Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([OH:9])[CH:6]([CH3:8])[CH3:7].C>[Pd].C1COCC1.CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@@:5]([OH:9])([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)CC(O)(CCc1ccc(OCc2ccccc2)cc1)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C[C@@](O)(CCc1ccc(O)cc1)C(C)C

Procedure:
The title compound was prepared as described in General Method 4 using 3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid methyl ester (8.6 g, 24.2 mmol) from Example SSSS. Three grams of 20% Pd over charcoal and THF:MeOH 1:1 (100 mL). The crude compound was recrystallized from hexanes-ethyl acetate to give racemic title compound (m.p. 89-91° C.). The title compound was obtained by resolution on a semi-preparative Chiralcel OD column eluting with 90% hexanes, 10% isopropanol and 0.1% trifluoroacetic acid. 1H-NMR (CDCl3) δ 0.93 (d, 3H), 0.95 (d, 3H), 1.68-1.85 (m, 2H), 1.93 (m, 1H), 2.53 (dd, 2H), 2.62 (m, 2H), 3.63 (br s, 1H), 3.71 (s, 3H), 4.97 (br s, 1H), 6.73 (d, 2H), 7.03 (d, 2H).
Reaction SMILES: O1CCCC1.C([Sn](CCCC)(CCCC)[C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1)CCC.[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[I:39][C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Ic1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a tetrahydrofuran solution (15 mL) of 2-(4-(5-tributylstannyl-isoxazol-3-ylmethyl)-benzyloxy)-pyridine (5.1 g) described in Manufacturing Example 1-8-1 was added iodine (2.5 g) at 0° C. This mixture was stirred at that temperature for 20 minutes. To the mixture were then added 10% sodium thiosulfate aqueous solution and ethyl acetate. The organic layer was isolated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1 to 4:1) to obtain the title compound (2.4 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2(O)[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(O)[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:46]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:26]2[C:27]3[C:32]([C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:20]4[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]4)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: OC1(c2ccccc2-c2ccccc2-c2ccccc2)c2ccccc2C(O)(c2ccccc2-c2ccccc2-c2ccccc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2ccccc2-c2ccccc2-c2c3ccccc3c(-c3ccccc3-c3ccccc3-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
9, 10-bis(2-(2-Phenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (2.9 g, 4.3 mmole) was suspended in acetic acid (45 ml). To the resultant suspension, a 57% hydroiodic acid (6 ml, 45 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (2.4 g, 88%) was obtained.
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].[C:6]([Cl:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>C1(C)C=CC=CC=1>[ClH:11].[CH3:9][C:7](=[CH2:8])[C:6]([O:3][CH2:2][CH2:4][NH2:5])=[O:10]
Reactant: NCCO
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCN
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
In a 500 mL three-neck flask equipped with a thermometer and a reflux condenser were placed 300 g of toluene and 60.0 g (0.62 mol) of ethanolamine hydrochloride, followed by heating to 110° C. with stirring. After the inner temperature reached 110° C., 77.1 g (0.74 mol) of methacryloyl chloride was added dropwise thereto over a period of 30 minutes. After completion of the dropwise addition, the mixture was continued to stir for further 3 hours and then cooled to 0° C. with stirring. The precipitated solid was collected by filtration and then the resulting solid was washed with 300 g of diisopropyl ether. The solid was collected by filtration and then dried under reduced pressure to obtain 85.2 g of 2-aminoethyl 2-methylacrylate hydrochloride.
