Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:39])[CH:24]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:23]([NH:21][NH:22][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:39])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl (2-hydrazinyl-2-oxo-1-phenylethyl)carbamate 249 (0.360 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g. 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 250 (0.40 g, 84%) as a white foam.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:32]([N:36]=[C:37]=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:37]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N=C=O
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and tert-butyl isocyanate (29 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (90 mg, 78%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C:7]2([O:16][CH3:17])[CH2:11][N:10]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1C[C@@](OC)(c2ccc(-c3ccccc3)cc2)CN1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(OC)(c2ccc(-c3ccccc3)cc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (150 mg, 0.482 mmol), (S)-2-(tert-butoxycarbonylamino)non-8-enoic acid (144 mg, 0.530 mmol), and HATU (260 mg, 0.723 mmol) in DCM (5 ml) was added N,N-diisopropylethylamine (0.252 ml, 1.445 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 18 h. It was then diluted with DCM, washed with 5% citric acid, and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to yield 2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylate (140 mg, 51.5% yield) as white foam.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:10])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=4)=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3cc(NC(=O)C=Cc4ccc(F)cc4)ccc3o2)C1
Yield: 69.3 %

Procedure:
Prepare according to Method C (Example 9), using 4-fluorocinnamic acid (107 mg, 0.643 mmol), oxalyl chloride (300 μL, 3.43 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (97 mg, 0.399 mmol) to afford the title compound (109 mg, 69%). mass spectrum (m/e): 395.3 [M+H], 393.3 [M−H]. 1H NMR (400 MHz, CDCl3): δ 7.68 (m, 1H), 7.53-7.35 (m, 4H), 7.17 (m, 1H), 7.07-6.95 (m, 2H), 6.49 (d, 1H, J=15.4 Hz), 3.94-3.77 (m, 2H), 3.59 (m, 1H), 3.44 (m, 1H), 2.89 (m, 1H), 2.31 (s, 6H), 2.24 (m, 1H), 1.96 (m, 1H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: NCCCCc1ccccc1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: O=S1(=O)N=C(NCCCCc2ccccc2)Nc2ccc(Cl)cc21

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.19 mmol) and 4-phenylbutylamine (1.5 g; 4.12 mmol) and with the use of same procedure as in example 21 120 mg (27.7%) of the title compound was prepared.; 1H-NMR (DMSO-d6) ppm; 10.8 (s, 1H, NH), 7.75 (d, 1H, H-8), 7.60 (dd, 1H, H-5), 7.2 (m, 7H), 3.29 (t, 2H, CH2), 2.66 (t, 2H, CH2), 1.5 (m, 4H, 2×CH2); MS:EI/70eV: 363 (M+), 272, 259, 231, 180, 91, 44.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(CCCCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>ClCCl.O1CCCC1>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.9 %

