LiOH (28.5 ml, 57.0 mmol). The mixture was vigorously stirred for 15 hours at room temperature, then 2 N HCl (28.5 ml) was gradually added dropwise, and the mixture was adjusted to a pH of 2 to 3 by further adding 2 N HCl (2.0 ml) while checking the pH. The mixture was stirred for 20 minutes at room temperature, and then filtered using a membrane filter (H010A047A, Advantec). The filtered product was successively washed with water, methanol, and then chloroform, and dried under reduced pressure to obtain the target product Compound 1 (110 mg, 91%) as a glossy silvery-red film-like solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7]C[C@H](C(OCC)=O)C[CH2:3]1.C[Mg]Br.[CH3:16][C:17](=O)OCC.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[OH:1][C:2]([C@H:26]1[CH2:17][CH2:16][C@H:24]([OH:25])[CH2:23][CH2:22]1)([CH3:7])[CH3:3]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: C[Mg]Br
Product: CC(C)(O)[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-ethyl 4-hydroxycyclohexanecarboxylate (1 g, 5.8 mmol) in THF (50 mL) was added dropwise methylmagnesium bromide (7.7 mL, 23.2 mmol) at −78° C. The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was quenched by the addition of NH4Cl (100 mL) and extracted with EtOAc (100 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give trans-4-(2-hydroxypropan-2-yl)cyclohexanol (0.88 g, 96%) as a yellow solid.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].[CH2:37](Cl)[CH2:38]Cl.[CH3:41][N:42](C=O)C>>[CH2:37]([NH:42][C:41]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:7]([C:13]4[CH:18]=[CH:17][C:16]([C:19]5([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1)[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: ClCCCl
Reactant: CN(C)C=O
Product: CCNc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Temperature: 80 °C

Procedure:
To a microwave vial was added {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (51.2 mg, 0.106 mmol), EDC (102 mg, 0.532 mmol) and DMF (0.6 mL). The reaction mixture was heated under microwave irradiation for 5 minutes at 80° C. (high absorption). Acetic acid (0.5 mL) was added and the reaction mixture was heated under microwave irradiation for 5 minutes at 80° C. (high absorption), The resulting residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (1-{4-[3-(ethylamino)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate (3-1) as an off-white solid. HRMS (M+H)+: observed=535.2800, calculated=535.2816.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[C:7](O)[CH:8]=[CH:9][CH:10]=1.IC1C=CC([OH:21])=CC=1>>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)C#Cc1cccc(O)c1
Reactant: Oc1ccc(I)cc1
Product: C[Si](C)(C)C#Cc1ccc(O)cc1

Procedure:
4-TMSE-phenol was prepared in a similar manner as 3-TMSE-phenol, using 4-iodophenol (5.0 g) instead of 3-iodophenol. This gave 3.5 g (82% yield) of a brown oil. 1H NMR (acetone-d6, 300 MHz, ppm): 8.80 (s, 1H, Ar—OH), 7.34 (d, 2H, J=8.4 Hz, Ar—H), 6.85 (d, 2H, J=8.4 Hz, Ar—H), 0.21 (s, 9H, TMS). 13C NMR (CDCl3, 75 MHz, ppm): 156.1, 133.9, 115.6, 115.5, 105.3, 92.7, 0.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[C:33]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:33]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][NH:41][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:18])=[CH:37][CH:38]=1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(-c5ccccc5)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol) in dichloromethane (1 ml) and a drop of DMF was added oxalyl chloride (2M in dichloromethane) (72.985 μL, 0.145 mmol) at ambient temperature. Gas evolution was observed. The mixture was stirred at ambient temperature for 30 minutes. 2-(Biphenyl-4-yl)ethanamine (27.488 mg, 0.139 mmol) and triethylamine (36.992 μL, 0.265 mmol) were added and the mixture was stirred for 1 hour at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 62.5 mg of the title compound as a solid (85%).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])=[CH:12]3)=[O:7])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C)C=O>[CH3:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:19]=[CH:20][C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:3]([C:21]([F:24])([F:23])[F:22])[CH:4]=1)=[CH:17][CH:16]=2
Reactant: Cc1cc2cc(NC(=O)c3ccc(F)c(C(F)(F)F)c3)ccc2[nH]1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: Cc1cc2cc(NC(=O)c3ccc(N4CCNCC4)c(C(F)(F)F)c3)ccc2[nH]1
Temperature: 125 °C

Procedure:
Synthesis: 4-Fluoro-3-trifluoromethyl benzoyl chloride (0.42 mL, 2.77 mmol) was added to a solution of 2-methyl-1H-indol-5-ylamine (472 mg, 3.23 mmol) and triethylamine (0.42 mL, 3.01 mmol) in anhydrous dichloromethane at room temperature. The reaction mixture was stirred at room temperature for two hours then diluted with a 1:1 mixture of ethyl acetate and water (80 mL). The organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3, water, saturated NaCl and dried over anhydrous sodium sulfate. The desired 4-fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide was obtained as a purple solid in nearly quantitative yield. This material was taken onto the next step without further purification. 4-Fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide (1.02 g, 3.03 mmol) and piperazine (1.83 g, 21.21 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was heated in a sealed glass tube at 125° C. for two and a half hours. The crude mixture was then cooled to room temperature, concentrated and the residue chromatographed with 10% MeOH/CH2Cl2+2% triethylamine to afford N-(2-Methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide, the title compound (86% yield). 1H NMR (400 MHz , CD3OD) δ 8.26 (d, J=2.3 Hz, 1H), 8.18 (dd, J=8.6, 2.3 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H, 7.55 (d, J=8.6 Hz, 1H), 7.28-7.17 (m, 2H), 2.99 (s, 8H), 2.41 (s, 3H).