Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)CCCCC1.[OH:8][C:9]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]([OH:17])=[C:11](C)[C:10]=1[OH:19]>>[OH:19][C:10]1[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]([OH:16])[C:12]([OH:17])([CH3:1])[CH:11]=1
Reactant: Cc1c(O)c(O)c(C)c(O)c1O
Reactant: O=C1CCCCC1
Product: CC1=C(O)C(O)=CC(C)(O)C1O

Procedure:
Attempts to form acetals from polyhydric phenols with two or more pairs of ortho-positioned hydroxy groups have been less successful. Soloway in U.S. Pat. No. 2,927,096 describes the preparation of resins from aldehydes and polyhydric phenols, such as 1,2,4,5-tetrahydroxybenzene and pentahydroxy benzene. Dallacker et al in Annalen, Band 719 (1968), pp. 112- 118 describe the preparation benzo[ 1.2-d: 4.5-d'] bis[ 1.3] dioxoles of the formula (III) wherein R is hydrogen, methoxy or allyl, by heating the corresponding mono-dioxole (IV) with chlorobromomethane in dimethyl formamide in the presence of potassium carbonate ##STR3## Kaye describes in the 13th Annual Report on Research, Petroleum Research Fund (1968) how reaction of catechol with cyclohexanone in the presence of toluene sulphonic acid in benzene gives only a 49% yield of the acetal, with some alkylation of the aromatic ring. Under the same conditions, no reaction took place between cyclohexanone and 1,2,4,5-tetrahydroxy- 3,6-dimethylbenzene. He showed, however, in Abstracts of Research Supported by the Petroleum Research Fund (196 ) p. 21 that 1,2,4,5-tetrahydroxy-3,5-dimethylbenzene formed an acetal (V) when heated with dichlorodiphenyl methane. ##STR4##
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[O:16]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C>[ClH:1].[ClH:1].[O:16]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:6]2[CH2:5][CH2:4][CH2:3][N:2]=[C:7]2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [Cl-]
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Solvent: CC(C)O
Product: C(=C1CCCN=C1c1cccnc1)c1ccc(Oc2ccccc2)nc1
Product: Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 147.2 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (101 mg, 0.40 mmol) and 6-phenoxynicotinaldehyde (120 mg, 0.60 mmol) were combined in a reaction vessel and treated with isopropanol (15 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature. The precipitate that formed was recovered by vacuum filtration and washed with a 20% solution of isopropanol in hexane and then with ether. The recovered solid was then dried under vacuum giving 122 mg (73%) of a pale yellow solid. LC-MS: RT=5.08 min, [M+H]+=342.1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2I)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28]([O-])([O-])=[O:29].[K+].[K+]>C(#N)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.[Cu]I>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:28](=[O:29])[C:18]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(S(C)(=O)=O)cc2I)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(S(C)(=O)=O)cc3c(=O)o2)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirring solution of 2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene (1.89 g, 3.72 mmol) in acetonitrile (50 mL) was added K2CO3 (2.53 g, 18.6 mmol) followed by Pd(PPh3)4 (0.22 g, 0.19 mmol) and CuI (0.036 g, 0.19 mmol). The mixture was placed under an atmosphere of CO and heated to 75° C. After 2 h, the heat was removed and the mixture was diluted with ethyl acetate and washed with water, then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a gradient of 10% to 20% ethyl acetate in dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 0.485 g (32%) of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.Br[CH2:15][C:16](=[O:18])[CH3:17].[C:19](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C)C=O.CO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:19])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Reactant: CC(=O)CBr
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC(C)=O)c(O)c1

Procedure:
Following a procedure similar to that described in Preparation 21, but using 10 g of 3,4-dihydroxyphenylacetic acid, 30 ml of absolute methanol, 20 ml of a 4N solution of hydrogen chloride in dioxane, 200 ml of anhydrous dimethylformamide, 8.74 g of bromoacetone and 8.02 g of potassium carbonate, the title compound was obtained having an Rf=0.37 (thin layer chromatography over silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([F:23])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[S:18]1[C:14]([C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[F:23])[NH:10][N:9]=2)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 71.5 %

Procedure:
To a solution of 152 mg of 3-benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-f in a mixture of 2 ml of tetrahydrofuran and 2 ml of methanol was added 1 ml of 5 N aqueous sodium hydroxide solution, and the mixture was stirred at 55° C. for 2.5 hours. After standing to cool, 5.5 ml of 1 N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was recrystallized from tetrahydrofuran-ethyl acetate, to give 104 mg of the title compound as pale red crystals. 1H-NMR (400 MHz, DMSO-D6) δ 7.36-7.43 (2H, m), 7.47 (1H, d, J=8.8 Hz), 7.88 (1H, dd, J=6.4, 8.8 Hz), 7.95-8.00 (2H, m), 8.03 (1H, s), 13.16 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](NC)[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14]2([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C@H:30]1CCCC[C@@H]1N>O1CCOCC1.[Cu]I.O>[NH2:29][CH2:30][C:4]1[CH:3]=[C:2]([N:15]2[C:14]([CH3:22])([CH3:21])[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=3)[C:16]2=[O:20])[CH:7]=[N:6][CH:5]=1
Reactant: CNc1cncc(Br)c1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CN)c1
Temperature: 150 °C
Yield: 176.7 %

