Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][NH2:16])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][N:26]1[C:32](=[O:33])[N:31]2[CH2:34][C@H:27]1[CH2:28][CH2:29][C@H:30]2[C:35](O)=[O:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][NH:16][C:35]([C@@H:30]1[CH2:29][CH2:28][C@@H:27]2[CH2:34][N:31]1[C:32](=[O:33])[N:26]2[O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:36])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl[(1R,2R)-2-(hydrazinylcarbonyl)cyclopentyl]carbamate 285 (0.15 g, 0.54 mmol) in 20 mL of DCM were added compound 1 (0.2 g, 0.82 mmol), HOBt (0.11 g, 0.82 mmol), DMAP (0.2 g, 1.64 mmol) and EDCl (0.16 g, 0.82 mmol). The mixture was stirred at room temperature for 18 h and purified by column chromatography to afford compound 286 as a solid (0.22 g, 82%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[CH:16][CH:15]=[CH:14][C:13]=2[NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[CH:16][CH:15]=[CH:14][C:13]=2[NH:24][C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 3-tert-butoxycarbonylamino-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (869 mg) in dichloromethane (2 ml) was added trifluoroacetic acid (5 ml) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from isopropyl alcohol to give 3-amino-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (581.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[Cl:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:9]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10][C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:19])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)ccc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 5-[(3-bromo-benzylidene)-amino]-2-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(Cl)(C(Cl)=O)=O.[Br:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C(Cl)Cl.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].S1C=CC=C1C([O-])=O.[Cu+].CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:6]([C:7](=[O:9])[C:28]2[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=2)[CH:5]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 5-isopropoxy-isophthalic acid monomethyl ester (1.90 g, 7.98 mmol) in DCM (50 mL) was added (COCl)2 (1.39 mL, 16.9 mmol) and DMF (0.03 mL, 0.400 mmol) at rt. After stirring at rt for 2 hr, the mixture was concentrated. The resulting residue was azeotroped with 50 mL anhydrous toluene and then re-dissolved in Et2O (40 mL). Palladium bis(dibenzylideneacetone) (229 mg, 0.400 mmol), copper (I) thiophene-2-carboxylate (1.52 g, 7.98 mmol), triphenylphosphohine (209 mg, 0.798 mmol), and 4-bromophenylboronic acid (3.20 g, 16.0 mmol) were added to the reaction flask. The resulting mixture was stirred at rt for 3 hr, filtered through a pad of Celite, rinsed with Et2O. The combined Et2O layers were concentrated. The residue was purified by silica gel flash chromatography (6×25 cm, hexane/EtOAc, v/v=5:1, 3:1). Fractions containing the coupling product were pooled and concentrated to give the title compound (2.60 g, 86%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.91 (m, 1H), 7.77 (m, 1H), 7.63-7.69 (m, 3H), 7.48 (m, 1H), 7.38-7.43 (m, 1H), 4.57 (m, 1H), 3.92 (s, 3H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propylamine (348 mg, 1.3 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (310 mg, 1.3 mmol) and DIPEA (1.1 mL, 6.4 mmol) in IPA (4 mL) was heated for 72 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford 247 as a white solid (320 mg, 63%). LCMS (Method K): RT 3.17 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.85 (1H, br s), 8.65 (1H, s), 8.15-8.03 (2H, m), 7.99 (1H, s), 7.84-7.76 (2H, m), 7.71 (1H, dd, J=8.75, 4.90 Hz), 7.55-7.48 (1H, m), 7.20-7.08 (2H, m), 5.73 (1H, s), 2.15-2.06 (1H, m), 2.05-1.95 (1H, m), 0.90 (3H, t, J=7.30 Hz)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH:29][CH2:30][CH2:31][CH3:32])[CH3:28]>C(#N)C>[CH2:27]([N:29]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1)[CH2:30][CH2:31][CH3:32])[CH3:28]
Reactant: CCCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(CC)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-ethylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 282 (5), 101 (8), 100 (bp), 72 (6), 58 (9).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][C:13]([CH3:25])([O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:14]#[CH:15]>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:13]([CH3:25])([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[C:14]#[C:15][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: Ic1ccc2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1ccc2ccccc2n1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
5.1 g of 2-iodoquinoline were added at room temperature to a solution of 18 mg of palladium(II) chloride, 52 mg of triphenylphosphine and 38 mg of copper(I) iodide in 100 ml of diethylamine. 3,7 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were added. After stirring at room temperature for 18 hours the mixture was evaporated and the residue was dissolved in ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 5.8 g of 4-[1,1-dimethyl-3-(2-quinolyl)-2-propynyloxy]benzonitrile as a yellow gum.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1>>[CH3:4][C:3]([CH2:2][S:13][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)=[O:5]
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Product: CC(=O)CSc1ccc(Cl)cc1

