Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:22])[CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[C:4]([F:22])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1F
Agent: [K+]
Solvent: CI
Product: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-2-fluoro-phenyl)-hexanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=380.2 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][NH2:27])=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([NH:26][N:27]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:25]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CCNCC(O)COc2ccc(NN)nn2)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(CCNCC(O)COc2ccc(NN=Cc3ccccc3)nn2)cc1OC
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of (RS)-3-[3-[[2-(3,4-Dimethoxyphenyl)ethyl)amino]-2-hydroxypropoxy]-6-hydrazinopyridazine dihydrochloride (2 g) in 40 ml of 90% aqueous methanol, (1 ml) of benzaldehyde was added. Stirring was continued at room temperature for two hours, then the solvent was evaporated under vacuum and the residue was triturated with isopropanol to afford the title compound in 8% yield. m.p. 207°-210° C. (with decomp).
Reaction SMILES: C([BH3-])#N.[Na+].O.[OH-].[Na+].Cl.[F:9][C:10]1[CH:11]=[C:12]([C:17]2[C:18]3[C:19]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26][C:20]=4[NH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)[CH:13]=[C:14]([F:16])[CH:15]=1>C(O)(C(F)(F)F)=O.CO>[F:9][C:10]1[CH:11]=[C:12]([C:17]2[C:18]3[C@@H:19]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26][C@@H:20]4[NH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: Fc1cc(F)cc(-c2cccc3[nH]c4c(c23)CCNCC4)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL 2-neck round-bottomed flask 10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride was dissolved in TFA (3 mL) and cooled to 0° C. A solution of sodium cyanoborohydride (0.084 g, 1.34 mmol) in MeOH was added and the mixture was stirred at room temperature for 2 h. Water was added, followed by 15% NaOH until the pH of the mixture was basic, and the mixture was extracted with EtOAc. The organic layer was concentrated to give 0.21 g of a brown oil. Column chromatography (elution with 2-6% MeOH/chloroform) gave 0.060 g (74%) of the title product as a clear oil: MS (EI) m/z 300 (M+), 300, 256, 255, 244, 243, 242, 240, 229, 201, 56; HRMS (FAB) calcd for C18H18F2N2+H1 301.1516, found 301.1500.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].[N:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:41]3[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=3)[CH:25]=[C:24]([C:41]3[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=3)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccncc3)c2)c1CCC(=O)OCC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.2 %

Procedure:
A solution of 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (321 mg, 0.5 mmol) in dimethoxyethane (10 mL) was stirred for 5 minutes at room temperature under a nitrogen atmosphere. Then, tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) was added at room temperature and the resulting light yellow solution was heated to 80° C. and stirred for 5 minutes. At this point, a solution of pyridin-4-ylboronic acid (368 mg, 3.0 mmol) in ethanol (10 mL) was added followed by a solution of sodium carbonate (318 mg, 3.0 mmol) in water (1.0 mL). The resulting light yellow suspension was stirred for 24 h at reflux. Then, the reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with water (100 mL), brine solution (100 mL), and dried over anhydrous magnesium sulfate. Filtration and concentration of the solvent gave the crude residue which was purified by using an ISCO 40 g column, eluting with 0-50% ethyl acetate/hexanes to afford 4-{3-[6-(3,5-di-pyridin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (205 mg, 64%) as a light brown oil: ES(+)-HRMS m/e calculated for C39H46N2O6 (M+H)+ 639.3429, found 639.3426.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)c(OC)c1-c1cccnc1
Reactant: OB(O)c1ccccc1
Product: COc1ccc(-c2ccccc2)c(OC)c1-c1cccnc1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 3 using 1,3-dimethoxy-2-(pyrid-3-yl)-4-bromobenzene 30 and phenyl boronic acid to yield 31.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:15]([F:14])([F:26])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CC(O)CCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 1,3-butanediol (2.00 g, 22.193 mmol) and triethylamine (2.695 g, 26.631 mmol) in 10 mL of methylene chloride was stirred at −20° C. under nitrogen. (4-trifluoromethyl)benzene sulfonyl chloride (5.429 g, 22.193 mmol) in 10 mL of methylene chloride was added drop wise to the solution, over 1 hr. The reaction was kept at −20° C. for an additional 3 hours and then stirred at room temperature for 24 hours. The reaction was quenched with water and then washed with 10% aqueous HCl (5×30 mL), sat. NaHCO3 (3×20 mL), H2O (2×20 mL) and brine (1×20 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The product obtained was purified by column chromatography to get a white solid. (1.541 g, 23% yield). 1H NMR (400 MHz, CDCl3) δ1.19 (d, J=6.29, 3H, CH3), 1.66-1.76 (m, 1H, CH2), 1.80-1.91 (m, 1H, CH2), 3.93 (br. s, 1H, CH—OH), 4.14-4.23 (m, 1H, CH2O—SO2), 4.25-4.36 (m, 1H, CH2O—SO2), 7.81 (d, J=8.08, 2H, aromatic), 8.04 (d, J=8.71, 2H, aromatic). Repeat synthesis: To a solution of 1,3-butane diol (4.34 g, 48 mmol) and TEA (3.19 g, 31.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added p-(trifluoromethyl)benzene-sulfonyl chloride (3.97 g, 16.2 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 40 min. The organics were extracted with CH2Cl2 (50 mL) and washed with 1 M HCl (3×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give the desired product (3.28 g, 65%). 1H NMR (400 MHz CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.80 (d, 2H, J=8.3), 4.29 (m, 1H), 4.17 (m, 1H), 3.91 (m, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.17 (d, 3H, J=6.2 Hz); Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.16; H, 4.17.
Reaction SMILES: [C:1]1([C:7]2(C3C=CC=CC=3)OCC[O:8]2)C=CC=CC=1.[OH:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[OH:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]2([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[O:8][CH2:7][CH2:1][O:24]2)=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: c1ccc(C2(c3ccccc3)OCCO2)cc1
Agent: O=C(c1ccccc1)c1ccccc1
Product: Oc1ccc(C2(c3ccc(O)cc3)OCCO2)cc1

