Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CCCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH2:20][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:17][CH:18]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C2(F)CN(C(=O)OC(C)(C)C)C2)cc1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Temperature: 60 °C

Procedure:
In a clean and dry seal tube, to a stirred solution of 3-(4-acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (4 g, 13.652 mmol, 1eq.) in heptane (40 mL) was added 1-(3,5-dichlorophenyl)-2,2,2-trifluro-ethanone (6.60 gm, 27.304 mmol, 2eq.) followed by addition of triethyl amine (TEA, 3.80 ml, 27.304 mmol, 2eq.) at room temperature. Resulting reaction mixture was heated at 60° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature, solid precipitated out. Solid was filtered over Buchner funnel and washed with heptane (2×30 mL) and n-Pentane (70 mL) and dried under reduced pressure to get product as white solid. Yield: −5.0 g (68.31%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.68 (d, J=17.36 Hz, 1H), 3.85 (d, J=17.44 Hz, 1H), 4.17-4.24 (m, 2H), 4.39-4.47 (m, 2H), 5.69 (s, 1H), 7.33-7.35 (m, 1H), 7.48 (d, J=1.16 Hz, 2H), 7.62 (d, J=8.44 Hz, 2H), 7.98 (d, J=8.28 Hz, 2H). LC-MS (m/z): =534.0 (M−H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1([CH3:19])[O:18][CH2:17][CH2:16][O:15]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[C:8]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:9]=1
Reactant: CC1(c2cc(F)ccc2Br)OCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cc(F)ccc2B(O)O)OCCO1
Temperature: -78 °C
Yield: 75 %

Procedure:
A solution of t-butyl lithium (19.0 mL) was added dropwise to a solution of 2-(2-bromo-5-fluorophenyl)-2-methyl-1,3-dioxolane (4.02 g, 15.40 mmols) and triisopropyl borate (4.6 mL, 19.93 mmols in anhydrous THF (40 mL), stirring under an inert atmosphere at −78° C. The resulting yellow solution was stirred at −78° C. for ½ h and then allowed to warm to −15° C. The resulting boronic ester was hydrolyzed in situ with sat'd NH3Cl (aq) at room temperature. The reaction mixture was transferred to a separatory funnel, diluted with H2O (50 mL), and extracted with EtOAc (3×50 mL). The combined organics were washed with H2O, brine, dried over Na2SO4, and concentrated. The resulting residue was recrystallized from EtOAc and hexanes to give 4-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)phenylboronic acid as an orange solid (2.62 g, 75%). 1H NMR (DMSO, 300 MHz) δ1.60 (s, 3H), 3.61-3.67 (m, 2H), 3.87-3.93 (m, 2H), 7.02-7.08 (m, 2H), 7.24-7.30 (m, 1H), 7.59 (s, 1H) ppm; 1H NMR (DMSO+D2O, 300 MHz) δ1.61 (s, 3H), 3.61-3.67 (m, 2H), 3.78 (brs, 2H) 3.89-3.94 (m, 2H), 7.04-7.10 (m, 2H), 7.26-7.31 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:44][C:43]([CH3:46])([CH3:45])[C:42]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:47].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Into a mixture solution of 2.6 g (5 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 0.63 g (6 mmoles) of triethylamine, 0.12 g (1 mmole) of 4-dimethylaminopyridine, and 15 g of methylene chloride was added 0.72 g (6 mmoles) of pivaloyl chloride, and they were stirred at room temperature for 8 hours. Thereafter, the reaction was terminated by adding 11 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added a mixture solution of methyl isobutyl ketone and methylene chloride, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended triphenylsulfonium 2-(2,2-dimethylpropionyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.8 g of white crystals (yield 58%)). The structure of the intended product is shown below.
