Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18](Cl)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([N:22]([CH3:21])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CNc1ccccn1
Reactant: Nc1nccc(-n2nc(C(=O)Cl)c3ccc(I)cc32)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carbonyl chloride (330 mg, 0.83 mmol) in DCM (5 mL) was added N-methylpyridin-2-amine (0.1 ml, 0.99 mmol) followed by triethylamine (0.29 ml, 2.06 mmol). The reaction was stirred at RT overnight and then concentrated in vacuo. The residue was diluted with water (10 ml) and extracted with DCM (2×20 ml). The title intermediate was obtained as a precipitate which was collected by suction filtration. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The precipitate and organic extracts were combined to give the crude title intermediate; LC-MS purity=79%: 1H NMR (500 MHz, DMSO) delta 3.54 (3H, s), 6.28 (1H, d, J=5.5 Hz), 7.15 (2H, s), 7.25 (1H, dd, J=6.7, 5.0 Hz), 7.40 (1H, d, J=8.1 Hz), 7.74 (1H, dd, J=8.5, 1.3 Hz), 7.79-7.84 (2H, m), 8.19 (1H, d, J=5.5 Hz), 8.32 (1H, dd, J=4.6, 1.5 Hz), 9.24 (1H, s); LC-MS: m/z=+472.00 (M+H)+.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](Cl)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([C:46]([C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-chlorobenzoyl chloride and isolated as light-yellow solid. MS(m/e): 421.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C@@H:19]([CH3:27])[C:20](OC(C)(C)C)=[O:21])[C:15]2=[O:28])(=[O:12])=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.[CH:48]1[CH:49]=[CH:50]C2N(O)N=[N:54][C:52]=2[CH:53]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[S:10]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C@@H:19]([CH3:27])[C:20](=[O:21])[N:54]3[CH2:50][CH2:49][CH2:48][CH2:53][CH2:52]3)[C:15]2=[O:28])(=[O:11])=[O:12])=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)/C=C/c2ccc(Cl)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](NS(=O)(=O)/C=C/c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
tert-Butyl (2S)-2-[(3S)-3-({[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]propanoate (0.192 g) was dissolved in DCM (2 ml) and treated with trifluoroacetic acid (2 ml) and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently dissolved in DCM (5 ml) and treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.256 g), HOBT (0.184 g) and triethylamine (0.375 ml). After the solution had been stirred at room temperature for 30 min, piperidine (0.133 ml) was added and the resultant mixture stirred for a further 20 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM and water. The organic component was washed with water and brine, and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane; cyclohexane:ethyl acetate 4:1, 1:1, 1:4; ethyl acetate; methanol:ethyl acetate 1:10; methanol) to give the title compound (0.042 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[O:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCC(=O)c1cccnc1

