Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH3:18])[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:19])#[N:2].C12BC(CCC1)CCC2.C([O-])(O)=[O:30].[Na+].OO>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH3:18])[CH2:10][CH2:11][CH2:12][OH:30])=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: O=C([O-])O
Reactant: C=CCC(c1ccc(C#N)c(F)c1)n1ccnc1C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nccn1C(CCCO)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the olefin from Step J (1.303 g, 5.11 mmol) in 10 mL of THF at 0° C. was added a solution of 9-borabicyclo[3.3.1]nonane in THF (50 mL, 25.5 mmol, 0.5 M). After one hour, the reaction was warmed to room temperature for 3 hours, then recooled to 0° C. A solution (20 mL) of sat. aq. NaHCO3 and 30% aq. H2O2 (2:1) was added, and the reaction was warmed to room temperature. After 30 minutes, the mixture was partitioned between CHCl3 and aq. NaHCO3 solution, and the aqueous phase was extracted with CHCl3. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (5-8% MeOH/CH2Cl2, then rechromatographed using 50-100% acetone/CH2Cl2) provided the titled compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].C(O[C:16](=[O:18])[CH3:17])(=O)C>>[CH3:1][CH:2]([CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:3][C:4]([O:6][C:16](=[O:18])[CH2:17][CH:2]([CH3:1])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CC(=O)O)CC(C)(C)C
Product: CC(CC(=O)OC(=O)CC(C)CC(C)(C)C)CC(C)(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A reactor was charged with 633.0 g of 3,5,5-trimethylhexanoic acid (4.00 mol, manufactured by KH Neochem Co., Ltd.) and 817.5 g of acetic anhydride (8.00 mol, manufactured by Wako Pure Chemical Industries, Ltd.), and the resulting mixture was stirred for 1 hour at 120° C. After completing the reaction, the reaction product was distilled at 157° C. to 162° C. under the reduced pressure of 0.4 kPa, to thereby yield 496.4 g of 3,5,5-trimethylhexanoic anhydride.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1

Procedure:
A solution of 1 g of β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl ]-4-fluorostyrene in 10 ml of toluene and 5 ml of ethanol is hydrogenated with 500 mg of 5 percent palladium-charcoal at room temperature and normal pressure until the hydrogen uptake comes to a standstill. The black suspension is subsequently filtered. Evaporation of the filtrate gives 1-[2-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]ethyl]-4 -fluorobenzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH:15]=2)[O:10][CH2:9]1.[H][H]>CCO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)[CH:15]=2)[O:10][CH2:9]1
Reactant: O=C1C(=Cc2ccccn2)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCC1Cc1ccccn1

Procedure:
A solution of 150 mg 3-(pyridin-2-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)chroman-4-one (0.38 mmol) in 20 mL EtOH with catalytic Pd/C was stirred under 1 atm of hydrogen gas for 16 h. The reaction was filtered through celite and the filtrate concentrated. The filtrate was purified on silica gel column eluting with EA:Hex. 85 mg of an off-white solid was collected. m/z=400.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[C:7]([CH:21]=[O:22])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2.[Cl-].[Na+]>O1CCCC1>[Cl:5][C:6]1[C:7]([CH:21]([OH:22])[CH2:1][CH3:2])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2
Reactant: CC[Mg]Br
Reactant: COc1nc2cc(Cl)c(Cl)c(C=O)c2nc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Ethylmagnesium bromide (9.08 mL, 3M in diethyl ether) was added to a suspension of 6,7dichloro-2,3-dimethoxy-5-formylquinoxaline (3.91 g, 13.62 mmol) (Preparation 2) in dry tetrahydrofuran (200 mL) under nitrogen at room temperature. After 30 minutes, saturated sodium chloride (50 mL) was added, and the product was extracted into ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane) gave 6,7-dichloro-2,3-dimethoxy-5-(1-hydroxypropyl)-quinoxaline (1.86 g, 43%), as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc([N+](=O)[O-])c(F)c1
Yield: 97.7 %

