Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:25]=[N:26][C:27]([NH:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41])=[CH:28][C:29]=4[C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=4)=[CH:21][CH:22]=3)[C:17](=[O:45])[C:16]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:15]2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>ClCCl.CO.O>[CH2:43]([NH:42][C:40](=[O:41])[NH:39][C:27]1[N:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]([C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:15]=[C:16]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:17]3=[O:45])=[C:29]([C:30]2[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=2)[CH:28]=1)[CH3:44]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H]2CCCNC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
(S)-ethyl 1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline -3-carboxylate (Example 259, 5.00 g, 7.00 mmol) was taken up in dichloromethane (10 mL) and 4M HCl in dioxane (0.486 mL, 13.99 mmol) was added while stirring at RT for 1 h. Removed solvent in vaccuo and residue was taken back up in methanol and water. The reaction was neutralized using NaHCO3 and a precipitate was collected, washed with ether and dried under high vacuum overnight to give (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (3.10 g, 72.1%).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([O:31][CH2:32]C)=[O:30])[CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[CH:23]=2)[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)cc(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc(C)n1
Yield: 34.5 %

Procedure:
The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (409 mg, 1.36 mmol), ethyl 4-chloro-6-methylpyridine-2-carboxylate (272 mg, 1.36 mmol), palladium acetate (30.6 mg, 0.14 mmol), BINAP (169 mg, 0.27 mmol) and cesium carbonate (1.33 g, 4.08 mmol), to obtain 194 mg of the title compound as a yellow oily substance.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([OH:20])[C:17]([O:21][CH3:22])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[N+:26]([O-])([OH:28])=[O:27].O>[Cl-].[Na+].O>[C:1]([C:9]1[C:19]([N+:26]([O-:28])=[O:27])=[C:18]([OH:20])[C:17]([O:21][CH3:22])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(OC)c(O)cc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a mixture of ethyl 2-benzoyl-4-hydroxy-5-methoxy-benzoate (reference example 17-1) (550 mg) and dichloromethane (10 mL) was added fuming nitric acid (85 μL) at room temperature. After stirring for 20 minutes, water and dichloromethane were added to the mixture. The separated organic layer was brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (806 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[O:17][C:18]3[C:19]([N:28]=2)=[C:20]2[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.Cl>N1CCCCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:21]1\[C:22](=[O:27])[NH:23][C:24]2[CH:25]=[CH:26][C:18]3[O:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:28][C:19]=3[C:20]\1=2
Reactant: COc1cc[nH]c1C=O
Reactant: O=C1Cc2c(ccc3oc(-c4ccccc4)nc23)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3oc(-c4ccccc4)nc3c21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (15 mg, 0.12 mmol) (prepared according to F. Bellamy et. al., J. Chem. Research (S) (1979), 18-19; J. Chem Research (M) (1979) 0101-0116), piperidine (3 drops)(Aldrich), and 2-phenyl-6,8-dihydro-oxazolo[4,5-e]indol-7-one (25 mg, 0.10 mmol)(from Example 2) were dissolved in DMF (1 mL). The mixture was heated to 90° C. and stirred at that temperature for 1 h. The mixture was cooled, poured into water, and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC with acetonitrile—water mixture as solvent. (Yield 3.6 mg, 8.4%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CN(C)C=O.O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:17]
Reactant: COc1ccccc1S
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CSc1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.6 %

Procedure:
To a suspension of 2-methoxybenzenethiol (10 g, 71.4 mmol) and potassium carbonate (20 g, 143 mmol) in dry N,N-dimethylformamide (100 mL) was added dropwise over 20 mins a solution of bromoacetaldehyde diethyl acetal (10.3 mL, 71.4 mmol) in dry N,N-dimethylformamide (50 mL). The resulting suspension was allowed to stir at room temperature for 45 mins before being diluted with water (500 mL) and extracted with hexane (200 mL). The organic phase was further extracted with brine (4×100 mL), with the resulting organic phase being dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (18.6 g) which was ca 95% pure. This material was further purified by flash chromatography eluting silica gel with hexane:ether [10:1] to give a colourless oil (18 g, 98%). δH (300 MHz, CDCl3) 7.34 (1H, d, Ar), 7.2 (1H, m, Ar), 6.92-6.80 (2H, m, Ar), 4.62 (1H, t, J=7 Hz, CH(OEt)2), 3.85 (3H, s, OCH3), 3.70-3.42 (4H, m, OCH2CH3), 3.10 (2H, d, J=7 Hz, SCH2), 1.12 (6H, t, J=7 Hz, OCH2CH3).
Reaction SMILES: CC1CCN2C(=O)C3C4CCCC(=[O:20])C=4SC=3N=C2CC1.[CH2:22]([O:24][C:25]([CH:27]1[CH2:33][CH2:32][N:31]2[C:34](=[O:45])[C:35]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:39]=4[S:38][C:36]=3[N:37]=[C:30]2[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([CH:27]1[CH2:33][CH2:32][N:31]2[C:34](=[O:45])[C:35]3[C:40]4[CH2:41][CH2:42][CH2:43][C:44](=[O:20])[C:39]=4[S:38][C:36]=3[N:37]=[C:30]2[CH2:29][CH2:28]1)=[O:26])[CH3:23]
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Reactant: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4
Product: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O

