Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11]Br)[CH2:8][CH2:9][F:10])[CH3:2].[P:17]([O:26]C(C)C)([O:22][CH:23]([CH3:25])[CH3:24])[O:18][CH:19]([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11][P:17]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCF)NC=O
Product: CCOC(=O)C(C=C(CCF)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
1.43 g (4.82 mmol) of 4-bromomethyl-6-flouro-2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml (19 mmol) of triisopropyl phosphite (96%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.C(O)(=O)C.[NH:41]1[CH2:44][CH:43]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:42]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:41]2[CH2:44][CH:43]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])[CH2:42]2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)N2CC(NC(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 88.8 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (711 mg) and tert-butyl 3-azetidinylcarbamate acetic acid salt (418 mg) in methylene chloride (8 ml) was added N-ethyldiisopropylamine (0.62 ml), and the mixture was stirred under reflux for 16 hours. To the reaction mixture was added methylene chloride, and the solution was washed successively with 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of ethyl acetate and hexane to give tert-butyl [1-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-azetidinyl]carbamate (735 mg) as a solid;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][N:34]2S(C2C=CC(OC)=CC=2)(=O)=O)=[CH:30][CH:29]=1.Cl.N1C=CC=CC=1.O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)n2ncc3ccc(-c4c(N)ncnc4N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)cc32)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cn[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 180 °C
Yield: 20.9 %

Procedure:
(S)-2-(1-((6-amino-5-(1-((4-methoxyphenyl)sulfonyl)-1H-indazol-6-yl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (77 mg, 0.12 mmol) was treated with pyridine hydrochloride (2.7 g, 115 mmol) and heated at 180° C. for 2 h. Water and ethyl acetate were added and the organic phase was washed with water and brine and then concentrated. The residue was purified using SP1® Purification System (0% to 75%, hexane-ethyl acetate) to obtain 12 mg (22% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[N:29]=[C:30]([CH2:33][NH:34][CH2:35][CH:36](C)[CH3:37])[S:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].CC(C)CN>>[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[N:29]=[C:30]([CH2:33][N:34]5[CH2:2][CH2:37][CH2:36][CH2:35]5)[S:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNCC(C)C)n4)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(C)CN
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)n4)cc23)CC1
Yield: 50 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (74 mg, 0.3 mmol) for 2-methyl-1-propanamine to afford 6.3 mg of the title compound (50%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[CH:11][N:10]=[CH:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[CH:11][N:10]=[CH:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cncn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Solvent: c1ccncc1
Product: Cc1cncn1-c1ccc(N2C[C@H](COS(C)(=O)=O)OC2=O)cc1F
Reaction time: 18 h
Yield: 62.2 %

Procedure:
3-(3-Fluoro-4-(5-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (0.86 g, 2.96 mmol) was stirred in a mixture of pyridine (30 ml) and triethylaminc (0.36 g, 3.55 mmol) under nitrogen in an ice-bath. Methanesulfonyl chloride (0.37 g, 3.26 mmol) was added dropwise, and the mixture stirrd for 18 hours, allowing the temperature to rise to ambient. Solvent was evaporated. and the residue dissolved in dichloromethane (50 ml), and washed with aqueous sodium bicarbonate (5%, 25 ml), water (2×25 ml), brine (20 ml), and dried (magnesium sulfate). The residue after evaporation was triturated with diethyl ether to give the title product (0.68 g).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]([CH3:19])([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([Si:5]([CH3:20])([CH3:21])[O:6][CH2:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)([CH3:19])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A mixture of tert-butyl-dimethyl-[2-methyl-2-(4-nitro-phenyl)-propoxy]-silane (as prepared in the previous step, 1.70 g, 5.49 mmol) and 10% Pd/C (850 mg, 50 wt %) in 30 mL of EtOAc was stirred at RT under H2 (balloon pressure) for 6 h. The Pd catalyst was removed by filtration on Celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (5-10% EtOAc/DCM) to give 1.43 g (93%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C16H29NOSi, 280.2 (M+H). found 280.4.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15](C(C)(C)C)[C:16]([NH2:18])=[O:17])=[CH:11][N:10]=[C:9]2[CH3:23])=[CH:5][C:4]=1[F:26])#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[O:17])=[CH:11][N:10]=[C:9]2[CH3:23])=[CH:5][C:4]=1[F:26])#[N:2]
