Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCCBr
Solvent: ClCCl
Solvent: CO
Product: O=C(CCBr)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50W×4 resin (Alfa Aesar, Ward Hill, Mass.) is washed with deionized water to remove color. A mixture of 225 gm D-mannose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50W×4 is treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction is monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction is complete after about four hours, and then allowed to cool to room temperature. The solution is filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate is stripped to an amber oil in a rotory evaporator.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=1.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2([C:31]([F:34])([F:32])[F:33])[O:1][N:2]=[C:3]([C:4]3[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[O:9])=[C:6]([CH3:20])[CH:5]=3)[CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Cc1cc(C=NO)ccc1C(=O)NCc1ccccn1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In a solution of 0.45 g of 4-hydroxyiminomethyl-2-methyl-N-(2-pyridylmethyl) benzoic acid amide in 10 ml of N,N-dimethylformamide, 0.25 g of N-chlorosuccinc acid imide was added, and stirred at 70° C. for 1 hour. Then, the reaction mixture was left and cooled to room temperature, 0.41 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.25 g of potassium hydrogen carbonate were added, and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was poured in 50 ml of ice water, extracted with ethyl acetate (60 ml×1), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:1), and 0.30 g of the aimed product was obtained as white crystal.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:29]5[CH:30]=[CH:31][C:26]([CH2:25][OH:24])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (3.0 g, 8.1 mmol), 4-(hydroxymethyl)phenylboronic acid (1.5 g, 9.7 mmol), 1 M K2CO3 (16 mL, 16 mmol), Pd-FibreCat 1007 (640 mg), and N,N-dimethylformamide (80 mL) were combined. The mixture was heated at 80° C. for 3 h. The volatiles were removed in vacuo and residue was redissolved in dichloromethane (100 mL). The organics were washed with 1N HCl (100 mL×2), then dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (1.9 g, 59%). ESI-MS m/z calc. 401.5, found 402.5 (M+1)+; retention time 3.18 minutes.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (95.5 ml) is dissolved in dichloromethane (500 ml), and thereto is added dropwise a suspension of 2-amino-5-chloropyridine (128.6 g) and triethylamine (169 ml) in dichloromethane (1000 ml) under ice-cooling. The reaction solution is warmed to room temperature and stirred for 0.5 hours. The reaction solution is concentrated under reduced pressure, and thereto is poured ice-water. The reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and treated with activated charcoal. Insoluble materials are removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in diisopropyl ether. The precipitates are collected by filtration, washed with diisopropyl ether and dried to give 2-chloro-N-(5-chloropyridin-2-yl)acetamide (153.4 g).
Reaction SMILES: [OH-].[Na+].C(OC([NH:10][C:11]1[S:12][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=2)=[CH:14][N:15]=1)=O)(C)(C)C>CO.C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:16][C:13]2[S:12][C:11]([NH2:10])=[N:15][CH:14]=2)[CH:18]=1
Reactant: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 N aqueous sodium hydroxide solution (50 mL, 50 mmol) was added dropwise to a stirred solution of 2-tert-butoxycarbonylamino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.8 g, (contaminated with bis(tert-butoxycarbonyl)amino adduct)) in a methanol-THF mixture (160 mL, 3:1). The solution was stirred at rt. for 24 h and concentrated. The residue was acidified with 2 N aqueous HCl (30 mL) and the suspension was extracted with dichloromethane-methanol mixture (120 mL, 3:1, 2×). The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo to obtain the titled compound (1.32 g, 75% overall yield from Example 1, part A) as an off-white solid. D. 5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-ylcarbamic acid 1,1-(dimethylethyl) ester
Reaction SMILES: C(O)[C@H]1[O:7][C@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].O.[OH-].[Na+].OO>>[OH:21][C@H:4]([CH2:3][OH:22])[CH2:5][C:6]([OH:8])=[O:7].[C:6]([OH:8])(=[O:7])[CH2:5][OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CO
Product: O=C(O)C[C@H](O)CO
Temperature: 70 °C

Procedure:
Maltose monohydrate (0.10 g, 0.28 mmoles) was dissolved in 0.16M sodium hydroxide solution (5 ml, 0.8 mmoles) and 30% hydrogen peroxide (40 l, 0.37 mmoles ) was added. The mixture was heated at 70° C. for 24 hours to produce (S)-3,4-dihydroxybutanoic acid and glycolic acid in the reaction mixture which can be separated by liquid chromatographic techniques if necessary or desired.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:8].[C:21]1(=[O:27])[NH:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[Cl:20][C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:27])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:8]
Reactant: O=C(NCCc1ccccc1Cl)c1cc(Br)ccc1Cl
Reactant: O=C1CCCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NCCc1ccccc1Cl)c1cc(N2CCCCC2=O)ccc1Cl
Temperature: 25 °C
Yield: 1.2 %

