Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][CH:24]=2>>[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH:31][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:25][CH:24]=2
Reactant: CO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Product: CO[C@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(C)c5c4)c3s2)C1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone and 2,3-dimethyl-1H-indol-5-ylamine by a procedure analogous to Example 99. MS: 421.2 (MH+); HPLC Rf: 4.80 min.; HPLC purity: 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:17]([CH3:16])[C@H:18]2[CH2:37][N:22]3[C:23]4[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]3[CH2:20][CH2:19]2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:11])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(F)cc1C(F)(F)F
Product: CN(C(=O)Cc1ccc(F)cc1C(F)(F)F)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-fluoro-2-(trifluoromethyl)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 463.
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:4]3[O:3][C:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:6][CH:5]=3)[N:12]=2)[CH:19]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)n2)c1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccccc4)o3)n2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
A solution of [6-(2-iodo-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (46 mg, 0.121 mmol), phenylboronic acid (30 mg, 0.246 mmol), K2CO3 (37 mg, 0.268 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) in a mixture of THF (4 ml) and water (2 ml) was stirred at 90° C. for 18 h. The cooled reaction mixture was treated with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 eluting with 30% EtOAc in cyclohexane to afford the title compound as a pale orange solid (30 mg, 75%). 1H NMR (DMSO-d6, 300 MHz): δ=9.79 (s, 1H), 8.12 (m, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.78 (m, 2H), 7.58 (m, 2H), 7.40 (t, J=7.0 Hz, 1H), 7.33 (t, J=7.0 Hz, 1H), 6.78 (d, J=5.0 Hz, 1H), 2.37 (s, 3H). (ESI+) m/z 329 (M+H)+. Retention time=2.84 mins (method 1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C-:13]#[N:14].[K+]>ClCCl>[CH2:1]([C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#CCc1ccccc1
Temperature: 52.5 °C
Yield: 195.4 %

Procedure:
To a solution of 40.00 g(180 mmoles) of benzyl alcohol in 530 ml of dichloromethane was added within 5 min 32.7 ml (450 mmoles) of thionyl chloride. The solution was evaporated in vacuo to dryness, which was repeated after toluene addition: 46.30 g (106.9%) of crude benzyl chloride, which was dissolved in 230 ml of dimethylformamide and treated with 23.50 g (360 mmoles) of potassium cyanide. The mixture was heated for 4 hours to 50-55° C. The salt was filtered off and the filtrate evaporated in vacuo to dryness, which was repeated after the addition of water, the residue was taken up in ether and extracted with 1N NaOH. The ether phase is evaporated to dryness to yield 41.20 g (99.0%) of crude benzyl cyanide.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].O>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: CNc1c(N)cc(Br)nc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(Br)nc(Cl)c1NC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-bromo-2-chloro-N3-methylpyridine-3,4-diamine 2.59 (410 mg, 2.74 mmol) was dissolved in pyridine (10 mL). Mixture was cooled down to 0° C. and then propanoyl chloride (207 mg) was added portion wise. Mixture was stirred at 0° C. for 1 h. Reaction mixture was poured into water and extracted with ethyl acetate. Organic phase was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Resulting residues were purified by silica gel chromatography (5% MeOH in DCM) to provide N-(6-bromo-2-chloro-3-(methylamino)pyridin-4-yl)propionamide (2.78). LC/MS found for C9H11BrClN3O as (M+H)+ 291.9.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:3]12.[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.Cl>CN(C)C=O.O1CCOCC1>[CH:28]1([CH2:27][N:8]2[CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]3[CH2:13][CH2:14][NH:15][CH2:16][CH:3]3[C:2]2=[O:1])[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3CNC(=O)C2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C1C2CNCCN2c2ccccc2CN1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate (100 mg, 0.315 mmol, Example 1) in anhydrous N,N-dimethylformamide (2 mL) was added sodium hydride (13.86 mg, 0.347 mmol). After stirring for 1 hour at room temperature, (bromomethyl)cyclopropane (102 mg, 0.756 mmol) was added to the reaction mixture. The reaction was stirred for 20 hours. The reaction was then