Procedure:
To the phenol resin (100 mg), 4-phenylbutan-1-ol (0.42 mmol) was added at room temperature, followed by the addition of dry tetrahydrofuran (0.4 mL) and dichloromethane (0.4 mL). At room temperature, tri-n-butylphosphine (0.42 mmol) was added dropwise thereto and further 1,1′-azobis(N,N-dimethylformamide) (0.42 mmol) was added. The mixture was shaken at room temperature for 5 hours. The resin was taken up by filtration, washed with a mixed solvent (dichloromethane:tetrahydrofuran=1:1) 4 times and dichloromethane 2 times and then dried to give a phenyl ether resin (about 100 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C[O:7][C:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:27])[CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1>CO.O>[OH:3][NH:2][C:8](=[O:7])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:27])[CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1
Reactant: COC(=O)C=Cc1cccc(NC(=O)C=Cc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1cccc(NC(=O)C=Cc2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.14 g, 2.01 mmol) (Acros) in methanol (2.0 ml) a solution of NaOH (0.16 g, 4.00 mmol) in H2O (0.2 ml) was added and the resultant mixture was stirred at ambient temperature for 5 min. To the reaction mixture a 3-[3-(3-phenylacryloylamino)-phenyl)-acrylic acid methyl ester (8) (0.15 g, 0.49 mmol) solution in methanol (2.0 ml) was added and stirred at ambient temperature for 1.5 hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was crystallized from ethyl acetate-methanol giving pure title compound (0.040 g, 26%), m.p. 178° C. 1H NMR (DMSO-d6, HMDSO), δ: 6.45 (d, 1H, J=16.0 Hz); 6.85 (d, 1H, J=16.0 Hz); 7.14-7.76 (m, 10H); 8.00 (br s, 1H); 9.03 (br s, 1H); 10.32 (br s, 1H); 10.83 (br s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 4.5% (column size 4.6×150 mm; mobile phase acetonitrile −0.1% H3PO4, gradient from 30 to 100%; sample concentration 0.25 mg/ml; flow rate 1.5 ml/min; detector: UV 270 nm). Anal. Calcd for C18H16N2O3×0.25 H2O, %: C, 69.11, H, 5.32, N, 8.95. Found, %: C, 69.09, H, 5.06, N, 8.81.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.C(O)(=O)C>O>[OH:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11][CH:10]=1
Reactant: Cc1c(OCc2ccccc2)ccc2c1OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(O)ccc2c1OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O

Procedure:
A mixture of 13.5 g or 7-benzyloxy-2,8-dimethyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 15, 40 ml of concentrated aqueous hydrochloric acid and 80 ml of acetic acid was heated under reflux for 3 hours. At the end of this time, the reaction mixture was poured into water and extracted with benzene. The benzene solution was washed with water and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. Cyclohexane was added to the residue to crystallize it. 9.55 g of the title compound were obtained as a pale red powdery substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C(N(CC)CC)C.[Cl:38][C:39]1[C:44]([NH:45][C:46]2[N:51]=[C:50]([N:52]([CH:62]3[CH2:64][CH2:63]3)[CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[C:49]3=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]3[N:47]=2)=[CH:43][C:42]([C:70]#[N:71])=[CH:41][C:40]=1[N:72]1[CH2:77][CH2:76][C@@H:75]([NH:78][C:79](=[O:82])[O:80][CH3:81])[C@H:74](O)[CH2:73]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][C@@H:76]1[C@@H:75]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH2:74][CH2:73][N:72]([C:40]2[CH:41]=[C:42]([C:70]#[N:71])[CH:43]=[C:44]([NH:45][C:46]3[N:51]=[C:50]([N:52]([CH:62]4[CH2:64][CH2:63]4)[CH2:53][C:54]4[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=4)[C:49]4=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]4[N:47]=3)[C:39]=2[Cl:38])[CH2:77]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@@H]1OC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (30.4 mg, 0.140 mmol), Tetramethylfluoroformamidinium hexafluorophosphate (37.0 mg, 0.140 mmol) and triethyl amine (0.039 mL, 0.280 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 h. (+/−)-methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (Example 171, 18 mg, 0.028 mmol) and DMAP (0.342 mg, 2.80 mol) were added and the reaction solution was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-30% ethyl acetate/dichloromethane). (+/−)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (23 mg) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:32]3[CH2:33][CH2:34][CH2:35][C@@H:30]([OH:29])[CH2:31]3)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCC[C@@H](O)C2)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 5b, 100 mg, 0.23 mmol) in DMF (2 mL) is added (R)-3-hydroxypiperidine hydrochloride (96 mg, 0.70 mmol) and N-ethyldiisopropylamine (362 μL, 2.1 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:7][NH:6][C:5]1=[S:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:29])=[C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27]Cl)[N:23]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC#N>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:29])=[C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27][S:14][C:5]3[N:4]([CH2:3][CH2:2][OH:1])[C:8]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[N:7][N:6]=3)[N:23]=2)[CH:21]=1
Reactant: OCCn1c(-c2cccs2)n[nH]c1=S
Reactant: Fc1ccc(Cl)cc1-c1nc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Yield: 62.7 %