Procedure:
Reaction of chloroacetone with 4-chlorothiophenol gave (4-chlorophenyl)thiomethyl methyl ketone, which was cyclized by reaction with polyphosphoric acid to 5-chloro-3-methylbenzothiophene. Bromination of the latter compound by photochemical reaction with N-bromosuccinimide provided 5-chloro-3-bromomethylbenzothiophene, which was reacted with sodium cyanide to give 5-chloro-3-cyanomethylbenzothiophene. The latter compound was hydrolyzed and esterified to give methyl α-(5-chloro-3-benzothienyl)acetate. Reaction of the ester with sodium methoxide and n-butyl nitrite afforded methyl α-hydroxyimino-α-(5-chloro-3-benzothienyl)acetate. Reduction of the oxime by reaction with zinc and formic acid and subsequent reaction with di-tert.-butyl carbonate gave N-tert.-butoxycarbonyl-(5-chloro-3-benzothienyl)glycine. NMR (CDCl3): δ 1.1-1.5 (broad s, 9H); δ 5.4-5.7 (broad s, 1H); δ 7.2-8.0 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Ethyl N-(3-chlorobenzyl)indole-2-carboxylate (0.47 g) was dissolved in THF/MeOH (1:1) and sodium hydroxide (2M, 4.5 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo to dryness and the residue dissolved in water. The solution was acidified to pH 3 by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered off, washed with water and dried in vacuo to give the desired end product (0.35 g, 82%), mp 188-189°; NMR δ(CD3SOCD3) 5.85 (s, 2H), 6.90 (d, 1H), 7.1 (m, 2H), 7.3 (m, 4H), 7.55 (d, 1H), 7.70 (d, 1H); M/z (−) 284 (M−H+).
Reaction SMILES: [Li].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.[CH3:12]I>C1COCC1>[CH3:12][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:2]1
Reactant: O=c1[nH]sc2ccccc12
Reactant: CI
Agent: [Li]
Solvent: C1CCOC1
Product: Cn1sc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of 1,2-benzisothiazolin-3-one lithium salt in THF (3 ml per gram of BIT salt) was added methyl iodide (1.1 molar equivalents). The resulting slurry was stirred at ambient temperature for 72 hours. HPLC analysis showed greater than 97% alkylation of 1,2-benzisothiazolin-3-one lithium salt. The mixture was allowed to cool and the crude product isolated as a mixture of N-methyl-1,2-benzisothiazolin-3-one and 3-methoxy-1,2-benzisothiazolin-3-one in 98.8:1.2 ratio.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].S(O[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)(=O)C.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Reactant: [O-]CCCN1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCOCCCN2CCCCC2)cc1
Yield: 75 %

Procedure:
According to the method disclosed in EP-982300, Example 78, sodium 3-piperidinopropanolate (2.127 kg; 12.88 mol), 3-(4-chlorophenyl)propyl mesylate (1.121 kg; 4.51 mol) and 0.322 mol of 15-crown-5 in 4.5 kg of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol (90/10)). The obtained oil was distilled in a fractionating equipment at reduced pressure (0.3-0.7 mmHg) and with a heating jacket at 207-210° C. The head fractions and the distilled fraction at 0.001-0.010 mmHg with a jacket temperature of 180-200° C. were collected. The obtained oil (1.0 kg; 3.38 mol) corresponds to 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine. Yield 75%.
Reaction SMILES: [C:1]([C:3]1[C:4](=N)[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)=[CH:10][CH:9]=[C:8]1[N:20]([CH3:23])[CH:21]=[CH:22][C:7]=21)#[N:2].[OH-:25].[Na+]>Cl.CS(C)=O.O>[C:1]([C:3]1[C:4](=[O:25])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)=[CH:10][CH:9]=[C:8]1[N:20]([CH3:23])[CH:21]=[CH:22][C:7]=21)#[N:2]
Reactant: Cc1cncc(-c2c(C#N)c(=N)oc3c2ccc2c3ccn2C)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cncc(-c2c(C#N)c(=O)oc3c2ccc2c3ccn2C)c1
Yield: 68 %

Procedure:
A solution of 3-cyano-2-imino-4-(5-methyl-pyridin-3-yl)-7-methyl-2H-pyrrolo[2,3-h]chromene (50 mg, 0.14 mmol) in 10% HCl (2 mL) and DMSO (0.5 mL) was stirred at room temperature for approximately 4 h. The yellow suspension was diluted with water (5 mL), neutralized to approximate pH=9 using 10% NaOH, and extracted with EtOAc (3×20 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes, 50-80% EtOAc) to yield a yellow solid (31 mg, 68%). 1H NMR (DMSO-d6): 8.71 (d, J=1.8 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.88 (m, 1H), 7.61 (d, J=3.0Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 6.91 (d, J=3.3 Hz, 1H), 3.88 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1C(C(O)=O)=C(C(O)=O)[C:12]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[C:29]([O:32][C:33](=[O:35])[CH3:34])(=[O:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]1[C:30]2[C:29](=[O:31])[O:32][C:33](=[O:35])[C:34]=2[C:12]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=C(O)c1c(C(=O)O)c(OCC(F)(F)F)c2ncccc2c1OCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c1c(OCC(F)(F)F)c1cccnc1c2OCC(F)(F)F
Yield: 96 %

