Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-])=O.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]3[NH:20][C:19]4[CH:18]=[CH:17][C:6]([NH:7][C:8](=[O:16])[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[OH:15])=[CH:5][C:4]=4[N:1]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccccc1O
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccccc1O

Procedure:
Compound 427 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(2-hydroxybenzoyl)aniline and 4-morpholinobenzaldehyde. [M+H]+ calcd for C24H22N4O3: 415.18; found: 414.98.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[N:17]=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=[C:14]([Cl:19])[N:13]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (19.52 g, 136.3 mmol) was added to a solution of 2,4,6-trichloropyrimidine (25.0 g, 136 mmol) in CH2Cl2 (475 mL) at −78° C. with vigorous stirring. Diisopropylethylamine (26.4 g, 205 mmol) was added dropwise to the above mixture and stirred for 3 hours at −78° C. The resulting mixture was brought to 0° C. over a period of 3 hours and quenched with water (250 mL). The organic layer was separated, washed with aqueous citric acid (2×100 mL), brine (2×200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography [eluent: EtOAc/hexanes (1:9)], giving the desired product (7.40 g, 19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccc(C)cc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccc(C)cc4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(4-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 431 (M++1)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: COc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cn1

Procedure:
The title compound, off-white solid (67 mg, 82%), MS (ISP) m/z=326.4 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-methoxy-pyridin-3-ylboronic acid (49.7 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]>O>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(O)CCCc1ccccc1
Solvent: O
Product: CC1(C)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 18 ml of ice-cold concentrated H2SO4 was added 17.8 g (0.1 mol) of 2-methyl-5-phenyl-2-pentanol over 10 minutes. The mixture was then stirred at 0° C. for 15 minutes and at room temperature for 15 minutes. The mixture was treated with 50 ml of water and then extracted with ether. The ether extracts were combined and washed with water and saturated NaCl and NaHCO3 solutions and then dried (MgSO4). The solution was filtered and the solvent removed in-vacuo. The residue was purified by distillation (93° C.; 10 mm) to give the title compound as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:39]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:40])[CH2:38][CH2:37][CH2:36]1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CCC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 90.8 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclobutanecarboxylic acid (28 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(cyclobutanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (101 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23][CH3:24])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23]([CH3:24])=[O:38])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 96.2 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (250 mg, 0.58 mmol) were dissolved in 20 mL of dichloromethane, m-CPBA (110 mg, 0.64 mmol) was added and reacted at room temperature for 12 h, washed with water after the reaction is complete, extracted with dichloromethane, the organic layer was dried, dried by rotation to obtain yellow solid 250 mg, yield 97%, this product was directly used in the next reaction without purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1([CH2:22][C:23](O)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:22][C:23]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)CC1CCCC1
Product: O=C(CC1CCCC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-cyclopentylacetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56-11.57 (m, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.11-8.17 (m, 1H), 8.04-8.08 (m, 1H), 8.00-8.05 (m, 1H), 2.34 (d, J=7.4 Hz, 2H), 2.16-2.28 (m, 1H), 1.77-1.86 (m, 2H), 1.57-1.66 (m, 2H), 1.48-1.57 (m, 2H), 1.21-1.32 (m, 2H); MS (ESI) m/z 340 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.N1C=CC=CC=1.C(OC(O)C)C.C(=O)(O)[O-].[Na+]>>[NH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(N)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(N)c3)c2cc1OC

Procedure:
A stirred mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile (3.73 g, 15 mmol), 1,3-diaminobenzene (4.86 g, 45 mmol), pyridine (1.21 ml, 15 mmol), and 45 ml of ethoxyethanol was refluxed for 30 m, cooled,and stirred with aqueous sodium bicarbonate. The resulting solid was filtered, washed with water, and dried. Recrystallization from ethanol gave a brown solid, mp 222-228° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(NC(C2C3N=C(O[N:47]4[C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=5[N:49]=N4)N=CC=3SC=2)=O)C=CC=1OC.N[C@@H]1CCCC[C@@H]1N>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20]([NH:47][C@@H:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]4[NH2:49])[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2csc3cnc(On4nnc5ccccc54)nc23)cc1OC
Reactant: COc1ccc(NC(=O)c2csc3cnc(Cl)nc23)cc1OC
Agent: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)cc1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of the mixture of 85 mg of 2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4-dimethoxy-phenyl)-amide and 2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4-dimethoxy-phenyl)-amide (from step a) and 0.17 g (1.41 mmole) of cis-1,2-diaminocyclohexane in Dioxane (3 mL) was stirred at 60° C. for overnight. The reaction were cooled down and diluted with CH2Cl2, washed with aqueous Na2CO3, brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, 40 g, 0% to 30% MeOH (0.7 N) in CH2Cl2) to 50 mg of 2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4-dimethoxy-phenyl)-amide as light yellow solid. MH+/Z=428.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[OH:36])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:55][CH2:56][CH2:57][CH:58]=[CH2:59]>CC(C)=O>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[O:36][CH2:59][CH2:58][CH2:57][CH:56]=[CH2:55])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)c(Cl)c21
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCOc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4Cl)N(CC=C)CCO5)n3n2)c1
Temperature: 70 °C
Yield: 44.9 %