Procedure:
In a 25 mL sealed tube, a mixture of (5-bromo-pyridin-3-yl)-methylamine (281 mg, 1.5 mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12, 196 mg, 1.0 mmol), CuI (38 mg, 0.2 mmol), Cs2CO3 (652 mg, 2.0 mmol) and (+)—(S,S)—1,2-diaminocyclohexane (68.4 mL, 0.6 mmol) were dissolved in dioxane (3 mL). The resulting reaction mixture was heated at 150° C. for 7 hours before it was poured into water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (320 mg, 100%). Without further purification, it was used directly in the next step. MS: 302.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@:14]([CH3:26])([O:16][CH2:17][P:18](=[O:25])([O:22]CC)[O:19]CC)[C@@H:13]([OH:27])[C@H:12]1[OH:28].N1C(C)=CC=CC=1C.C[Si](I)(C)C>C(#N)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@:14]([CH3:26])([O:16][CH2:17][P:18](=[O:19])([OH:22])[OH:25])[C@@H:13]([OH:27])[C@H:12]1[OH:28]
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: C[C@]1(OCP(=O)(O)O)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 397.9 %

Procedure:
To a solution of compound 31.4 (20 mg, 0.048 mmol) in acetonitrile (2 mL) was added 2,6-lutidine (0.034 mL, 0.29 mmol) and then trimethylsilyl iodide (0.068 mL, 0.48 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was done, 0.08 mL of 2,6-lutidine was added to the mixture and the mixture was concentrated under reduced pressure. The residue was then put into solution with water (2 mL) and treated with sodium hydroxide 1N to pH=10. The solution was then acidify to pH=3 using acetic acid and subjected to a reverse phase (YMC-Pack ODS-A) to give compound 31.5 (69 mg, 72% yield). 1H NMR (300 MHz, D2O): δ 1.42 (s, 3H), 3.33 (t, 1H, J=10.7), 3.51 (t, 1H, J=11.9), 4.12 (d, 1H, J=4.6), 5.18 (m, 1H), 6.10 (d, 1H, J=7.1), 8.24 (s, 1H), 8.55 (s, 1H). LRMS (ESI) MH+ C11H16N5O7P requires 362.3. Found 361.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[NH2:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:36]([CH3:38])[C:34]([CH2:33][NH:32][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:15])=[O:35]
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 29.5 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (35.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 537.6; and 1H NMR (DMSO-d6, 400 MHz): δ 8.59 (1H, m), 7.90 (1H, br. s), 7.72 (1H, br. s), 7.56-7.54 (1H, m), 7.38-7.31 (2H, m), 7.18 (1H, m), 4.30-4.27 (2H, t), 4.11-4.10 (2H, d), 3.70-3.67 (2H, t), 3.25 (3H, s), 3.03 (3H, s), 2.87 (3H, s), —NH proton signal was not observed.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=[C:20]([Cl:23])[C:21]=1Cl.Cl>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: Cc1ccc2ncc(O)cc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 3-Hydroxy-6-methylquinoline (92) (348 mg, 2.19 mmol) in DMF (3.5 mL), was added NaH (60% oil suspension, 90 mg, 2.25 mmol) in one portion at room temperature. After 5 min 3,4,5-trichloronitrobenzene (509 mg, 2.25 mmol) in DMF (2 mL) was added and the reaction mixture was heated at 50° C. with stirring for 2 h. After cooling to room temperature. Ice/water was added to the reaction mixture, which was then acidified with 2N HCl and extracted twice with AcOEt. Organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt=4/1, 80 g of silica gel) to afford compound 93 (510 mg, 67%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].[K].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C(Cl)(Cl)Cl.O>CN(C=O)C>[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)C#CCOC(=O)CCCCCBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C#CCOC(=O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
3-(trimethylsilyl)prop-2-ynyl 6-bromohexanoate (0.606 g, 2 mmol, 1 eq.) was added to a solution of phthalimide potassium salt (0.4412 g, 2.4 mmol, 1.2 eq.) in 50 mL of DMF and stirred overnight under argon. CHCl3 was added to the solution flask and was transferred to a separatory funnel containing water. The aqueous layer was separated and twice extracted with CHCl3. The combined organic layers were twice extracted with water then the solvent was removed on a rotary evaporator. Remaining solvent was removed under high vacuum overnight to yield a brown oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@@H:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:24][OH:25])[O:11][C@H:10]1[O:26][CH2:27][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:66](Cl)(=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68]>C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@@H:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:12]([CH2:24][O:25][C:66](=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68])[O:11][C@H:10]1[O:26][CH2:27][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Temperature: -5 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Compound 6 (687 mg, 0.831 mmol) was dissolved by addition of pyridine (12 mL). Pivaloyl chloride (130 μl, 1.08 mmol) was added to the solution, and the mixture was stirred at −5° C. for 1 hour. Pivaloyl chloride (130 μl, 1.08 mmol) was further added thereto, and the mixture was stirred at −5° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, then filtered through Celite, and washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 7 (716.6 mg, 94.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:12]1([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2cc(N3CCNCC3)ncc2c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3cc4ccccc4cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.38 g of 4-methoxybenzoyl chloride are added dropwise to 10 g of 3-(piperazin-1-yl)-isoquinoline, dissolved in 40 ml of pyridine. After stirring for 1 hour at room temperature, the mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate phase is dried and the solvent is removed by evaporation. 5.8 g, melting point 156°-159° C., can be isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:48][S@@](C(C)(C)C)=O)([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:16][C:17]2[N:18]=[N:19][N:20]([C:22](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)([NH2:48])[CH2:16][C:17]2[N:18]=[N:19][N:20]([CH3:22])[N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1nnc(C[C@@](N)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.3 %

