Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([NH:22]C(=O)OC(C)(C)C)[CH:20]=5)[NH:15][C:14]4=[O:30])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:43][CH:42]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1(CC1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(-c3n[nH]c4cc([C@@H]5C[C@@]56C(=O)Nc5ccc(N)cc56)ccc34)cc2)CC1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
The Suzuki coupling was executed according to the method in Example A45, except substituting tert-butyl 2-(3-iodo-1H-indazol-6-yl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-ylcarbamate (70 mg, 0.136 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (57 mg, 0.190 mmol). The resulting product was was dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. After 1 h the reaction was complete, the solvent was removed and the residue purified by prep-HPLC to give a white powder (3.2 mg, 15%); 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.05-7.02 (m, 3H), 6.04 (s, 1H), 4.01-3.97 (bs, 2H), 3.75-3.65 (bs, 2H), 3.46 (t, J=8.4 Hz, 1H), 3.32-3.28 (bs, 2H), 3.18-3.08 (bs, 2H), 3.00 (s, 3H), 2.35-2.31 (m, 1H), 2.29-2.25 (m, 1H); MS ESI [M+H]+ 465.1, calcd for [C28H28N6O+H]+ 465.24.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:27]2.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=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:2](=[O:1])[CH2:7]1)=[O:36])[CH:28]=[CH:27]2
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(O)CCn1ccc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(CCn1ccc2cc(Cl)ccc21)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15 mmol), 3-(5-chloro-1H-indol-1-yl)propanoic acid (22 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=574.0; tR=3.23 min.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]([NH:10][C:11](=[O:15])[CH2:12][C:13]#[N:14])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>CC(O)C>[NH2:14][C:13]1[N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:9])[NH:10][C:11](=[O:15])[CH:12]=1
Reactant: N#CCC(=O)NC(=O)NCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Yield: 98.6 %

Procedure:
155.6 g of 1-(4-chlorobenzyl)-3-cyanoacetyl-urea in 230 ml of 2-propanol were added to a solution of 14.0 g of KOH in 450 ml of 2-propanol and heated under reflux for 1 hour. After cooling the solid was collected and washed to give the title compound (153.4 g) as a white solid mp 238-41° C.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:18]\[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1
Reactant: COC(=O)/C=C1\CCc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCc2ccc(O)cc21
Reaction time: 24 h
Yield: 68 %

Procedure:
Under hydrogen, a mixture of (E)-methyl 2-(6-(benzyloxy)-2,3-dihydroinden-1-ylidene)acetate (1.3) (1.64 g, 5.57 mmol), palladium on carbon (10%) (0.462 g, 3.90 mmol) in MeOH (30 mL) were stirred for 24 hours. The mixture was then filtered through silica gel to remove the Pd—C, eluting with EtOAc. After removing solvent by rotary evaporation, the residue was purified using column chromatography (1:1 EtOAc/hexane). Product 1.4 was obtained in 68% yield as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O[CH2:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[N:17]([CH2:36][CH2:37][C:38]4[S:39][CH:40]=[CH:41][CH:42]=4)[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: c1ccc(CCN2CCC(Nc3nc4ccccc4n3CCc3cccs3)CC2)cc1
Yield: 23.2 %

Procedure:
A mixture of 3.2 parts of N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.9 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 1 part of sodium carbonate and 135 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone, yielding 1 part (23.2%) of N-[1-(2-phenylethyl)-4-piperidinyl]-1-[2-(2-thienyl)ethyl]-1H-benzimidazol-2-amine; mp. 118.3° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pt]=O>[NH2:1][CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Yield: 92.3 %

Procedure:
(3R,4S)-3-Azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine (1.35 g) was dissolved in ethanol (30 mL). To this solution, platinum oxide (IV) (190 mg) was added and the mixture was stirred at room temperature for 2 hours in a stream of hydrogen (provided from a balloon). Subsequently, the catalyst was collected from the reaction mixture by filtration through a Celite pad. The collected catalyst and the Celite pad were washed with ethanol. The filtrate and the washing solution were combined and the combined organic layer was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate: methanol=10:1) to give 1.13 g of (3S,4S)-3-aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:27]1CCC[C@H]1C(O)=O.[OH-].[NH4+]>CS(C)=O.[Cu]I.CC(OC)(C)C>[NH2:27][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(CCCOC2CC2)c2cc(Br)ccc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC1(C)C(=O)N(CCCOC2CC2)c2cc(N)ccc21
Temperature: 90 °C