Reaction SMILES: F[C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].O.Cl.O1CCC[CH2:17]1>>[CH3:17][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([F:11])=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: C1CCOC1
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: O
Product: Cc1c(F)c(F)c(F)c(F)c1CO
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of methyl bromide (9.6 g) in dry tetrahydrofuran (25 cm3) was added dropwise in a stirred mixture of magnesium turnings (5.0 g), dry tetrahydrofuran (50 cm3) and a small crystal of iodine at the ambient temperature (ca. 22° C.). When the addition was complete the mixture was stirred for a further 1 hour at the ambient temperature and the solution of methyl magnesium bromide thus formed was then added dropwise to a stirred solution to pentafluorobenzyl alcohol (17.8 g) in tetrahydrofuran (50 cm3) whilst the temperature was maintained at 30° C. When the addition was complete the mixture was stirred for a further 2 hours at the ambient temperature and for 3 hours at the reflux temperature. Water at 0° C. was added to the mixture, which was then acidified with dilute hydrochloric acid and extracted with diethyl ether (2×80 cm3). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (4.6 g) was shown by gas liquid chromatographic examination of a sample to consist of ca. 70% by weight of unreacted starting material and ca. 30% by weight of product. The oil was subjected to vigorous purification by column and thin-layer chromatography using a silica gel support and eluting with a mixture of diethyl ether and hexane (3:7 by volume), to obtain 2-methyl-3,4,5,6-tetrafluorobenzyl alcohol as a colourless oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCCC)(CCCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[Li+].[Cl-]>[Cu]I.O1CCOCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Reactant: CCCCC[Sn](CCCC)(CCCCC)c1ccccn1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: c1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1
Temperature: 140 °C
Yield: 10.9 %

Procedure:
To a microwave tube was added 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4 (120 mg, 0.37 mmol), 2-(butyldipentylstannyl)pyridine (168 mg, 0.45 mmol), Pd(PPh)3 (12 mg, 0.015 mmol), LiCl (48 mg, 1.14 mmol), CuI (12 mg, 0.06 mmol) and 1,4-dioxane (0.3 mL). The tube was flushed with nitrogen for 2 minutes and heated in a Biotage microwave at 140° C. for 15 minutes. The solvent was distilled off and the crude product was purified via reverse phase combiflash eluting with 10% to 80% CH3CN in aqueous 0.5% NH4OH solution to afford 204 as a pale red solid (11 mg, 11%). 1H NMR (400 MHz, DMSO) 1H NMR (500 MHz, DMSO) δ 14.0 (s, 1H), 9.30 (s, 1H), 9.25 (s, 1H), 8.97 (s, 1H), 8.81 (d, J=4.0 Hz, 1H), 8.62-8.61 (m, 1H), 8.45 (d, J=8.5 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.97-7.94 (m, 1H), 7.55-7.53 (m, 1H), 7.45-7.43 (m, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(NC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(OCC(=O)O)cc2)CC1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
To an ice-cold stirred solution of methyl [4-({[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}amino)phenoxy]acetate (Example 175, 0.240 g, 0.564 mmol) in THF (5 mL) was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 1 h the reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide [4-({[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}amino)phenoxy]acetic acid (0.228 g, 98%) as a white powder.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[C:32](=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].O>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[CH:33]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C)cc1)c1ccc(C)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccc(C)cc1)(c1ccc(C)cc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.373 g of fluorene (2.25 mmol) was dissolved in 60 ml of dehydrated diethylether in a nitrogen atmosphere. To the reaction solution, 1.6 ml of a n-butyl lithium/hexane solution (1.56M: 2.50 mmol) was gradually added dropwise in an ice bath and thereafter stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 1.10 g of 3-tert-butyl-1-methyl-6,6-di(p-tolyl)fulvene (3.36 mmol) in 60 ml of dehydrated diethyl ether was added and stirred under reflux for 10 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and thereafter the organic layer was separated by adding diethyl ether and washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate and then the drying agent was filtered off. The solvent was distilled off from the filtrate under reduced pressure to give a red brown liquid. The red brown liquid was purified by a column chromatography using 80 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The residue product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 0.140 g (0.282 mmol) as a pale yellow solid (yield: 13%).