Reaction SMILES: CO[C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])[N:6]=1)=[NH:4].[Cl-:19].[NH4+:20].N>CO>[ClH:19].[C@@H:10]1([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:4])=[NH:20])=[N:6]2)[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]1[OH:12]
Reactant: COC(=N)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: [NH4+]
Reactant: [Cl-]
Agent: N
Solvent: CO
Product: Cl
Product: N=C(N)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The compound (4) residue was dissolved in a minimum amount of methanol (15 mL) and transferred to a pressure bottle. Ammonium chloride (0.61 g, 11.4 mmol) and a solution of methanol saturated at 0° with dry ammonia gas (75 mL) were added, the bottle sealed and the solution stirred at room temperature overnight. The solution was concentrated to dryness in vacuo and the resulting residue crystallized from acetonitrile-ethanol to yield compound (6) as a crystalline solid (2.95 g, 93%). This sample was identical in all respects to an authentic sample prepared as per the above referenced J. T. Witkowski, et al., J. Med. Chem., 1973, 16, 937.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>C(O)C>[ClH:26].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([NH:19][C:20]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:27]3[CH:28]=[CH:29][CH:30]=[C:31]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1cc(Cl)ccc1-n1cccc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cl
Product: Clc1ccc2c(c1)NC1(CCN(Cc3ccccc3)CC1)c1cccn1-2

Procedure:
5.29 g (0.028 mole) of 1-benzyl-4-piperidone and 2 ml. of glacial acetic acid are added to a solution of 5.0 g (0.026 mole) of 1-(2-amino-4-chlorophenyl)pyrrole [Example 13(b)] in 80 ml. of absolute ethanol. The solution is refluxed, leaving a yellow oil. The oil is washed with a potassium hydroxide solution, then water, and placed in a refrigerator overnight. The tan solid which forms is dissolved in ether, and ethereal hydrogen chloride is added. The resulting precipitate is washed with water and dried to give 1'-benzyl-7-chloro-4,5-dihydrospiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine]hydrochloride, m.p. 282°-283° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C:9]([CH3:10])([C:11]([O:13][CH3:19])=[O:12])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(CCC#N)C(C)(C)C(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N(CCC#N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
62 g (0.23 mol) of N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalanine were dissolved in 350 ml of DMF and 50 g of KHCO3 were added. Few minutes after, 30 ml of methyl iodide (MeI) were dropped and the mixture was stirred at room temperature for 6 hours. Then a further 15 ml of MeI were added. The mixture was left at room temperature overnight. After dilution with 1.5 l of water, the solution was extracted with ethyl acetate (3 times). The organic phases were washed with a small amount of water, dried over sodium sulfate, evaporated and dried at the mechanical pump. 60.5 g (97%) of methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate were thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: C1CSCCN1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCSCC1)c1cccc3c1N2CC3
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of 7.88 g (0.025 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 25.8 g (0.250 mole) of thiomorpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for 3 hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from 100 ml of hot methanol to give 8.8 g (88%) of product. Recrystallization from a hot solution of dichloromethane (50 ml, charcoal) to which methanol (100 ml) was added provided the analytical sample, mp 165°-167° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl.CCOCC>O1CCCC1.C([Li])CCC>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:38]([NH:37][C:28]2[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])=[O:39])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred room temperature solution of 3-dodecyl-5-(phenylmethyl)isoxazole (38.3 g, 0.117 mol) in tetrahydrofuran (600 mL) was cooled to -78° C. under nitrogen. To the resulting precipitate was added dropwise a 2.01M solution (58 mL, 0.12 mol) in n-butyl lithium in hexanes over 10 minutes. The mixture was stirred for 1.25 hours before a solution of 2,4,6-trimethoxyphenyl isocyanate (24.43 g, 0.1168 mol) in tetrahydrofuran (350 mL) was added dropwise over 30 minutes. The mixture was stirred for 45 minutes then quenched with a dropwise addition of 1M HCl (235 mL, 0.235 mol) followed by ether (500 mL). The mixture was allowed to warm to room temperature. The organic layer was washed with 0.2M HCl, water, saturated sodium bicarbonate, and saturated sodium chloride, dried (MgSO4), and rotoevaporated to a solid. The material was recrystallized twice from diisopropyl ether and chromatographed on silica gel (830 g, 230-400 mesh) using petroleum ether-ethyl acetate (2:1, 20×900 mL) to give a white solid; yield 40.7 g (65%), mp 106°-107° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2SC)[C:3]=1[CH3:27].O[O:29][S:30]([O-:32])=O.