Procedure:
To a suspension of 6-bromo-1-(3-cyclopropoxypropyl)-3,3-dimethylindolin-2-one (360 mg, 1.06 mmol) and K2CO3 (441 mg, 3.19 mmol) in DMSO (2 ml) were added L-proline (49.0 mg, 426 μmol), copper (I) iodide (40.5 mg, 213 μmol) and ammonium hydroxide (373 mg, 414 μl, 2.66 mmol). The tube was sealed and heated to 90° C. for 7 hours. The reaction mixture was poured into TBME (50 ml) and extracted with 1 M HCl. The combined aqueous layers were basified with 2M Na2CO3. The aqueous phase was extracted two times with TBME. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as brown viscous oil (228 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
To a solution of ethyl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylate (2.1 g, 5.41 mmol) in a mixture of THF (40 mL) and MeOH (14 mL) was added a solution of aq. 1 M sodium hydroxide (13.52 mL, 13.52 mmol). The mixture was stirred at room temperature for 2 days. Removal of solvents left a solid which was suspended in water (150 mL), This was acidified with 1N HCl to pH 2-3 and the solid was collected by filtration, washed with H2O(3×20 mL), and dried under vacuum to afford 1.78 gm of the desired product (83% yield). MS (ESI) m/z 361.1 (M+H). 1H NMR (DMSO-d6) δ ppm 12.79 (1H, br. s.), 11.70 (1H, s), 8.76 (1H, s), 8.38-8.47 (2H, m), 8.35 (2H, dd, J=4.58, 3.36 Hz), 7.82 (1H, d, J=7.93 Hz), 7.59 (1H, br. s.), 7.40-7.52 (3H, m), 6.96 (1H, dd, J=7.93, 2.14 Hz), 3.89 (3H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.CO.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][CH:4]=[C:3]2[NH:22][C:21]1[CH:23]=[C:24]([OH:28])[C:25]([CH3:27])=[CH:26][C:20]=1[F:19])#[N:14]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1C#N
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1C#N
Yield: 48.9 %

Procedure:
A mixture of 4-chloro-6-cyano-7-methoxyquinoline hydrochloride (500 mg, 2 mmol), (prepared by an analogous procedure to that described for the starting material in Example 1 but using methanol instead of 2-methoxyethanol), and 2-fluoro-5-hydroxy-4-methylaniline (141 mg, 1 mmol), (prepared as described for the starting material in Example 1), in isopropanol (10 ml) was heated at reflux for 4 hours. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyquinoline hydrochloride (176 mg, 54%) as a light brown solid.
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]=[C:8]([CH3:15])[N:7]=[C:6]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.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>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([O:16][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[C:8]([CH3:15])[N:7]=4)=[CH:22][CH:21]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nc(C)nc(Oc3ccc(N)cc3)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 1.9 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.100 g, 0.321 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.056 g, 0.386 mmol) in DMF was added DIEA (0.168 mL, 0.963 mmol), followed by HATU (0.183 g, 0.482 mmol). The reaction mixture was stirred at RT for 15 hours. The mixture was diluted with EtOAc, washed with 5% LiCl aq solution three times, dried over Na2SO4, and concentrated in vacuo. The crude product was purified on preparative HPLC to give ′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (3.2 mg) as a white solid. 1H NMR (DMSO-d6) 10.15 (bs, 1H), 10.01 (bs, 1H), 7.69-7.75 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (s, 1H), 7.32 (s, 1H), 7.23-7.29 (m, 2H), 7.12-7.19 (m, 2H), 3.93 (d, 6H), 2.43 (s, 3H), 1.53 (s, 4H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2SC(NC3C=CC(O)=CC=3)=N[CH:7]=2)=[CH:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[S:29])=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1.NC(N)=S.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[S:29][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][N:30]=2)=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:22]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: COc1ccc(NC(N)=S)c(C(F)(F)F)c1
Agent: NC(N)=S
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (4-methoxy-2-trifluoromethyl-phenyl)-thiourea. After addition of the thiourea, the reaction mixture is heated to 50° C. for 30 min. The mixture is heated to 70° C. for 16 h, after addition of DIEA. The title compound: ES-MS: 357.0 [M+H]+; single peak at tR=4.36 min (System 2); Rf=0.56 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:16](O)[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[C:9]1=[O:34].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:9](=[O:34])[C:10]2[C:11]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])=[C:12]3[CH:27]=[CH:26][CH:25]=[CH:24][C:13]3=[C:14]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[C:15]=2[CH2:16]1
Reactant: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2O)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(N2Cc3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Reaction time: 0.08 h