quenched carefully with water and extracted with ethyl acetate. The organic layer was separated, dried with MgSO4, and concentrated. The residue was purified via flash chromatography (0-40% ethyl acetate/hexanes). The material obtained was dissolved in 1,4-dioxane (0.8 mL) and 4 M HCl in 1,4-dioxane (0.8 mL). The mixture was stirred for 20 hours. at room temperature. The title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.19 (s, 1H), 7.07-6.94 (m, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.70 (t, J=7.2 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (s, 1H), 4.17 (d, J=16.1 Hz, 1H), 3.51-2.79 (m, 8H), 0.66 (m, 1H), 0.15-0.05 (m, 1H), 0.05-0.08 (m, J=4.1 Hz, 1H); MS (DCI) m/z 221.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:14](=[O:29])[C:13]=1[CH:12]=2.[NH2:30][CH2:31][C@@H:32]([OH:43])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1[CH3:42].CCN(CC)CC>CCO>[CH3:42][C:36]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C@H:32]([OH:43])[CH2:31][NH:30][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:14](=[O:29])[C:13]=1[CH:12]=2
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (448.3 mg, 1.35 mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (303.0 mg, 1.55 mmol) in EtOH (10 mL) was added Et3N (410 mg, 4.05 mmol). After it was heated at 100° C. for 14 h, the reaction mixture was concentrated under reduced pressure. The chromatography of the crude residue (150:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) afforded the title compound (498 mg, 45%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.95 (m, 2H), 2.18 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.39 (m, 2H), 2.90 (m, 2H), 3.57 (m, 1H), 3.71 (m, 1H), 3.90-4.08 (3H), 4.18 (m, 1H), 5.55 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 6.92 (d, J=6 Hz, 1H), 6.97 (s, 1H), 7.39 (d, J=6 Hz, 1H), 7.64 (s, 1H), 8.09 (s, 1H), 10.96 (br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MS m/z 571.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][C:36]3[CH:39]=[C:40]([C:43](O)=O)[CH:41]=[CH:42][C:35]=3[O:34]2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:43]([C:40]3[CH:39]=[C:36]4[C:35](=[CH:42][CH:41]=3)[O:34][C:31]3([CH2:30][CH2:29][NH:28][CH2:33][CH2:32]3)[CH2:38][CH2:37]4)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCc3cc(C(=O)O)ccc3O2)CC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc5c(c4)CCC4(CCNCC4)O5)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 50 °C
Yield: 79.9 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and N-tert-butoxycarbonyl-6-carboxy-3,4-dihydrospiro[2H-1-benzopyran-2,4′-piperidine] (75.4 mg, 0.228 mmol) were reacted. The crude reaction was concentrated, then taken up into 4N HCl/dioxane and heated at 50° C. for 4 hours. The reaction mixture was then concentrated and chromatographed on Gilson HPLC 0-45% CH3CN/H2O. The desired fractions were lyophilized to produce 65 mg (47%) of the title compound as the TFA salt. mp: lyophilate, 1H NMR (300 MHz, DMSO-d6): 13.19 (s, 1H), 8.59 (m, 1H), 8.42 (m, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.89 (d, 1H), 7.76 (s, 1H), 7.25 (s, 2H), 7.00 (d, J=8 Hz, 1H), 6.38 (s, 2H), 5.19 (t, J=8 Hz, 1H), 3.23 (m, 2H), 3.14 (m, 2H), 2.88 (m, 3H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.96-1.85 (m, 4H), 1.39 (d, J=8 Hz, 1H). MS: 551 (M+H), HPLC: 1.94 min (G method).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10]/[C:9](=[C:12](/[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)\[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)/[C:8]1=[O:30])(=O)C.[OH-].[Na+]>C(O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23](/[C:12](=[C:9]2\[C:8](=[O:30])[N:7]([CH2:6][CH2:5][OH:4])[CH2:11][CH2:10]\2)/[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CC(=O)OCCN1CC/C(=C(/c2ccc(Cl)cc2)c2ccc(S(C)(=O)=O)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C2\CCN(CCO)C2=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
1 g (0.0022 mole) of (Z)-2-[3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-oxo-pyrrolidin-1-yl]ethyl acetate are placed in solution in a mixture of 13 ml of ethanol and 11 ml of water and treated with 0.1 g (1.1 eq.) of sodium hydroxide. The medium is stirred at ambient temperature for 4 h, then the ethanol is evaporated off. The aqueous phase is extracted with dichloromethane. The organic phase is washed with water, dried and concentrated. The residue is taken up into t-butyl methyl ether. 0.7 g of (Z)-3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-1-(2-hydroxyethyl)-pyrrolidin-2-one are thus obtained as a yellow solid of melting point 187-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([SH:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:26][C@H:21]2[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([S:8][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[C@@H:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](O)[C@@H](Sc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
