Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[CH:5]1[C:10](N=C=S)=[CH:9][C:8]2[C:14]([O:16][C:17]3([C:27]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=4[O:25][C:19]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]3=4)[C:7]=2[CH:6]=1)=[O:15]>O.CS(C)=O>[CH:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]2[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[O:25][C:26]3[C:27]=2[CH:28]=[CH:29][C:30]([CH:31]=3)=[O:32])[CH:6]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
This HA-HZ was dissolved in distilled water (Milli Q water), and an equal amount of 100 mM carbonate buffer (Ph 9.0) was then added thereto to a final concentration of 1 mg/ml. Thereafter, FITC dissolved in DMSO that was 1/10 the volume of the HA-HZ solution was added to the mixture at an additive ratio of FITC/HA unit=3.0 mol/mol, and the obtained mixture was then reacted in the dark at room temperature for 1 hour. Thereafter, 25 ml of the reaction solution was poured in PD-10 columns (10 columns) that had previously been equilibrated with a 50 mM carbonate buffer (pH 9.0), so as to remove unreacted FITC. Succinic anhydride dissolved in DMSO (3.5 ml) was added to the thus roughly purified solution at an additive ratio of succinic anhydride/HZ=250 mol/mol, and the same above reaction was carried out. The reaction mixture was dialyzed against large excess amount of distilled water (Milli Q water) for purification, followed by freeze-drying, so as to obtain fluorescein-labeled HA-HZ-SUC, which was formed by labeling HA-HZ with FITC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:11][C:12](=[O:13])[CH3:14])=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
4-Methoxybenzaldehyde (1e, 0.63 ml, 5.2 mmol) and acetone (19, 4.00 ml, 54.0 mmol) were combined in ethanol (4 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (4 ml) was added dropwise and the mixture stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ether/hexane to give 0.57 g (62%) of a yellow solid: mp 71-73° C. [expected mp 68° C.]; 1H NMR: δ 2.34 (s, 3H), 3.83 (s, 3H), 6.59 (d, 1H, J=16.3 Hz), 6.90 (d, 2H, J=8.7 Hz), 7.46 (d, 1H, J=16.3 Hz), 7.48 (d, 2H, J=8.7 Hz); 13C NMR: δ 27.5, 55.4, 114.4, 125.0, 127.1, 129.9, 143.1, 161.5, 198.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:44])[N:31]([CH2:35][CH2:36][C:37](=[O:43])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]([Cl:45])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:45][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:25]=1)[C:30]([N:31]([CH2:35][CH2:36][C:37](=[O:43])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:32]([CH3:34])[CH3:33])=[O:44]
Reactant: CCN(CC)C(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C(C)C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of (2-{3-chloro-5-[(2-diethylcarbamoyl-ethyl)-isopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.06 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 3 h and then concentrated under reduced pressure to give the title compound as a colourless oil (0.043 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2].[C:26]([O:30][C:31]([NH:33][C:34]1([C@H:37]2[CH2:41][NH:40][CH2:39][C@H:38]2[F:42])[CH2:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN1CCCCC1>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:40]2[CH2:41][C@H:37]([C:34]3([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:35][CH2:36]3)[C@H:38]([F:42])[CH2:39]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Solvent: CN1CCCCC1
Solvent: CS(C)=O
Product: CC(=O)Nc1c(F)c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (54.4 mg, 0.154 mmol), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (54.5 mg, 0.223 mmol), 1-methylpiperidine (51.3 mg, 0.517 mmol) and dimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 49%. Also, residual ratio of the material was 34%.
