Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.FC(F)(F)OC1C=C(C=CC=1)CBr.C[O:32][C:33]([CH:35]1[CH2:39][C:38](=[O:40])[N:37]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][C:56]([F:59])([F:58])[F:57])[CH:50]=3)=[CH:43][CH:42]=2)[CH2:36]1)=O>C(O)C>[CH3:6][NH2:7].[CH3:6][NH:7][C:33]([CH:35]1[CH2:39][C:38](=[O:40])[N:37]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][C:56]([F:59])([F:58])[F:57])[CH:50]=3)=[CH:43][CH:42]=2)[CH2:36]1)=[O:32]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(OC(F)(F)F)c3)cc2)C1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: FC(F)(F)Oc1cccc(CBr)c1
Solvent: CCO
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(OC(F)(F)F)c3)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 3-trifluoromethoxybenzyl bromide giving the (RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid [40% of theory, MS: m/e=410 (M+H)+] which, thereupon, by treatment with methylamine in ethanol at 80° C. yields the (RS)-5-oxo-1-[4-(3-trifluoromethoxy-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide. Yield: 59% of theory as a white powder. MS: m/e=409 (M+H)+.
Reaction SMILES: [Cl:1]N(Cl)S(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[Cl:1][C:25]1[CH:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]=1[O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(Cl)Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1Cl
Reaction time: 8 h
Yield: 128.2 %

Procedure:
N,N-dichloro-p-toluenesulfonamide (hereinafter abbreviated to "dichloramine T") (7.5 g, 0.032 mol) was dissolved in acetic acid (100 ml), followed by adding to the solution, hydrochloric acid (0.4 ml), dropwise adding to the acetic acid solution of dichloramine T, a solution of 4'-octyloxy-4-biphenycarboxylic acid (20 g, 0.063 mol) dissolved in acetic acid (100 ml), refluxing the mixture, allowing it to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3'-chloro-4'-octyloxy-4-biphenylcarboxylic acid (14.8 g) (C-Sc 146° C., Sc 'N' 224° C. and N'-I 232° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:16].[Cl:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1cc(Cl)ccc1Cl
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1cc(Cl)ccc1Cl
Yield: 6.3 %

Procedure:
A mixture of 2-amino-3-(2,5-dichlorobenzyloxy)pyridine (5.08 g, 18.8 mmol) and ethyl phenylacetimidate hydrochloride (3.52 g, 25.5 mmol) in ethanol (150 ml) was heated under reflux for 2 hours, then evaporated. Flash chromatography (dichloromethane/methanol) and trituration with ether gave the product (0.25 g), m.p. 191°-193° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][N:29]3[CH2:32][CH2:31][CH2:30]3)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1
Reactant: C1CNC1
Reactant: CCC(=O)Nc1ccc(Sc2nc(CCBr)cc(Nc3cc(C)[nH]n3)n2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1ccc(Sc2nc(CCN3CCC3)cc(Nc3cc(C)[nH]n3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(2-bromoethyl)pyrimidin-2-ylthio)phenyl)propionamide (100 mg, 0.21 mmol) and azetidine (36 mg, 0.63 mmol) in dimethylformamide (2 ml) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml). The organic layer was washed with a saturated solution of sodium bicarbonate (10 ml) and brine (10 ml), then dried over magnesium sulfate. The residue was purified by Gilson HPLC to afford the title compound as a bis-trifluoro acetic acid salt (0.5 mg, 1%). 1H NMR (CD3OD): 1.30-1.37 (3H, m), 2.15-2.20 (3H, s), 2.40-2.50 (4H, m), 2.80-2.90 (2H, t), 3.50-3.55 (2H, t), 4.00-4.15 (4H, s), 6.50-6.55 (1H, s), 7.55-7.65 (2H, m), 7.75-7.80 (2H, m). ES+ 438
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(-c6cccnc6)ccn45)nc23)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: F[C@@H]1CNCC[C@H]1Oc1cccc2ccc(-c3cnc4cc(-c5cccnc5)ccn34)nc12
Reaction time: 1 h
Yield: 31 %