In a 25 ml flask equipped with thermometer and nitrogen admission, there are introduced 26 mg of zinc acetate dihydrate, 948 mg of 5-chloro-2-nitrothiophenol and 5 ml of toluene. To the suspension are added dropwise, within 5 mn, a solution of 1.093 g of methyl (-) (2R,3S) 3-(4-methoxyphenyl)-2,3-epoxy-propionate in 9 ml of toluene at 25° C. The temperature rises to 29° C., whilst stirring is maintained for 45 mn. The mixture is evaporated in vacuo, and a yellow oil is obtained, which is used as it is in the subsequent example.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>CC(O)(C)C.C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:35][CH:36]=3)=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc2c(Cc3ccc(N)cc3)ccnc2c1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc2c(Cc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 1-chloro-4-phenylphthalazine (0.082 g, 0.34 mmol) and 4-((7-methoxyquinolin-4-yl)methyl)benzenamine (0.090 g, 0.34 mmol) in tBuOH (2.5 mL) was heated to 105° C. in a resealable tube. After 3 hrs, the mixture was cooled to RT, diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic fraction was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography using 50-100% Hexanes:EtOAc to afford N-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-4-phenylphthalazin-1-amine as a light yellow solid. MH+=469.2@1.47 min
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](S)[N:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(C)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)nc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
A solution of 25.0 grams (g) 4,6-dimethyl-2-mercaptopyrimidine, 25.1 g 4-fluoronitrobenzene and 24.6 g potassium carbonate in 750 milliliters (ml) acetonitrile was refluxed for 16 hours. The solution was then filtered hot through a pad of dicalite. The dicalite was washed with 300 ml hot acetonitrile. The solvent was evaporated from the combined filtrates giving a waxy yellow solid. This solid was triturated with hexanes giving 42.5 g yellow solid.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(O)C>[CH2:13]([O:20][N:21]=[C:4]1[CH:5]2[CH2:10][N:1]3[CH2:8][CH:7]([CH2:9][CH:3]1[CH2:2]3)[CH2:6]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: Cl
Solvent: CCO
Product: c1ccc(CON=C2C3CC4CC2CN(C4)C3)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-azatricyclo[3.3.1.13,7]decan-4-one (45 mg, 0.30 mmol) (prepared as reported in Becker, D. P. and Flynn, D. L. Synthesis 1992, 1080-1082) and O-benzylhydroxylamine hydrochloride (Aldrich, 51 mg, 0.32 mmol) were combined in a test tube with ethanol (3 mL). Concentrated hydrochloric acid (12 M, 0.1 mL) was added, and the mixture was heated at reflux until the solids dissolved. The solution was allowed to stand at room temperature overnight, then concentrated under vacuum. The residue was dissolved in acetonitrile (0.7 mL), and the solution was diluted with ethyl acetate (5 mL). The resulting white precipitate was collected by filtration, washed with ethyl acetate (2 mL) and dried under vacuum to provide the title compound as the hydrochloride salt. 1H NMR (300 MHz, CD3OD) δ 1.89-2.07 (m, 2 H), 2.15-2.37 (m, 3 H), 2.85 (s, 1 H), 3.42-3.85 (m, 7 H), 5.08 (s, 2 H), 7.24-7.40 ppm (m, 5 H); MS (DCI/NH3) m/z 257 (M+H)+; Anal. C16H20N2O-2HCl requires C, 58.36; H, 6.73; N, 8.51; Found C, 58.61; H, 6.49; N, 8.48.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][C:12]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.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.O>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10]([C:34]#[N:35])=[CH:11][C:12]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:21])[CH3:20])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(OS(=O)(=O)C(F)(F)F)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C#N)c12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a mixture of methyl(4-(((trifluoromethyl)sulfonyl)oxy)-6-((triisopropylsilyl)oxy)-1-benzothiophen-3-yl)acetate (5.8 g) and DMF (dry) (80 mL) were added zinc cyanide (2.095 mL) and Pd(Ph3P)4 (1.273 g) at room temperature, and the mixture was stirred at 100° C. for 20 h. The mixture was cooled to room temperature. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.920 g).