Reactant: Cc1ncc(CCN(C(N)=O)C(C)(C)C)n1Cc1ccc(C#N)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(CCNC(N)=O)n1Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
{2-[3-(4-cyano-3-fluoro-benzyl)-2-methyl-3H-imidazol-4-yl]-ethyl}-tert-butyl urea (as described above in Step A) (0.41 g) was dissolved in TFA/CH2Cl2 3:1 (5.0 mL) and stirred at ambient temperature for 72 hr. The solvents were removed in vacuo to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O)(C)C>O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: C1COCCN1
Solvent: O
Solvent: CC(C)O
Product: N#Cc1ccc2nc(N3CCOCC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 79.8 %

Procedure:
A mixture comprising 338 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 435 mg of morpholine and 20 ml of isopropyl alcohol was heated under reflux for 3 hours, followed by the addition of 30 ml of water under heating. The precipitate thus formed was recovered by filtration and washed with 30 ml of water and 30 ml of ethyl acetate. Thus, 310 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:35])[CH:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21](=[O:27])[C:20]3=[O:28])=[O:18])[C:11](=[O:36])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[K+].[I-].[Na+].Br[CH2:52][C:53]1[CH:62]=[CH:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1>C(OCC)(=O)C.O.CC(C)=O.CN(C)C=O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:35])[CH:15]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21](=[O:27])[C:20]3=[O:28])=[O:18])[C:11](=[O:36])[N:6]2[C:7]=1[C:8]([O:10][CH2:52][C:53]1[CH:62]=[CH:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1)=[O:9]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(C)CS[C@H]23)c2ccccc2)C(=O)C1=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)=C(C)CS[C@H]23)c2ccccc2)C(=O)C1=O
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
3-Methyl-7-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]ceph-3-em-4-carboxylic acid (4.48 g., 8.7 mmoles) was dissolved in 30 ml. of dimethylformamide. Triethylamine (8.79 mg., 8.7 mmoles) was added and the mixture stirred for 30 minutes. Potassium bicarbonate (1.74 g., 17.4 mmoles) was added and stirring continued for 1 hour. Finally sodium iodide (1.3 g., 8.7 mmoles) and 2-(bromomethyl)naphthalene (2.11 g., 9.6 mmoles) were added (a slight exotherm was noted), and the mixture allowed to stir about 16 hours at room temperature. Since tlc (9:1 acetone:water) monitoring of the reaction mixture over the next 8 hours indicated that reaction had ceased prior to complete conversion to the ester, one-tenth quantities of potassium bicarbonate, sodium iodide and 2-(bromomethyl)naphthalene were added and the reaction allowed to proceed for a further 16 hours. The reaction mixture was diluted with 1:1 ethyl acetate:water, and the organic layer was separated and back-washed several times with water. The organic phase was layered with fresh water, the pH lowered to 2.5, and the organic layer separated, washed with several portions of water, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to yield 2-naphthylmethyl 3-methyl-7-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]ceph-3-em-4-carboxylate [4.8 g., 84%; Rf 0.39 (ethyl acetate)].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Cl[C:43]1[N:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]=1>C1COCC1.C(Cl)Cl.[NH4+].[Cl-].C(OCC)C>[N:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:51]=[N:52][C:43]=1[O:17][CH2:16][C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:12][CH:11]=[CH:10][N:9]2[CH:13]=1
Reactant: OCc1cn2ccnc(N3CCOCC3)c2n1
Reactant: Clc1ncc2ccccc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc2nc(OCc3cn4ccnc(N5CCOCC5)c4n3)ncc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 1d (600.0 mg, 2.50 mmol) in THF (10 mL) was added 18-crown-6 (677 mg, 2.60 mmol), followed by potassium tert-butoxide (575 mg, 5.12 mmol). The reaction mixture was stirred at rt for 10 min and treated with 2-chloroquinazoline (632 mg, 3.84 mmol). The resulting mixture was stirred for 10 more min at rt and then at 120° C. for 1 h. The reaction mixture was then allowed to cool to rt, diluted with 20 mL of DCM and 20 mL of saturated aqueous NH4Cl. The organic layer was separated, dried over Na2SO4, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (1:0-4:1 DCM/EtOAc) to obtain a white solid. The solid was then suspended in diethyl ether (50 mL) and sonicated for 5 min, before collecting by filtration to yield compound 22a. Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H18N6O2: 363.1 (M+H). Found 363.1.