Procedure:
tert-Butyl trans-3-fluoro-4-(2-(7-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (22 mg, 0.041 mmol) was added to 2 ml DCM at ambient temperature. TFA (2 mL) was added and the reaction was stirred for 1 hour, then diluted with DCM and water. The mixture was washed with 1N NaOH amine and extracted with DCM, followed by extraction with 20% IP A/Chloroform. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC, eluting with 15% MeOH/0.5% NH4OH in DCM to provide the desired product as a film (5.6 mg, 31% yield). MS APCI (+) m/z 440.1 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH:14]2[S:19][CH2:18][CH2:17][CH2:16][S:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Cl.O>O1CCCC1.CCCCC>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][C:14]2([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[S:15][CH2:16][CH2:17][CH2:18][S:19]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC2SCCCS2)cc(OC)c1OC
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(CC2(Cc3cc(OC)c(OC)c(OC)c3)SCCCS2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 46.3 g of the compound prepared in (a) above in 230 ml of tetrahydrofuran at 0° C. was added, over a period of 20 minutes, 99.6 ml of a 1.7M solution of tert.-butyl lithium in pentane. The resultant mixture was then stirred for 20 minutes, after which time 34.9 g of 3,4,5-trimethoxybenzyl chloride in 150 ml of tetrahydrofuran at 0° C. was added over a period of 15 minutes. The reaction mixture was then stirred for 45 minutes, while the temperature was maintained at 0° C., and then 100 ml of water was carefully added. The resultant slurry was then extracted with a mixture of ethyl acetate and water and dried. The organic layer was then evaporated and the crude product was washed with diethyl ether to yield a solid.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CCOCC.C(Cl)Cl>[C:19]([N:9]1[CH2:10][CH:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:12]2)[CH2:8]1)(=[O:21])[CH3:20]
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)N1CC2CC2(c2ccccc2)C1
Reaction time: 8 h

Procedure:
To 15.9 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane in 20 ml. of pyridine is added 20 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature and then evaporated to give an oil. This oil is dissolved in a mixture of ether and methylene chloride, washed with dilute hydrochloric acid and then sodium bicarbonate and dried over magnesium sulfate and evaporated to a pale amber liquid. This liquid is crystallized from hexane to give the product, mp 63°-65° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31]C(=O)C)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=O)C>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)Oc1ccc(CCc2ccc(OC(C)=O)cc2)cc1
Agent: O=C(O)c1cccc(C(=O)O)c1
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 250 °C

Procedure:
A charge consisting of 8.2 parts of isophthalic acid and 14.8 parts of 1,2-bis(4-acetoxyphenyl)ethane is placed in a reaction vessel equipped with a stirrer, condenser and receiver. The vessel is evacuated and purged with nitrogen three times. A nitrogen blanket is maintained in the reactor while it is heated to 250° C. for about three hours during which period approximately 3.5 to 4.0 parts of acetic acid distills. Thereupon the vessel is evacuated to a pressure of about 125 mm. and heating at 275° C. is continued for one half hour during which period an additional 1 to 1.5 parts of acetic acid distills. The vacuum is then increased to reduce the pressure to about 0.1 to 0.2 mm. and the temperature is raised to 290° C. for an additional hour. At this point the reaction mixture becomes so viscous that further stirring is difficult. Heating is stopped, the reaction mixture is again blanketed with nitrogen and allowed to cool. The resultant polymer is light yellow in color, crystalline and demonstrates an inherent viscosity of 0.57 in the phenol-tetrachloroethane solvent.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH:21]([CH:23]2[CH:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:26][NH:25][CH2:24]2)[CH3:22])=[N:18][CH:19]=1.N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH:21]([CH:23]2[CH:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:26][N:25]([C:7]([Cl:10])=[O:6])[CH2:24]2)[CH3:22])=[N:18][CH:19]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 129.6 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (48 mg, 0.16 mmol) in CH2Cl2 (10 mL) at −78° C., was added a solution of 5-chloro-2-{(RS)-1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-pyridine (intermediate XV-B-2) (150 mg, 0.40 mmol) and pyridine (0.072 mL, 0.88 mmol) in CH2Cl2 (5 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded and column chromatography (SiO2, EtOAc/H, 1:1) yielded 90 mg (50%) of the title compound as a viscous colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]([C@H:20]1[C@H:27]2[C@H:23]([CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26]2)[CH2:22][CH2:21]1)=[N+]=[N-].C(N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][CH2:11][CH3:13])[C:14](=[O:16])[NH:17][C@H:20]1[C@H:27]2[C@H:23]([CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26]2)[CH2:22][CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21