Procedure:
A mixture of 5-bromo-2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-benzamide (200 mg, 0.536 mmol), δ-valerolactam (106 mg, 1.07 mmol), potassium carbonate (156 mg, 1.13 mmol), dioxane (1 ml, purged with nitrogen), and copper (I) iodide (5 mg) in an oven-dried round bottom flask equipped with a reflux condenser under a nitrogen atmosphere was heated in an oil bath at 120–125° C. After 21 hours the mixture was cooled to room temperature, filtered through a pad of silica gel and concentrated under reduced pressure to give 50 mg of crude product. Purification by preparative HPLC (Shimadsu LC-8A preparative liquid chromatograph) eluting with a gradient of 0.1% aqueous formic acid in acetonitrile provided 2.5 mg of the title compound as a colorless amorphous solid. Mass Spectrum (ES+) 391.6; LC retention time=2.3 minutes (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[N+:11]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][O:2][C:1]2=[O:10])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=C1OCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1OCc2ccc([N+](=O)[O-])cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a stirred solution of 3H-Isobenzofuran-1-one (30.0 g, 0.220 mol) in H2SO4 (38 mL) was added KNO3 (28.0 g, 0.290 mol) in H2SO4 (60 mL) at 0° C. After the addition, the mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into ice and the resulting precipitate was filtered off and recrystallized from ethanol to give 6-nitroisobenzofuran-1(3H)-one (32.0 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2.1, 1H), 8.57 (dd, J=8.4, 2.1, 1H), 7.72 (d, J=8.4, 1H), 5.45 (s, 2H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1.CO>[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCC)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, ˜8 eq) of sodium hydroxide and methyl 3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, prepared in the preceding step, in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 200 mg of 3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=77-78° C.). Yield=64% over the two steps a and b.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]1[O:33][C:32]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:25]1.Cl>C(O)(C)C>[O:33]1[C:32]2[CH:31]=[CH:30][C:28]([NH:29][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4c(c3)OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 1), and 3,4-(methylenedioxy)aniline (53 mg, 0.24 mmol) in a solution of isopropanol (3.5 ml) containing 5.5M hydrogen chloride in isopropanol (42 μl) was heated for 3 hours. After cooling to ambient temperature, the reaction mixture was cooled to 0° C. and maintained at this temperature overnight. The precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give 4-(1,3-benzodioxol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (82 mg, 76%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[SH:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(N(CC)C(C)C)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=CN1CCN(CCO)CC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCC#N
Product: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 86.1 %

Procedure:
To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.90 g, 12 mmol), 2-mercaptobenzimidazole (1.50 g, 10 mmol), and N,N-diisopropylethylamine (1.80 g, 14 mmol) in propionitrile (16 mL), cyanomethyltrimethylphosphonium iodide (2.80 g, 11.5 mmol) was added under argon, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into water (100 mL), and the liquid was subjected to extraction with chloroform (100 mL×3) . The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and removing the solvent through filtration. The thus-formed crude product was crystallized from acetone-diethyl ether, thereby yielding 2.50 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 86%) as a colorless crystalline powder.
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH:29]=[C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1)[CH3:31]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:31][C:30]1([C:32]2[CH:41]=[CH:40][C:39]3[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=3[CH:33]=2)[C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH2:29]1
Reactant: COC(=O)c1ccc(I)c(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)OCC2(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C

Procedure:
A mixture of tributylamine (0.5 ml, 2.1 mmol), palladium diacetate (0.03 g, 0.2 mmol), formic acid (0.06 ml, 1.3 mmol) and methyl 4-iodo-3-[2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]-1-propenyloxy]benzoate (0.65 g, 1.3 mmol) in acetonitrile (10 ml) is heated at 60° C. for 4 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. 20 ml of water and 20 ml of ethyl ether are added. After separation of the phases by settling, the organic phase is washed twice with 20 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:37])[CH2:33][C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:34](=[O:35])[CH2:33][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:38])([F:23])[F:39])=[O:37])[C@H:7]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(F)(F)F
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2ccccc2C(F)(F)F)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 14 h