Reaction SMILES: [OH-].[K+].[C:3]([CH2:5][C:6]([NH2:8])=[S:7])#[N:4].Br[CH2:10][C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13].O>C(O)C>[CH3:13][C:12]([C:11]1[N:8]=[C:6]([CH2:5][C:3]#[N:4])[S:7][CH:10]=1)([CH3:15])[CH3:14]
Reactant: N#CCC(N)=S
Reactant: CC(C)(C)C(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1csc(CC#N)n1
Yield: 51.8 %

Procedure:
To a solution of 16.5 g of 85% KOH in 250 ml ethanol was added 25.0 g of 2-cyanothioacetamide. After all of this reagent had dissolved, 44.8 g of bromopinacolone was added dropwise over ca 5 min. The reaction temperature spontaneously climbed to 65° C. and a white solid began to deposit. The mixture was stirred and heated at reflux for 1 hour, cooled, poured into 1000 ml water, and extracted with ether. The extract was washed with brine, dried (MgSO4), and concentrated. Kugelrohr distillation of the residual oil gave 23.3 g of the desired product as a light yellow oil b.p. 90°-95° C. (1 mm Hg).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].Cl[C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=2[N:11]=1>CO>[OH:3][NH:2][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: ONc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 20 °C
Yield: 56.3 %

Procedure:
21.81 g of hydroxylamine hydrochloride are added to 17.61 g of potassium hydroxide in solution in 350 ml of methanol at a temperature in the region of 20° C. and the reaction mixture is brought to reflux for 10 minutes. 13.24 g of 2-chloro-6-(trifluoromethoxy)benzothiazole are then added and the reaction is continued at reflux for 5 hours. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered off and the filtrate concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa). The crude product thus obtained is purified by flash chromatography on a silica column, using an ethyl acetate/cyclohexane (20/80 by volume) mixture as eluent. 7.35 g of 2-hydroxyamino-6-(trifluoromethoxy)benzothiazole are thus isolated in the form of an orangey-yellow powder melting with decomposition at 119° C. [(Analysis % calculated C: 38.40, H: 2.01, F: 22.78, N: 11.20, S: 12.82; % found C: 38.7, H: 1.9, F: 22.3, N: 11.1, S: 12.6); 1H N.M.R. spectrum (250 MHz, d6-(CD3)2SO, at a temperature of 373 K, δ in ppm): 7.22 (mt, 2H, H 4 and H 5), 7.62 (broad s, 1H, H 7), 9.55 and from 9.50 to 11.00 (respectively broad s and unresolved peak, each 1H, NHOH)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][C:28]([NH2:30])=[S:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]=[C:28]([CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:29][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)CCc1ccccc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2sc(CCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3)(0.115 g, 0.340 mmol) in ethanol (4 mL) in a 10 mL round bottom flask was added 3-phenylthiopropionamide from Step 1 (0.059 g, 0.357 mmol) and the mixture was heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with Na2CO3 (10% solution), brine, dried over Na2SO4, filtered and concentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-(2-phenylethyl)thiazole (0.090 g, 65%) as oily crystals: mp 97°-99° C.; 1HNMR (CDCl3) 300 mHz 7.50 (d of d, J=5.38 and 8.80, 2 H), 7.35-7.15 (m, 9H), 6.99 (t, J=8.80, 2H), 3.35 (t, J=8.80, 2 H), 3.19 (t, J=8.56 Hz, 2H), 2.49 (s, 3H); MS (EI) m/z 405.10 (MH+), HRMS (M+) Δ=0.0 mmu.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2](=[O:10])[N:1]=2)[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2ccccc2N1
Agent: O=S(=O)(O)O
Product: O=C1C=c2cc([N+](=O)[O-])ccc2=N1
Yield: 92.4 %

Procedure:
1,3-Dihydro-indol-2-one 30a (20.0 g, 150 mmol) was dissolved in sulfuric acid (100 ml, 98%) in an ice-water bath under stirring, and added dropwise with nitric acid (10 ml, 65%-68%) while maintaining the temperature below 0° C. Upon completion of the addition, the mixture was stirred for 1 hour at 0° C. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ice and filtered after ice-out. The filter cake was washed with water (20 ml×3), and the resulting solid was recrystallized to obtain the title compound 5-nitro-indol-2-one 30b (25.3 g, yield 92.4%) as an orange solid.