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.C1C[O:18][CH2:17]C1>>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([CH:17]=[O:18])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: C1CCOC1
Agent: [CH2-]CCC
Agent: [Li+]
Product: COc1ccc(C=O)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
N-butyllithium, 1.6 M solution in hexanes (1.05 eq, 7.0 ml) was added dropwise to a solution of 5-bromo-2-methoxy-pyridine (2 g, 10.63 mmol) in THF, Acros dry (25 ml) under argon atmosphere at −78° C. After complete addition the mixture was stirred for another 90 minutes at −78° C. at which time DMF, acros dry (2 eq, 1.65 ml) was added dropwise. The mixture was then stirred at −78° C. for another 90 minutes. The mixture was then warmed-up to room temperature and poured into 150 ml of NaHCO3 saturated water solution. The organics were extracted with 3×70 ml of diethyl ether. The gathered ether layers were dried over Na2SO4 the solvent was evaporated and the obtained crude was purified by chromatography on BIOTAGE SP1 purification device using 25 g normal phase silica SNAP coloumn and cyclohexane/EtOAc solvent system (gradient 1-10% of EtOAc in 20 coloumn volumes) Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 6-methoxy-pyridine-3-carbaldehyde (1.04 g, yield=71.2%, purity=95%) in form of white crystals. MS: [M+H]+=138.09 1H NMR (300 MHz; CDCl3) δ/ppm 4.04 (s, 3H), 6.85 (d, J=8.70 Hz, 1H), 8.07 (dd, J=8.70 Hz, J=2.34 Hz, 1H), 8.64 (d, J=2.34 Hz, 1H), 9.96 (s, 1H)
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3]O.[CH3:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=1[NH2:9].[I-].[K+].ClCCl>O>[CH3:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:8]=1[NH:9][CH2:1][CH:2]([CH3:5])[CH3:3]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)CO
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1NCC(C)C
Yield: 36.7 %

Procedure:
2-methyl-1-propanol (0.556 mL, 6.00 mmol), 2-methyl-5-(trifluoromethyl)aniline (525 mg, 3 mmol), potassium iodide (996 mg, 6.00 mmol) and [Cp*IrCl2]2 (33.1 mg, 0.030 mmol) were dissolved in water (2 mL). The resulting mixture was irradiated under microwaves (CEM microwave) at 170° C. for 1 hour. To the reaction mixture was added dichloromethane (5 mL) and the crude material was purified by mass directed autoprep (250 mg scale ×3, Method C, formic acid modifier). Relevant fractions were combined and evaporated to give 2-methyl-N-(2-methylpropyl)-5-(trifluoromethyl)aniline (260 mg, 1.102 mmol, 36.7% yield) as a dark yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C@@H:12]([CH:16]([CH3:19])[CH2:17][CH3:18])[C:13](Cl)=[O:14]>>[Cl:11][C@@H:12]([CH:16]([CH3:19])[CH2:17][CH3:18])[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC(C)[C@H](Cl)C(=O)Cl
Product: CCC(C)[C@H](Cl)C(=O)Oc1ccc(C(=O)O)cc1

Procedure:
Using p-hydroxybenzoic acid (1.93 g, 14.0 mmol) and (S)-2-chloro-3-methylpentanoylchloride (2.28 g, 13.5 mmol), the reaction was carried out in the same manner as described in Example 4, (1), to give the title compound as white crystals; yield: 2.95 g; mp. 97.0°-100.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)(=[O:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:23]([C:20]2[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:18][C:19]=2[N+:27]([O-:29])=[O:28])(=[O:24])=[O:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Yield: 70.7 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloro-quinolin-8-ylamine (Intermediate 27) (200 mg, 1.12 mmol), 4-methanesulfonyl-2-nitro-benzenesulfonyl chloride (Intermediate 439) (456 mg, 1.46 mmol), DMAP (cat.) and pyridine (5 ml) gave the title compound (350 mg, 60%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[C:5]([Cl:13])[CH:4]=1.Cl.