Procedure:
By the method of Example 1, Step K, 1.71 g (0.010 mole) of 3-fluoro-4-nitrophenol and 2.85 g (0.011 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 1.66 g (0.012 mole) of anhydrous potassium carbonate in 100 mL of N,N-dimethylformamide, yielding 3.55 g of methyl 2-[2-(3-fluoro-4-nitrophenoxymethyl)-5-methylphenoxy]propionate as a yellowish solid, m.p. 92°-94° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:12]2[N:13]([CH:18]3[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[CH2:19]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CCC(n2nc3c(c2OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC3)C1
Product: CC1(C)CCC(n2nc3c(c2-c2ccc(Cl)cc2)CCNCC3)C1
Yield: 17.6 %

Procedure:
The title compound (25.6 mg) was prepared as in Example 177, Steps C and D, using 203.3 mg of 2-(3,3-dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 221 Step A) and 204.1 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C20H26ClN3, 343.89; found, m/z 344.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 4.62-4.54 (m, 1H), 3.43-3.39 (m, 2H), 3.32-3.28 (m, 2H), 3.20-3.16 (m, 2H), 2.79-2.75 (m, 2H), 2.19-2.03 (m, 2H), 1.99-1.94 (m, 1H), 1.80-1.73 (m, 2H), 1.49-1.40 (m, 1H), 1.16 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:17]#N)([CH:14]([F:16])[F:15])[C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:32]C(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:14]([F:16])[F:15])([CH:17]=[O:32])[C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 3 h
Yield: 39 %

Procedure:
Method LLL To a stirred solution of 7-chloro-5-cyano-5-(difluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (92) (747 mg, 2.55 mmol) in anhydrous methylene chloride (40 mL) at −78° C. was added DIBAL (1.0 M in CH2Cl2, 7.67 mL) dropwise. After 3 h at −50° C., the reaction was quenched with 1.0 N HCl (40 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 30% EtOAc-hexane) furnished 93 (299 mg, 39% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:30][NH2:31].CO.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]I>[CH3:30][NH:31][C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1cccc2c1CCn1cc(-c3ccccc3)nc1C2OC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (276 mg, 0, 55 mmole) in dimethylformamide (5 mL) in a screw-capped vial are added a 3M solution of methylamine in methanol (2.8 mL, 5.5 mmoles), copper(I) iodide (100 mg, 0, 52 mmole) and cesium carbonate (250 mg, 0.77 mmole). The vial is evacuated and filled with argon. The reaction mixture is stirred at 100° C. for 36 hours. Water and ammonia are added to the reaction mixture, and the aqueous phase is extracted three times with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 11% (B) to 21% (B) in 10 minutes) to afford methyl-[4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-8-yl]-amine melting at 189° C.
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([P:32](=[O:35])([OH:34])[OH:33])[CH3:31])=[O:28])[CH3:26])=[O:23])C)=O)C1C=CC=CC=1>>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([P:32](=[O:33])([OH:35])[OH:34])[CH3:31])=[O:28])[CH3:26])=[O:23])[CH3:17]
Reactant: C[C@H](NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CNCC(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 1(B)(ii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-sarcosyl-L-alanylamino)-ethylphosphonic acid of melting point 245°-246° C. (decomposition); [α]D20 =-84.2°; [α]36520 =-312° (c=0.5% in water).
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[Br:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][C:5]([CH3:3])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(Cc1ccccc1Br)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.3 %