Procedure:
The title compound was prepared from 3-pyridinecarboxaldehyde (20 g) and ethyl acrylate (22.4 g) as described in Example 1 to yield 5.1 g, ESMS (M+1)+208.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.[C:37]1([Mg]Br)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCOCC>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:34])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 13 (36 mg, 0.071 mmol) in 0.35 mL of dry THF was cooled to 0° C. A 26 μL aliquot of a 3 M solution of phenyl magnesium bromide in ether (0.078 mmol) was added to the mixture and the reaction was allowed to warm up to room temperature. The reaction was worked up in 30 minutes when the reaction was complete as indicated by TLC. The mixture was diluted with EtOAc and washed with water. The product 14 was purified by column chromatography using 20% EtOAc-Hex solvent system to provide 33 mg (80%) of the product as a solid. 1H NMR (300 MHz, CDCl3) δ 1.20 (s, 18H), 1.52-1.68 (m, 3H), 2.95 (s, 1H), 3.93 (s, 3H), 4.08 (d, 1H, J=15 Hz), 4.77 (d, 1H, J=15 Hz), 6.85 (t, 2H, J=9Hz), 7.19-7.25 (m, 2H), 7.25-7.35 (m, 3H), 7.39-7.49 (m, 3H), 8.26 (d, 1H, J=8 Hz), 8.84 (br d, 1H, J=4 Hz); 19F NMR (282.6 MHz, CDCl3) δ −76.2, 60.7; EI MS (m/z) 587.5 [MH+], 609.4 [M+Na].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][NH:10][C:11]([C@@:13]2([CH3:27])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[C:33]1([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:18][C:15]1([CH3:19])[N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@@:13]([CH3:27])([C:11](=[O:12])[NH:10][CH2:9][C:8](=[O:28])[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:3]([C:29]([F:31])([F:32])[F:30])[CH:4]=2)[CH2:17][O:16]1
Reactant: OCCCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(O)c(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (114 mg, 0.25 mmol, 1.0 equiv) and 6-phenylhexan-1-ol (45 mg, 0.25 mmol, 1.0 equiv) in DCM (1 mL) was added polymer bond PPh3 (125 mg, 0.75 mmol, 3.0 equiv). The reaction mixture was stirred at rt for 0.5 hour and cooled to 0° C. A solution of DIAD (0.053 mL, 0.25 mmol, 1.0 equiv) in DCM (0.5 mL) was added drop wise to the reaction mixture. The reaction mixture was stirred at rt for 2 hours, filtered and evaporated under reduced pressure to give a residue, which was purified by SiO2 column chromatograph (30-50% EtOAc in hexanes) to give (R)-tert-butyl 2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate in 75% (155 mg) yield. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 3.31 min with gradient 50-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=621.6.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@H](C=O)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[CH:1]([C@@H:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1)=[O:2]
Reactant: C[C@]12CCCCC1C[C@@H](C=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1C[C@@H](C=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7α-Formylandrostane-3,17-dione was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7α-formylandrostane (2.36 g) by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 9.95 (1H, d), 2.57-0.80 (21H, m), 0.95 (3H, s), 0.80 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:40])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH2:30])([CH3:26])([CH3:25])[CH3:24].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:40])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:30][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:21][CH:20]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-(benzyloxycarbonylaminomethyl)benzoic acid as obtained in Reference Example 35 (1.0 g), glutamic acid di-t-butyl ester hydrochloride (1.15 g) and DEPC (860 mg) in dimethylformamide (20 ml), triethylamine (1.06 g) was added drop by drop, followed by stirring at room temperature for 1 hour. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield the title compound (1.86 g, yield 100%) as a colorless wax-like substance.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[NH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 105.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.86 min, m/z=459.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([CH:8]=1)N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:28].[K+].C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([I:28])[CH:8]=1
Reactant: [I-]
Reactant: Nc1cc(Br)ccc1C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(C2CC2)c(I)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Bromo-2-cyclopropylaniline (4.74 g) is added to a solution of para-toluene sulfonic acid monohydrate (12.2 g, 0.064 mol) in acetonitrile (130 ml), followed by stirring for 10 minutes at room temperature. The suspension is then cooled to 10° C. and a mixed solution of sodium nitrite (8.9 g, 0.054 mol) and potassium iodide (3.1 g, 0.044 mol) in water (16 ml) is added dropwise over 30 minutes. Once the addition is complete the reaction mixture is allowed to stir at 10° C. for 20 minutes and then at room temperature for 4 hours. The reaction mixture is basified to pH 9-10 with aqueous sodium bicarbonate, followed by addition of ethyl acetate and 10% aqueous sodium metabisulphite. The phases are separated and the aqueous layer is extracted again with ethyl acetate (×2). Organics are combined, washed with brine, dried over magnesium sulfate then concentrated in vacuo to give the crude product which is purified by flash column chromatography on silica gel (isohexane eluant) to afford 5-bromo-2-cyclopropyliodobenzene as a colourless oil.
Reaction SMILES: [CH2:1]([C:4]1([C:19]([OH:21])=[O:20])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]=[CH2:3].[Li].[CH2:23](I)C=C.[Cl-].[NH4+]>C1COCC1.CCCCCC.C1COCC1>[CH2:1]([C:4]1([C:19]([O:21][CH3:23])=[O:20])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: C=CCC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1(C(=O)OC)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesis of (RS)-2-allyl-N-(benzyloxycarbonyl)proline ##STR5## N-benzyloxycarbonylproline methyl ester (13 g) in THF (20 ml) was added dropwise to lithium dilsopropylamide (27.5 ml, 2M in hexane/THF) in THF (100 ml) at -78° C. under nitrogen. The mixture was stirred for 30 minutes and then allyl iodide (5.5 ml) was added dropwise and the mixture stirred for a further 30 minutes and then allowed to warm to ambient temperature. The mixture was then added to aqueous ammonium chloride (200 ml) and extracted with ether (2×200 ml). The ether layer was evaporated and the residue was purified by chromatography on silica using a gradient of hexane increasing to 20% ethyl acetate:hexane. The appropriate fractions, evaporated to dryness, gave methyl (RS)-2-allyl-N-(benzyloxycarbonyl)prolinate (9 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11].C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(Cl)c(F)cc(F)c1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Reaction time: 2 h

