Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:28]=2)[N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=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>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
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: CN(C)C=O
Solvent: O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12
Temperature: 80 °C

Procedure:
The mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-ylamine (62.8 mg 0.200 mmol), 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (79.1 mg, 1.2 eq.), Pd(PPh3)4 (14.0 mg, 6% eq.) and Na2CO3 (53.0 mg, 2.5 eq.) in DMF (5 ml)/H2O (1 ml) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under N2. After that time, the reaction mixture was treated with H2O (20 ml), and was then extracted with CH2Cl2 (2×25 ml). The extracts were washed with H2O (2×20 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, the crude yellow oil (105 mg) was purified by MS directed purification system to obtain a yellow solid of 3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine; 1H NMR (CDCl3, 400 MHz) δ 2.05-2.09 (m, 1H), 2.15-2.22 (m, 1H), 2.48-2.56 (m, 2H), 2.62-2.72 (m, 2H), 3.85 (quintet, 1H, J=8.4 Hz), 5.27 (s, 2H), 7.09-7.10 (d, 1H, J=4.8 Hz), 7.15-7.16 (d, 1H, J=4.8 Hz), 7.36-7.39 (m, 1H), 7.86-7.90 (m, 1H), 7.97 (m, 2H), 8.31-8.33 (d, 1H, J=8.8 Hz), 8.43 (s, 1H), 8.59-8.61 (d, 1H, J=8.8 Hz), 8.67-8.69 (d, 1H, J=7.6 Hz), 8.75-8.76 (d, 1H, J=4.0 Hz); MS (ES+): 393.4 (M+1), tR(polar-5 min)=2.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17]C(C)C)=[O:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.O.[Li+].[OH-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\n1cnc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.8 %

Procedure:
In 3-neck 100 mL RBF, (Z)-isopropyl 3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylate (1.0 g, 1 eq.) was mixed with THF-Water (1:1) (20 mL, 20 Vol.) and LiOH (0.288 g, 2.0 eq.) was added. The reaction mixture was stirred at RT for 2-3 h. Reaction completion was monitored on TLC using neat ethyl acetate as mobile phase. Reaction mixture was quenched into the ice-water slurry (50 mL) and acidified with approximately 5 N HCl to 4 PH. Compound was extracted in the ethylacetate (50 mL×3) and organic layer was washed with brine solution (50 mL×3) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 0.7 g of pure (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylic acid. Yield (81.8%). LC/MS: 250.0
Reaction SMILES: [C:1]([C:4]1[S:25][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]3[CH2:16][C:15](=[O:17])[N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:13]=[C:12]3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CS(C)=O.S([O-])(O)=O.[Na+]>Br.C(O)(=O)C>[C:1]([C:4]1[S:25][C:7]2[CH2:8][CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(s1)CCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1cc2c(s1)CCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Yield: 33.5 %

Procedure:
To a solution of 1.2 g of 9-acetyl-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in 15% hydrogen bromide-acetic acid solution was added 0.23 ml of dimethylsulfoxide at room temperature with stirring. After stirring at the same temperature for 15 minutes, the mixture was poured into 0.5% sodium hydrogensulfite solution and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column using chloroform as an eluent. The resulting solid was recrystallized from ethanol to give 0.4 g of 9-acetyl-2-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a white crystal, melting at 164°-166° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].NCC([O-])=O.[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: NCC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 110 °C
Yield: 86.1 %