Procedure:
In a reaction vessel purged with nitrogen was weighed 14.0 g of sodium hydroxide (349 mmole), and suspended in 200 ml of toluene, to which 100 ml of a toluene solution of diethyl ethylmalonate (60.0 ml, 320 mmole) was added dropwise in an ice bath. After the addition was completed and the mixture was stirred at room temperature for 3 hours, 100 ml of a toluene solution of 2-bromobenzyl bromide (80.0 g, 320 mmole) was added dropwise, and the mixture was stirred overnight. The reaction was terminated by pouring the reaction mixture to dilute hydrochloric acid, and the organic layer was washed with water, dried and concentrated to give 120 g of diethyl 2-(2-bromobenzyl)-2-methylmalonate as a yellow oil (yield, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([P:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+]([O-])(O)=[O:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([P:10]([OH:14])(=[O:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(P(O)O)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(P(=O)(O)O)c1

Procedure:
According to my invention phenylphosphorus dichloride is converted to benzenephosphonous acid (B), which is nitrated (I) with nitric acid at a temperature around 0° C. to form m-nitrobenzenephosphonous acid (E) which, to my knowledge, is a compound not previously described in the literature. Compound E is conveniently oxidized by heating (II) the reaction mixture in the presence of additional nitric acid to form m-nitrobenzenephosphonic acid (C), and then compound (D) by subsequent reduction. My contribution, then, includes the nitration of benzenephosphonous acid (B), which is considerably less costly than benzenephosphonic acid (A), to form the novel compound m-nitrobenzenephosphonous acid (E), followed by oxidation to form m-nitrobenzene phosphonic acid (C) which is converted by conventional reduction to form the desired m-aminobenzenephosphonic acid (D).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[S:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=1)=[O:4].[OH-].[Li+]>>[F:22][C:19]([F:20])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:23]2[S:24][C:25]([C:28]([F:31])([F:29])[F:30])=[N:26][N:27]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1nnc(C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1nnc(C(F)(F)F)s1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=476.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11](I)[CH:10]=[N:9]2)[CH2:4][O:3]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: Cc1c(I)cnn1C[C@H]1COC(C)(C)O1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@H]1COC(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-4-iodo-5-methyl-1H-pyrazole (55.0 mg, 0.171 mmol) in THF (1 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.53 mL, 0.68 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.14 mL, 0.85 mmol) and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 5-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=322.21/323.20/324.20 (50/100/50) [MH+]. HPLC: tR=1.49 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[CH:4][C:3]=1[CH2:16][CH3:17].[F:18][C:19]([F:32])([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:20]([F:23])([F:22])[F:21]>C1CCCCC1.CCOCC.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:10][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:19]([F:18])([F:32])[C:20]([F:21])([F:23])[F:22])[CH:25]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:16][CH3:17]
Reactant: CCc1cc(Oc2cccc(N)c2)ccc1Cl
Reactant: FC(F)(F)C(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCc1cc(Oc2cccc(NCc3cccc(C(F)(F)C(F)(F)F)c3)c2)ccc1Cl
Temperature: 25 °C
Yield: 35.1 %

Procedure:
EX-66° C.) A solution of 3-(4chloro-3-ethylphenoxy)aniline (1.7 g, 6.9 mmol) was prepared in cyclohexane (13 mL). A solution of crude 3-pentafluoroethyl benzylbromide (1 g, 3.5 mmol) product from EX-660B in cyclohexane (10 mL) was added dropwise over 3 min. The reaction mixture was refluxed under N2 for 24 h and then was cooled to room temperature. The mixture was diluted with Et2O and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with Et20. The organic layer was washed with brine, dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes in ethyl acetate (95:5) which gave 0.56 g (35%) of the desired N-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl] methyl]amine product as an amber oil. 1H NMR (CDCl3) δ 7.53 (m, 4H), 7.27 (d, 1H), 7.15 (t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt, 2H), 6.30 (t, 1H), 4.41 (s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). 13C NMR (CDCl3) δ 158.6, 156.1, 143.4, 141.3, 140.2, 131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8, 108.8. 103.9, 48.5, 27.5, 14.1. 19F NMR (CDCl3) δ −85.1 (s, 3F), −115.2 (s, 2F). HRMS calcd. for C23H19CIF5NO: 456.1154 [M+H]+, found: 456.1164.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[OH-].[Na+].Br[C@H:11]([CH3:15])[C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:4]1[N:3]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:2]=[N:1][CH:6]=[CH:5]1
Reactant: O=c1ccnc[nH]1
Reactant: C[C@@H](Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1cnccc1=O
Temperature: 85 °C

