Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Cl:26])[C:23](Cl)=[N:22][CH:21]=1>COCCOC.O.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>[CH3:17][O:18][C:19]([C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([C:11]2[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[N:22][CH:21]=1)=[O:28]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cc1ccc(B(O)O)cn1
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: COCCOC
Solvent: O
Product: COC(=O)c1cnc(-c2ccc(C)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 888.2 %

Procedure:
0.29 of Na2CO3 (0.273 mmol), 0.25 g of 6-methylpyridin-3-ylboronic acid (11) (0.18 mmol) and 0.11 g of Pd(PPh3)4 were added to 0.4 g of 5,6-dichloro-nicotinic acid methyl ester (10) (0.2 mmol) prepared in Example 7 dissolved in 14 mL of 1,2-dimethoxyethane and 7 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.42 g of 3-chloro-6′-methyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (yield 88%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)[CH:3]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: CC1(C)OC(=O)Nc2c(Br)cc(O)cc21
Product: Cc1ccc(SCCCCOc2cc(Br)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 8-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>O1CCCC1>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:2]([CH3:3])[CH3:1])(=[O:21])=[O:20])#[N:12]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccccc1C#N
Reaction time: 2 h

Procedure:
(Step 1) To a mixture of dimethylamine (49.6 ml, 2M tetrahydrofuran solution) and triethylamine (3.46 ml) was added a solution of 2-cyanobenzene-1-sulfonyl chloride (5.0 g) in tetrahydrofuran (20 ml) at room temperature. The mixture was stirred at the same temperature for 2 hr, and concentrated under reduced pressure. The residue was suspended in water, and filtered. The filtered solid was dissolved in dichloromethane, the solution was washed with water, and the organic layer was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 2-cyano-N,N-dimethylbenzenesulfonamide (5.1 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([OH:17])=O)[CH:6]=1)[CH3:3].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[CH2:58][C:57]([CH2:81][C:82]#[N:83])([N:59]3[CH:63]=[C:62]([C:64]4[C:65]5[CH:72]=[CH:71][N:70](COCC[Si](C)(C)C)[C:66]=5[N:67]=[CH:68][N:69]=4)[CH:61]=[N:60]3)[CH2:56]2)[CH2:51][CH2:50]1>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:8]=[C:7]([C:15]([N:49]2[CH2:50][CH2:51][CH:52]([N:55]3[CH2:56][C:57]([CH2:81][C:82]#[N:83])([N:59]4[CH:63]=[C:62]([C:64]5[C:65]6[CH:72]=[CH:71][NH:70][C:66]=6[N:67]=[CH:68][N:69]=5)[CH:61]=[N:60]4)[CH2:58]3)[CH2:53][CH2:54]2)=[O:17])[CH:6]=1)[CH3:1]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
6-[(Dimethylamino)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (22.8 mg, 0.0913 mmol, from Step B) was dissolved in tetrahydrofuran (0.67 mL), and triethylamine (33.9 μL, 0.244 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (32.4 mg, 0.0852 mmol) were added. The mixture was stirred for 15 minutes, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (30.0 mg, 0.0609 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After two hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until the deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH), afforded the desired compound as a white powder. Yield: 0.014 g (39%); LC-MS: 594.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.61 (dd, 1H), 7.07 (dd, 1H), 4.07 (ddd, 1H), 3.77-3.72 (m, 2H), 3.70 (s, 2H), 3.63-3.48 (m, 5H), 3.31-3.22 (m, 1H), 3.16-3.07 (m, 1H), 2.60-2.53 (m, 1H), 2.25 (s, 6H), 1.85-1.73 (m, 1H), 1.71-1.59 (m, 1H), 1.37-1.18 (m, 2H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[S:15]>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:14]([NH:13][CH2:12][C:11]([F:17])([F:16])[F:10])=[S:15])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: FC(F)(F)CN=C=S
Solvent: CC(C)=O
Product: OCc1cccc(NC(=S)NCC(F)(F)F)c1

