Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].[I:28]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:28])=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a −78° C. solution of Example 135A (250 mg, 0.741 mmol) in 10 mL tetrahydrofuran was added lithium diisopropylamide (2.0M solution in tetrahydrofuran, 0.556 mL, 1.112 mmol) slowly over the course of 5 minutes. The resulting solution was stirred at the same temperature for 30 minutes after which iodine (376 mg, 1.483 mmol) in 5 mL of tetrahydrofuran was slowly added over 10 minutes. The reaction was stirred at −78° C. for 2.5 hours, and was quenched by addition of 1M aqueous sodium thiosulfate solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound. MS (ESI+) m/z 462 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a solution of example 5 (0.180 g, 0.493 mmol) in methanol (4 ml) cooled to 0° C., sodium borohydride (0.018 g, 0.493 mmol) was added and stirred for 1 h. The reaction was quenched by the addition of ice-cold water, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a yellow solid (0.070 g, 39%). M.P.: 187-189° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H), 8.12 (d, J=8.7 Hz, 1H), 8.02 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 6.20 (s, 2H), 5.32 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H). MS (m/z): 367.88 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[C:30](#[N:39])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:30]([CH2:31][CH:32]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)#[N:39]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Reactant: N#CC=Cc1ccccc1
Product: N#CCC(c1ccccc1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and cinnamonitrile. LCMS (M+H)+: m/z=531.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:25][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Temperature: 0 °C

Procedure:
4-(2-Hydroxyethyl)phenylboronic acid (step 1, 1.00 g, 6.02 mmol) was treated with pyridine (90 mL) and p-toluenesulfonylisocyanate (1.01 mL, 6.63 mmol) at room temperature for 2 h. The mixture was poured into ice-2 M HCl (200 mL) and extracted with ethyl acetate, (300 mL), and the organic fraction was dried (MgSO4). After removal of solvent, the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (20:1) to give 2.20 g (quant.) of the title compound as white solids: MS (ESI) m/z 381 [M+NH4]+, 362 [M−H]−, 1H-NMR (DMSO-d6) δ 11.95 (1H, br.s), 7.97 (1H, s), 7.75-7.67 (2H, m), 7.40 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=7.7 Hz), 4.18 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz), 2.40 (3H, s).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH2:12]2
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3cc(Cl)cc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.389 g, 1.0 mmol), 4-methoxy-benzylamine (0.169 mL, 1.2 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.111 g, 27%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.79 (s, 3H), 4.12 (s, 2H), 4.71 (s, 2H) 6.86 (d, 2H), 7.25 (m, 2H), 7.36 (s, 1H), 7.90 (s, 1H). GC-MS: m/z 413 (M)+, 382 (M−31)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[ClH:11].[N:12]#[C:13][NH2:14]>C(O)C>[ClH:11].[NH:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:13]([NH2:14])=[NH:12]
Reactant: N#CN
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1cccc(C(=O)O)c1
Yield: 24.3 %

Procedure:
A mixture of 3-aminobenzoic acid (Aldrich, 2.74 g, 0.02 mol), hydrochloric acid (12N, 1.66 g, 0.02 mol), and cyanamide (1.64 g, 0.04 mol) in absolute ethanol (50 mL) was heated at reflux for 16 h. The mixture was cooled and the precipitate separated by filtration. The cake was washed several times with ether and dried under vacuum to give 1.05 g (26.6%) of the title compound as an off-white amorphous powder, mp 278° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:22][O:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](O[N:51]2N=[N:58][C:53]3C=CC=C[C:52]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:52]([CH2:53][NH:58][C:31](=[O:32])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:21]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)=[N:24][O:23][N:22]=1)#[N:51]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)C[C@H](Nc1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N

