Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH3:34].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH3:32][N:33]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:34]
Reactant: CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)C)c4)cc23)CC1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in THF (500 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for h before addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol). The reaction was then stirred overnight. Compound was purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound (19.2%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([NH2:26])=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (5.2 g), 1-hydroxybenzotriazole monohydrate (3.6 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.5 g) and N,N-dimethylformamide (200 mL) was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature and 10% aqueous ammonia (12 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (5.18 g, yield 100%) as pale-yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:24]1[CH:26]=[CH:27][C:19]([CH:18]=[O:17])=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a flask was added 1-bromomethyl-2,4-bis-trifluoromethyl-benzene (2.27 g, 7.39 mmol), vanillin (1.12 g, 1 equiv), DMF (23 mL) and fine mesh K2CO3 (5.11 g, 37 mmol). The reaction slurry was stirred at 70° C. for 15 h. The reaction solution was diluted with EtOAc (120 mL), filtered through a Buchner funnel, washed with sat NH4Cl (50 mL×2), dried over Na2SO4, filtered, and concentrated. The crude material was chromatographed (SiO2, Hex/EtOAc: 100:0 to 70:30) to yield intermediate product (2.79 g, 86%). 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=8 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 5.48 (s, 2H), 3.99 (s, 3H); MS (ESI) 379 (MH+).
Reaction SMILES: C(#N)C1C=CC=NC=1.[F:9][C:10]1[C:11]([NH:38][C@@H:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:40][OH:41])=[N:12][C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)=[C:14]([CH:17]=1)[C:15]#[N:16].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH3:53][S:54]([O:41][CH2:40][C@@H:39]([NH:38][C:11]1[C:10]([F:9])=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:19]=2)[N:12]=1)[C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:56])=[O:55]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Agent: N#Cc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a cold (0° C.) solution of (S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yellow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) retention time=2.03 minutes.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH3:20].[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[C:8]([CH3:20])[C:7]([B:21]([OH:24])[OH:22])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
n-Butyl lithium (1.6 M solution in hexanes, 37.5 ml, 0.060 mol) is added dropwise to a solution of 4-bromo-4′-chloro-3-methylbiphenyl (11.5 g, 0.041 mol) in tetrahydrofuran (120 ml) at −78° C., under an atmosphere of nitrogen, and the mixture is stirred at −78° C. for 30 minutes. Trimethyl borate (27.4 ml, 0.245 mol) is added slowly at −78° C. and the mixture is stirred for 1 hr. The reaction mixture is allowed to warm to room temperature over 2-3 hours and then stirred at room temperature for 1 hr. 0.1N Aqueous hydrochloric acid (320 ml) is added and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate (3×300 ml) and the organic extracts are combined, dried with anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4′-chloro-3-methylbiphen-4-ylboronic acid (6.0 g) as white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:27][O:28][CH3:29])[CH2:26][CH2:25][NH:24][CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][C:49]([F:52])=[CH:48][N:47]=3)=[C:42]([F:53])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:27][O:28][CH3:29])[CH2:26][CH2:25][N:24]([CH2:31][C:32]([N:34]6[CH2:35][CH:36]=[C:37]([C:40]7[CH:45]=[CH:44][C:43]([C:46]8[N:47]=[CH:48][C:49]([F:52])=[CH:50][N:51]=8)=[C:42]([F:53])[CH:41]=7)[CH2:38][CH2:39]6)=[O:33])[CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Reactant: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncc(F)cn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxymethyl-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1H-indazol-5-yl]-amide (26AB) (85 mg, 0.217 mmol, 1 equiv) and 2-Chloro-1-{4-[3-fluoro-4-(5-fluoro-pyrimidin-2-yl)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone (23AB) (84 mg, 0.239 mmol, 1.1 equiv) were weighed out in a flask and dissolved in anhydrous N,N-dimethylformamide (5 mL). Triethyl amine (33 mg, 46 uL, 0.326 mmol, 1.5 equiv) was added to the reaction mixture and the reaction content was stirred at room temperature overnight.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N+:24]([O-])=O)[CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.O.O.Cl[Sn]Cl>OS([O-])(=O)=O.[Na+].O1CCOCC1>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1N
