Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl.O>[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:12][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][F:1])=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC(O)CF
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)OC(CF)CCCCCCCC)cc2)cc1
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of optically active 1-monofluoro-2-decyl alcohol (0.1 g) and triethylamine (0.06 g) in methylene chloride (10 ml) was slowly added under ice cooling a solution of 4-n-octyloxybiphenyl-4'-carboxylic acid chloride (0.22 g) in methylene chloride (10 ml). The mixture was left to stand until it reached room temperature and stirred overnight. The mixture was poured in water and extracted with methylene chloride. The solution extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. After the solution was distilled under reduced pressure to remove the solvent, purification was made by silica-gel column chromatography to obtain the titled compound (0.16 g).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].Cl[C:37](OCC)=O>>[C:3]1([CH3:37])[CH:4]=[CH:5][CH:6]=[C:1]([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27]3)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCCC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3cccc(C)c3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid m-tolylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chloroformate. 1H NMR (300 MHz, CDCl3) δ 8.65 (d, 1H), 8.35 (d, 1H), 8.27 (m, 2H), 7.70 (m, 2H), 7.60 (s, 1H), 7.52 (m, 1H), 7.28 (m, 2H), 7.02 (d, 1H), 5.10 (d, 1H), 4.07 (m, 1H), 3.58 (m, 1H), 3.23 (m, 1H), 2.90 (m, 1H), 2.50 (m, 1H), 2.14 (m, 2H), 1.57 (m, 4H), 1.21 (m, 1H), 1.04 (m, 1H), 0.89 (t, 3H); LC/MS m/z 494 (M+H)+.
Reaction SMILES: Cl.C([N:9]([C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29](=[O:39])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:28]=[C:14]12)[C:10](=O)[OH:11])C1C=CC=CC=1.[CH:42](N(C(C)C)CC)(C)C.C(Cl)(=O)C.N(C)C.CO>C(Cl)Cl>[C:10]([NH:9][C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:22])([CH3:23])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29]([NH:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[O:39])[N:28]=[C:14]12)(=[O:11])[CH3:42]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N(Cc1ccccc1)C(=O)O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N[C@H]1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a stirred solution of benzyl((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.025 g, 0.055 mmol) and diisopropyl-ethylamine (0.175 mL, 1 mmol) in CH2Cl2 (3 mL) was added acetyl chloride (0.036 mL, 0.5 mmol). After 4 h, 2M Me2NH/methanol (1 mL) was added and stirring continued at room temperature. After 16 h, the reaction mixture was concentrated and purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0188 g, 0.038 mmol, 69% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 11.99 (1H, s), 7.56 (1 H, t, J=5.8 Hz), 7.33 (2 H, dd, J=8.5, 5.2 Hz), 7.04-7.09 (2 H, m), 6.42 (1 H, d, J=9.2 Hz), 5.52 (1 H, d, J=9.2 Hz), 5.17 (1 H, dd, J=15.4, 8.7 Hz), 4.54-4.66 (2 H, m, J=14.8, 14.6, 14.6, 6.0 Hz), 3.70 (1 H, d, J=15.3 Hz), 3.48 (3H, s, from CH3OH), 2.09 (1 H, t, J=8.1 Hz), 1.94 (3 H, s), 1.78-1.87 (1 H, m), 1.41-1.49 (1 H, m), 1.38 (3 H, s), 1.30-1.37 (1 H, m), 0.99 (3 H, s), 0.95-0.98 (1 H, m), 0.94 (3 H, s). LCMS (M+H) calcd for C24H30FN4O4: 457.23; found: 457.27. Purity: >98%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]34[CH2:23][CH:18]5[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]5)[CH2:15]3)[CH2:21]4)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:26]=1[NH2:27]>>[CH3:33][O:32][C:30]1[C:29]([O:34][CH3:35])=[CH:28][C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([C:14]45[CH2:23][CH:18]6[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]6)[CH2:15]4)[CH2:21]5)[O:11][N:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:25]([CH3:24])[CH:31]=1
Reactant: Clc1nccc(Nc2cc(C34CC5CC(CC(C5)C3)C4)on2)n1
Reactant: COc1cc(C)c(N)cc1OC
Product: COc1cc(C)c(Nc2nccc(Nc3cc(C45CC6CC(CC(C6)C4)C5)on3)n2)cc1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(5-adamantylisoxazol-3-yl)-4-pyrimidineamine and 2-methyl-4,5-dimethoxyaniline. MS (MH+)=462.2; Calc'd for C26H31N5O3— 461.57.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:17][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-5-carbaldehyde (1.0 g, 6.75 mmol) in glacial acetic acid (8 mL) was added sodium acetate (664 mg, 8.1 mmol) and bromine (0.7 ml, 13.5 mmol) at 10° C. slowly. The reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with a saturated aqueous solution of sodium thiosulfate (10 mL), washed with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. Organics were combined, dried over sodium sulfate and dried in vacuo to give the desired compound (1.4 g, 91%).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCCCC.O1CCCC1>[C:7]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:3][CH2:1][CH3:4]