Reaction SMILES: C([NH+](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=S)[SH:17])=[C:11]([F:19])[CH:10]=1.[OH-].[Na+].[N-:22]=[N+:23]=[N-:24].[Na+].Cl>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16](=[S:17])[NH:24][N:23]=[N:22]2)=[C:11]([F:19])[CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(Cl)ccc1NC(=S)S
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Fc1cc(Cl)ccc1-n1nn[nH]c1=S
Temperature: 25 °C

Procedure:
A stirred mixture of 5.0 g (0.016 mole) of the triethylammonium salt of 4-chloro-2-fluorophenyl dithiocarbamic acid, 0.62 g (0.016 mole) of sodium hydroxide, and 4.0 g (0.062 mole) of sodium azide in 10 ml of water was heated at reflux for three hours. The mixture was cooled to room temperature and was acidified with concentrated hydrochloric acid. A precipitate formed and was collected by filtration. The filter cake was washed with water and was dried to yield 3.2 g of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-thione, m.p. 128° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[Li][CH2:18][CH2:19][CH2:20]C.CN1C(=O)N(C)CCC1.C(Br)C=C>C1COCC1>[CH2:20]([O:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:19]=[CH2:18]
Reactant: [Li]CCCC
Reactant: O=C(N[C@@H](CO)c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CN1CCCN(C)C1=O
Product: C=CCOC[C@H](NC(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Step Q (2): (R)-2,2,2-Trifluoro-N-(2-hydroxy-1-phenylethyl)acetamide from step Q (1) (3.34 g, 14.3 mmol) was dissolved in THF (30 mL) and chilled to −78° C. n-BuLi (12 mL, 29 mmol, 2.5 M in hexanes) and DMPU (3.45 mL, 29 mmol) were added to the mixture. After 10 min, allyl bromide (12 mL, 143 mmol) was added. The mixture was warmed to rt and then heated to reflux for 16 h. The mixture was quenched with saturated NH4Cl, diluted with 1 N NaOH, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica-gel column chromatography (0-25% EtOAc/Hexanes) afforded 2.88 g (73% yield) of (R)-N-(2-(allyloxy)-1-phenylethyl)-2,2,2-trifluoroacetamide as a yellow residue. LC-MS (M+H)+=274.06. 1H NMR (300 MHz, CDCl3) δ ppm 3.66-3.79 (m, 2H) 3.95-4.01 (m, 2H) 5.07-5.26 (m, 3H) 5.73-5.89 (m, 1H) 6.95-7.06 (m, 1H) 7.24-7.37 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([OH:3])=[O:2].[CH:14]([NH2:16])=O>>[C:1]([C:4]1[CH:5]=[C:6]2[C:7]([C:8](=[O:9])[NH:16][CH:14]=[N:13]2)=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: NC=O
Product: O=C(O)c1ccc2c(=O)[nH]cnc2c1

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, 4-carboxyanthranilic acid (14.2 g) was reacted with formamide to give 7-carboxyquinazolin-4-one (8.5 g). A mixture of a portion (4 g) of the material so obtained, methanol (40 ml) and concentrated sulphuric acid (2 ml) was stirred and heated to reflux for 6 hours. The mixture was cooled to ambient temperature and the precipitate was isolated. There was thus obtained 7-methoxycarbonylquinazolin-4-one (5.7 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].Br[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].[CH:17]1[CH:22]=[C:21]([CH:23]([NH2:27])[C:24]([OH:26])=[O:25])[C:20]([F:28])=[CH:19][CH:18]=1.Cl>CN(C)C(=O)C.[Cu]>[C:12]([C:11]1[CH:10]=[C:9]([NH:27][CH:23]([C:21]2[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=2[F:28])[C:24]([OH:26])=[O:25])[CH:16]=[CH:15][CH:14]=1)#[N:13]
Reactant: NC(C(=O)O)c1ccccc1F
Reactant: N#Cc1cccc(Br)c1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(NC(C(=O)O)c2ccccc2F)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