[NH2:15][C@@H:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)C(C)C)(C)C.C(O)CCC>>[Cl:13][C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:11])[N:15]([C@@H:16]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:2][C:3]=2[CH:4]=1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1cnc(Cl)cc1CBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Cl)ncc2C1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)-6-chloronicotinate (200.0 mg, 0.7561 mmol) (prepared according to Example 119, Steps A, B and C), 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione hydrochloride (244 mg, 0.754 mmol) (prepared from Example 79, Step A) and N,N-diisopropylethylamine (0.526 mL, 3.02 mmol) in 1-butanol (5.0 mL, 55 mmol) was stirred at 140° C. for 2 h under microwave irradiation. Direct purification on prep.HPLC afforded 182 mg (55.1% yield) of the desired product. LC-MS found: 438.1 (M+H)+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[C:10](=[O:22])[N:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:12]=[CH:13][C:14]=1Cl>O1CCCC1>[Cl:8][C:9]1[C:10](=[O:22])[N:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:12]=[CH:13][C:14]=1[O:5][CH:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(Cl)c(OC2CCC2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A solution of cyclobutanol (7.2 g, 100 mmol) in tetrahydrofuran (200 mL) was treated with sodium hydride (3.6 g, 150 mmol) and stirred at 25° C. for 15 min. At this time, 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 20.0 g, 80 mmol) in tetrahydrofuran was added dropwise. The resulting mixture was stirred at 25° C. for 2 h. At this time, the reaction was concentrated in vacuo. Chromatography (8/1 petroleum ether/ethyl acetate) afforded 4-chloro-5-cyclobutoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (16.3 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([NH:10]C(=O)C)[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.Cl.[N:17]([O-])=O.[Na+]>CC(O)=O.O>[Cl:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:5]([CH:9]=[N:17][NH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(Cl)cc(C)c(C)c1NC(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)cc(C)c2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(3-Chloro-2-methoxy-5,6-dimethyl-phenyl)-acetamide (3.36 g, 17.4 mmol) is dissolved in HOAc (75 mL) and conc. HCl (30 mL) in a 1 L round bottom flask. The reaction is cooled to 0° C. with an ice/salt bath. Although some starting material crystallizes, a solution of NaNO2 (5.9 g, 86 mmol) in water (25 mL) is added portion-wise over 5 min. All material goes into solution and the reacion is stoppered and stirred 45 min. HPLC shows very little sm. Ice cold water (800 mL) is was added slowly and the reaction was stirred 1 h. A precipitate forms. The solid is filtered and washed with ice cold water (500 mL). The material is dried with suction and then pumped to a constant weight 3.3 g. The solid is partially dissolved in toluene (35 mL) and stirred under N2. After stirring 18 h, the reaction is heated for 4 hours and cooled. The reaction is diluted with EtOAc and washed with NaHCO3, brine, dried (MgSO4) and concentrated. The crude product is purified by column chromatography (silica, 30% EtOAc/hexanes) to provide the desired product, 6-chloro-7-methoxy-4-methyl-1H-indazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 57 %

Procedure:
A stirred solution of 1-benzylpiperazine (8.81 g, 50.0 mmol), 4-fluoronitrobenzene (5.31 mL, 50.0 mmol), and K2CO3 (6.90 g, 50.0 mmol) in ethanol is heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water, and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo to give a solid residue. The solid is triturated with 20:80 ethyl acetate:hexanes and filtered. The filtercake is air-dried to afford the title compound as orange crystals, 8.45 g (57% yield), mp 218-219° C., characterized by NMR and mass spectral analyses.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (64 mg, 83%), MS (ISP) m/z=385.4 [(M+H)+], mp 187.5° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and propionic acid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:35]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCC=C(c1ccccc1)c1ccccc1
Yield: 75.2 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g), dimethylsulfoxide (100 mL), (4-carboxybutyl)triphenylphosphonium bromide (36.5 g), benzophenone (18.2 g), and tetrahydrofuran (100 mL). The crude product, isolated in the usual manner, was crystallized from hexane to give 16.5 g of 6,6-diphenyl-5-hexenoic acid, mp 111°-112.5° C. Anal. Calculated for C18H18O2 : C, 81.17; H, 6.81. Found: C, 81.39; H, 6.88.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]>O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: Cc1c(Cl)ccc(O)c1Cl
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Cl)ccc(OS(=O)(=O)c2nc[nH]n2)c1Cl