Procedure:
Compound 19 was synthesized by the method described for compound 17 using compound 16 as a starting material.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C#N)n2)c(C(N)=O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (110 mg, 222 μmol) in CH2Cl2 (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol) and the reaction mixture stirred to room temperature for 18 h. Solvents evaporated and residue purified by flash column (spherical silica 20-45 μM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (50 mg, 57% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.47 (s, 1H), 8.76 (s, 1H), 8.06 (d, J=3.0 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 5.60-5.77 (m, 2H), 4.25 (br. s., 1H), 3.11-3.24 (m, 1H), 1.32-1.92 (m, 16H); LC-MS 395.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15](S(C)(=O)=O)[N:14]=[C:13]([NH:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O-:33].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([O:33][CH3:32])[N:14]=[C:13]([NH:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Nc3ccc4c(c3)OCCO4)nc(S(C)(=O)=O)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Nc2ccc3c(c2)OCCO3)cc(-c2ccc(C(C)(C)C)cc2)n1

Procedure:
To a 50-mL, round-bottomed flask containing a solution of 6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)pyrimidin-4-amine from step (c) above (0.20 g, 0.46 mmol) in MeOH (10 mL) was added NaOMe (76 mg, 1.4 mmol, Aldrich). The reaction mixture was refluxed for 2 h, and the solvent was removed in vacuo. Purification of the residue by silica gel column chromatography (4:1 hexane/EtOAc) provided the title product as a yellow solid. MS (ESI, pos. ion) m/z: 392 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5-chloro-2-nitroanisole (0.094 g, 0.50 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (0.19 g, 0.60 mmol), Na2CO3 (0.16 g, 1.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.019 g, 0.030 mmol) in dioxane (3 mL) and H2O (1.5 mL) was degassed for 30 min. The mixture was heated at 120° C. for 20 min in the microwave. Upon completion by TLC, the reaction was placed under H2 (1 atm.). The mixture was transferred to a separate flask and diluted with EtOH and subsequently stirred under H2 (1 atm.) overnight. Upon completion by TLC, the reaction was filtered through Celite®, washed with EtOAc, dried (MgSO4), concentrated and purified by flash chromatography to provide the title compound of step A (0.12 g, 0.40 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.52-1.64 (m, 2H), 1.79 (d, J=12.8 Hz, 2H), 2.54 (tt, J=12.1, 3.5 Hz, 1H), 2.77 (t, J=11.9 Hz, 2H), 3.65 (d, J=2.6 Hz, 1H), 3.70 (d, J=6.2 Hz, 1H), 3.83 (s, 3H), 4.22 (br. s., 2H), 6.60-6.66 (m, 3H).
Reaction SMILES: C([O:4][C:5](=[O:64])[C@@H:6]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:7][C:8]1[CH:55]=[CH:54][C:11]([O:12][C:13]([NH:15][C@H:16]([C:26]([NH:28][C@H:29]([C:51]([NH2:53])=[O:52])[CH2:30][S:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:27])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[CH:10][CH:9]=1)C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:22]([O:21][C:19]([NH:18][CH2:17][C@@H:16]([C:26]([NH:28][C@H:29]([C:51]([NH2:53])=[O:52])[CH2:30][S:31][C:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[NH:15][C:13]([O:12][C:11]1[CH:54]=[CH:55][C:8]([CH2:7][C@H:6]([NH:56][C:57]([O:59][C:60]([CH3:61])([CH3:63])[CH3:62])=[O:58])[C:5]([OH:64])=[O:4])=[CH:9][CH:10]=1)=[O:14])=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Temperature: 25 °C