Reactant: [Li]C(C)(C)C
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCCCCCCCCC)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.21 ml, 0.36 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (124.5 mg, 0.37 mmol) in tetrahydrofuran (5 ml) at 0 degrees under argon. After 5 minutes, the cooling bath was removed and lauroyl chloride (88 microliter) was added. The mixture was stirred at room temperature for 16 hours and quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 1000u silica plate; developed with 5% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[C:11]([CH2:15][C:16](OC)=[O:17])(=O)[CH2:12][CH3:13].Cl>CO>[CH2:12]([C:11]1[N:10]=[CH:8][NH:9][C:16](=[O:17])[CH:15]=1)[CH3:13]
Reactant: N=CN
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(=O)[nH]cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium methoxide (4.19 kg, 77.6 mol) and formamidine acetate (3.0 kg, 28.8 mol) in methanol (45 L) at 5°-10° C. was added slowly a solution of methyl propionylacetate (2.5 kg, 19.2 mol) in methanol (10 L) maintaining the temperature below 20° C. throughout the addition. The resulting mixture was stirred at room temperature overnight after which time the pH was adjusted to 7 by the addition of concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure to ca. 10 L in volume, diluted with water (10 L) and was extracted with 2-butanone (2×30 L). The combined organic extracts were concentrated under reduced pressure to ca. 2 L in volume and diluted with ethyl acetate (4 L). The desired product crystallised from the solution (2,4 kg, 70%) and was recrystallised from isopropanol to yield a product of m.p. 132°-134° C. Found: C,58.45; H,6.37; N,22.41; C6H8N2O requires: C,58.05; H,6.50; N,22.57%.
Reaction SMILES: [C:1]([C:3]1([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1([S:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(Sc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 252A (1.0 g, 3.1 mmol) in THF (5 mL) at 0° C. was treated dropwise with 1M LiAlH4 in THF (3 mL), warmed to room temperature, stirred for 2 hours, quenched with methanol (1 mL), treated with 1N NaOH (50 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 323(M+H)+.
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.S(N=[N+]=[N-])([N:27]=[N+:28]=[N-])(=O)=O>C(#N)C>[N+:27](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH:8]([C:13]([Cl:14])([Cl:15])[Cl:16])[CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[N-:28]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Reactant: [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 1-trichloromethyl-3-methyl-2-butenyl acetoacetate (0.575 g, 2 mmole) and triethylamine (0.404 g, 4 mmole) in 10 ml of acetonitrile was added 1 g of polymer-bound sulfonyl azide (prepared by the method of Roush, et al., loc. cit.). The mixtre was stirred overnight at room temperature and filtered. The filter cake was washed with ether, and the slurry was filtered. Solvent was removed by evaporation from the combined filtrates to give 1-trichloromethyl-3-methyl-2-butenyl 2-diazoacetoacetate (0.60 g, 96% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:13]2[C:5](=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9]C(=O)[C:7]3=[O:15])[CH2:4][CH2:3]1.[OH-:17].[Na+].OO.Cl>O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:2](=[O:1])(=[O:16])[CH2:3][CH2:4][C:5]=2[C:6]=1[C:7]([OH:15])=[O:17]
Reactant: O=C1Nc2ccc3c(c2C1=O)CCS3(=O)=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ccc2c(c1C(=O)O)CCS2(=O)=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 60.6 %

Procedure:
1.5 g (6.32 mmol) of 3,3-dioxo-1,2,3,6-tetrahydro-3λ6-thieno[3,2-e]indole-7,8-dione were introduced into a 10 ml three-neck round-bottom flask and dissolved in 6.5 ml of 1M (207.2 mmol) sodium hydroxide solution. 1.5 ml (1.32 mmol) of a 30% strength hydrogen peroxide solution were slowly added dropwise over the course of 30 minutes. The internal temperature during the addition was kept between 30-40° C. despite the exothermic reaction. After the addition was complete, the mixture was stirred at 40° C. for 1.5 h. The mixture was then cooled to RT and, after addition to a little water (about 7 ml), acidified with a 10% strength HCl to pH 1, and the precipitated solid was filtered off with suction. The latter was washed successively with water and diethyl ether and dried in vacuo overnight. 870 mg of the desired compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc(Cl)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.047 g, 0.11 mmol), ethanol (8 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane and then 1% and 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.004 g, 7%); 1H-NMR (500 MHz, DMSO-d6) 2.60 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.57 (s, 2H, NCH2), 3.63 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=9.00 Hz, 2H) and 8.01 (d, J=8.82 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.41 (m, 4H) (3,5-ArH and 2,6-ArH), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.12 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[F:8][C:9]([F:26])([F:25])[O:10][CH:11]([F:24])[C:12]([F:23])([F:22])[O:13]NCC1C=CC=CC=1.[Cl:27][C:28]1[C:29]([CH2:37][CH3:38])=[N:30][N:31]([CH3:36])[C:32]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[Cl:27][C:28]1[CH:32]=[C:7]([CH:38]=[CH:37][C:29]=1[O:13][C:12]([F:22])([F:23])[CH:11]([O:10][C:9]([F:8])([F:25])[F:26])[F:24])[CH2:6][NH:3][C:33]([C:32]1[N:31]([CH3:36])[N:30]=[C:29]([CH2:37][CH3:38])[C:28]=1[Cl:27])=[O:34]