Reaction SMILES: CC1C=CC(S([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=4)[N:23]=3)[CH:15]=[CH:16]C=2)(=O)=O)=CC=1.ClC1C=CC2N(C=C(NC(=O)C)N=2)N=1.[F:45]C1C=C(B(O)O)C=CN=1>>[F:45][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=3)[N:23]=2)[CH:15]=[CH:16][N:11]=1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Reactant: OB(O)c1ccnc(F)c1
Agent: CC(=O)Nc1cn2nc(Cl)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3ccnc(F)c3)ccc2n1

Procedure:
Following the procedure described for N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.040 g, 0.19 mmol) was reacted with 2-fluoropyridin-4-ylboronic acid (0.054 g, 0.38 mmol, Synthonix, Wake Forest, N.C.) to afford the title compound as a yellow solid. MS (ESI positive ion) m/z: 272 (M+1). 1H NMR (400 MHz, DMSO-d6): δ pp, 11.00 (s, 1H), 8.43 (d, J=5.3 Hz, 1H), 8.18 (d, J=10.0 Hz, 1H), 8.05 (t, J=1.6 Hz, 0.5H), 8.04 (t, J=1.6 Hz, 0.5H), 7.96 (d, J=9.4 Hz, 1H), 7.86 (s, 1H), 2.13 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:24])[CH2:14][N:15]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]1)(C)(C)C>C(Cl)Cl>[F:22][C:20]([F:21])([F:23])[C:18]1[CH:17]=[N:16][N:15]([CH2:14][C:13]([OH:24])=[O:12])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(C(F)(F)F)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
Trifluoroacetic acid (10 mL) was added to tert-butyl[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (Preparation 77, 1.3 g, 5.2 mmol) in dry DCM (10 mL) and the mixture was stirred for 18 hours at 25° C. Then the mixture was evaporated in vacuo and the residue was purified by trituration with diethyl ether:pentane (1:9, 2 mL) to afford the title compound as a white solid (79%, 800 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1[CH3:18].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([Cl:26])=[O:25]>C1C=CC=CC=1>[ClH:26].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])[CH2:13][C@@H:12]1[CH3:18]
Reactant: Cc1ccccc1CCCN1C[C@@H](C)NC[C@@H]1C
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: Cc1ccccc1CCCN1C[C@@H](C)N(C(=O)c2ccco2)C[C@@H]1C
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-[3-(o-methylphenyl)propyl]-2,5-dimethylpiperazine [b.p. 130° - 140°C (4 mmHg), dipicrate, 250° - 252°C], 2-furoyl chloride and benzene.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:23])[CH:7]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[CH:16]2)C(OCC)=O)C>CO>[N:19]1[C:20]2[C:15](=[CH:14][C:13]([CH2:7][C:6]([OH:23])=[O:5])=[CH:22][CH:21]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2ncncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2ncncc2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Sodium hydroxide [2M] (0.77 mL) was added to a solution of 2-quinazolin-6-yl-malonic acid diethyl ester (0.20 g, 0.77 mmol) in methanol (10 mL) and stirred at room temperature for several hours. The reaction was evaporated, ethyl acetate was added and then 1N HCl was added dropwise until the compound went into the organic layer. The organic layer was evaporated to give 0.123 g (85%) of quinazolin-6-yl -acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[N:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:33]([NH2:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(Cl)Cl>[CH2:33]([NH:35][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[N:18][N:19]=3)[N:16]=2)=[CH:10][C:2]=1[F:1])[CH3:34]
Reactant: CCN
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.02 mmol), 2.0 M of ethylamine in tetrahydrofuran (23 μL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12 mg, 0.028 mmol), and N,N-diisopropylethylamine (10.0 μL, 0.059 mmol) in methylene chloride (0.5 mL) was stirred at RT for 2 h. The solvent was evaporated. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=454.0. 1H-NMR (400 MHz, CD3OD): 1.12 (t, 3H), 1.84 (m, 2H), 2.02 (m, 2H), 3.42 (q, 2H), 7.80 (m, 2H), 7.90 (d, 2H), 7.98 (m, 1H), 8.18 (m, 2H), 8.32 (d, 1H), 9.00 (d, 1H), 9.10 (d, 1H), 9.32 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16](OC)=[O:17].O.[NH2:27][NH2:28]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:27][NH2:28])=[O:17]
Reactant: COC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1

Procedure:
