Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.[OH-:19].[Na+]>O.S(=O)(=O)(O)O>[OH:19][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: Nc1ccc(Cc2cccnc2)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cc2cccnc2)cc1
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium nitrite (0.350 g) in water (1.5 ml) is cooled in ice, and added, with stirring, to a cold (ice-bath) solution of 3-(4'-aminobenzyl)pyridine (Preparation 8, 0.920 g, 0.0050 mole) in water (3.75 ml), concentrated sulfuric acid (2.5 ml), and ice (7 g). This solution in turn is added dropwise to a third solution of water (5 ml) and sulfuric acid (6.25 ml) that is maintained at 160° C. in an oil bath. The resulting solution is kept at 160° C. for 10 min and then cooled to room temperature. The pH of the solution is adjusted to 7.0 by addition of aqueous 50% sodium hydroxide. The resulting mixture is extracted 4 times with 25 ml of ether. The aqueous portion is further extracted continuously with ether for 40 hr. The ether extracts are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crystalline residue is decolorized with activated charcoal and is recrystallized from acetone-hexane, giving a first crop (0.426 g) of the titled crystals, with a melting point of 182°-185° C. A second crop (0.034 g) and third crop (0.050 g, total 0.510 g, 0.00276 mole, 55%) of titled crystals are also obtained. Recrystallization of the first crop from acetone-hexane gives the titled product as colorless crystals with a melting point of 184°-186° C. IR (nujol) peaks are observed at 2900, 2800, 2720, 2680, 2600, 1615, 1590, 1580, 1515, 1485, 1280, 1250, 845, 800, 710, and 640 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].[C:29](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH3:29])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 64 h
Yield: 56.3 %

Procedure:
A mixture of (R)-N-[2-chloro-4-(4-methylphenylsulphonamido)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 356) (0.137 g), anhydrous potassium carbonate (0.043 g) and iodomethane (0.038 ml) in acetone (8 ml) was stirred for 64 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by elution through a Varian Isolute silica 10 g column with 30% ethyl acetate/hexane as eluent to give the title compound (0.079 g). NMR: 1.60 (s, 3H), 2.38 (s, 3H), 3.11 (s, 3H), 7.11 (d, 3H), 7.32 (s, 1H), 7.43 (m, 4H), 7.94 (d, 1H), 9.67 (brs, 1H); MS (ESP−): 449.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([S:14]([NH:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N:41](C(OC(C)(C)C)=O)[C:42]([NH2:51])=[N:43]C(OC(C)(C)C)=O)[CH:36]=3)(=[O:34])=[O:33])[CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([S:14]([NH:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42]([NH2:51])=[NH:43])[CH:36]=3)(=[O:34])=[O:33])[CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
2 ml of trifluoroacetic acid were added to a solution of 246 mg of (1g) in 2 ml of methylene chloride. The reaction was stirred at room temperature for 4 h and the solvent was then removed on a rotary evaporator. 100 mg of a viscous oil were obtained by means of chromatographic purification (dichloromethane/methanol 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10](/[CH:9]=[CH:8]/[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(/C=C/c2ccc(Cl)nc2)CCN1Cc1ccc(Cl)nc1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
A mixture comprising 6.0 g of 1{2-(2-chloropyridin-5-yl)vinyl}-2-nitroiminoimidazolidine, 8.0 g of 2-chloro-5-chloromethylpyridine, 6.8 g of potassium carbonate and 60 ml of dimethylsulfoxide was stirred at 75° C. for 2.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 3.9 of 1-(2 chloropyridin-5-ylmethyl)-2-nitroimino-3-{trans-2-(2-chloropyridin-5-yl)vinyl}imidazolidine.