Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1.[I-:26].[K+].C(=O)(O)[O-].[Na+]>O.S(=O)(=O)(O)O>[I:26][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: [I-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CNC(=O)COC(=O)N1CCN(c2ccc(I)cn2)CC1
Temperature: 85 °C
Yield: 57.7 %

Procedure:
A solution of 0.16 g (2.2 mmol) of sodium nitrite dissolved in 3.5 ml of water is slowly added to a solution, cooled to 0° C., of 0.47 g (1.5 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-amino-2-pyridyl)-1-piperazinecarboxylate, prepared in step 5.4, in 15 ml of aqueous sulfuric acid solution (0.33N). Stirring is continued at about 0° C. for half an hour, and 0.83 g (5 mmol) of potassium iodide is slowly added. Stirring is continued at this temperature for half an hour and the reaction mixture is then maintained at 85° C. for 2 hours. After cooling to room temperature, the reaction medium is basified to pH=14, by adding saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted three times with dichloromethane, the combined organic phases are washed with aqueous 35% thiosulfite solution, water, brine and dried over sodium sulfate. The filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. After washing with diisopropyl ether, 0.35 g of product is obtained in the form of a beige-colored solid, and is used without further purification in the following step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: O=C1C(=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Oc2cc(O)ccc21
Temperature: 25 °C
Yield: 60.7 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4-dibenzyloxybenzaldehyde 2.35 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.82 g.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:40][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]3[N:21]([CH:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[N:22]=[CH:23][C:24]=23)=[CH:36][CH:35]=1)(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reaction time: 3 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid (38.0 mL, 512 mmol) was added to a cooled solution of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59; 12.0 g, 25.4 mmol) in dichloromethane (70 mL) at about 0° C. The reaction mixture was stirred for 3 h. The solvent was evaporated under reduced pressure, and the residue was coevaporated three times with toluene to give 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (12.0 g, 97%) as an off-white solid which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 2.14-2.17 (m, 2H), 2.32-2.41 (m, 2H), 3.22-3.30 (m, 2H), 3.30 (methyl sulfonyl peak and water peak), 3.45-3.50 (m, 2H), 5.15-5.21 (m, 1H), 7.62-7.64 (m, 2H), 8.06-8.08 (m, 2H), 8.44 (s, 1H), 8.50-8.58 (br s, 1H), 8.59 (s, 1H), 8.76-8.83 (br s, 1H). Mass spectrum (ES) MH+=374.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=2[Cl:38])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5].[CH2:39]=O>>[Cl:38][C:31]1[C:32]([F:37])=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:3]([CH2:2][NH:1][CH3:39])[C:4]([N:6]([CH:16]2[CH2:17][CH2:18]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[O:5])=[CH:21][CH:22]=1
Reactant: NCC(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reactant: C=O
Product: CNCC(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1

Procedure:
Prepared according to the procedure described in Example 19 but using instead 3-amino-2-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (Example 15) and paraformaldehyde. The title compound was obtained as a colorless oil. MS (ESI+): 595.3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)[C:10]1=[O:27].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)[C:10]1=[O:27]
Reactant: CN1C(=O)N(c2nccn2C)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)N(c2nccn2C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (0.200 g, 1.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-1-methyl-1H-imidazole (0.146 ml, 1.500 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1.062 g, 5.00 mmol), copper(I) iodide (0.190 g, 1.000 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.155 ml, 1.000 mmol) and the mixture heated at reflux under argon overnight. The mixture was cooled to room temperature and diluted with dichloromethane. The solid was filtered off, washed with dichloromethane and the filtrate reduced under vacuum. The residue was re-dissolved in dichloromethane and washed with 0.880 ammonia solution (×2), water then brine and passed through a hydrophobic frit and the organic layer reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylate (145 mg, 37.8% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (0.059 ml, 0.517 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylate (145 mg, 0.517 mmol) in DCM (2 ml) and the reaction stirred at room temperature overnight. The reaction mixture was co-evaporated with toluene and dried to give 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylic acid (assume ˜0.517 mmol) which was used which was used in the next step. LC/MS [M+H]+=225.