Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO>C1COCC1>[OH:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (10 g, 32.64 mmol) was dissolved in anhydrous THF (200 mL) under nitrogen at 0° C. and BH3.THF (1M in THF, 65.3 mL, 65.3 mmol) was added over 15 min. The reaction was maintained at this temperature and after 3 h a further portion of BH3.THF (1M in THF, 10 mL, 10 mmol) was added. After 2 h, MeOH (30 mL) was added and the reaction was warmed to rt. The reaction mixture was partitioned between EtOAc (150 mL) and brine (200 mL). The aqueous layer was re-extracted with EtOAc (100 mL) and the combined organics were washed with a saturated aqueous solution of NaHCO3 (150 mL) and then dried (MgSO4) and filtered. On concentration of the solution the title compound (8.57 g, 90%) precipitated as a white solid and was collected by filtration. 1H NMR (CDCl3) 1.51 (9H, s), 8.14 (4H, t), 3.62 (4H, t), 4.62 (2H, d), 6.94 (2H, d), 7.31 (2H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O[NH:23][C:24](=[NH:31])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:31]=[C:24]([CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[N:23]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N=C(Cn1cncn1)NO
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cn2cncn2)no1

Procedure:
Method as for preparation 2 and 3 combined using 2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (preparation 168) (2.98 g, 10 mmol) and N-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethanimidamide (preparation 148) (1.01 g, 10 mmol) as starting materials.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH2:14][O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: OCc1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCc1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 0 °C

Procedure:
8.7 g. 4-(2,3-epoxypropoxy)-6-hydroxymethyl-indole (cf. the preparation of the starting material in Example 15) were dissolved in 50 ml. anhydrous pyridine. To this solution were added dropwise, while stirring and cooling to 5°-10° C., 5 ml. pivalic acid chloride, 1.5-2 hours after the ending of the addition, the reaction mixture was poured into ice water. The aqueous phase was extracted 3 or 4 times with diethyl ether. The ethereal extract was successively washed with 1 N sulfuric acid, a saturated aqueous solution of sodium bicarbonate and water, then dried, treated with active charcoal and fullers' earth and subsequently evaporated. The crude 4-(2,3-epoxypropoxy)-6-pivaloyloxymethyl-indole thus obtained (12.5 g.; about 100% of theory) was further reacted without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]([C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=3)[CH2:17][CH:16]2[C:27](OC)=[O:28])=[O:14])=[C:11]([N+:35]([O-:37])=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1.Cl.C(OCC)(=O)C.CO>[CH2:1]([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]([C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=3)[CH2:17][CH:16]2[CH:27]=[O:28])=[O:14])=[C:11]([N+:35]([O-:37])=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2N1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2c3cc([N+](=O)[O-])ccc3CC2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
Methyl 1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-6-nitroindoline-2-carboxylate (258b) (1.023 g, 2.016 mmol) was dissolved in a mixture of anhydrous dichloromethane (2.5 mL) and toluene (7.5 mL) and cooled to −78° C. in a dry ice and acetone bath. After 15 minutes DIBAL-H (1.0M in THF) (4.03 mL, 4.03 mmol) was added via a syringe pump over about a 20 minute period. The resulting solution was stirred for 2 hrs at −78° C. after which methanol (1 ml) was added dropwise to quench the reaction at −78° C. The reaction was then diluted with 5% HCl and ethyl acetate and warmed to room temperature. The aqueous layer was washed with additional ethyl acetate and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The reaction mixture was passed through a layer of celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 40% acetone in hexane to give 1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-6-nitroindoline-2-carbaldehyde (258c) (621 mg, 1.301 mmol, 64.5% yield). 1H NMR (400 Hz, CDCl3): δ 3.15-3.60 (m, 2H), 3.90 (s, 0.6H), 3.92 (s, 1.2H), 3.97 (s, 1.2H), 4.57 (d, 0.2H, J=4.8 Hz), 5.21 (m, 7.19-7.41 (m, 5.6H), 7.60-7.77 (m, 1.6H), 7.86-7.91 (m, 0.8H), 8.94 (s, 0.4H), 9.34 (s, 0.4H), 9.74 (s, 0.4H), 9.90 (s, 0.2H). MS (m/z), found 500.1 ([M]++Na).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[C:63]=3[CH3:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[Cl:68][C:64]1[C:63]([CH3:69])=[C:62]([N:59]2[C:55]3[N:56]=[CH:57][N:58]=[C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=4)=[O:43])[C:54]=3[CH:61]=[N:60]2)[CH:67]=[CH:66][CH:65]=1