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH3:40][C:41]([CH3:43])=[O:42]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH2:17][C:41]([OH:42])([CH3:43])[CH3:40])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: CC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-ethan-1-one (Example 2) (1.07 g, 4.3 mmol) in CH2Cl2 (65 mL) is cooled to -78° C., and diisopropylethylamine (0.97 mL, 5.6 mmol) and trimethylsilyltriflate (1.08 mL, 5.6 mmol) are added sequentially via syringe. The reaction is stirred at -78° C. for 10 min and then is allowed to warm to 24° C. and is stirred at that temperature for 45 min. The solution is once again cooled to -78° C., and acetone (0.54 mL, 4.3 mmol) is added, followed by TiCl4 (1M solution in CH2Cl2, 4.3 mL, 4.3 mmol). After 1 h at -78° C., the reaction mixture is allowed to warm to 24° C. and evaporated. The residue is partioned between MeOH/1N HCl and CH2Cl2. The CH2Cl2 layer is dried (MgSO4), filtered, evaporated, and chromatographed over SiO2 using EtOAc/hexane (1:6), to yield 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-hydroxy-3-methylbutan-1-one.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH:14]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([CH3:16])[CH3:15]>>[CH:14]([N:17]1[CH2:22][CH2:21][C:20]2[NH:2][C:4]3[C:13]([C:19]=2[CH2:18]1)=[C:8]1[C:9]([CH3:12])=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: Cc1csc2ccc(NN)cc12
Agent: Cl
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(C(C)C)CC4

Procedure:
The compound is formed analogously to that described in Example 15, from 11 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 10 g of 1-isopropyl-4-piperidone. Melting point: 199°-203° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.[N:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[N:15]([C:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Reactant: O=C(Cl)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCCC1)n1c(CN2CCN(c3ccccn3)CC2)nc2ccccc21
Temperature: 25 °C
Yield: 46.6 %

Procedure:
To a stirred solution of Example 1A (0.66 g, 2.2 mmol) in dichloromethane (7 mL) was added 1-pyrrolidinecarbonyl chloride (0.28 mL, 2.2 mmol) and triethylamine (0.625 mL, 4.5 mmol). The mixture was heated in a sealed vial for 17 hours, allowed to cool to room temperature, diluted dichloromethane, washed with 5% NaHCO3, dried and concentrated under reduced pressure. The residue was purified by flash column on SiO2 eluting with 20% hexanes/ethyl acetate to give 0.4 g (40%)of the title compound. mp 120–121° C. 1H NMR (CDCl3, 300 MHz) δ 1.79–2.10 (m, 4H), 2.70 (m, 4H), 3.13 (m, 1H), 3.35–3.78 (bm, 8H), 4.32 (m, 1H), 6.65 (m, 2H), 7.30 (m, 3H), 7.49 (m, 1H), 7.76 (m, 1H), 8.28 (m, 1H). MS (DCI/NH3) m/z 391 (M+H)+. Anal. Calcd for C22H26N6.½H2O: C, 66.14; H, 6.81; N, 21.04. Found: C 66.22, H 6.68, N 21.11.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:59])[NH:17][C@@H:18]2[CH2:22][CH2:21][N:20]([C:23]3[N:31]=[C:30]4[C:26]([N:27]=[CH:28][N:29]4[C@@H:32]4[CH2:36][C@H:35]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C@@H:34]([OH:42])[C@H:33]4[OH:43])=[C:25]([NH:44][CH2:45][CH:46]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:24]=3)[CH2:19]2)C=C(Cl)N=1.[S:61]1C=CC=[C:62]1N=C=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:47]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:45][NH:44][C:25]2[N:24]=[C:23]([N:20]3[CH2:21][CH2:22][C@@H:18]([NH:17][C:16]([NH:15][C:13]4[S:61][CH:62]=[CH:9][CH:14]=4)=[O:59])[CH2:19]3)[N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][N:29]3[C@@H:32]2[CH2:36][C@H:35]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C@@H:34]([OH:42])[C@H:33]2[OH:43])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cc(Cl)nc(Cl)c5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C=Nc1cccs1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccs5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-{(R)-3-[3-(2,6-dichloro-pyridin-4-yl)-ureido]-pyrrolidin-1-yl}-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate (Example 73) by replacing 2,6-dichloro-4-isocyanato-pyridine with 2-thienyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:8][N:9]([C:13](OC)=O)[CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:8][N:9]([CH3:13])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)N1Cc2cc(OC)ccc2[C@H](c2ccc3ccccc3c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C)C[C@H]2c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