Procedure:
tert-Butyl((S)-1-oxo-1-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate was prepared by substituting N-(tert-butoxycarbonyl)-L-norvaline for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 16 Step D for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.58 (d, J=7.2, 1H), 7.91 (d, J=8.3, 1H), 7.42 (d, J=7.3, 2H), 7.36 (t, J=7.4, 2H), 7.27 (t, J=7.2, 1H), 4.64 (dd, J=14.4, 7.7, 1H), 4.45-4.34 (m, 1H), 3.56 (d, J=13.1, 1H), 3.40 (d, J=13.2, 1H), 2.74 (d, J=8.9, 1H), 2.48 (d, J=0.7, 2H), 2.39-2.27 (m, 2H), 2.26-2.19 (m, 1H), 2.14 (dq, J=12.0, 6.0, 1H), 2.07-1.96 (m, 1H), 1.85 (td, J=13.8, 8.2, 2H), 1.65 (td, J=14.3, 7.3, 1H), 1.49 (d, J=8.5, 11H), 1.45-1.33 (m, 1H), 0.81 (t, J=7.3, 3H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[F:31][C:32]([F:36])([F:35])[CH2:33]I.Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]([CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: FC(F)(F)CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 505.2 %

Procedure:
To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was added ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. After completion of starting material (by TLC), diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×30 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (300 mg) as liquid.
Reaction SMILES: ClC1C=C2C(C(=O)CCN2)=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[C:26](Cl)([Cl:28])=[O:27]>>[Cl:28][C:26]([N:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:16]1[CH:23]=[CH:24][CH:25]=[C:14]([Cl:13])[CH:15]=1)=[O:27]
Reactant: O=C(Cl)Cl
Reactant: O=C(O)CCNc1cccc(Cl)c1
Agent: O=C1CCNc2cc(Cl)ccc21
Product: O=C(O)CCN(C(=O)Cl)c1cccc(Cl)c1

Procedure:
A process of the preparation of 7-chloro-1,2,3,4-tetrahydro-4-quinolinone which comprises treating 3-(m-chloro-anilino)propionic acid with phosgene to produce N-chloroformyl-3-(m-chloroanilino)propionic acid, converting the said product, by the action of an organic base or by heating, into 3-(m-chlorophenyl)-2,6-dioxo-1,3-perhydrooxazine, and treating the latter with aluminium chloride in an inert organic solvent or with a strong acid, to provide 7-chloro-1,2,3,4-tetrahydro-4-quinolinone.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:54])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S(=O)(=O)(O)O.[C:62](=O)(O)[O-].[Na+]>O1CCCC1>[CH3:62][O:53][C:52]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:49])([F:50])[F:51])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:54]
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 45 °C
Reaction time: 20 h
Yield: 66.5 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 16a (0.49 g, 0.64 mmol) in tetrahydrofuran (2 mL) were added methanol (8 mL) and concentrated sulphuric acid (0.24 mL) at room temperature. The mixture was stirred at 45° C. for 20 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 16b as a white solid (322 mg, 66.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48 (d, 1H), 7.44-7.38 (m, 2H), 7.32 (m, 7H), 7.26 (m, 3H), 7.21 (d, 1H), 7.16 (m, 4H), 7.05 (d, 2H), 6.87 (d, 2H), 4.90-4.81 (m, 2H), 4.79 (d, 1H), 4.63 (d, 1H), 4.53 (d, 1H), 4.32 (d, 1H), 4.20 (dd, 2H), 4.10 (t, 2H), 4.02 (dd, 1H), 3.89 (d, 1H), 3.74 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH2:7]2)([O-])=O.[CH3:14][OH:15].[C:16](O)(=O)C>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:14](=[O:15])[C:7]2([CH3:16])[CH3:8]
Reactant: CC(=O)O
Reactant: CO
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Product: CC1(C)C(=O)Nc2ccc(N)cc21
Temperature: 40 °C