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(Cl)c2C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2cccc(Cl)c2C)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.832 mL, 0.83 mmol) was added dropwise to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AE3) (500 mg, 0.69 mmol) in THF (15 mL) over a period of 1 minute and the resulting solution stirred at ambient temperature for 3 hours. Saturated ammonium chloride (20 mL) was added to the reaction mixture which was then diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 60 to 100% EtOAc in isohexane. This was further purified by chiral HPLC to give the product (76 mg, 52%). 1H NMR (400 MHz, DMSO) δ 2.06 (3H, s), 2.24 (3H, s), 3.53-3.58 (2H, m), 3.58-3.68 (2H, m), 4.00-4.05 (1H, m), 4.08-4.13 (1H, m), 4.61 (1H, t), 5.93-6.01 (1H, m), 7.45-7.02 (2H, m), 7.57-7.60 (1H, m), 7.66-7.69 (1H, m), 7.88-7.95 (1H, m), 8.17-8.18 (1H, m), 8.54 (1H, s), 8.62 (1H, s), 10.86 (1H, s); m/z (ESI+) (M+H)+=483; HPLC tR=2.14 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[F:11].[NH2:12][CH2:13][CH2:14][OH:15]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc(C2CO2)ccc1Br
Reactant: NCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCNCC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-oxirane (4.69 g) in THF (11 ml) was added 2-aminoethanol (13.2 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined organic layers was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(4-bromo-3-fluoro-phenyl)-2-(2-hydroxy-ethylamino)-ethanol (5.37 g) as a yellow viscous oil which was used in the next step without further purification. MS (ISP): 280.2 ([{81Br}M+H]+), 278.1 ([{79Br}M+H]+).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:59][C:60]1[CH:68]=[C:67]2[C:63]([C:64]([CH3:71])([CH3:70])[C:65](=[O:69])[NH:66]2)=[CH:62][CH:61]=1>>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:59][C:60]4[CH:68]=[C:67]5[C:63]([C:64]([CH3:71])([CH3:70])[C:65](=[O:69])[NH:66]5)=[CH:62][CH:61]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=S1(=O)CCCN1c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2cc(Nc3ncc4ccc(-c5cccc(N6CCCS6(=O)=O)c5)n4n3)ccc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
7-[3-(1,1-dioxo-1,2-thiazolidin-2-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-ol (47 mg, 0.14 mmol) and N-Phenylbis(trifluoromethanesulphonimide) (55.9 mg, 0.156 mmol) were treated with N,N-Diisopropylethylamine (0.100 mL, 0.575 mmol) and N,N-Dimethylformamide (3.00 mL, 38.7 mmol) for 30 min, then 6-Amino-3,3-dimethyl-1,3-dihydro-indol-2-one (31.3 mg, 0.178 mmol) was added and the mixture was stirred at 65° C. overnight. Conc. of the reaction gave a residue, which was chromatographed (silica gel, 20-100% EtOAc:Hex) to afford 6-({7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-yl}amino)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (39 mg; Yield=56%) as a yellow foam. LCMS (HPLC): 1.05 min, m/z=489 (M+H); 1H-NMR (DMSO-d6): 10.28 (s, 1H), 9.50 (s, 1H), 9.01 (s, 1H), 7.96 (d, 1H, J=7.8 Hz), 7.79 (s, 1H), 7.56 (m, 2H), 7.33 (d, 1H, J=8.3 Hz), 7.16 (m, 2H), 7.08 (s, 1H), 6.97 (d, 1H, J=4.7 Hz), 3.80 (t, 2H, J=6.5 Hz), 3.52 (t, 2H, J=7.4 Hz), 2.39 (m, 2H), 1.24 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][CH2:13][OH:14])[CH:5]=[O:6]
Reactant: OCCBr
Reactant: O=Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCO)c(F)c1
Temperature: 150 °C
Reaction time: 10 h

Procedure:
5.00 g (35.69 mmol) of 3-fluoro-4-hydroxybenzaldehyde are dissolved in 50 ml of dry DMF. 5.35 g (42.82 mmol) of 2-bromoethanol and 19.73 g (142.74 mmol) of potassium carbonate are added. The reaction mixture is stirred at 150° C. for 10 h. The mixture is then filtered, and the filtrate is freed from the solvent on a rotary evaporator. The residue is taken up in 30 ml of ethyl acetate, and 20 ml of sat. aqueous sodium bicarbonate solution are added. The phases are separated and the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reaction.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N:7]([CH3:18])[CH:6]=1)=[O:4].[OH-:21].[Na+].Cl>>[CH3:18][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:21])=[CH:6]1