6.5 g (47.0 mmol) of potassium carbonate and 597 mg (3.10 mmol) of copper(l) iodide are added to a solution of 5.70 g (31.3 mmol) of 3-bromobenzonitrile and 5.30 g (31.3 mmol) of 2-fluoro-dl-alpha-phenylglycine in 30 ml of N,N-dimethylacetamide, and the mixture is stirred at 90° C. for 48 hours. The reaction mixture is then poured into 80 ml of 1N HCl and extracted twice with diethyl ether. The combined organic phases are extracted twice with 50 ml of 1N NaOH each time. The two basic aqueous phases are combined, acidified using 25% HCl and extracted twice with 80 ml of diethyl ether each time. These two organic phases are combined, dried using sodium sulfate and subsequently evaporated, giving (3-cyanophenylamino)-2-fluorophenylacetic acid as a yellowish solid; ESI 270.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C>O>[Cl:1][C:2]1[N:9]=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(F)cnc1Cl
Yield: 51.2 %

Procedure:
Into a 50 mL round bottomed flask, 2,6-dichloro-5-fluoronicotinonitrile (1 g), acetic acid (5 mL) and water (0.5 mL) were charged, and reacted and post-treated in the same manner as in Example 1 and then purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to obtain the title compound (420 mg, yield: 52%). As a result of the HPLC analysis, the purity was 100%.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:55][C:56]1[CH:57]=[N:58][C:59]([C:62]2[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=2)=[N:60][CH:61]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>O>[CH2:49]([O:55][C:56]1[CH:61]=[N:60][C:59]([C:62]2[CH:63]=[CH:64][C:65]([O:68][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:66][CH:67]=2)=[N:58][CH:57]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.42 g, 11.4 mmol, Example 24) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.0 mmol). Product was isolated by addition of water (100 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 170-180° C. at 2.0 torr; yield of 5.4 g).
Reaction SMILES: [CH2:1]([C@H:4]1[N:9]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:8][CH2:7][NH:6][C:5]1=[O:20])[C:2]#[CH:3].[N:21]([CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=[N+:22]=[N-:23]>O1CCOCC1.CC(O)(C)C.O.CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[O:20]=[C:5]1[NH:6][CH2:7][CH2:8][N:9]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@@H:4]1[CH2:1][C:2]1[N:23]=[N:22][N:21]([CH2:24][CH2:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH:3]=1
Reactant: N#Cc1ccc(CCN=[N+]=[N-])cc1
Reactant: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2Cc2cn(CCc3ccc(C#N)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(prop-2-ynyl)-4-tosylpiperazin-2-one (292 mg, 1 mmol) and 4-(2-azidoethyl)benzonitrile (172 mg, 1 mmol) in dioxane (3 mL) and t-BuOH (4 mL) was added a solution of copper(2+) sulfate, pentahydrate (249 mg, 1 mmol) in 0.5 mL of water, followed with a solution of (+)-sodium 1-ascorbate (198 mg, 1 mmol) in 0.5 mL of water. The resulting solution was stirred at room temperature for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, and evaporated to dryness. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:10 to 100:15) afforded the title compound as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5].[Br:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>CN(C=O)C>[Br:16][CH2:17][CH2:18][NH:19][C:20]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5])=[O:21]
Reactant: O=C=NCCBr
Reactant: NCCC(=O)NC(=O)c1ccccc1S
Solvent: CN(C)C=O
Product: NCCC(=O)NC(=O)c1ccccc1SC(=O)NCCBr
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of N-(2-mercaptobenzoyl)-β-alaninamide (0.90 g, 4.0 mmol) in DMF (20 ml) was added 2-bromoethyl isocyanate (0.91 g, 6.0 mmol). The reaction mixture was stirred for 6 h. The solvent was evaporated to dryness, and the residue was treated with ethyl ether (20 ml) with vigorous stirring. The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield: 87%. 1H NMR (DMSO-d6): 2.36(t, 2H, CH2), 3.42(q, 2H, CH2), 3.54(s, 4H, 2CH2), 6.88(brs, 1H, NH2), 7.36-7.66(m, 5H, Ar—H, NH2), 8.26(t, 1H, NH), 8.66(brs, 1H, NH).