Procedure:
To N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)leucine (350 mg, 0.763 mmol), PyBOP (440 mg, 0.84 mmol), aminoacetonitrile hydrochloride (155 mg, 1.68 mmol) in dry DMF (10 mL) under dry nitrogen was added triethylamine (0.38 mL, 2.67 mmol) dropwise and the reaction stirred for 2½ hours. Aqueous sat. NaHCO3 was added and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6) to afford N1-(cyanomethyl)-N2-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)leucinamide.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18](I)[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:28]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:29]#[CH:30]>CN(C=O)C.[Cu]I.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>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([C:30]#[C:29][CH2:28][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of (35) (400 mg, 1.0 mmol) in dry DMF (10 ml) was added CuI (38 mg, 20 μmol) and triethylamine (300 μl, 2.0 mmol). The propargyltrifluoroacetamide (453 mg, 3.0 mmol) was added drop wise, followed by Pd(PPh3)4 (110 mg, 9.5 μmol). The reaction was stirred for 16 h in the dark. The reaction was quenched by adding MeOH (10 ml), DCM (10 ml) and bicarbonate dowex. The mixture was stirred for 30 min and then filtered. The solvents were removed under vacuum and the crude product was purified by chromatography on silica (EtOAc: petrol 3:7 to 7:3). The product was isolated as slightly yellow crystals (398 mg, 95%). 1H NMR (d6 DMSO) δ 2.25-2.43 (m, 2H, H-2′), 3.65-3.76 (m, 2H, H-5′), 4.07-4.17 (m, 3H, H-4′, CH2), 4.21-4.23 (m, 1H, H-3′), 4.34 (d, J=5.5 Hz, 2H, CH2N), 5.25-5.27 (m, 2H, ═CH2, OH), 5.38 (dd, J=1.83, 17.3 Hz, 1H, ═CH2), 5.96-6.06 (m, 1H, ═CH), 6.17 (t, J=6.9 Hz, 1H, H-1′), 8.29 (s, 1H, H-6), 10.17 (t, J=5.5 Hz, 1H, NHTFA), 11.78 (s, 1H, NH). Mass (−ve electrospray) calcd for C17H18F3N3O6 417.11. Found 416.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH3:13])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[CH3:10][C:11]1([CH3:13])[O:1][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[O:9]1
Reactant: Oc1ccc(F)cc1O
Reactant: CC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CC1(C)Oc2ccc(F)cc2O1
Yield: 56.2 %

Procedure:
In a flask were placed 40 g (0.31 mole) of 1,2-dihydroxy-4-fluorobenzene, 36.25 g (0.625 mole) of acetone, and 400 mL of methylene chloride. To this solution was added 133 g (0.937 mole) of phosphorus pentoxide in portions during a five minute period. This mixture was stirred at ambient temperature for approximately 16 hours after which the methylene chloride was decanted from the solid material in the flask. Ice was added to the flask, and the solid residue was dissolved in water and extracted with methylene chloride. The phases were separated, and the organic phase was combined with the methylene chloride solution that had been decanted from the reaction mixture. This solution was washed in succession with a 5% aqueous solution of sodium hydroxide and then with water. After being dried over anhydrous magnesium sulfate and filtered, the organic solution was evaporated under reduced pressure, leaving 29.3 g of 2,2-dimethyl-5-fluoro-1,3-benzodioxole as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]3=[O:17])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 42.6 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 38 parts of 1-(diphenylmethyl)piperazine, 48 parts of sodium carbonate and 400 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(O)C.[Sn](Cl)[Cl:32].[OH-].[Na+]>Cl.C(OCC)(=O)C>[ClH:32].[NH2:25][C:21]1[CH:20]=[C:19]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C(NC(=O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]benzamide (3.24 g) [prepared as described in step (c) above] was added in small portions to a 1:1 by volume mixture of ethanol and concentrated hydrochloric acid at ambient temperature. Tin (II) chloride (6.78 g) was then added in small portions to the mixture in an ice bath. The mixture was stirred at ambient temperature for 20 minutes and then heated under reflux for 2 hours. After cooling, the reaction mixture was neutralized with aqueous solution of sodium hydroxide and the insoluble material was removed by filtration using a Celite (trade mark) filter aid. The filtrate was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 2:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford a colorless oil. This oil was dissolved in a solution of hydrogen chloride in ethyl acetate (4N) and the solvent was evaporated to dryness. The residual solid was suspended in diethyl ether and filtered, to afford the title compound (2.68 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A mixture of 2,3-dichloronitrobenzene (92.5 g), tert-butylamine (138 ml) and ethanol (50 ml) is heated in a bomb at 150° for 3 days. Dilution with water, extraction with ethylacetate several times, drying with sodium sulfate, and concentration gives the title compound, IR (neat) 2970, 1532, 1484, 1447, 1366, 1348, 1192 and 755 cm-1 ; NMR (CDCl3) 7.73, 7.61, 7.07, 4.77 and 1.22 δ; MS (m/z) 172, 154, 142, 126, 114, 99 and 90.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14].[Cl:16]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:16])[C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1c(O)c(Cl)cc(C(=O)OC)c1O
Reaction time: 17 h