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH2:15][CH3:16])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:6][C:5]([CH3:17])=[CH:4][N:3]=1.[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:2]2[C:7]([CH2:8][N:9]([C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[CH2:15][CH3:16])=[CH:6][C:5]([CH3:17])=[CH:4][N:3]=2)[CH:24]=1)[CH3:19]
Reactant: CCN(Cc1cc(C)cnc1Cl)C(=O)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
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: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarboxylic acid (2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amide (0.120 g, 0.48 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.183 g, 0.57 mmol), and potassium carbonate (0.198 g, 1.43 mmol) were combined in DME and H2O. The mixture was purged with N2 for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.05 mmol) was added, and the reaction was stirred at 80° C. for 2 hours. Once no starting material was seen by analytical tlc, the mixture was diluted with H2O and extracted three times with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Product: Fc1cccc(C(F)(F)F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-fluoro-6-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 127. 1H NMR(CDCl3) δ 7.42 (d, 1H, J=7.7 Hz), 7.33 (app q, 1H), 7.23 (d, 1H J=8.0 Hz), 6.45 (d, 1H, J=2.2 Hz), 6.26 (d, 1H, J=1.8 Hz), 4.52 (ABq, 2H, JAB=14.3 Hz), 4.33 (s, 2H), 4.12 (app d, 1H, J=12.4 Hz), 3.65 (app t, 1H), 3.25-3.00 (m, 4H), 2.95-2.85 (m, 2H), 2.57 (app t, 1H), 2.42 (app t, 1H), 1.92-1.82 (m, 2H). LRMS (ES)+: 422.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: NCCc1ccncc1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccncc3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 2-Pyridin-4-yl-ethylamine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 417. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.72 (d, 2H) 88.3-8.5 (m, 2H) 8.06 (d, 2H) 7.88 (d, 1H) 7.72 (m, 1H) 7.58 (d, 1H) 4.59 (d, 2H) 4.12 (br s, 2H) 3.85 (m, 1H) 3.62 (m, 2H) 3.1-3.45 (m, 6H) 2.48 (m, 2H) 2.18-2.24 (m, 2H) 1.35 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:19]=3)(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1
Reactant: COc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: COc1ccc2sc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c(C)c2c1
Yield: 44.2 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-methoxy-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 8) (42 mg, 0.15 mmol) and 5-(3-amino-phenyl)tetrazole (49 mg, 0.30 mmol) giving 26.6 mg (44%) of the title compound. MS (ESI+) calcd for C17H15N5O3S2 401.061631, found 401.062391.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14].C(N(CC)CC)C>C1COCC1>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ncccn1
Reactant: ClCCCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: ClCCCCCSc1ncccn1
Yield: 51.7 %

Procedure:
2.8 g (25 mmol) of 2-mercaptopyrimidine, 4.64 g (25 mmol) of 1-bromo-5-chloropentane and 2.58 g (25.5 mmol) of triethylamine in 100 ml of THF were refluxed for 4 hours. After cooling, filtration with suction and concentration, the residue was purified by chromatography (mobile phase: cyclohexane/ethyl acetate=92/8). 2.8 g of product were obtained (=52% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)=[O:22])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:29]=2)=[O:22])[CH2:11]1
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 23.8 g portion of 4-(methoxycarbonyl)phenyl (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine-1-carboxylate was dissolved in 80 ml of THF, and a THF solution of TBAF (1.0 M, 76 ml) was added dropwise thereto. After 2 hours of stirring at room temperature, the reaction solution was concentrated under a reduced pressure. The residue was mixed with water and extracted with ethyl acetate, and then the extract was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (ethyl acetate-chloroform) to obtain 16.6 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])=[CH:27][CH:26]=1.[OH-].[Na+]>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:33]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:34]=2)([OH:35])[CH3:32])=[CH:29][CH:30]=1