Procedure:
4-(2-Hydroxyethyl)-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (101 mg), 5-(5-chloro-2-fluorophenyl)-3-(chloromethyl)-1,2,4-oxadiazole (116 mg), and potassium carbonate (86 mg) was stirred in a mixture of DMF (2 ml) and MeCN (15 ml) at r.t. for 3 h before concentration to dryness and washing of the residue with water, and then with EtOAc, to provide 122 mg of the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>>[N:18]([CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:11]=1)=[N+:19]=[N-:20]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)n1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN=[N+]=[N-])n1
Reaction time: 25 h
Yield: 75.5 %

Procedure:
A mixture of 2-[(tert-butyldimethylsilyloxy)methyl]-6-hydroxymethylpyridine (1) (2.14 g, 8.42 mmol), sodium azide (2.73 g, 42.0 mmol), triphenylphosphine (2.65 g, 10.10 mmol), and carbon tetrabromide (3.07 g, 9.29 mmol) was dried in vacuo, and dissolved in DMF (64 mL). To the solution was added triethylamine (2.64 mL) and stirred for 25 hours under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, the mixture was subjected to extraction with EtOAc and water. The organic layer was washed with sat. NaCl aq., dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Hex:EtOAc=50:1) to give 2-azidomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (2) (1.77 g, 76%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
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: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cccn3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-2-pyrroleboronic acid pinacol ester (96.8 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrrol-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.61 (dd, 1H), 7.57 (d, 1H), 7.4 (s, 1H), 7.37 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.8 (d, 1H), 6.21 (d, 1H), 6.1 (dd, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.7 (m, 3H), 3.57 (m, 1H), 3.2 (m, 4H), 3.03 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[C-:23]#[N:24].[Na+]>CS(C)=O>[C:23]([CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)#[N:24]
Reactant: [C-]#N
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC#N)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3.82 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 50 ml of dimethyl sulfoxide (DMSO) was added 0.75 g of sodium cyanide. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-water. The resultant mixture was extracted with benzene and the extracts were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to yield 2.4 g of 3-cyanomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole. It was recrystallized from ethyl acetate-diisopropyl ether to give colorless plates, m.p. 111°-112° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
2-Chloroquinoline (0.12 moles, 20.0 g), 4-nitrothiophenol (0.13 moles, 20.8 g), and potassium carbonate (0.13 moles, 18.5 g) were dissolved in 800 ml ethanol and stirred at room temperature for 1.5 hr. The mixture was filtered and the solid washed with ethanol. The solid was dissolved with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to yield 2-(4-nitrophenylthio)quinoline 26.0 g, 77%. Mass Spec (FD) 282. Calculated for C15H10N2O2S: C, 63.82, H 3.57; N, 9.92. Found: C, 63.55, H 3.59; N, 9.71.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2O.S(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[N:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1nnc2ccc(Cl)cc2c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2ccc(Cl)cc2c1Cl

Procedure:
A solution of 6 g of ethyl 6-chloro-4-hydroxy-3-cinnolin carboxylate in 300 cm3 of thionyl chloride and 1 cm3 of dimethyl formamide was stirred for 16 hours at reflux and the thionyl chloride was concentrated under reduced pressure. The residue was taken up several times in 50 ml of toluene to obtain 6 g of ethyl 4,6-dichloro-3-cinnolin carboxylate as a greenish residue melting at ≈50° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[N:4]([C:31]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:32])[CH2:3]1
Reactant: CC1(C)CNc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)N2CC(C)(C)c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc32)CC1

Procedure:
N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-nitro-benzamide (Example 7, Step A)(300 mg, 0.96 mmol) was treated with 4-methyl-piperazine-1-carbonyl chloride (200 mg, 1 mmol) in the presence of DIEA (40 mL) in THF overnight at 65° C. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with H2O and brine, then dried over Na2SO4. The organic solution was concentrated in vacuo to yield the desired compound.