Procedure:
2.38 g (2.03 mmol) of the compound from example 25A was dissolved in approx. 35 ml tetrahydrofuran. 1.42 ml (10 mmol) Triethylamine, 0.38 ml (10 mmol) formic acid and 0.24 g (0.20 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 20 ml water and twice extracted with approx. 30 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 70 ml silica gel. Solvents used were dichloromethane/methanol 10/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure to yield 0.72 g (41% of theory) product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O:31]CCCC)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.41 g, 0.7 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added 1N sodium hydroxide (2 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.34 g, 91.9%) as crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:19])[C@@H:6]([CH3:20])[N:5]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:4]=2[N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:37])[CH:31]=[C:32]2[C:36]=1[NH:35][N:34]=[CH:33]2.C(O)C(F)(F)F.FC(F)(F)C(O)=O>>[CH:21]1([N:5]2[C:4]3[N:3]=[C:2]([NH:37][C:30]4[CH:31]=[C:32]5[C:36](=[C:28]([F:27])[CH:29]=4)[NH:35][N:34]=[CH:33]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:19])[C@H:6]2[CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Reactant: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Cl)nc2N1C1CCCCC1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Nc3cc(F)c4[nH]ncc4c3)nc2N1C1CCCCC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-5-(1-oxidopyridin-3-yl)-7,8-dihydropteridin-6(5H)-one (30.4 mg, 0.081 mmol) and 7-fluoro-1H-indazol-5-amine (37.2 mg, 0.25 mmol) in trifluoroethanol (2.0 mL, 27 mmol) in a microwave reactor vial was added trifluoroacetic acid (42 mg, 0.37 mmol). The vial was then sealed, and the mixture was stirred at 100° C. (oil bath). More 7-fluoro-1H-indazol-5-amine (29.5 mg, 0.195 mmol) and trifluoroacetic acid (0.025 mL, 0.32 mmol) was added after 15 h, and heating at 100° C. was continued for additional 24 h. The reaction mixture was cooled to rt and quenched with saturated aq. NaHCO3 solution (5 mL). The resulting mixture was extracted with 5% MeOH in dichloromethane (15 mL×4). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue, which was then purified by silica gel column chromatography (eluent: 8% methanol in dichloromethane) to give the desired product (24%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:31])[CH:19]([NH:23]C(OC(C)(C)C)=O)[CH:20]([CH3:22])[CH3:21])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:31])[CH:19]([NH2:23])[CH:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(N)C(C)C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 49 (302 mg, 0.6 mmol) in DCM (10 mL) was added TFA (2 mL) at ambient temperature. After 2 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 235 mg (97%) of 50 as an orange oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.86-7.83 (m, 1H), 7.43-7.34 (m, 1H), 7.27-7.19 (m, 3H), 4.49 (m, 1H), 4.14 (q, J=6.9 Hz, 2H), 3.60-3.53 (m, 2H), 3.32 (d, J=12.9 Hz, 1H), 3.12 (app t, J=7.2 Hz, 2H), 2.81-2.74 (m, 2H), 2.42 (app t, J=12.3 Hz, 1H), 2.10-1.91 (m, 2H), 1.74-1.66 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.06-0.99 (m, 6H) ppm. Mass spectrum: m/z 401 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14]CC)=O)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:18][NH2:19]>C(O)C.ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:18][NH2:19])=[O:14])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Reactant: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: NNC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Temperature: 80 °C

Procedure:
In a round bottom flask equipped with reflux condenser, a yellow solution of ethyl [(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetate (2.095 mmol) in ethanol (5 mL) was treated with hydrazine monohydrate (41.9 mmol). The resultant yellow solution was stirred at 80° C. (reflux) overnight. The reaction was cooled to room temperature and concentrated in vacuo. Ethanol (10 mL) was added and the reaction was concentrated to give a clear oil. The oil was dissolved in dichloromethane (white solution observed), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a clear oil (quantitative). MS(ES)+ m/e 212.1 [M+H]+, 423.2 [2M+H]+.
Reaction SMILES: [NH2:1][C@@:2]1([CH2:9][C:10]#[C:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].N>CC#N.CO.CCOC(C)=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][N:4]1[CH2:5][CH2:6][C@:2]2([N:1]=[C:11]([C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:9]2)[C:3]1=[O:8]
Reactant: CN1CC[C@@](N)(CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)C1=O
Agent: [Ag+]
Agent: N
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CC[C@@]2(CCC(c3cc(-c4cccc(OC(F)(F)F)c4)ccn3)=N2)C1=O
Reaction time: 18 h
Yield: 74.1 %

Procedure:
Silver trifluoromethanesulphonate (564.86 mg, 2.2 mmol) was added to a solution of (3S)-3-amino-1-methyl-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-2-one (which may be prepared as described in Description 107) (4.28 g, 10.99 mmol) in MeCN (60 mL) at 40° C. and the reaction was stirred for 18 hours. Additional AgOTf (10 mol %) was added and stirring was continued for 24 hrs. The solvent was evaporated and the residue was suspended in EtOAc. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated to afford a light brown oil. This was purified using an Isolera, with a (50+100)g SNAP cartridge, eluting with 0 to 100% (mixture of 1% of 2M NH3 in MeOH; 9% MeOH; 90% EtOAc) in EtOAc affording the (5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D108) (3.17 g, 8.1414 mmol, 74.1% yield) as a light brown solid;
Reaction SMILES: C([NH:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:14]3[CH:15]([CH3:18])[CH2:16][O:17][C:12]([C:13]=23)=[C:11]([CH:27]2[CH2:29][CH2:28]2)[C:10]=1[F:30])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[NH2:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:14]3[CH:15]([CH3:18])[CH2:16][O:17][C:12]([C:13]=23)=[C:11]([CH:27]2[CH2:28][CH2:29]2)[C:10]=1[F:30]
Reactant: CC1COc2c(C3CC3)c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn1c23
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1COc2c(C3CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 50.6 %

Procedure:
In 5 ml of acetic acid was dissolved 50 mg of 8-benzylamino-10-cyclopropyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. To the resulting solution was added 50 mg of 5% palladium-carbon. The resulting mixture was stirred at room temperature for 1.5 hours at atmospheric pressure in a hydrogen stream. The reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure. Ethanol was added to the residue obtained. The resulting crystals were collected by filtration to obtain 19.7 mg (yield: 50.5%) of 8-amino-10-cyclopropyl9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. Melting point: >280° C. (recrystallized from chloroform-ethanol)