Procedure:
A solution of 2.1 g (0.01 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.6 g (0.012 mol) of N-chlorosuccinimide in 50 mL of carbon tetrachloride was stirred at reflux for 9.5 hours. Additional N-chlorosuccinimide (1.6 g) was added and reflux was continued for 17 hours. 0.8 g of N-chlorosuccinimide was added and reflux was continued for 8 hours. Water was added. The organic layer was separated and washed with sodium thiosulfate solution, sodium bicarbonate solution, dried and concentrated under reduced pressure to give 5-chloro-2,4-dihydroxy-3-propylbenzoic acid methyl ester. Recrystallization from hexane gave analytically pure material, mp 75°-76°.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](O)=[O:22])[N:4]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:38]([O:42][C:43](=[O:49])[C@H:44]([CH3:48])[C@@H:45]([NH2:47])[CH3:46])([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:38]([O:42][C:43](=[O:49])[C@H:44]([CH3:48])[C@@H:45]([NH:47][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[CH3:46])([CH3:39])([CH3:41])[CH3:40]
Reactant: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: C[C@H](N)[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
A flask was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid (40 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol) and CH2Cl2 (2 mL). EDC (35 mg, 0.18 mmol) was added, and the mixture was stirred for 10 min. (2R,3S)-3-Amino-2-methyl-butyric acid tert-butyl ester (22 mg, 0.13 mmol) and Hunig's base (0.050 mL, 0.26 mmol) were then added, and the resulting mixture was stirred for 3 days at r.t. Hydrochloric acid (0.1 M) was added to acidify the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-10% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound as a white solid. MS: (−) m/z 460.31 (M−1).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.[NH2:16][OH:17]>CO>[OH:17][N:16]=[CH:1][C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Solvent: CO
Product: CNc1nc(C=NO)c(-c2ccncc2)s1
Reaction time: 2 h

Procedure:
A solution of 4-formyl-2-methylamino-5-(4-pyridyl)thiazole (0.9 g) in methanol (15 ml) was added to a 1N-methanolic hydroxylamine solution (5.8 ml) at ambient temperature with stirring, which was continued under the same condition for 2 hours. The precipitate was collected by filtration and recrystallized from an aqueous tetrahydrofuran to afford 4-hydroxyiminomethyl-2-methylamino-5-(4-pyridyl)thiazole (1.02 g).
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:14]([C:16]1([CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)#[N:15]>O1CCOCC1>[CH2:29]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:14][N:15]1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)C2
Reaction time: 16 h
Yield: 85.5 %

Procedure:
Under ice-cooling, 1M sodium hydroxide aqueous solution (6.0 ml) and benzyl chloroformate (1.03 g) were sequentially added to a dioxane (50 ml) suspension of tert-butyl 4-cyano-4-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate (2.15 g), and stirring was performed at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, and extracted with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 2-benzyl 7-tert-butyl 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate (1.68 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc(C(F)(F)F)nc2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 5-bromo-2-trifluoromethyl-pyridine (1.356 g, 6 mmol), K3PO4 (1.272 g, 6 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (70 mg, 0.4 mmol) in dry DMF (5 mL) was stirred at 150° C. for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100-200 mesh) and 3% MeOH:DCM to yield 2,8-dimethyl-5-(6-trifluoromethyl-pyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (150 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 8.85 (s, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 3.9-3.85 (m, 1H), 3.6-3.59 (m, 1H), 3.25-3.2 (m, 1H), 3.2 (s, 3H), 3.1-3.0 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 76.1 %

Procedure:
To a solution of 10.75 gm (50 mMol) 5-fluoro-3-[1,2,5,6-tetrahydro-4-pyridyl]-1H-indole in 500 mL ethanol were added 2.0 gm 5% palladium on carbon and the reaction mixture hydrogenated at ambient temperature for 18 hours at an initial hydrogen pressure of 60 p.s.i. The reaction mixture was then filtered through a pad of celite and the filtrate concentrated under reduced pressure to give an off-white solid. The solid was recrystallized from methanol to give 8.31 gm (76.2%) of the title compound as a colorless solid.