Procedure:
A solution of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.058 g, 0.089 mmol) and K2CO3 (0.042 g, 0.304 mmol) in dry acetone (5 mL) was treated with 5-bromopent-1-ene (0.026 g, 0.174 mmol), and the reaction was stirred with heating (70° C. oil bath) for 16 h. The reaction was cooled, then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (5 mL) and washed with 1N HCl (5 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by biotage column chromatography (5%-50% EtOAc in hexanes). Product fractions were pooled and concentrated under reduced pressure. The product, (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methyl-2-(2′-(pent-4-en-1-yloxy)-[1,1′-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.031 g, 0.040 mmol, 45.4% yield) was isolated as a clear film. 1H NMR (400 MHz, CDCl3) δ 8.04-7.99 (m, 1H), 7.85-7.79 (m, 1H), 7.54-7.49 (m, 1H), 7.44-7.38 (m, 1H), 7.36 (dd, J=7.5, 1.8 Hz, 1H), 7.31 (td, J=7.8, 1.6 Hz, 1H), 7.03 (td, J=7.5, 0.9 Hz, 1H), 7.01-6.94 (m, 3H), 6.90 (s, 1H), 6.03 (ddt, J=16.9, 10.5, 6.0 Hz, 1H), 5.74 (ddt, J=17.0, 10.3, 6.7 Hz, 1H), 5.33 (dd, J=17.1, 1.5 Hz, 1H), 5.24 (d, J=10.0 Hz, 1H), 5.05 (s, 1H), 4.96-4.86 (m, 2H), 4.26 (t, J=4.4 Hz, 2H), 3.96 (t, J=6.4 Hz, 2H), 3.78-3.69 (m, 1H), 3.65 (s, 3H), 3.64-3.55 (m, 1H), 3.20 (q, J=4.2 Hz, 2H), 2.84 (s, 3H), 2.11 (q, J=6.9 Hz, 2H), 1.83-1.71 (m, 2H), 1.63 (s, 1H), 1.17 (s, 9H). LCMS (M+H)=721.5.
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]=1[N:20]=[C:19]1[C:14](C=[CH:16][CH:17]=[CH:18]1)=[NH+:13]2.C(=O)([O-])[O-].[Na+].[Na+]>O>[O:2]=[C:1]1[C:14]2[C:19](=[N:20][C:21]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:7])[CH:18]=[CH:17][CH2:16]1
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1cccc2[nH+]c3ccccc3nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2nc3c(nc12)C=CCC3=O
Reaction time: 24 h
Yield: 35.9 %

Procedure:
2 g (0.011 mol) of 9-methylphenazinium methylsulphate are dissolved in 2 l of distilled water and then exposed for 24 hours to UV-radiation (from a source having a power 1.5 kW, at a distance of 30-40 cm) at the temperature of 40° C. in a closed quartz flask, then added with a 0.1M solution of sodium carbonate to the pH of 9.0. Then the irradiation is continued for additional 4 hours. The solution is filtered, added with 40 ml of a 10% solution of sodium carbonate and extracted four times with 200 ml portions of chloroform. The extracts are combined, dried with potassium carbonate and evaporated to the volume of 70 ml, then 250 ml of hot hexane are added and the mixture is cooled. The formed precipitate is filtered off, washed with 200 ml of hexane, recrystallized from 50 ml of water to give 0.83 g of 4-keto-9-methylphenazine (61%) in the form of blue crystals melting at 133°-135° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11][CH3:12])(=[O:9])[CH3:8].[OH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>C(#N)C>[C:7]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])(=[O:9])[CH3:8]
Reactant: N#Cc1ccccc1O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCOc1ccccc1C#N
Reaction time: 8 h