Reactant: C#CC(C)(O)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Agent: [Na+]
Agent: [OH-]
Product: CC(O)(c1ccc(F)cc1)c1cnnn1C1CCc2c(CC(=O)O)c3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-70% EA/Hex afforded two enantiomeric mixtures. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 50×400 mm Chiralcel OD column eluting with 8% iPrOH, 8% EtOH, 83.75% Hexanes and 0.25% Et3N at 60 mL/min and 254 nm. The resulting esters (retention times=18.4 and 22.1 min) were hydrolyzed separately in THF/MeOH (2:1, 0.1M) at room temperature using 1M solution of sodium hydroxide (10 eq). The reaction mixture was stirred at room temperature for 2 h then quenched by adding HCl 10% until acidic pH and diluted with DCM. Filtration through a phase separator followed by evaporation afforded the desired EXAMPLE 5.1 and 5.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 50×400 mm Chiralcel OD eluting with 30% iPrOH, 70% Hexanes at 60 mL/min and 254 nm. The resulting esters (retention times=18.3 and 34 min) were hydrolyzed in a similar fashion as described above to afford EXAMPLE 5.3 and 5.4 respectively. 1H NMR data is for EXAMPLE 5.1: 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 H), 7.97 (s, 1 H), 7.45 (d, 1 H), 7.36 (dd, 2 H), 7.31 (d, 1 H), 7.20 (t, 2 H), 7.11-7.00 (m, 2 H), 6.68 (s, 1 H), 5.03 (s, 1 H), 4.54 (dd, 1 H), 4.24 (t, 1 H), 3.60-3.48 (m, 2 H), 3.01-2.91 (m, 1 H), 2.37-2.26 (m, 1 H), 2.02-1.93 (m, 1 H), 1.90 (s, 3 H), 1.36-1.24 (m, 1 H). MS (+ESI) m/z: 435.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][N:41]4[CH:45]=[CH:44][CH:43]=[CH:42]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: BrCCn1cccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCn3cccc3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 86.4 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.11 g, 0.25 mmol) was dissolved in DMF at room temperature and K2CO3 (0.207 g, 1.5 mmol) was added. 1-(2-Bromo-ethyl)-1H-pyrrole (0.088 g, 0.5 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (70% EtOAc/30% Hexane) to afford the product (0.114 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](N)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[I-:22].[K+]>Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([I:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
To N1-(4-fluorophenyl)-5-aminoindazole (25.6 g, 113 mmol) suspended in 500 mL 6 M HCl and cooled to 0° C. was added a solution of sodium nitrite (8.2 g, 119 mmol) dissolved in 75 mL water, portionwise. After 3 h, potassium iodide (22.5 g, 136 mmol) dissolved in 80 mL water was added and the reaction was stirred overnight. The next day, the reaction was transferred to a beaker and carefully quenched by adding solid sodium carbonate. After neutralization and addition of water, the aqueous phase was extracted 4× EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated, and filtered from hot EtOAc. The filtrate was concentrated and purified on a 330 g SiO2 MPLC column using DCM. Obtained 13.2 g of 1-(4-fluorophenyl)-5-iodo-1H-indazole (39%). MS found: (M+H)+=339.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12][N:13]2[N:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12][N:13]2[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cccc(Cn3ncc([N+](=O)[O-])n3)c2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cccc(Cn3ncc(N)n3)c2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-4-nitro-2H-[1,2,3]triazole (33 mg, 0.11 mmol), iron powder (19 mg, 0.34 mmol) and NH4Cl (31 mg, 0.57 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.78 min; [M+H]+=261.13.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[B:32]1(B2OC(C)(C)C(C)(C)O2)[O:36]C(C)(C)C(C)(C)[O:33]1.C([O-])(=O)C.[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:16]1([C:13]2[S:12][C:11]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=3)(=[O:24])=[O:23])[CH:3]=[C:2]4[B:32]([OH:36])[OH:33])=[N:15][N:14]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(B(O)O)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
In a 20 mL microwave tube, a mixture of 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-phenyl-1,3,4-thiadiazole (493 mg, 0.884 mmol), bis(pinacolato)diboron (674 mg, 2.65 mmol), potassium acetate (434 mg, 4.42 mmol), PdCl2(dppf), complex with DCM (108 mg, 0.133 mmol) and DMF (4.0 mL) was stirred at 90° C. in the oil bath for 1 h. The mixture was treated with H2O, extracted with EtOAc (50 mL) and washed with brine (2×20 mL), dried over MgSO4, filtered and concentrated affording a brown oil which crystallized upon standing. It was used in the next step without further purification.