Procedure:
To pyrimidin-4(3H)-one (0.908 g, 9.45 mmol) was added a 5 N sodium hydroxide solution (3.8 ml) followed by (2R)-2-bromopropanoic acid (0.95 ml, 11 mmol). The reaction mixture was heated at 85° C. for 1 h. After cooling to ambient temperature the reaction was neutralized with 2 N hydrochloric acid (5.2 ml) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in aeetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. 1H NMR (DMSO-d6) δ: 8.48 (d, J=2.7 Hz, 1H), 7.88 (dd, J=7.8, 2.8 Hz, 1H), 6.12 (d, J=7.6 Hz, 1H), 5.04 (q, J=7.3 Hz, 1H), 1.64 (d, J=7.5 Hz, 3H). LC/MS 169.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1.[C:15]1([OH:26])[C:24]2[CH2:23][CH:22]([OH:25])[CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1>COCCO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([O:26][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=[N:3][C:4]=2[CH:10]=1
Reactant: Oc1cccc2c1CC(O)CC2
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Solvent: COCCO
Product: OC1CCc2cccc(Oc3nc4cc(C(F)(F)F)ccc4[nH]3)c2C1
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (89 mg, 0.4 mol, prepared according to the procedure described in WO 2004/035549 A1), 5,6,7,8-tetrahydronaphthalene-1,7-diol from step (a) above (49 mg, 0.3 mmol) and 2-methoxy-ethanol (1 mL, Aldrich) was subjected to microwave irradiation at 180° C. with stirring for 60 min twice. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexane to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 349 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:29])(Cl)[CH3:27])[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]([CH3:29])[CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(Cl)CN1CCOCC1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Product: CC(COc1c2c(oc(=O)c1-c1ccccc1)CCCC2)CN1CCOCC1
Yield: 83.5 %

Procedure:
Prepared as indicated in Example 14, Stage B, from 29 g. (0.12 mol) of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin and 27.3 g. (0.156 mol) of 3-morpholino-2-methyl-2-chloropropane. 38.2 g. of an oil which cannot be crystallised are obtained. Yield 83.5% (theoretical yield 45.6 g.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]([S:21]([Cl:20])(=[O:23])=[O:22])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(Cl)c1cc(Br)cc2cnccc12
Temperature: 25 °C

Procedure:
7-Bromo-isoquinoline (22.7 g, 109 mmol) is added to a stirred chlorosulfonic acid (230 mL) solution and the resultant mixture is heated at 150° C. under nitrogen for 22 hours. The solution is cooled to ambient temperature and poured very slowly into ice (2 Kg) cooled in a −10° C. bath. While cold, the mixture is adjusted to pH ˜10 with powered Na2CO3 (ca. 200 g) and 5N NaOH. The mixture is extracted with dichloromethane (1 L×2). The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to give 16.3 g (crude yield 49%) of 7-bromo-isoquinoline-5-sulfonyl chloride as a tan solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH:15][CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Cl)c1
Solvent: O=CO
Product: O=CNc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Acetic anhydride (189 ml, 2.0 mol) was mixed with formic acid (91 ml, 2.4 mol) at 0° C. and the mixture was stirred at 60° C. for 1 h and then cooled to 0° C. To the solution was added dropwise 3-chloroaniline (105.7 ml, 1.0 mol) and the mixture was stirred at room temperature for 18 h. After removal of solvent in vacuo, the residue was extracted with EtOAc-H2O. The organic layer was washed with 5% aqueous citric acid, saturated aqueous NaHCO3 and brine, dried over Na2SO4 and then concentrated. The residue was crystallized from iPr2O to give the title compound (115 g, 0.739 mol, 74%) as a colorless solid.