A solution of methyl 3-[(2-naphthyl)methoxy]-5-nitrobenzoate (0.97 g, 2.87 mmol) and hydrazine hydrate (0.56 mL, 11.5 mmol) in MeOH (50 mL) was stirred under reflux overnight. Formation of solid hydrazide from a boiling mixture was observed in the morning. Mixture was cooled, solid filtered and air-dried. Greenish-white plates, yield 0.60 g (62%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.15 (br.s, 1H); 8.27 (s, 1H); 8.05-7.91 (m, 6H); 7.63 (d, J=7.5 Hz, 1H); 7.59-7.52 (m, 2H); 5.48 (s, 2H); 4.66 (br.s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:23])[C:16]#[C:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([CH2:33][N:34]=[N+:35]=[N-:36])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:23])[C:16]2[N:36]=[N:35][N:34]([CH2:33][C:32]3[CH:37]=[CH:38][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C#CC(O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(O)c2ccc(NC(=O)OC(C)(C)C)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 132.7 %

Procedure:
Ethyl 4-(4-t-butoxycarbonylamino-2-nitrophenyl)-4-hydroxy-2-butynoate (693 mg, 1.90 mmol) prepared in the step (a) and 4-methoxybenzylazide (776 mg, 4.76 mmol) were dissolved in toluene (30 ml), and the solution was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give a 1:1 mixture (1.33 g) of ethyl 4-((4-t-butoxycarbonylamino-2-nitrophenyl)hydroxymethyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate and ethyl 5-((4-t-butoxycarbonylamino-2-nitrophenyl)hydroxymethyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate. This mixture (1.33 g) was dissolved in methylene chloride (30 ml), active manganese dioxide (3.5 g) was added to the solution, and the mixture was stirred for 30 min. Manganese dioxide was filtered off through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give a 1:1 mixture (872 mg, 87%) of ethyl 4-(4-t-butoxycarbonylamino-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate and ethyl 5-(4-t-butoxycarbonylamino-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1O.[OH-].[Na+].C1COCC1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]3[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Oc1ccc2nc(-c3cccc(Cl)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
4.5 ml (35.2 mmol) of 3-chlorobenzoyl chloride and 1.0 g (6.19 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 170° to 235° C. for 1 hour, then the excessive acid chloride was removed by distillation. To the residue, 1.5 g (38.5 mmol) of NaOH, 20 ml of THF, 20 ml of water and 10 ml of ethanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 250 mg (1.02 mmol) of 2-(3-chlorophenyl)-6-hydroxybenzoxazole. The yield was 16.5%.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:11][CH3:12])(=[O:10])[CH3:9].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:31])=[C:18](/[C:20](=[N:24]\[S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])/[CH:21]([F:23])[F:22])[CH:19]=1>O1CCCC1.CCCCCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:31])=[C:18]([C:20]([NH:24][S@:25]([C:27]([CH3:29])([CH3:28])[CH3:30])=[O:26])([CH:21]([F:23])[F:22])[CH2:9][C:8]([O:11][CH3:12])=[O:10])[CH:19]=1
Reactant: CC(C)(C)[S@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Reactant: COC(C)=O
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)CC(N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
A solution of diisopropylamine (6.52 g, 9.19 ml, 64.5 mmol) in tetrahydrofuran (115 ml) was treated dropwise at −70° C. with n-butylithium (1.6 M in hexane) (40.3 ml, 64.5 mmol) and stirring was continued for 15 minutes at −70° C. The solution was treated with methyl acetate (4.77 g, 5.13 ml, 64.5 mmol) and after 30 minutes chlorotitanium triisopropoxide (0.85 M in tetrahydrofuran) (85.7 ml, 72.85 mmol) was added dropwise After stirring at −70° C. for 30 min., the mixture was treated with a solution of (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.9) (8.2 g, 23.0 mmol) in tetrahydrofuran (76.4 ml) and stirring was continued at −70° C. for 2 hours. For the workup, the mixture was quenched with a saturated aqueous solution of ammonium chloride (100 ml), diluted with ethyl acetate (200 ml). After filtration over Dicalite®, the organic layer was separated and washed with water and brine. The aqueous layers were re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and evaporated to give a yellow oil (11.5 g; 116%). The residue was purified by chromatography on 50 g silica gel using a gradient of ethyl acetate/heptane=0:100 to 50:50 as the eluent to give a 1:1 diastereomeric mixture of methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (7 g, 16.3 mmol, 70.7% yield) as a colorless oil. MS (ISP): m/z=430.2 [M+H]+ and 432.1 [M+2+H]+.