Procedure:
m-Aminobenzyl alcohol (0.123 g.) and 2,2,2-trifluoroethylisothiocyanate (0.141 g.) were heated under reflux in acetone (5 ml.) for 2 hours. Volatile material was evaporated in vacuo and the crude residue was fractionated on a silica gel column (20 cm.×1 cm. diameter) eluted with ethyl acetate to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)thiourea. The n.m.r. spectrum in CDCl3 using tetramethylsilane as internal standard (δ=0) had the following resonances (δ):-7.2 (4H, multiplet); 4.6 (2H, singlet); 4.3 (2H, multiplet).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([S:24]([C:27]4[S:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:30][CH:31]=4)(=[O:26])=[O:25])[C@@H:20]([C:38]([NH:40][O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[O:39])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.CN(C=O)C>[C:32]1([C:29]2[S:28][C:27]([S:24]([N:21]3[CH2:22][CH2:23][NH:18][CH2:19][C@@H:20]3[C:38]([NH:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[O:39])(=[O:25])=[O:26])=[CH:31][CH:30]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (16.5 g) was dissolved in a solution (160 ml) of 20% piperidine in DMF at room temperature. After stirring for 30 minutes at said temperature, the solution was concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: 1% MeOH in CHCl3, then 4% MeOH in CHCl3) to give 9.57 g of (2R)-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)=[CH:15][CH:14]=1
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(Br)cc1
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(Br)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (26.610 mmol) and 3-(4-bromo-phenyl)-propionaldehyde (6.350 g; 29.803 mmol) afforded 8-[2-(4-bromo-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.74 min.; [M+H]+=460.01 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=1)[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-iodophenyl)propanoic acid [Aldrich] (4.0 g, 10. mmol) in tetrahydrofuran (10 mL) with stirring was added 1.0 M borane-THF complex in THF (40 mL) dropwise to keep temperature at 0° C. (about 15 min). The reaction mixture was stirred at room temperature for 1 h, then cooled down with ice-bath, quenched with AcOH:MeOH (1:5, 20 mL) and partitioned between saturated aqueous NaHCO3 solution and DCM, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by combi-flash chromatography to give 2.0 g (52% yield) of the desired product. LC-MS found: 278.0 (M−Boc+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C1COCC1>[Cl:1][CH2:2][C:3]1[N:4]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Reaction time: 72 h
Yield: 67.7 %

Procedure:
To a stirred solution of 2-chloromethylbenzimidazole (1.89 g, 11.4 mmol) in dry THF (57 mL) was added N,N-diisopropylethylamine (3.00 mL, 17.2 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.90 mL, 10.8 mmol) both via syringe under nitrogen at room temperature. The mixture was stirred for 3 days at which time the solvent was removed in vacuo. The residue was taken up in CH2Cl2 (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. Purification by flash chromatography (silica gel, 100:2:1 CH2Cl2-methanol-ammonium hydroxide) provided 2.17 g (65%) of the title compound as a yellow oil, which solidified on standing. 1H NMR (CDCl3) δ−0.06 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 3.57 (t, 2H, J=7.5 Hz), 4.91 (s, 2H), 5.65 (s,−2H); 7.31-7.36 (m, 2H), 7.50 (d, 1H, J=7.5 Hz), 7.78 (d, 1H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:12])=[O:11].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:21](=[O:22])[NH:1][C:2]3[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=3[S:10]2(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c(N)c1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)NC(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Yield: 90.5 %

Procedure:
A mixture of 2-amino-4-methoxy-N-(4-chlorophenyl)-benzenesulfonamide (24.37 g) and 1,1'-carbonyldiimidazole (18.93 g) in dried dioxane (500 ml) was refluxed overnight and then concentrated to dryness. The residue was washed with methanol and collected by filtration to yield 2-(4-chlorophenyl)-6-methoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (23.9 g).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[F:21])[CH:3]=1.[NH4+].[Cl-].O>CCO.[Fe]>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:21])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reaction time: 0.67 h
Yield: 91.3 %