Procedure:
A pressure flask was charged with 3e (30.92 g), glycine (22.52 g), methanol (155 mL), sodium methoxide solution (64.81 g) and sealed (as an alternative, sodium glycinate was used in place of glycine and sodium methoxide). The reaction was heated to about 110° C. until reaction was complete. The mixture was cooled, filtered, washed with methanol, dried under vacuum, dissolved in water and washed with ethyl acetate. The ethyl acetate was removed and to the resulting aqueous layer an acetic acid (18.0 g) solution was added. The suspension was stirred at room temperature, filtered, and the solid washed with water (3×30 mL), cold acetone (5-10° C., 2×20 mL), and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid (Yield: 86.1%, HPLC: 99.8%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:48])[CH:21]([C:23]1[CH:28]=[CH:27][C:26](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:25][CH:24]=1)[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:48])[CH:21]([C:23]1[CH:24]=[CH:25][C:26]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:27][CH:28]=1)[CH3:22]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.04 g, 0.17 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.075 g, 0.26 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel 230–400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a brown oil (0.018 g, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C=O)C>[Br:1][C:2]1[CH:16]=[N:15][C:5]2[N:6]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (300 mg, 1.1 mmol) in DMF (2.5 mL), under an inert atmosphere, was added sodium hydride (65 mg, 1.3 mmol) and the reaction mixture was allowed to stir at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.3 mmol) was added dropwise and then the resultant suspension was allowed to warm to room temperature. Water (0.5 mL) was added to the resultant suspension to quench the reaction, the solvent was removed in vacuo and the resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-15% ethyl acetate in cyclohexane) to afford the title compound as an off-white crystalline solid (266 mg, 62%). 1H NMR (CDCl3, 400 MHz): 9.18 (d, J=1.2 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H), 5.98 (s, 1H), 3.56-3.60 (m, 2H), 0.94-0.98 (m, 2H), 0.08 (s, 9H). LCMS (Method B): RT=4.55 min, M+H+=(403, 405).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]([NH2:10])([CH3:9])[CH3:8]>CCOCC>[CH3:8][CH:7]([NH:10][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: CC(C)N
Solvent: CCOCC
Product: CCOC(=O)NC(C)C

Procedure:
To a solution of ethyl chloroformate (21.7 g, 0.2 mol) in 200 ml ether cooled to 0° C. was added dropwise 35.7 ml of isopropylamine with stirring and cooling. After complete addition of the amine, the reaction mixture was stirred at room temperature for an additional 0.5 hour. The reaction mixture was filtered, and the ether solution was washed with water, and dried over magnesium sulfate. Evaporation of the ether and distillation of the residue in a Kugelrohr apparatus resulted in 22.6 g ofthe title compound S.p.: 50°-66° C. (bath temperature) at 1.5mm Hg.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5]O)[CH3:2].C(N(S(F)(F)[F:26])CC)C.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][F:26])[CH3:2]
Reactant: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCN(CCF)CCN1C(=O)c2ccccc2C1=O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of compound 3 (100 mg, 0.38 mmol) in dimethoxyethane (DME, 7 mL) was added at −50° C., under argon, (diethylamino)sulfur trifluoride (DAST, 100 μL, 0.76 mmol). The mixture was stirred at −50° C. for 10 min and then at room temperature for 1.5 h. Dichloromethane (5 mL) and a saturated aqueous sodium carbonate solution (5 mL) were then successively added. The organic layer was dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (SiO2, AcOEt/pentane, 1/1, v/v) to give compound 21 (51 mg, 0.19 mmol) as a white solid. Yield 50%; Rf (SiO2, AcOEt/pentane, 1/1, v/v) 0.53; mp 57-59° C.; IR (KBr) ν 1023, 1403, 1715, 1769, 2700-3000 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.00 (t, 3H, J=7.1 Hz), 2.68 (q, 2H, J=7.1 Hz), 2.86 (m, 4H), 3.78 (t, 2H, J=6.6 Hz), 4.47 (td, 2H, 2JH-F=47.5 Hz, J=5.1 Hz), 7.70 (m, 2H), 7.83 (m, 2H); MS m/z 264 (M+, 1), 104 (100), 76 (38), 56 (18).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:17][CH2:18]Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:17][CH2:18][N:12]1[C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]1[O:2][CH3:1]
Reactant: COc1nc2c(c(=O)[nH]1)CCCC2
Reactant: COC(CCBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2c(c(=O)n1CCC(OC)OC)CCCC2
Temperature: 100 °C
Reaction time: 5 h
Yield: 20.4 %