To a solution of Compound 25 (51 mg, 0.15 mmol) in THF (8 mL) at 0° C. was added lithium aluminum hydride (0.6 mL, 1 M in THF) dropwise. After the addition, the reaction solution was heated under reflux for 1 h, cooled to 0° C. and quenched by sequential addition of water (1.8 mL), aqueous sodium hydroxide (0.6 mL) and water (0.6 mL). The resultant mixture was stirred at 0° C. for 10 min before it was filtered. The filtrate was extracted with dichloromethane (2×). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. Purification by preparative thin layer chromatography (dichloromethane/methanol/concentrated ammonia 95:4.5:0.5) provided Compound 7 (32.0 mg, 70%, AUC HPLC 96.8%, Chiralpak AD 100%) as a light yellow oil: [α]23D +50.7° (c 0.18, methanol); 1H NMR (500 MHz, CDCl3) δ 7.79-7.68 (m, 3H), 7.68 (s, 1H), 7.47-7.43 (m, 2H), 7.28-7.26 (m, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.65-6.62 (m, 2H), 4.39 (dd, J=8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.77 (d, J=15.0 Hz, 1H), 3.65 (d, J=14.5 Hz, 1H), 3.09 (dd, J=11.5, 5.5 Hz, 1H), 2.64 (dd, J=11.5, 9.0 Hz, 1H), 2.44 (s, 3H); ESI MS m/z 304 [M+H]+. This compound co-elutes with authentic Compound 7 on Chiralpak AD (90:10:0.1 heptane: IPA: diethyl amine, 1 mL/min, RT=14.3 min. The RT of the (−)-enantiomer of Compound 7=6.2 min).
Reaction SMILES: [CH2:1]([C:3]([OH:9])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH3:2].S(=O)(=O)(O)O.[CH3:15]O>>[CH2:1]([C:3]([OH:9])([CH2:7][CH3:8])[C:4]([O:6][CH3:15])=[O:5])[CH3:2]
Reactant: CCC(O)(CC)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCC(O)(CC)C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 2-ethyl-2-hydroxybutyric acid (5.00 g) in methanol (35 mL) was added conc. sulfuric acid (0.25 mL), and the mixture was refluxed at room temperature for 18 hours and then refluxed under heating for 18 hours. After cooling, the reaction mixture was concentrated in vacuo, and the resultant residue was diluted with diethylether. The mixture was washed successively with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The residue was distilled to give methyl 2-ethyl-2-hydroxybutyrate (3.70 g) as a colorless oil.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([CH2:10][CH:11]=O)=[CH:8][N:7]=[C:6]2[N:13]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:5]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>ClCCCl>[Cl:3][C:4]1[C:9]([CH2:10][CH2:11][NH:2][CH3:1])=[CH:8][N:7]=[C:6]2[N:13]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:5]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CC=O)cnc32)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: CNCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
Methylamine gas was bubbled into a solution of 2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetaldehyde (1.45 g, 4.16 mmol) in DCE (50 mL) for about 10 min. NaBH(OAc)3 (1.69 g, 7.97 mmol) was added and the mixture was stirred at rt. After about 45 min, the mixture was concentrated under reduced pressure then dissolved in MeOH (25 mL) and treated with NaBH4 (0.236 g, 6.24 mmol). After about 10 min, the mixture was concentrated under reduced pressure then partitioned between DCM (50 mL), saturated aqueous NaHCO3 (20 mL) and water (30 mL). The layers were separated then the aqueous layer was extracted with DCM (20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by preparative reverse phase HPLC (Table 2, Method i). The desired fractions were collected then most of the MeCN was removed under reduced pressure. The solution was basified with saturated aqueous NaHCO3 and the solids were collected by filtration to give 2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylethanamine (0.67 g, 44%): LC/MS (Table 2, Method a) Rt=1.88 min; MS m/z 364 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O.C(O)(=O)C>C1COCC1.O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.88 g, 22 mmol) in THF (20 ml) was added ethyl diethylphosphonoacetate (4.93 g, 22 mmol) dropwise while ice cooling and the mixture was further stirred at room temperature for 15 minutes and again ice cooled. To the ice cooled mixture was added dropwise a solution of picolinaldehyde (2.14 g, 20 mmol) in THF (10 ml). After the addition, the reaction mixture was heated at 60° C. for 1 hour. Thereafter, the reaction was stopped by treating with 1M aqueous acetic acid. The mixture was diluted with water, and extracted with methylene chloride. The organic layer was treated according to conventional techniques. Evaporation of the solvent yielded a residue which was subjected to recrystallization from hexane to afford ethyl 3-(pyridin-2-yl)-acrylate, yield: 80%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CCN(CC)CC.