Procedure:
A solution of 5,8-bis(2,2,2-trifluoroethoxy)quinoline-6,7-dicarboxylic acid 4 (180 mmol) in acetic anhydride (500 ml) was heated to reflux for 3 h and concentrated to dryness. The solid residue was triturated into 400 ml ether:hexane 1:4 to afford 68.2 g (96% yield for the last two steps) of the anhydride as a brownish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:19])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:19]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(S(=O)(=O)c2ccccc2)ccc1O

Procedure:
In 120 ml of dehydrated ethanol was suspended 11.05 g of 2-nitro-4-phenylsulfonylphenol followed by addition of a catalytic amount of Raney nickel for reduction in a hydrogen stream at atmospheric temperature and pressure. After completion of the reduction reaction, the catalyst was filtered off and the solvent was distilled off. The residue was dried under reduced pressure to give 9.73 g-of crude 2-amino-4-phenylsulfonylphenol. This product was dissolved in 19 ml of N,N-dimethylformamide and the solution was added dropwise to a mixture of 5.89 g of potassium fluoride, 7.61 g of ethyl 2-bromoisobutyrate and 11 ml of N,N-dimethylformamide. The mixture was then stirred at 60° C. overnight. The reaction mixture was poured in ice-water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with hexane-ethyl acetate (2:1). The crude crystals from the eluate were recrystallized from 15 ml of ethanol to recover 4.706 g of 3,4-dihydro-2,2-dimethyl-3-oxo-6-phenylsulfonul-2H-1,4-benzoxazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C=O)C>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A mixture of 2-methyl-4-nitrophenol (3.0 g, 19.6 mmol), TBS-Cl (3.0 g, 19.6 mmol), and TEA (2.2 g, 21.6 mmol) in DMF (30 mL) stirred at ambient temperature for 16 h. The mixture was partitioned between 10% aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with 10% aqueous sodium bicarbonate (3×100 mL) and water (100 mL), and evaporated under vacuum. The residue was chromatographed in hexanes-ethyl acetate gradient, providing 3.9 g of tert-butyldimethyl(2-methyl-4-nitrophenoxy)silane, in 75% yield; 1H NMR (DMSO-d6) δ 0.29 (s, 6H), 1.00 (s, 9H), 2.24 (s, 3H), 7.03 (d, J=8.9 Hz, 1H), 8.02 (dd, J=2.8, 8.9 Hz, 1H), 8.12 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.I[CH3:14].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: Oc1nccc2cc(Br)ccc12
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
6-Bromo-1-hydroxyisoquinoline (140 mg, 0.63 mmol, 1.0 equiv), tetrabutylammonium bromide (30 mg, 0.09 mmol, 0.15 equiv), and iodomethane (50 uL, 0.75 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting was mixture stirred rapidly at ambient temperature. After an additional 14 h at room temperature, the mixture was diluted with diethyl ether and washed with water, saturated NaHCO3, and brine. The organic phase was dried over Na2SO4 and concentrated to give a white solid of 6-bromo-2-methylisoquinolin-1-one (104 mg, 0.44 mmol, 70%). This crude material was taken forward without further purification and converted, via Methods 1 and 2, to compound 1 (45 mg, 38%) and isolated as a beige solid. [M−H]−=202.1 m/z. Activity: B
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:24][CH:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH2:26][CH3:27]>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13]([O:34][C:31]3[CH:32]=[CH:33][C:28]([CH:25]([CH3:24])[CH2:26][CH3:27])=[CH:29][CH:30]=3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCC(C)c1ccc(O)cc1
Reactant: CCCCCCCCC(Br)C(=O)Nc1cccc2cnccc12
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1cccc2cnccc12

Procedure:
N-(isoquinolin-5-yl)-2-bromodecanoic amide, prepared according to the procedures described in Example 3 and 25, was coupled with 4-(1-methylpropyl)phenol according to the procedure described in Example 6 to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[I:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>>[I:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:23]
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Reactant: O=C(Cl)c1ccccc1I
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccccc2I)CC1
Yield: 98 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 2-iodobenzoyl chloride (200 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude 2-[1-(2-iodo-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile was obtained as a solid. (320 mg; 98% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27](O)[C:28](=[CH:30][CH:31]=1)[OH:29].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:24][C:25]1[CH:26]=[CH:27][C:28]2[O:29][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)([C:15]3[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=3)[O:23][C:30]=2[CH:31]=1
Reactant: Oc1ccc(F)cc1O
Reactant: CSc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CSc1ccc(C2(C3CCNCC3)Oc3ccc(F)cc3O2)cc1
Yield: 33.6 %

Procedure:
A solution of 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 28) (168 mg, 0.50 mmol), 4-fluorocatechol (128 mg, 2.0 mmol) and p-TsOH.H2O (190 mg, 1.0 mmol) in xylene (50 mL) was heated at reflux under a Dean-Stark trap for 41 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (58 mg, 34%).