Procedure:
To a mixture of compound 50 (1.0 g, 2.96 mmol) and NH4Cl (46 mg, 0.86 mmol) in EtOH (29 mL)/water (15 mL) at 100° C., Fe (1.4 g, 25.15 mmol) was added in one portion and the mixture was refluxed with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined filtrate concentrated under reduced pressure. The residue was suspended in EtOAc, washed with water; the organic phase was dried over anhydrous Na2SO4 and evaporated affording title compound 225 (916.15 mg, 91% yield). MS (m/z): 338.9 (96%), 340.9 (100%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH:12]=[CH2:13])[C:5]=1[OH:14])=[O:3]>C(O)C>[CH3:13][CH2:12][CH2:11][C:6]1[C:5]([OH:14])=[C:4]([C:2]([CH3:1])=[O:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: C=CCc1c(O)ccc(C(C)=O)c1O
Solvent: CCO
Product: CCCc1c(O)ccc(C(C)=O)c1O

Procedure:
Dissolve 9.6 gm of 3-allyl-2,4-dihydroxyacetophenone in 100 ml of ethanol; flush with nitrogen and add 0.5 gm of 5% palladium/charcoal catalyst. Hydrogenate in a Parr apparatus at room temperature until 45 p.s.i. of hydrogen is taken up. Filter and strip the filtrate to dryness to obtain the title product. (mp 125°-127° C.)
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14]Br.[NH4+].[Cl-]>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH:11]2[CH2:14][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCC/C=C\c1ccccc1
Reactant: BrCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C(=C\c1ccccc1)\CCC1CO1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
(Z)-5-Phenylpent-4-enal (0.475 g, 2.97 mmol) and dibromomethane (0.626 g, 3.60 mmol) were taken up in THF (20 mL) and chilled to −78° C. under argon n-butyl lithium (1.6M in hexane, 2.0 mL, 3.20 mmol) was added dropwise over 5 minutes. The resulting mixture was warmed slowly to room temperature and stirred overnight. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL), extracted with MTBE (2×30 mL) and solvent removed under reduced pressure. The resulting oil was purified by column chromatography (0-20% EtOAc/n-hexane, silica) to give (Z)-2-(4-Phenylbut-3-enyl)oxirane as a pale yellow oil. 1H NMR (CDCl3): δ 7.32-7.27 (m, 2H), 7.25-7.19 (m, 3H), 6.47 (d, 1H, J=11.7), 5.68 (J1=11.6, J2=7.3), 2.97-2.93 (m, 1H), 2.77-2.74 (m, 1H), 2.55-2.52 (m, 1H), 2.53-2.48 (m, 2H), 1.76-1.67 (m, 2H). Contains ca. 18% (E)-2-(4-phenylbut-3-enyl)oxirane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](Cl)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:22][NH:23][CH3:24]>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([N:23]([CH3:24])[CH3:22])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CNC
Reactant: O=C(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 3.5 g of 3-chloro-2-(4-chloro-3-chloroformylphenyl)-5-trifluoromethylpyridine in 10 ml of methylene chloride was added dropwise to 75 ml of a 40% by weight aqueous dimethylamine solution cooled to 0° C. The mixture was stirred at 0 to 5° C. for 4 hours and then diluted with 225 ml of water, after which it was extracted three times with 100 ml of tert-butyl methyl ether each time. The combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel with cyclohexane/ethyl acetate (7:3). Yield: 2.2 g (61%) of colorless crystals; melting point: 90°-91° C.
Reaction SMILES: CC1(C)[O:7][C@@H:6]2[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11][C@@H:5]2[CH2:4][O:3]1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[OH:3][CH2:4][C@@H:5]1[C@H:6]([OH:7])[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@H]2OC[C@H](O)[C@H](O)[C@H]2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
To a solution of (−)-(4aR,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (22 mg, 0.10 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature. Aqueous saturated NaHCO3 (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The mixture was washed with saturated NaHCO3 (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were dried over Na2SO4, and concentrated in vacuo