Reactant: FC(OC(F)(F)F)C(F)(F)ONCc1ccccc1
Reactant: CCc1nn(C)c(C(=O)Cl)c1Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nn(C)c(C(=O)NCc2ccc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2)c1Cl
Temperature: 25 °C

Procedure:
A mixture consisting of 2 ml of methylene chloride, 0.11 ml of triethylamine and 250 mg of 3-chloro-4-((2-trifluoromethoxy-1,1,2-trifluoroethoxy)-benzylamine (0.77 moles) is slowly added dropwise to a solution of 166 mg (0.8 mmoles) of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride in 3 ml of methylene chloride. The solution obtained is maintained under agitation at ambient temperature for 5 hours.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]\[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].CO.Cl>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]\[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCC(=O)O)c2ccco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (402 mg, yield 93%) as colorless crystals. m.p. 131-133° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]#[CH:30])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:38]([Si](C)(C)C)=[N+:39]=[N-:40]>CO.CN(C=O)C.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]5[N:38]=[N:39][NH:40][CH:30]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nn5)cccc4c3=O)cc2)CCC1
Temperature: 100 °C
Reaction time: 3.75 h

Procedure:
A solution of {1-[4-(8-Ethynyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (34 mg, 0.069 mmol) in MeOH (0.2 mL) and DMF (1.8 mL) was treated with copper(I) iodide (1 mg, 0.003 mmol) and azido trimethylsilane (0.014 ml, 0.104 mmol). The reaction mixture was the stirred at 100° C. for 3.75 h. The resultant mixture was allowed to cool to RT, diluted with EtOAc, washed with brine. The aqueous extracts were further washed with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% EtOAc in DCM) to give the title compound. LCMS (Method G) RT=3.88 min, [M+H]+=535.
Reaction SMILES: CCN(CC)CC.[O:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][O:8][CH2:9]1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1NC1CCCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
Et3N (1.6 mL, 11.3 mmol) was added to a stirred mixture of N-(tetrahydropyran-3-yl)benzene-1,2-diamine (0.61 g, 3.17 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.78 g, 4.14 mmol), HOAt (0.56 g, 4.14 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.79 g, 4.14 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. Stirring was continued for 10 min at 0° C. then the mixture was slowly warmed to RT and stirred at RT for 3 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[2-(Tetrahydropyran-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester as a white solid (0.96 g, 70%). LCMS: RT 3.00 min [M+H]+ 364.1.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[F:19].ClC(Cl)(O[C:24](=[O:30])OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:51]=[N:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=1>C1COCC1.CN(C=O)C>[F:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH:1][C:24]([NH:41][C:42]1[CH:51]=[N:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=1)=[O:30])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cnc2ccccc2n1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cnc4ccccc4n3)c(F)c2)ccn1
Temperature: 75 °C
Yield: 27.5 %

Procedure:
To a solution of 4-[4-amino-3-(fluoro)phenoxy]-N-methylpyridine-2-carboxamide (150.0 mg, 0.57 mmol) in anhydrous THF (5.7 mL) was added triphosgene (63 mg, 0.21 mmol, 0.37 eq) and diisopropylethyl amine (0.12 mL, 0.69 mmol, 1.2 eq), and the reaction mixture was stirred at 75° C. After 3 h a solution of 2-aminoquinoxaline (83.3 mg, 0.57 mmol, 1.0 eq) in anhydrous DMF (2.8 mL) was added, and the reaction mixture was stirred at 75° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude was absorbed onto silica and purified by MPLC (biotage) eluted with 10% MeOH/EtOAc. Trituration from DCM/MeOH afforded 25.0 mg (10.1%) of the title product as a yellow solid. 1H-NMR (DMSO-d6) δ 11.75 (s, 1H), 10.75 (s, 1H), 8.89 (s, 1H), 8.79 (br q, J=5.1 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.38 (t, J=9.0 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.82 (d, J=3.9 Hz, 2H), 7.70 to 7.64 (m, 1H), 7.47 to 7.42 (m, 2H), 7.20 (dd, J=5.4, 2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H) 2.78 (d, J=4.8 Hz, 3H); TLC (100% EA), Rf=0.20; MS LC-MS [M+H]+=433), RT=2.86 min.