Reactant: [OH-]
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [Na+]
Product: Cn1cc(C(=O)O)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 67 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1-methyl-6-(trifluoromethyl)-1H-indol-3-yl)ethanone (195 mg, 0.66 mmol) and 20% aqueous sodium hydroxide solution (5 mL) was refluxed with stirring for 10 hours. After cooling to room temperature, the mixture was poured into 1 M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual solid was washed with 2-propanol to give 107 mg (67% yield) of the title compound as a pale orange solid:
Reaction SMILES: [CH:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([C:13](O)=[O:14])[CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[OH:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:8]1
Reactant: CC(C)OC(=O)[C@@H]1CCC[C@H](C(=O)O)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@@H]1CCC[C@H](CO)C1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
140 g of (1S,3R)-3-isopropoxycarbonylcyclohexanecarboxylic acid are dissolved in THF, and 100 ml of triethylamine was added. At −10° C., 68.4 ml of ethyl chloroformate were added dropwise, and the suspension was stirred overnight. After filtration through celite, 55 g of sodium borohydride are added at 0° C., and the suspension is stirred at RT for a further 6 h. A further 25 g of sodium borohydride are added, and the suspension is stirred overnight. Water is added and the solution was stirred for 2 h. The phases are separated and the aqueous phase is extracted with MTBE, and the combined organic phases were washed with sat. NaCl solution, dried over MgSO4 and concentrated. 105 g of isopropyl (1R,3S)-3-hydroxymethylcyclohexanecarboxylate were obtained as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=O)=O.[N-:23]=[N+]=[N-].[Na+].C(O)C>CN(C=O)C.[Pd]>[NH2:23][CH2:6][CH:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (Intermediate 23) (535 mg, 1.53 mmol) in DMF (8 mL) was treated with sodium azide (199 mg, 3.06 mmol) and the mixture was heated at 80° C. for 1 hour. The mixture was cooled and allowed to stir at room temperature overnight. The solution was partitioned between ethyl acetate and water. The organic layer was washed twice with water then dried with magnesium sulfate, filtered and concentrated until the final volume was approximately 5 mL. Ethanol (20 mL) and 10% palladium on carbon (75 mg, 0.07 mmol) were added. The resulting suspension was stirred under an atmosphere of hydrogen at ambient pressure and temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate as a gum (410 mg, 99%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18]O)[CH2:8][O:7][CH:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:5][CH2:4]1)C.CCN(CC)CC.CS(Cl)(=O)=O.Cl.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.CN(C=O)C.O.CCOC(C)=O>[N:33]([CH2:18][C:3]1([CH3:1])[CH2:4][O:5][CH:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:7][CH2:8]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1(CO)COC(c2c([N+](=O)[O-])cnn2C)OC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1ncc([N+](=O)[O-])c1C1OCC(C)(CN=[N+]=[N-])CO1
Temperature: 25 °C

Procedure:
To a solution of (5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (trans isomer) (248 mg, 1.02 mmol, intermediate 66) in dry DCM at 0° C. (10 mL) was added Et3N (0.20 mL, 1.53 mmol) followed by methanesulfonyl chloride (0.10 mL, 1.22 mmol). The reaction mixture was slowly warmed to room temperature over 1.5 hr. The mixture was re-cooled to 0° C. and 1 M aqueous HCl (5 mL) and DCM (20 mL) were added. The organic layer was washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure to yield a colourless oil. This oil was dissolved in DMF (20 mL) and sodium azide (400 mg, 6.12 mmol) was added. The reaction mixture was heated at 140° C. for 18 hr behind a blast shield. The reaction mixture was cooled to room temperature and diluted with water (20 mL) and EtOAc (50 mL). The organic layer was washed with water (3×20 mL), separated, dried over Na2SO4 and concentrated under reduced pressure to give 5-(5-(azidomethyl)-5-methyl-1,3-dioxan-2-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless solid (300 mg, quantitative over two steps). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 6.36 (s, 1H), 4.17 (s, 3H), 3.88 (s, 4H), 3.20 (s, 2H), 1.40 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][CH2:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC(F)(F)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(F)(F)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 130 °C