Procedure:
After dissolving 2-methoxy-5,6,7,8-tetrahydro-3H-quinazolin-4-one (CAS 94815-67-5) (2.0 g) and 3-bromopropionaldehyde dimethylacetal (2.44 g) in N,N-dimethylformamide (30 ml), sodium hydride (60% in oil) (533 mg) was added, and the mixture was stirred at room temperature for 30 minutes and at 100° C. for 5 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (640 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:17]([CH:19]=O)=[O:18].Cl>C(O)(=O)C>[C:1]([C:5]1[C:10]2[O:11][C:17](=[O:18])[CH2:19][C:9]=2[CH:8]=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCC(=O)O)ccc1O
Reactant: O=CC=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CCC(=O)O)cc2c1OC(=O)C2
Temperature: 0 °C

Procedure:
66.7 g (0.3 mol) of 3-(3-tert-butyl-4-hydroxy-phenyl)-propionic acid (prepared analogously to the method described in JP-A2-63/227542) in 58 g (0.4 mol) of aqueous glyoxal solution (40% by weight) and 3 ml of hydrochloric acid (32% by weight) are heated at reflux in 200 ml of acetic acid for 6 hours. The mixture is then poured into 600 ml of ice-water and the precipitate is filtered off. The filter residue is washed with water and then dried at 60° C. g. Recrystallisation from toluene results in 54.3 g (69% of theory) of 3-(7-tert-butyl-2-oxo-2,3-dihydro-benzofuran-5-yl)-propionic acid. Melting point 167-169° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].CO[C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:10]>>[OH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:10]
Reactant: CNCCCO
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(CCCO)C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 39 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-methylamino-propan-1-ol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (39%) as amorphous yellow solid.
Reaction SMILES: C[Li].Cl[C:4]12[C:11](=[N:12][OH:13])[CH2:10][CH:9]1[CH:8]=[CH:7][CH2:6][CH2:5]2.[Cl-].[NH4+]>C(OCC)C>[CH3:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][C:11](=[N:12][OH:13])[CH3:4]
Reactant: ON=C1CC2C=CCCC12Cl
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CC=CCCCC(C)=NO
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of 6.3 g of cuprous iodide in 70 ml of diethylether at 0° C. was added 44 ml of 1.5M methyllithium in ether over 15 minutes. The resulting solution was stirred for 20 minutes at 0° C., then cooled to -78° C. A solution of 6-chlorobicyclo[4.2.0]oct-2-en-7-one oxime, prepared as shown in Preparation 18, in ether was added and the mixture stirred at -78° C. to -60° C. for 30 minutes. Saturated ammonium chloride solution (10 ml) was slowly added and the mixture filtered. The filtrate was washed with ether, the combined washings dried over anhydrous sodium sulfate and solvent removed from the filtrate under reduced pressure, to give 6-methylbicyclo[4 2.0]oct-2-en-7-one oxime, the compound of formula (7A) where Y is hydrogen, 5.4 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]1([CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(NC(=O)C(C1C=CC(NS(C)(=O)=O)=C(F)C=1)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:27]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][NH:26][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: CC(C(=O)NC(c1ccccc1)c1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1
Product: CC(C(=O)NCC(c1ccccc1)c1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1