Procedure:
A suspension of 100 g. (0.48 mol) 5-nitroindolin-2-one in 2500 ml. methanol with 200 ml. glacial acetic acid is hydrogenated, while stirring well, at 40° C. in the presence of 10 g. of 10% Pd/C. The subsequently clear solution is freed from catalyst by suction filtration and the filtrate is evaporated. Yield: 82 g. (96% of theory); m.p. 185°-191° C. (HCl-salt from methanol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[N:9]=[C:8]2[C:15]1[N:16]=[C:17]2[C:23]([C:24]([OH:26])=O)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)(=[O:4])=[O:3].[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:28]([NH:31][C:24]([C:23]1[C:17]2=[N:16][C:15]([C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)[N:10]([CH3:14])[N:9]=3)=[CH:20][N:19]=[C:18]2[NH:21][CH:22]=1)=[O:26])([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(S(C)(=O)=O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(S(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 8.2 %

Procedure:
A mixture of 2-(5-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (75 mg, 0.20 mmol), 2-methylpropan-2-amine (15 mg, 0.20 mmol), HOBt (108 mg, 0.80 mmol), EDCI (153 mg, 0.80 mmol) and DIPEA (103 mg, 0.80 mmol) in DMF (6 mL) was stirred at room temperature for 15 hours, then water (30 mL) was added, product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure and residue purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% methanol/70% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 50% methanol/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give N-tert-butyl-2-(1-methyl-5-(methylsulfonyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (7 mg, 8.1%) as a white solid. LCMS: (M+H)+=427; 1H NMR (300 MHz, CD3OD): δ 9.08 (s, 1H), 8.99 (s, 1H), 8.33 (s, 1H), 8.01 (d, 1H, J=8.7 Hz), 7.90 (d, 1H, J=8.7 Hz), 4.28 (s, 3H), 3.17 (s, 3H), 1.57 (s, 9H).
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=O)[CH3:4].[CH:9]([NH2:11])=[O:10].[OH-].[Na+].[Na+].[Cl-]>O.C(O)=O>[C:6]([C:2]1[O:10][CH:9]=[N:11][C:3]=1[CH3:4])(=[O:8])[CH3:7]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CC(=O)c1ocnc1C
Temperature: 140 °C
Yield: 26.4 %

Procedure:
A mixture of 3-chloro-2,4-pentanedione (26.8 g), formamide (18.0 g), and formic acid (50.0 g) was heated in a 140° C. oil bath and refluxed for 4 hours. The resulting dark mixture was poured into 100 ml of water, basified with 50% NaOH solution, and saturated with NaCl. The mixture was extracted with ethyl ether (3×100 ml). The ether solution was dried over sodium sulfate and concentrated. The residue was vacuum-distilled to yield 6.59 g of 5-acetyl-4-methyloxazole as a colorless liquid, 84° C. (15 torr). NMR: 2.51 (s, 3H), 2.52 (s, 3H), 7.85 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
To a stirred solution of 1H-benzoimidazole-5-carboxylic acid (10 g, 61.7 mmol), morpholine (7.55 mL, 86.3 mmol), ethyldiisopropylamine (16.1 mL, 92.5 mmol) and 4-dimethylaminopyridine (380 mg, 3.08 mmol) in DMF (60 mL) at room temperature was added EDC (12.4 g, 64.8 mmol) in a single portion. The mixture was stirred at room temperature for 3 days then concentrated in vacuo. The product was purified by recrystallisation from acetonitrile (70 mL), providing (1H-benzoimidazol-5-yl)-morpholin-4-yl-methanone (8.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[O-:7][C:8]#[N:9].[K+].[CH3:11][OH:12]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:6])[CH2:4][NH:9][C:8]([O:12][CH3:11])=[O:7]
Reactant: N#C[O-]
Reactant: CO
Reactant: COC(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)OC
Yield: 64.3 %

Procedure:
10.71 grams of monobromo acetic acid methyl ester, 8.52 grams of potassium cyanate and 7.85 grams of methanol were heated in 70 ml of DMF following the procedure of Example 1 gave 6.62 grams (64.3%) of methoxycarbonylamino acetic acid methyl ester having a boiling point of 67°-8° C./0.0013 mbar.