Procedure:
2.33 g of 2.4-dichloro-3-methylphenol was dissolved in 15 ml of tetrahydrofuran, and 1.84 ml of triethylamine was added while stirring the solution. Then, 2.0 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while cooling with ice and stirring the solution. Then, the solution was stirred at room temperature for 14 hours. Tetrahydrofuran was removed by distillation at reduced pressure, 2N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was washed with brine, and dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 2.25 g of the titled compound was obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:5][C:6]([CH2:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].O1CCCC1.P(OCC)(OCC)([S-])=[S:25]>O>[C:1]([C:3]1[C:4]([CH:15]2[CH2:16][CH2:17][CH2:18]2)=[CH:5][C:6]([CH2:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:25])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: CCc1cc(C2CCC2)c(C#N)cc1C(=O)OC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C2CCC2)c(C(N)=S)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.1 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate (compound 181.5, 3.00 g, 12.3 mmol, 1.00 equiv) in a solvent mixture of tetrahydrofuran and H2O (80 mL/40 mL). To this was added O,O′-diethyl dithiophosphate (6.69 g, 35.9 mmol, 3.00 equiv) dropwise with stirring. The resulting solution was stiffed at 85° C. for 48 h (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was then concentrated in vacuo. The crude product was purified by re-crystallization from petroleum ether to furnish 1.30 g (38%) of methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate as a light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>CCOC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16]
Reactant: Cc1ccc2c(c1)N(CCCCl)C(=O)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc2ccc(=O)n(CCCCl)c2c1
Yield: 62.7 %

Procedure:
A microwave vial was charged with 1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.21 g, 0.88 mmol), DDQ (0.30 g, 1.3 mmol), dioxane (4 mL) and sealed. After microwave irradiation, 175° C., 10 min, the reaction was diluted with EtOAc (50 mL), washed with sat aqueous NaHCO3 (2×15 mL) and the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified with prep RP-HPLC to yield the crude title compound (0.130 g), which was used without further purification. HPLC-MS (ammonium acetate) [M+H]+=236.2.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=3[CH:22]=[O:23])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][CH2:36][Mg+].[Br-]>C(OCC)C>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:21]=3[CH:22]([OH:23])[CH2:35][CH3:36])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCC(O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.08 h

Procedure:
To a −78° C. solution of 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde (230 mg, 0.461 mmol) in diethyl ether (5 mL) was added a solution of EtMgBr (230 μL, 0.691 mmol). The solution was stirred for 5 minutes, followed by a second addition of EtMgBr solution (230 μL, 0.691 mmol). After 5 minutes, the reaction was quenched with saturated NH4Cl solution (5 mL), diluted with EtOAc (60 mL), and washed with brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 35% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-hydroxypropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.14 (25% EtOAc/hexanes). LCMS=512.1 (M+1−18)+. 1H NMR (CDCl3, 500 MHz, diastereomers present) δ 7.89-7.45 (m, 6H), 5.69-6.65 (m, 1H), 5.04-4.91 (m, 1H), 4.27-4.18 (m, 1H), 4.03-3.93 (m, 1H), 2.87 (m, 1H), 1.89-1.66 (m, 2H), 1.00-0.93 (m, 3H), 0.79-0.75 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C(O)CCC>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:12]=[C:11]([CH3:13])[C:5]3[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(N)cc2oc(=O)n(C)c12
Solvent: CCCCO
Product: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
300 mg (1.70 mmol) 6-amino-3,4-dimethyl-3H-benzoxazol-2-one, 276 mg (1.90 mmol) 4,6-dichloropyrimidine and 0.77 mL (60 μmol) TEA were combined in 5.0 mL 1-butanol and the mixture was stirred for 1 h at 100° C. The reaction mixture was cooled to RT, evaporated down and the residue was triturated in diethyl ether. The precipitate was washed with water and dried i. vac.