Procedure:
A solution of (1R*,3R*,4S*)-N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (47.4 mg, 0.11 mmol, see example 25b) in DMF (2 mL) was charged sequentially with N-(2-trifluoromethyl-phenyl)-malonamic acid (29.5 mg, 0.12 mmol), BOP (72 mg, 0.16 mmol), and N-methyl morpholine (60 uL, 0.54 mmol). The solution was stirred for 14 h and the reaction was partitioned between water and EtOAc. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC to afford the desired product as a white powder (presumed mono-TFA salt). MS found: (M+H)+=554.32.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:33]([O:35][CH:36]([O:43][CH2:44][CH3:45])[C:37]#[C:38][C:39]([O:41][CH3:42])=[O:40])[CH3:34]>C1COCC1.O>[CH2:44]([O:43][CH:36]([O:35][CH2:33][CH3:34])/[C:37](/[O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:11][CH:10]=1)=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])[CH3:45]
Reactant: Oc1ccc(C2CCCC2)cc1
Reactant: CCOC(C#CC(=O)OC)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a solution of 2.42 g (15 mmol) of 4-cyclopentylphenol in 50 mL of THF was added 1.12 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.73 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetate-hexane yielded 2.01 g (58%) of an oil, used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:19]#[N:20])=[CH:4][C:3]=1[NH:21][C:22]1[N:27]=[C:26]([NH:28][CH2:29][CH3:30])[C:25]2=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:24]2[N:23]=1.C1[CH2:40][O:39][CH2:38]C1.CCN(C(C)C)C(C)C.C[OH:51]>CCOC(C)=O>[Cl:1][C:2]1[C:3]([NH:21][C:22]2[N:27]=[C:26]([NH:28][CH2:29][CH3:30])[C:25]3=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:24]3[N:23]=2)=[CH:4][C:5]([C:19]#[N:20])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:18][O:17][CH2:16]2)[C:38](=[O:51])[O:39][CH3:40])[CH2:10][CH2:9]1
Reactant: CO
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CCC(NC4COC4)CC3)c2Cl)nn2c(C#N)cnc12
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Nc2cc(C#N)cc(N3CCC(N(C(=O)OC)C4COC4)CC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-((2-chloro-5-cyano-3-(4-(oxetan-3-ylamino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 363) (20 mg, 0.041 mmol) in MeOH (6 mL)/THF (3 mL) at 0° C. (ice bath) was added DIPEA (21.26 μl, 0.122 mmol) and methyl carbonochloride [(60 μl, 0.775 mmol) total 3× (20 μl, 0.258 mmol) portions]. The reaction stirred at 25° C. for 30 min and the mixture was diluted with EtOAc, washed with sat'd NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford methyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)(oxetan-3-yl)carbamate (5.8 mg).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28]C(C(O)=O)=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19].C(N(CC)CC)C>CN(C=O)C>[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19]
Reactant: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 1 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol, H. B. Gamper, M. W. Reed, T. Cox, J. S. Virosco, A. D. Adams, A. A. Gall, J. K. Scholler and R. B. Meyer, Jr. Nucleic Acids Res., 1993, Vol. 21, No.1, 145-150) was added dropwise to a solution of 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.4 g, 6.1 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.4 ml, 10 mmol) in 15 ml of anhydrous DMF. After 1 hr, the reaction mixture was concentrated under vacuum (0.2 mm). The residue was triturated with 2 ml of dry dichloromethane. Ethyl ether (50 ml) was added and the mixture was left at 0° C. overnight. The precipitate was collected by filtration on sintered glass funnel, washed first with 50% ether/CH2Cl2 (10 ml), then with ether (50 ml) and dried in vacuo. The product was obtained as a yellow solid (1.8 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.32 (s, 1H, NH), 8.13 (d, 1H, J=9 Hz, C4—H), 8.01 (m, 1H, C6F4H), 7.41 (s, 1H, C8—H), 7.26 (d, 1H, J=9 Hz, C5—H), 6.17 (s, 2H, CONH2), 3.99 (t, 2H, J=9 Hz, NCH2CH2), 3.30 (t, 2H, J=9 Hz, NCH2CH2). Anal. Calcd. for C18H11N3O3F4×2H2O: C, 50.3; H, 3.52; N, 9.7. Found; C, 50.81; H, 3.60; N, 9.95.
Reaction SMILES: CI.[Br:3][C:4]1[CH:14]=[N:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Br:3][C:4]1[CH:14]=[N:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:15])[C:6]=2[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1C(=O)COc2ncc(Br)cc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
0.16 mL (2.62 mmol) of methyl iodide is added to a suspension of 0.5 g (2.18 mol) of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, 0.24 g (1.09 mmol) of benzyltriethylammonium chloride and 0.75 g (5.46 mmol) of potassium carbonate in 25 mL of acetonitrile. The mixture is stirred for 6 hours at 60° C. After this time, a precipitate is removed by filtration. The filtrate is concentrated under reduced pressure and the resulting solid is taken up in 15 mL of dichloromethane and then washed successively with 20 ml of water, 10 mL of 0.1N hydrochloric acid solution, 10 mL of saturated sodium hydrogen carbonate solution and then 10 mL of water. After drying over sodium sulfate, the solution is finally concentrated under reduced pressure to give the expected product, which is used without further purification in the following step.