Temperature: 100 °C

Procedure:
A suspension of 5-(4-(difluoromethoxy)phenyl)-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 28a (1.5 mmol) and SnCl2.2H2O (4.5 mmol) in 1N NaHSO4 (50 mL) and 1,4-dioxane (50 mL) is heated at 100° C. for 1 h. The solvent is removed under vacuum and the residue dissolved in 5% NaOH and extracted with DCM (3×50 mL). The organic layer is washed with 5% NaOH (1×50 mL), water (1×50 mL), brine, dried over Na2SO4 and concentrated to afford N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine 29a which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1H), 8.76 (s, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.30 (t, J=74.4 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.90 (dd, J=2.0, 8.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.95 (bs, 2H), 2.02 (s, 3H). MS (m/z) (M+1)+: 343.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:29][CH2:30]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2nc(N3CCN(CCCCn4nnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl)piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.3 g compound (I-48) with a yield of 62.7%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:9]=2)=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][N:17]1[CH:18]=[C:14]([C:10]2[CH:9]=[C:8]([C:5]3[N:4]=[CH:3][C:2]([C:36]4[CH:35]=[N:34][N:33]([CH:30]5[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]5)[CH:37]=4)=[CH:7][N:6]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=[N:16]1
Reactant: Cn1cc(-c2cccc(-c3ncc(Br)cn3)c2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: Cc1ccccc1
Solvent: CCO
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cn3)c2)cn1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A solution of 5-bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2, 160 mg, 0.50 mmol), 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Combi-blocks, 287 mg, 0.76 mmol) and Na2CO3 (140 mg, 0.12 mmol) in dry Toluene: Ethanol (1:1) (5 mL) was purged with nitrogen for 30 min before the addition of Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was then heated at 100° C. O/N and filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the crude product. Purification by Flash chromatography on silica (hexane:EtOAc) afforded the title compound as a yellow solid (230 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 2H), 8.53 (d, J=8.0 Hz, 2H), 8.25 (s, 1H), 8.21 (d, J=7.76 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.91-7.48 (m, 10H), 4.45-4.44 (m, 1H), 4.07-4.04 (m, 2H), 3.88 (s, 3H), 2.12 (s, 2H), 2.70 (d, J=3.44 Hz, 1H), 2.08-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): Rt 4.68 min (purity 87%). MS (ESI+): 486.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=3)[C:12]#[N:13])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: CN1CCCNCC1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Product: CN1CCCN(c2ccc(-c3ccc(C#N)c(=O)[nH]3)cc2)CC1

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 13.8 g. of N-methylhomopiperazine in 180 ml. of dimethyl sulfoxide, there is obtained 6-[p-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.C1(O)C=CC=CC=1.[CH2:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:27]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN1CCC(N)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(OC)cc23)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 6,9-dichloro-2-methoxyacridine (100 mg, 0.36 mmol) and phenol (approximately 1.5 g) was heated to 100° C. under nitrogen atmosphere and stirred for 1 hour. 1-Ethylpiperidin-4-amine (92 mg, 0.72 mmol) was added to the mixture. The reaction was stirred at 100° C. for 5 hours, cooled to 20-25° C., and diluted with dichloromethane. The mixture was washed twice with sodium hydroxide solution (1 N) and twice with ammonium chloride solution. The phases were separated, and the organic layer was dried and concentrated. The residue was purified by Biotage column chromatography using triethylamine (5%) and methanol (5 to 15%) in dichloromethane to give the title compound; MS (Found: M+1=370).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1CN([P+](O[N:47]2N=[N:54][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:47]1[C:16](=[O:17])[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1)[OH:13]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccccc1N1C(=O)c2ccccc2C1(O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