Yield: 51 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-Amino-2,2-difluoro-propionic acid hydrochloride (122 mg, 0.75 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 3 mL, 1.5 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 150 minutes. The reaction mixture was diluted with water and treated with 1N hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The solvent was removed in vacuo to provide the title compound as an orange solid in 51% yield. MS ESI(−) m/e: 412.1027 (M−1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([CH3:12])=[N:5]1)([CH3:3])[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][CH:46]=1)[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[CH:34]=1>CN(C)C=O.CN(C)C(=O)C>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:26]=[C:25]([NH:24][C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:12])[CH:7]=5)=[O:11])[CH:46]=[CH:45][CH:44]=4)=[CH:34][N:33]3[N:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cc(C(=O)O)n(C(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C(C)C)n1
Yield: 88.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylic acid (218 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (264 mg, 89%) was obtained as a white solid.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[N:33]=[C:34]([C:45]4[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=4[F:52])[S:35][C:36]=3[NH:37]C(OC(C)(C)C)=O)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[NH2:37][C:36]1[S:35][C:34]([C:45]2[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=2[F:52])=[N:33][C:32]=1[C:30]([NH:29][C:12]1[C:13]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH2:21])[CH2:15]2)=[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]2=[N:10][CH:11]=1)=[O:31]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCC3O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.4 mg, 0.0167 mmol), MeOH (0.2 mL), THF (0.1 mL) and 1.0 M aq. NaOH (0.11 mL, 0.11 mmol) was stirred at room temperature for 20 min. The organic solvents and water were removed under reduced pressure to give a crude intermediate, which was dissolved in DCM (0.2 mL), followed by the addition of TFA (0.17 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 20 min. After removal of the solvent under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; Flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had the following properties:
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1C(C2[C:23]([Cl:29])=[N+:24]([O-:28])[CH:25]=CC=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[Cl:29][C:23]1[C:2]([CH:1]=[O:7])=[CH:3][CH:5]=[CH:25][N+:24]=1[O-:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc[n+]([O-])c1Cl
Agent: N
Solvent: CCO
Product: O=Cc1ccc[n+]([O-])c1Cl

Procedure:
Analogously to the process described in Example 1 there is obtained from 8.4 g of 2-chloropyridine-3-carboxaldehyde-1-oxide, 12.75 ml of ethyl acetoacetate and 5 ml of 30% aqueous ammonia in 35 ml of absolute ethanol, 2,6-dimethyl-4-(2-chloro-1-oxido-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from 500 ml of isopropanol, melts at 255°-256°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC1NC(=O)NN=C1c1ccc(-n2cccc2)cc1
Yield: 38.2 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g) and 2,5-dimethoxytetrahydrofuran (1.32 g) in acetic acid (6 ml) was refluxed for 45 minutes and the allowed to stand at room temperature. The resultant precipitates were washed with diisopropyl ether and dissolved in a mixture of acetic acid, methanol and chloroform (1:2:50). The solution was chromatographed on silica gel (300 g) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates were evaporated and the residue was crystallized from aqueous DMF to give 6-[4-(1-pyrrolyl)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.97 g).