[K+].[CH2:34]1COCC1>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:15]=2[S:30]([CH3:34])(=[O:32])=[O:29])[C:3]=1[CH3:27]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(OC(F)(F)F)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Product: Cc1c(-c2cc(OC(F)(F)F)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reaction time: 16 h

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)-5-(trifluoromethoxy)-phenyl)quinoline (560 mg, 1.30 mmol) was dissolved in a mixture of THF (10.0 mL) and water (3.3 mL). To the solution was added Oxone™ (2.1 g, 3.3 mmol) and the resulting slurry was stirred vigorously 16 h. The reaction mixture was added to 25 mL of water and stirred vigorously for 10 min and then filtered. The precipitate was dissolved in EtOAc and then dried over magnesium sulfate. The filtrate was cond to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)quinoline. Mass Spectrum (ESI) m/e=452.0 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[N:9](C(OCC(C)C)=O)[C:8]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:30][CH2:29][CH2:28][N:27]([C:31](OC(C)(C)C)=[O:32])[CH2:26][C:25]=4[CH:38]=3)=[CH:20][C:7]=2[N:6]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[F:55][C:56]1[CH:57]=[C:58]([CH:62]2[CH2:67][C:66](=[O:68])[CH2:65][CH2:64][N:63]2C(Cl)=O)[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:1][CH2:2][CH2:3][NH:4][C:5]1[NH:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:30][CH2:29][CH2:28][N:27]([C:31]([N:63]5[CH2:64][CH2:65][C:66](=[O:68])[CH2:67][CH:62]5[C:58]5[CH:59]=[CH:60][CH:61]=[C:56]([F:55])[CH:57]=5)=[O:32])[CH2:26][C:25]=4[CH:38]=3)=[CH:20][C:7]=2[N:6]=1
Reactant: O=C1CCN(C(=O)Cl)C(c2cccc(F)c2)C1
Reactant: CC(C)COC(=O)n1c(NCCF)nc2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc5[nH]c(NCCF)nc5c4)cc3C2)C(c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
1,1-Dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (59.4 mg, 0.11 mmol) was taken into neat TFA (1 mL) and allowed to stand for 1 h at room temperature then concentrated and dried. The residue was taken into THF (5 mL) followed by addition of DIPEA (0.2 mL, 1.1 mmol) followed by addition of 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (29 mg, 0.11 mmol) in a minimum of THF and the resulting solution was stirred at room temperature for 30 minutes. The mixture was then concentrated and taken up into methanol (5 mL) followed by addition of solid potassium carbonate (80 mg, 0.56 mmol) and stirring was continued for 30 minutes. The mixture was then concentrated and partitioned with ethyl acetate and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was triturated with ethyl ether and the solid collected by filtration and dried to afford 1-{[7-{2-[(2-fluoroethyl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3-fluorophenyl)piperidin-4-one (46.4 mg, 75% yield). 1H NMR (400 MHz, d6-DMSO): 7.51 (s, 1H), 7.42 (d, 1H), 7.36 (s, 1H), 7.31 (q, 1H), 7.18 (d, 1H), 7.12-7.03 (m, 4H), 6.99 (d, 1H), 5.20 (tr, 1H), 4.66 (tr, 1H), 4.57 (dd AB, 2H), 4.54 (tr, 1H), 4.20 (br m, 2H), 3.75-3.56 (br m, 6H), 2.86 (m, 2H), 2.60 (m, 1H), 2.33 (br d, 1H). MS (EI) for C30H29F2N5O3: 547 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=1>C(OCCO)C>[OH:30][C:28]1[CH:29]=[C:24]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:25]=[CH:26][C:27]=1[O:31][CH3:32]
Reactant: COc1ccc(N)cc1O
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3c(OC)cccc23)cc1O
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 140.6 mg (1.0 mmol) of 5-amino-2-methoxyphenol in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 261.6 mg (89.0%) of the product as a deep yellow solid, m.p. 138-140° C. (dec.), mass spectrum (electrospray, m/e): M+H 321.9.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[F:31][C:32]([F:44])([F:43])[CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1>>[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:42]([C:39]3[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][C:32]([F:31])([F:43])[F:44])=[CH:37][CH:38]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(OCCC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: O=C1N(c2ccc(OCCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