Procedure:
The preparation of 2,2-diphenyl-1,3-dioxolane from benzopheone under similar conditions is reported to give over 80% yield in only 5 hours reaction time, [M. Sulzbacher et al., J. Amer. Chem. Soc., 70, 2827 (1948)]. It is readily apparent that the synthesis of the ketal of 4,4'-dihydroxybenzophenone is accomplished less advantageously than the corresponding ketal of benzophenone.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]=[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:10][CH2:9][N:8]2[C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22](=[N:28][OH:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>ClCCl>[C:18]([N:8]1[CH2:9][CH2:10][C:11]2([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[O:29][N:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: CC(=O)N1CCC(N2CCCC2)=CC1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)C(c3ccccc3)C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1-(2-phenyl-4-(pyrrolidin-1-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone in dichloromethane (15 mL) was added a solution of ethyl 2-chloro-2-(hydroxyimino)acetate (4.709 mmol, 1.4 eq.) in dichloromethane (5 ml) at 0° C. Then triethylamine (1.4 eq.) was added dropwise at same reaction conditions and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with 10% citric acid solution and extracted with dichloromethane (3×). The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, concentrated to dryness to give the desired product, which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:6]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:7][C:8]1[C:13]([CH2:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][N:18]2[C:22]3=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]3[N:20]=[C:19]2[CH2:29][CH3:30])=[CH:10][C:9]=1[CH2:31][CH2:32][CH3:33])([O:3]CC)=[O:2].[OH-].[Na+].Cl>C(O)C>[C:1]([CH:6]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:7][C:8]1[C:13]([CH2:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][N:18]2[C:22]3=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]3[N:20]=[C:19]2[CH2:29][CH3:30])=[CH:10][C:9]=1[CH2:31][CH2:32][CH3:33])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(CCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a magnetically stirred solution of 0.138 g (0.25 mmol) of the product of Step A in 1.0 mL ethanol was added 0.5 mL of a 5.0N solution of sodium hydroxide and the reaction was stirred at room temperature overnight. The reaction mixture was adjusted to pH=6 with 1.0N hydrochloric acid and then concentrated in vacuo. The residue was then purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.103 g (79%) of the title compound.
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S:25]1[CH:29]=[N:28][N:27]=[C:26]1[NH2:30].Cl>N1C=CC=CC=1>[CH2:1]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:30][C:26]2[S:25][CH:29]=[N:28][N:27]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Nc1nncs1
Reactant: CCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.6 %

Procedure:
To a solution of p-tetradecylbenzenesulfonyl chloride (440 mg, 1.18 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (179 mg, 1.77 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (240 mg, 0.55 mmol, 47% yield), mp 116-117° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.9 Hz), 1.25 (m, 22H), 1.60 (m, 2H), 2.64 (t, 2H, J=7.2 Hz), 7.29 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.4 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.6, 148.6, 167.4; MS (LCQ, ESI+) Calcd for C22H36N3O2S2 438.2. found 438.3 (M+H)+. HRMS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2243. found 438.2243 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[K+].[O:12]1[CH2:24][CH:13]1[CH2:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[O:15][CH2:14][CH:13]([OH:12])[CH2:24][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:19]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCNCC(O)COc1ccccc1C#N