Procedure:
20 g of 2,6-dichloro-3,5-difluorophenol are introduced into 70 ml of acetic acid, and 8 g of 98% strength nitric acid are added dropwise. Stirring of the mixture is subsequently continued for 2 hours at room temperature, and the mixture is taken up in 150 ml of dichloromethane and washed twice with water. After the dichloromethane has been distilled off, 18 g of product remain. 94% pure according to GC analysis.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:24])[CH:19]=[N:18][C:17]=2[C:16]([C:30](O)=[O:31])=[CH:15][CH:14]=1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl.CO>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[NH:33][C:30]([C:16]1[C:17]2[N:18]=[CH:19][C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH3:24])=[N:21][C:22]=2[C:13]([C:3]2[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[Cl:12])=[CH:14][CH:15]=1)=[O:31]
Reactant: Nc1ccccn1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccccn3)c3ncc(N(C)CCN(C)C)nc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylic acid (Step 85.1) and 2-aminopyridine. Title compound: ESI-MS: 555.0/557.2 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.42 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21](=[O:22])[NH:20][NH:19][C:18]2=[O:23])=[CH:13][CH:12]=1)[C:2]#[CH:3]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:18](=[O:23])[N:19]=[N:20][C:21]2=[O:22])=[CH:13][CH:12]=1)[C:2]#[CH:3]
Reactant: C#CCOCCOCCOc1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Solvent: ClCCl
Product: C#CCOCCOCCOc1ccc(N2C(=O)N=NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
To 4-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenyl)-1,2,4-triazolidine-3,5-dione (I-7d: 153 mg, 0.479 mmol) in CH2Cl2 (4.792 mL) was added SiO2-HNO3 (300 mg). The mixture was stirred at room temperature for 15 minutes, then filtered, concentrated in vacuo and dried giving 4-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenyl)-3H-1,2,4-triazole-3,5(4H)-dione (112 mg, 74%) as a red oil. 1H NMR (400 MHz, CD3CN) δ ppm 2.60 (t, J=2.40 Hz, 1 H) 3.44-3.62 (m, 4 H) 3.68-3.75 (m, 2 H) 4.02-4.12 (m, 4 H) 7.02 (d, J=9.09 Hz, 2 H) 7.23 (d, J=8.84 Hz, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:11][N:10]([CH3:31])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[B-](F)(F)(F)[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[K+].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[C:12]1[C:4]2[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:3]=2)[N:10]([CH3:31])[CH:11]=1
Reactant: COc1nc(Br)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: F[B-](F)(F)CN1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(CN2CCOCC2)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 52.7 %

Procedure:
A mixture of Example 182B (110 mg, 0.224 mmol), potassium trifluoro(morpholinomethyl)borate (55.7 mg, 0.269 mmol), palladium (II) acetate (3.02 mg, 0.013 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (12.83 mg, 0.027 mmol), and Cs2CO3 (219 mg, 0.673 mmol) in 4 mL dioxane-water (9:1) was heated under nitrogen in Biotage Initiator microwave oven at 150° C. for 45 minutes. Water was added, extracted with ethyl acetate (2×), washed with water (2×), saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel with a gradient of 0-8% methanol in dichloromethane to give the title compound (60 mg, 0.118 mmol, 52.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:31]([O:33]CC1C=CC=C(F)C=1)=[O:32].[OH-].[Na+].O.[CH3:48][C:49](O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:48][C:49]3[N:10]([C:11]([CH3:12])=[N:15][N:16]=3)[C:9]=2[CH:8]=[C:7]1[C:31]([OH:33])=[O:32]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(F)c3)n2Cc2cccc(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(F)c3)n12

Procedure:
A solution of di-tert-butyl 1-(1-(3-fluorobenzyl)-2-{[(3-fluorobenzyl)oxy]carbonyl}-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (0.33 g, 0.54 mmol, from Step 2) in AcOH (10 mL) was heated in portions, in the microwave, to 180° C. for 10 minutes each. The reactions were pooled and AcOH was removed in vacuo. The residue was dissolved in methanol (2 mL) and 1.0 M NaOH in water (10 mL, 10 mmol) was added. When the hydrolysis reaction was complete, it was filtered, diluted with MeCN and H2O and then purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (0.17 g, 97%). LCMS (M+H)+: 325.3.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[CH2:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CS(C)=O.O>[NH2:1][C:2]1[N:23]=[C:22]([NH:58][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: NCc1ccccc1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCc2ccccc2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 135 °C
Reaction time: 17 h
Yield: 14 %

Procedure:
To a solution of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (110 mg, 0.31 mmol) in dimethylsulfoxide (1 mL) were added benzylamine (1.8 mL, 16.5 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.94 mmol), and the solution was stirred for 17 hours at 135° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The obtained residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (23.4 mg, 0.0429 mmol, 14%) was obtained as a trifluoroacetic acid salt.