Off-white crystalline solid. MS (ESI): 567.2 (MH+). P This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(3,3,3-trifluoro-propoxy)-phenylamine.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Na].[NH:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1C=CC=CC=1.[OH-].[Na+].C(O)C>[C:1]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][CH:19]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: C/C=C/C(=O)Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: C/C=C/C(=O)Oc1ccc(Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
4-Anilinophenyl crotonate was prepared by adding a solution of 11.5 grams of crotonyl chloride in 50 milliliters of benzene to a solution of the sodium salt of 4-anilinophenol which was prepared by dissolving 18.5 grams of 4-anilinophenol in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol. The addition was accomplished in 30 minutes and the reaction mixture was stirred for one hour. The mixture was then poured into 150 milliliters of water. The organic layer was separated, washed three times with 10 percent sodium hydroxide solution and once with water, dried over anhydrous sodium sulfate, then allowed to evaporate. The residue was recrystallized from hexane yielding 13.3 grams of product which melted at 73°-76° C.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(OP([CH2:21][C:22]([O:24][CH3:25])=[O:23])(OCC)=O)C.C[O-].[Na+]>C1C=CC=CC=1.CO>[CH3:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCCCCCCCCC(C)=O
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCCCCCCCCC(C)=CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Undecanone (methyl nonyl ketone) (1′) (73.9 g, 434 mmols) and methyl (diethylphosphono)acetate (99.4 g, 433 mmols) were dissolved in dry benzene (300 ml). The solution was stirred at room temperature, and a 28% sodium methoxide solution (83.7 g) in methanol was slowly added. Stirring was continued overnight at room temperature. The reaction mixture was poured into ice water, and extracted with diethyl ether. The organic layer was washed (water and a saturated aqueous solution of sodium chloride), and dried (sodium sulfate), followed by removing the solvent in a vacuum to obtain methyl 3-methyl-2-dodecenoate (2′) as a geometric isomer mixture.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:32]([O:37][CH3:38])(=[O:36])[C:33]([CH3:35])=[CH2:34].O>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:34][CH:33]([CH3:35])[C:32]([O:37][CH3:38])=[O:36])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: C=C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)CSc1cc(C)c(N)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
To a stirred solution of 1.00 g (5.1 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 0.15 g (0.5 mmol) of tetrabutylammonium fluoride in 5 mL of toluene at -5° C. is added dropwise a solution of 0.51 g (5.1 mmol) of methyl methacrylate in 5 mL of toluene. The reaction mixture is stirred for 24 hours at room temperature. The reaction mixture is then poured into 50 mL of water. The phases are separated and the organic phase is dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by flash column chromatography (silica gel, 4:1, heptane:ethyl acetate eluent) to give 0.28 g (18%) of the title compound as a colorless liquid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([F:10])[C:7]3[O:11][C:12]4[C:17]([C@@:18]5([CH2:23][CH2:22][O:21][C:20]([NH2:24])=[N:19]5)[C:6]=3[CH:5]=2)=[CH:16][C:15]([NH2:25])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.C(N(CC)CC)C.CCCP(=O)=O>CCOC(C)=O>[NH2:24][C:20]1[O:21][CH2:22][CH2:23][C@:18]2([C:6]3[CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:9]=[C:8]([F:10])[C:7]=3[O:11][C:12]3[C:17]2=[CH:16][C:15]([NH:25][C:33](=[O:34])[C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][N:31]=2)=[CH:14][CH:13]=3)[N:19]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(C2CC2)nc1F
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(C2CC2)nc1F
Reaction time: 0.02 h
Yield: 12.2 %

Procedure:
To a solution of (S)-3-cyclopropyl-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.0864 g, 0.254 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.044 g, 0.279 mmol) in EtOAc (2 mL) was added triethylamine (0.106 ml, 0.762 mmol). The mixture was stirred for one minute and propylphosphonic anhydride solution, 50 wt. % in ethyl acetate (0.302 ml, 0.508 mmol) was added. Stirring continued for 1 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% MeOH/DCM and repurified by HPLC to afford (S)—N-(2′-amino-3-cyclopropyl-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.015 g, 0.031 mmol, 12.31% yield). MS m/z=480.0 [M+H]+.