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)butyramide (Compound 117, 1.75 g, 7.8 mmol) in CH2Cl2 (40 ml) at 0° C. was added Et3N (1.4 ml, 10.1 mmol) and Tf2O (1.7 ml, 10.2 mmol). After 10 min, the reaction was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[O:37]=[C:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:45][CH2:44][CH:43]([N:39]4[CH2:40][CH2:41][CH2:42][C:38]4=[O:37])[CH2:48][CH2:47]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(F)cc3)cc(N3CCC(N4CCCC4=O)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 39.3 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (53.3 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (20.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (26.1 mg, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C.Cl[CH2:50][C:51](=[O:53])[CH3:52]>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][CH2:50][C:51](=[O:53])[CH3:52])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C)c(SCC(C)=O)c1
Reaction time: 0.42 h

Procedure:
To a stirred solution of 4-Methyl-3-triisopropylsilanylsulfanyl-benzoic acid ethyl ester (crude from step 1) in THF (50 mL) at 0° C. was added TBAF (13.9 mmol, 13.9 mL of a 1.0 M solution in THF). After 25 minutes, triethylamine (34.7 mmol, 4.74 mL) was added, followed by chloroacetone (16.7 mmol, 1.33 mL). The reaction was stirred for an additional 5 minutes, then subjected to standard aqueous workup. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>CCOCC.O>[Cl:27][CH2:28][C:29]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14])=[O:30]
Reactant: Cc1cccc(C)c1NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2,6-dimethylaniline (7.8 grams), sodium bicarbonate (7.0 grams), dioxane (20 ml) and water (4 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (5.0 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about one hour. After this time ether (100 ml) was added to the mixture and the resulting solution was washed with water. The washed solution was then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from an ether-pentane mixture to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2,6-dimethylaniline having a melting point of 58° to 60°C.
Reaction SMILES: CN(C)C=O.[CH:6]1([O:10][CH2:11][C:12]2[C:20]3[C:19](=[O:21])[N:18](COCC[Si](C)(C)C)[N:17]=[CH:16][C:15]=3[NH:14][C:13]=2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH:41]3[CH2:43][CH2:42]3)[CH:31]=2)[CH2:9][CH2:8][CH2:7]1.[Br-].[Li+].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.C(Cl)(Cl)Cl.O1CCCC1>[CH:6]1([O:10][CH2:11][C:12]2[C:20]3[C:19](=[O:21])[NH:18][N:17]=[CH:16][C:15]=3[NH:14][C:13]=2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH:41]3[CH2:43][CH2:42]3)[CH:31]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COC3CCC3)c2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [F-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COC3CCC3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To 1 ml of N,N-dimethylformamide containing 193 mg (0.352 mmol) of 3-cyclobutoxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 13-(b) were added 38.2 mg (0.440 mmol) of lithium bromide, 10 μl of ethylenediamine and 3 ml of tetrahydrofuran solution containing 1M tetrabutylammonium fluoride, and the mixture was stirred at 100° C. for 8 hours while removing tetrahydrofuran. After completion of the reaction, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained crude solid was applied to silica gel column chromatography (Eluent; chloroform:ethyl acetate=1:0→0:1 (V/V)), the fractions containing the desired compound were concentrated under reduced pressure, and recrystallized from a mixed solvent of ethanol and water to obtain 70 mg of the title compound as a white solid. (Yield: 47%)