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 0.079 mmol) in MeOH (3 mL) was added 4 N HCl in dioxane (1 mL). The reaction mixture was stirred at room temperature for 20 min, then concentrated to yield (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine LCMS: RT=2.66 min [M+H] 418.55 (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 4 min gradient, flow rate 4 mL/min, wavelength 220 nm). To a solution of ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine in THF (3 mL) and MeOH (0.5 mL) was added (diazomethyl)trimethylsilane (2.0 M in hexanes, 0.05 mL). After stirring at room temperate for 20 min, the reaction mixture was concentrated and purified by ISCO flash column chromatography (silica gel, EtOAc) to give ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethanamine (10 mg, yield: 30%). LCMS: RT=2.83 min [M+H] 432.57 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.[Cl-].[Na+].O>[C:25]([O:13][CH:11]1[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10]1)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OC1CC(c2ccccc2)NC(c2ccccc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a -70° C. solution of 2.50 g (9.9 mmol) of 2,6-diphenyl-4-hydroxypiperidine in 80 ml of dry tetrahydrofuran (THF), 4.2 mL (10.5 mmol) of n-butyllithium (2.5M in hexanes) is added dropwise. The mixture is warmed to -20° C. and stirred for 30 minutes. The solution is then cooled again to -70° C. and a solution of 2.2 g (9.9 mmol) of lauroyl chloride in 20 mL of dry THF is then added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is added to 250 mL of brine and then extracted with 2×200 mL of ether. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by liquid chromatography (LC) (silica gel, ethyl acetate/hexane) to give 3.2 g (74%) of the title compound as a white solid: mp 40°-42° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[S:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([S:18][CH2:24][C:25](=[O:27])[CH3:26])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc3ccccc3[nH]c2=S)cc1
Reactant: CC(=O)CCl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CSc1nc2ccccc2cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(p-Fluorophenyl)quinolin-2-thione (5.05 g.) was added in portions to a stirred suspension of sodium hydride (1.0 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (30 ml.) at 0°-5°. When all the hydrogen had evolved, chloroacetone (1.83 g.) was added and the mixture was stirred at ambient temperature for 18 hr. The mixture was poured into ice-water (300 ml.) and extracted with ethyl acetate (3×100 ml.). The ethyl acetate extract was washed with brine (75 ml.) and then dried (MgSO4). The solvent was evaporated and the residue was chromatographed on basic alumina (200 g., Brockmann Grade III), eluted with increasing concentrations of ethyl acetate in petroleum ether. The eluate obtained with 10% v/v ethyl acetate in petroleum ether was evaporated to give 3-(p-fluorophenyl)-2-(2-oxopropylthio)quinoline, m.p. 95°-96°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[C:11]1(C)C=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.N.C(OCC)(=[O:25])C>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]3[CH2:14][CH2:13][CH2:12][CH2:11][O:25]3)[N:9]=[CH:10][C:3]=12
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ncnc2[nH]ncc12
Agent: N
Product: Clc1ncnc2c1cnn2C1CCCCO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 12.9 mmol, 1.0 eq.) and ethyl acetate. The mixture was heated to 50° C. After 10 minutes p-toluenesulfonic acid (50 mg) was added, followed by the addition of 2,3-dihydropurane (1.09 g, 15.5 mmol, 1.2 eq). The resulting reaction mixture was heated at 50° C. with stirring for 1 hour and was then cooled to room temperature at which time aqueous ammonia was added. After 5 minutes the organic layer was separated, and washed twice with water (100 ml) and once with brine (100 ml). The ethyl acetate was removed and petroleum ether was added. The mixture was heated and filtered thru cotton. Removal of the petroleum ether in vacuo afforded 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine as a light yellow colored solid (2.35 g, 77%). 1H NMR (400 MHz, CDCl3): 8.81(s, 1H), 8.22 (s, 1H), 6.05 (dd, 1H), 4.14 (m, 1H), 3.81 (m, 1H), 2.61 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.81 (m, 2H), 1.64 (m, 1H); MS (ESI) for C10H11ClN4O: 239 (MH+).