Procedure:
Potassium carbonate (30 mmol) and then ethyl acetate (11 mmol) are added to a solution of 2-hydroxybenzonitrile (10 mmol) in acetonitrile. After stirring overnight, the solution is filtered and evaporated, the residue is taken up in ethyl acetate, and the organic phase is washed, dried and then evaporated to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:13][C:14]([O:16]CC)=[O:15])[OH:12].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:13][C:14]([OH:16])=[O:15])[OH:12]
Reactant: CCOC(=O)CC1(O)CCc2c(Cl)cc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(O)CCc2c(Cl)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
A mixture of ethyl 2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetate (14.5 g, 0.05 mol), 1N sodium hydroxide (52 ml) and absolute ethanol (100 ml) was stirred for 18 h at room temperature. The mixture was concentrated in vacuo, diluted with H2O and washed with diethyl ether. The aqueous phase was neutralised with 1.0N hydrochloric acid (52 ml) and extracted with diethyl ether. The diethyl ether extracts were dried over sodium sulphate, filtered and concentrated in vacuo to give 12.5 g (96%) of crude 2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetic acid. This material was used immediately without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2>C(OCC)(=O)C.[Pd]>[F:27][C:2]([F:1])([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2
Reactant: CCCC(=O)C(F)(F)/C=C/C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(=O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of (1S,5R,6R,7R)-6-{(E)-4,4-difluoro-5-oxo-2-octenyl}-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one (31) (5.57 g) in ethyl acetate was added 5% Pd/C (catalytic amount) and the resulting mixture was shaken under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the tile compound (32) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=2[C:17](O)=[S:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=2[C:17]([NH:25][C:26]2[C:27]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[S:18])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(O)=S)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)n1
Product: Cc1ccc(C(=S)Nc2ccc(C)nc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 93 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-4-methylthiobenzoic acid and 3-amino-6-methyl-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white solid (7.4 g, 93%).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]1[CH:49]=[CH:48][C:38]([O:39][C:40]2[CH:41]=[C:42]([NH2:47])[C:43]([NH2:46])=[CH:44][CH:45]=2)=[CH:37][CH:36]=1.[CH2:50]([O:57][CH2:58][C@H:59]([NH:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:60](O)=[O:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:47][C:42]1[CH:41]=[C:40]([O:39][C:38]2[CH:48]=[CH:49][C:35]([F:34])=[CH:36][CH:37]=2)[CH:45]=[CH:44][C:43]=1[NH:46][C:60](=[O:61])[C@@H:59]([NH:63][C:64](=[O:65])[O:66][C:67]([CH3:68])([CH3:69])[CH3:70])[CH2:58][O:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1N
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Step (c) DIEA (0.88 mL, 5.10 mmol) and HATU (750 mg, 2 mmol) were added to a stirred solution of 4-(4-fluorophenoxy)benzene-1,2-diamine (370 mg, 1.7 mmol), (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (550 mg, 1.86 mmol) and DMF (4 mL) at ambient temperature. The mixture was stirred for 1 hour and then aqueous saturated sodium bicarbonate solution (8 mL) was added. The resulting solution was extracted with ethyl acetate (4×2 mL) and the combined extract was dried over magnesium sulfate and concentrated. Product was purified from the residue by silica gel column chromatography (eluting with a 3:1→2:1 mixture of hexane/EtOAc) to give (S)-tert-butyl 1-(2-amino-4-(4-fluorophenoxy)phenylamino)-3-(benzyloxy)-1-oxo-propan-2-ylcarbamate (610 mg, 72%) as a brown foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:31]([CH3:40])=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:43])[CH:21]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:41]=[CH:42][C:20]([NH:19][C:15]([C:10]5[C:9](=[O:18])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[C:13]([CH3:14])=[CH:12][CH:11]=5)=[O:17])=[CH:21][C:22]=4[F:43])=[CH:30][N:29]3[C:31]=2[CH3:40])=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Cc1c(NC(=O)C2CC2)nc2ccc(Oc3ccc(N)cc3F)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)c(C)n4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (56.7 mg, 0.229 mmol) and N-[6-(4-amino-2-fluorophenoxy)-3-methylimidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (60 mg, 0.176 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (61 μL, 0.352 mmol) and HATU (87 mg, 0.229 mmol), and the mixture was stirred at room temperature for 17 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to give a yellow oil. The obtained oil was dissolved in ethyl acetate (1 mL) and left standing at room temperature for 17 hr. The precipitated solid was collected by filtration, washed with diethyl ether and collected by filtration to give the title compound (76 mg, 75%) as a white solid.