Procedure:
15.36 g of the hydrochloride of ethyl 3-aminopropanoate and 6.2 g of potassium hydroxide were stirred in 150 ml of abs. ethanol until neutral reaction, ca 1 h. Under reflux was added 8.7 g of 2-(2,3-epoxypropoxy)benzonitrile in 125 ml of abs. ethanol. The mixture was refluxed for 8 h, filtered and evaporated. The residue was dissolved in ether, washed twice with water and extracted with 25 ml of 2-n hydrochloric acid. The aqueous phase was extracted with methylene chloride. The methylene chloride phase was dried over Na2SO4, filtered and evaporated to dryness. The hydrochloride of ethyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-aminopropanoate crystallized. Yield 5.75 g. Melting point 120° C. (HCl). The structure was determined using NMR and equivalent weight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([OH:33])=O)[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc([C@H]3CCCN3c3cc(F)cc(F)c3)c3oc(N4CCOCC4)cc(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (see Example 1.03b for preparation, 97 mg, 0.21 mmol), DIPEA (0.185 mL, 1.06 mmol) and 1-methylpiperazine (0.047 mL, 0.43 mmol) were mixed at room temperature in DCM (3 mL). N-propylphosphonic acid anhydride, cyclic trimer (50 wt % solution in EtAc) (0.633 mL, 1.08 mmol) was then added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by preparative HPLC to afford 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one (67 mg, 59%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[S:19]>CN(C)C=O>[CH3:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)Nc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g) and methylisothiocyanate (0.788 g) in dimethylformamide (20 ml) was heated with stirring at 110° C. for 4 hours, followed by after-treatment in the same manner as Example 8 to give 6-[4-(3-methyl-thioureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14]O)=[CH:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C>[C:13]([C:10]1[CH:11]=[CH:12][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:16]3[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][N:17]=3)=[CH:3][C:2]=2[F:1])[CH:9]=1)#[N:14]
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=NO)c3)c(F)c2)=NO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C#N)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-hydroximino-pyrrol-1-yl)phenyl)isoxazoline (Example 16) (486 mg) is combined with triphenylphosphine (1.48 g) and carbon tetrachloride (0.816 ml) in 14 ml acetonitrile in a 50 ml one neck round bottom flask under nitrogen. The mixture is stirred 1 hour at room temperature and the volatiles are removed in vacuo to give a pale yellow oil. The crude material is chromatographed over 35 g silica gel (230-400 mesh) eluting with 4% methanol/dichloromethane while collecting 5 ml fractions. Fractions 39-50 are combined and concentrated to give 224 mg of a white solid. The solid is washed with diethyl ether and is dried to give 160 mg of the title compound as a white solid, mp 159-161° C., [α]25D -72° (c 0.53, DMSO).
Reaction SMILES: [F:1][C:2]([F:30])([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1)[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]([F:30])([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([N:45]=[N+:46]=[N-:47])=[O:27])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1)[C:3]([F:9])([F:8])[C:4]([F:6])([F:5])[F:7]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ncn(-c3ccc(C(F)(F)C(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(C(F)(F)C(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 28.5 %

Procedure:
4-(1-(4-(Perfluoropropyl)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid (400 mg, 0.92 mmol) was dissolved in 7 mL of isopropanol and treated with diphenylphosphoryl azide (0.300 g, 1.09 mmol) and triethylamine (0.200 g, 2.0 mmol). The solution was allowed to stir for 6 h, then it was cooled to 0° C. and the resulting solid was filtered, washed with a minimum amount of iPrOH, and dried under high vacuum to give the azide as an off-white solid (0.120 g, 30%). This solid was not further characterized, but used directly in the subsequent Curtius rearrangement to prepare molecule A113, using conditions described in Example 39.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([O:23]CC)=[O:22])[C:6](=[O:20])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[N:7]2[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nc2c(Cl)cccc2n(-c2ccc(OC)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2c(=O)c(C(=O)O)nc3c(Cl)cccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
7.7 g (21.5 mmol) of ethyl 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in ethanol (100 ml), and 6.9 g (43.1 mmol) of a 25% aqueous solution of sodium hydroxide was added thereto. The mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue thus obtained, and the mixture was acidified using 10% hydrochloric acid. A solid precipitated therefrom was separated by filtration, washed with water, and then dried, to obtain 6.7 g (yield: 94%) of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:4]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:21][N:20]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]3[CH2:36][C:37]([O:39]CC3C=CC=CC=3)=[O:38])[CH2:19]2)[CH2:13][CH2:12]1)[C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].[H][H]>CO.[Pd]>[CH2:1]([N:4]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:21][N:20]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]3[CH2:36][C:37]([OH:39])=[O:38])[CH2:19]2)[CH2:15][CH2:16]1)[C:5]1[N:6]=[CH:7][CH:8]=[CH:9][N:10]=1)[CH2:2][CH3:3]
Reactant: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2cccc(F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2cccc(F)c2)CC1
Yield: 85.8 %

Procedure:
A solution of 2-(R)-(3-(S)-((4-(N-(prop-1-yl)-N-(pyrimid-2-yl)amino)-piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)cyclohexylacetic acid, benzyl ester (80 mg, 0.13 mmol) from Example 25 Step A, in 3.0 mL of MeOH was hydrogenated using 10% palladium on carbon (20 mg, 0.026 mmol) under one atmosphere of hydrogen gas. After TLC indicated the absence of the starting benzyl ester, the reaction was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated under reduced pressure to give 60 mg (80%) of the title compound as a white solid. HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 3.4 minutes. ESI-MS: 538.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 0.89-0.92 (t, J=7.4 Hz, 3H), 1.20-3.42 (25H), 3.87 (1H), 4.59 (1H), 6.42-6.43 (t, J=4.8 Hz, 1H), 6.91-6.95 (t, J=6.4 Hz, 1H), 7.03-7.09 (m, 2H), 7.24-7.31 (m, 1H), 8.24-8.25 (d, J=4.6 Hz, 2H).