Procedure:
Through similar procedure to that in Example 1-5 excepting using 2-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid (1-38) with the corresponding 2,2-Diphenylethylamine compound as a starting material, N-Benzhydryl-2-[3-fluoro-4-(methylsulfonylamino)phenyl]propionamide having following physicochemical properties was synthesized:
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C:31]1([C:37](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.O1CCCC1>CN(C)C=O>[CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[N:26][N:25]([C:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:24]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1[N+](=O)[O-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A mixture of t-butyl N-methyl-N-[2-nitro-5-(4-tetrazol-5-ylphenoxy)phenyl]carbamate (3.22 g), triphenylmethyl chloride (2.18 g), triethylamine (0.79 g), anyhdrous tetrahydrofuran (30 ml) and anhydrous N,N-dimethylformamide was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=5/1 as the eluant to give the title compound (3.15 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45](C)[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH2:55]([S:57](N1C=CC(N)=N1)(=[O:59])=[O:58])[CH3:56].N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CCS(=O)(=O)n1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
Triphenylphosphine (216 mg, 0.83 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (166 mg, 0.94 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 182 mg, 0.55 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The mixture was chilled to 0° C. and 1-ethanesulfonyl-1H-pyrazol-3-ylamine (88 mg, 0.50 mmol) was added followed by 2,6-lutidine (192 μL, 1.65 mmol). The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-ethanesulfonyl-1H-pyrazol-3-yl)-propionamide (112 mg, 46%) as a white foam: ESI-LRMS m/e calcd for C20H26ClN3O5S2 [M+] 487.1. found 488.2 [M+H+], 396.1 [M−SO2CH2CH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.18 (m, 2H, CH2), 1.22 (t, J=7.3 Hz, 1H, CH3), 1.40-1.89 (m, 8H, 4×CH2), 2.12-2.23 (m, 1H, CH), 3.29 (s, 3H, SO2CH3), 3.38 (q, J=7.3 Hz, 2H, SO2CH2), 3.67 (t, J=7.5 Hz, 1H, CH), 6.99 (d, J=2.7 Hz, 1H, Ar), 7.45 (d, Jo=8.1, 1H, Ar), 7.56 (d, Jm=1.3 Hz, 1H, Ar), 7.89 (d, J=2.7 Hz, 1H, Ar), 8.06 (d, Jo=8.1 Hz, 1H, Ar), 8.74 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)[CH2:3]1>C(O)C.O.[Fe]>[CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C(F)(F)F)cc21
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Yield: 95.1 %

Procedure:
A mixture of 4,4-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.99 g, 8.53 mmol) and iron powder (11.95 g, 0.21 mol) in ethanol/water/concentrated hydrogen chloride (24 mL/6 mL/0.08 mL) was kept at reflux for 2 h. The mixture was filtered and the mother liquor was concentrated in vacuo to give 2.6 g of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine as off-yellow solid (2.6 g, yield: 95.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:14][C:15](=O)[CH2:16][CH3:17])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH4+].[OH-]>>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][C:12](=[O:13])[N:14]=[C:15]2[CH2:16][CH3:17]
Reactant: CCC(=O)NC(=O)Nc1ccc(OC)c(OC)c1
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nc(=O)[nH]c2cc(OC)c(OC)cc12
Reaction time: 3.5 h
Yield: 24.6 %

Procedure:
A suspension of N-(3,4-dimethoxyphenyl)-N'-propionylurea (32.45 g, 128 mM) in polyphosphoric acid (375.12 g, 1109 mM) is heated at 130°-135° C. under nitrogen with vigorous stirring for 3.5 hours. The mixture is then poured onto 500 g ice-H2O and stirred. The solution is brought to pH 5.5 with concentrated NH4OH and allowed to stand at room temperature overnight. A brown precipitate forms. The resulting solid is filtered and dried to yield 7.40 g of a white solid. This filtrate is extracted with CHCl3 (5×250 ml), the organic extract is dried (MgSO4) and the solvent removed in vacuo to give a tan solid. The solid is triturated with acetone and filtered to give a tan solid (4.98 g). A sample is slurried in water and redried for additional purification, m.p. 263°-265° C. δTMSTFA 7.50 (s, 1H, 5--H), 7.23 (s, 1H, 8--H), 4.30 (s, 3H, 6 or 7-OCH3) 4.17 (s, 3H, 6 or 7--OCH3), 3.50 (q, 2H, J=8.0 Hz, CH2CH3), 1.70 (t, 3H, J=8.0 Hz, CH2CH3).