2-[(3-Oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]benzoic acid (100 mg, 0.34 mmol.) was taken into DMF (1 mL) followed by addition of 4-methylmorpholine (75 uL, 0.7 mmol.) and PyBOP (177 mg, 0.34 mmol.) and the resulting solution was stirred for 15 minutes at room temperature. o-Phenylenediamine (37 mg, 0.34 mmol.) was added to the solution thus obtained and the mixture was allowed to stir an additional hour then partitioned with ethyl acetate and water. The organic layer was washed with water (3×), 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (1×) and brine then dried over anhydrous sodium sulfate. A portion of the residue obtained on filtration and concentration of the organic solution was purified by silica gel flash chromatography (2:1 ethyl acetate:hexanes to 100% ethyl acetate) gave 6-[2-(2-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one (4.0 mg, 3% yield). The remainder of the crude residue was taken into acetic acid (5 mL) and heated to reflux for one hour. The solvent was removed in vacuo and the residue partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the residue was purified by silica gel flash chromatography (2.5:1 ethyl acetate:hexanes) to give 6-{[2-(1H-benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one (28 mg, 22% yield). 6-[2-(2-Aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one: MS (EI) for C22H17N3O4: 388 (MH+). 6-{[2-(1H-Benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one: 1H NMR (400 MHz, d6-DMSO): 12.84 (br s, 1H), 10.75 (br s, 1H), 8.00 (d, 1H), 7.73 (tr, 1H), 7.59 (tr, 1H), 7.44-7.37 (m, 3H), 7.32 (s, 1H), 7.15-7.06 (m, 3H), 6.87 (d, 1H), 4.58 (s, 2H). MS (EI) for C22H15N3O3: 370 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:19]([S:22][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)S
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccc([N+](=O)[O-])c(NC(=O)C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 88.1 %

Procedure:
A mixture of N-(5-chloro-2-nitropheny)-2,2-dimethylpropanamide (Step A, 1.54 g, 6.0 mmol), 2-methyl-2-propanethiol (675 μL, 6.0 mmol) and potassium carbonate (993 mg, 7.2 mmol) in N,N-dimethylformamide (25 mL) was stirred in a sealed tube at 100° C. for 17 h. Water (20 mL) was added and precipitate was collected by filtration and dried in vacuo at 50° C. to afford the title compound (1.64 g, 88%) as an orange solid.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21]Cl>O1CCCC1.CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][S:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1S
Reactant: ClCOc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1SCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of 28 g (0.25 mol) of potassium tert.-butylate in 120 ml of tetrahydrofuran was slowly added dropwise to a solution of 33.6 g (0.2 mol) of methyl 2-mercapto-benzoate in 50 ml of tetrahydrofuran at 5° C. At the end of the dropwise addition, stirring was continued at 5° C. for a further 30 minutes. The solid product precipitated was filtered off with suction and dissolved in 100 ml of dimethylformamide. A solution of 42.3 g (0.2 mol) of chloromethyl 2,4-dichlorophenyl ether in 60 ml of dimethylformamide was added dropwise to this solution, while stirring at 25° C. The mixture was subsequently stirred at 30° C. for 1 hour and then worked up by stirring into 1.5 liters of ice-water. The suspension thereby formed was filtered off with suction and the solid product precipitated was dried in air. 62 g (90.4% of theory) of 1-(2,4-dichlorophenoxy)-1 -(2-methoxycarbonyl-phenylthio)-methane were obtained in this manner in the form of colourless crystals of melting point 122°-124° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:20]2[O:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([OH:11])[C:4]=3[C:2]=2[CH3:1])=[O:22])=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cccc(O)c12
Yield: 17.4 %

Procedure:
A mixture of 2,6-dihydroxyacetophenone (4.5 g, 30 mmoles), p-chloro-ω-bromoacetophenone (6.9 g, 30 mmoles), potassium carbonate (4.1 g, 30 mmoles) and acetone (100 ml) was refluxed for 7 hours. The mixture was filtered and concentrated. The residue was partitioned between methylene chloride (250 ml) and in sodium hydroxide solution (100 ml). The aqueous phase was separated and acidified with 20% citric acid solution. The precipitated product was filtered and chromatographed to obtain 1.5 g of the title compound, m.p. 238°-241° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH2:38][C:39](Cl)=[O:40])[CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)([O-:28])=[O:27]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:39](=[O:40])[CH2:38][C:31]3[CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(3,5-Dinitrophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(3,5 -dinitrophenyl)acetyloxy] -2 (1H)-pyrimidinone as the residue.