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]1)[CH2:7]2.[BH4-].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([OH:15])[CH:8]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:21][CH2:22]1)[CH2:7]2
Reactant: COc1cc2c(cc1OC)C(=O)C(CN1CCN(c3ccccc3OC)CC1)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(O)C(CN1CCN(c3ccccc3OC)CC1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
A suspension of 4.9 g of 2,3-dihydro-5,6-dimethoxy-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1H-inden-1-one, hydrochloride in 100 ml of methanol is cooled to 0° C. and treated with a solution of 1.52 g of sodium borohydride in 10 ml of water (the sodium borohydride is added dropwise). The mixture is stirred at room temperature overnight followed by the addition of an additional 1.52 g of sodium borohydride in 10 ml of water at 0° C. The mixture is stirred for an additional 2 hours at room temperature. The reaction mixture is chilled to 0° C. and treated with 30 ml of water. After 30 minutes at 0° C., the solvents are removed in vacuo, and the residue is distributed between dichloromethane and water. The organic layer is dried with sodium sulfate and evaporated in vacuo to a foamy residue (4.1 g). The residue is dissolved in a small amount of dichloromethane and chromatographed on a 150 g-Activity III neutral alumina column using ethyl acetate/hexane (3:1) in 50 ml fractions (a total of 500 ml). After evaporation of the combined fractions there is 2.7 g of residue. Trituration with pentane gives 2.28 g of an amorphous solid with indeterminant melting point. Crystallization from ethyl acetate/pentane yields 1.80 g of the title compound, melting point 109.5°-111.5° C.
Reaction SMILES: C[Li].[CH:3]([Mg]Cl)([CH3:5])[CH3:4].[F:8][C:9]1([F:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12](=[O:20])[CH:11]([OH:21])[CH2:10]1>C1COCC1>[F:22][C:9]1([F:8])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12]([CH:3]([CH3:5])[CH3:4])([OH:20])[CH:11]([OH:21])[CH2:10]1
Reactant: O=C1c2ccc(F)cc2C(F)(F)CC1O
Reactant: CC(C)[Mg]Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A THF solution (3.75 mL) of methyl lithium (3.05 mL, 4.88 mmol) was cooled to −78° C. with a dry ice/acetone cooling bath. A hexanes solution of isopropyl magnesium chloride (1.44 mL, 2.68 mmol) was introduced by syringe. This mixture was allowed to age for one hour at this temperature. Then a THF solution (1.75 mL) of 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.263 mg, 1.22 mmol) was added to the cooled solution dropwise by syringe pump over one hour. The reaction was allowed to stir at −78° C. for 4 hours and then quenched by pouring into an aqueous solution of ammonium chloride, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product, 4,4,6-trifluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalene-1,2-diol, as a colorless oil (0.189 g, 0.727 mmol, 60% yield). 1H NMR (400 MHz, CDCl3) δ: 7.65 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.19 (m, 1H), 4.32 (m, 1H), 2.69 (m, 2H), 1.96 (q, J=8 Hz, 1H) 0.98 (d, J=4 Hz, 1H) 0.93 (d, J=4 Hz, 1H). MS (ESI−, infusion) 259 [(M−H)−].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:47]([CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:48]([NH:47][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Reactant: O=C=NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCN(C(=O)NC2CCCC2)C1
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 58% yield. LCMS for C30H35ClN7O2 (M+H)+: m/z=560.2.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])=[O:9])=[CH:5][N:4]=1
Reactant: Nc1ccccc1N
Reactant: N#Cc1ccc(C(=O)O)cn1
Product: NCc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 32.4 %

Procedure:
The title compound (157 mg, 65% yield) was prepared as a grey solid from 6-cyano-nicotinic acid (296 mg, 2 mmol) and o-phenylenediamine (864 mg, 8 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 243 (M+1).