Procedure:
To a solution of (3-chloro-4-{1-hydroxy-3-oxo-4,9-bis[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetic acid (0.235 g, 0.42 mmol) in trifluoroacetic acid (5 ml) cooled to 0° C., was added triethylsilane (0.10 ml, 0.63 mmol). Stirring continued at 0° C. for 5 minutes and then the mixture was evaporated. The crude mixture was purified using MDAP. The clean fractions were evaporated to give a white solid. This was triturated with ether, the resulting white solid collected by filtration (0.008 g, 0.015 mmol). LC/MS: Rt=3.49, [MH]+548.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([NH2:38])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:18][CH:19]=1)[C:36]([NH2:38])=[O:37])#[N:34]
Reactant: N#CCC(N)=O
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(N)=O)cc3)nc12
Yield: 96.4 %

Procedure:
To a 50 ml three necked round bottom flask 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.0005 mole) and 2-cyanoacetamide (0.094 g, 0.0011 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (3.3 M solution in water) (1.0 ml) was added drop wise at RT. After completion of the addition, reaction mixture was refluxed for 2 hr. After completion of the reaction, the ethanol was distilled out and water was added to residue. The aq. layer was extracted with ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane, pentane layer was decanted and solid was dried under vacuum to yield 0.25 g of 2-cyano-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(N)sc1C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1sc(N)nc1C(=O)O
Temperature: 110 °C
Yield: 117.3 %

Procedure:
To a solution of methyl 2-amino-5-(1-methylethyl)-1,3-thiazole-4-carboxylate (220 mg) (for example, available from ABCR) in 1,4-dioxane (5 ml) was added 2M hydrochloric acid (5 ml) and the mixture heated at 110° C. for 72 h. The mixture was evaporated in vacuo to give the title compound (240 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:19]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[N:6]=1.O.NN.C(#N)C>C(O)COCCO>[NH2:19][N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[N:6]=[C:2]1[NH2:1]
Reactant: Nc1nc(-c2ccc(-c3ccccc3)cc2)cn1N=Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CC#N
Solvent: OCCOCCO
Product: Nc1nc(-c2ccc(-c3ccccc3)cc2)cn1N
Temperature: 20 °C

Procedure:
A solution of 9.2 g (0.0189 mol) of 2-amino-1-benzylideneamino-4-(4-biphenylyl)-imidazole and 22 ml of hydrazine hydrate in 73 ml of diethylene glycol is stirred at 140° C. for 48 hours. After cooling to 20° C., 100 ml of acetonitrile are added to the reaction mixture, which is then cooled further to 5° C. The product that has separated out is filtered off and washed with acetonitrile and diethyl ether. In that manner there is obtained the title compound having a water content of 0.41 %, m.p. >280° C., 1H-NMR (DMSO): δ=7.29-7.73 (m, 9H); 7.12 (s, 1H); 5.55 (s, 2H); 5.39 (s, 2H).
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1.Cl[CH2:15][C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CO.O>[NH2:12][C:11]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[CH:8][CH:9]=2)[S:4][C:15]=1[C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(C#N)c(S)n1
Reactant: O=C(CCl)CS(=O)(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(N)c(C(=O)CS(=O)(=O)c3ccc(Cl)cc3)sc2n1
Yield: 67.2 %

Procedure:
To a mixture of 5.4 g (0.1 mol) of sodium methoxide and 7.5 g (0.05 mol) of 2-mercapto-3-cyano-6-methyl pyridine in 100 ml methanol was slowly added 13.3 g (0.05 mol) of 3-chloro-1-(4-chloro-phenylsulfonyl)-2-propanone. The reaction mixture was refluxed for 7 hours. It was then cooled, diluted with water and filtered to give 15.5 g of crude product which was crystallized from acetonitrile to give 12.8 g of pure product, m.p. 265°-7° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]2.[ClH:20].Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH2:26][CH2:25]1>>[ClH:20].[ClH:20].[OH:38][CH:35]1[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH3:19])[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:29][CH2:28]2)[CH2:37][CH2:36]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: CC(C)CCCOc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)CCCOc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(4-methyl-pentyloxy)-1H-indole-2-carboxylic acid (91) (preparation see below) and amine 21.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C@:4]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([NH2:20])=[CH:10][CH:11]=3)[N:3]=[C:2]1[NH2:21].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.CCOC(C)=O>[NH2:21][C:2]1[O:1][CH2:6][CH2:5][C@:4]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([NH:20][C:29](=[O:30])[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=2)=[CH:10][CH:11]=3)[N:3]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncccc12
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1ncccc12
Reaction time: 2 h
Yield: 29.6 %

Procedure:
The (S)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.008 g, 0.028 mmol) was dissolved in MeOH (1 mL). The 5-chloropicolinic acid (4.91 mg, 0.031 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (8.63 mg, 0.031 mmol) were added. After 2 h, additional MeOH (0.5 mL) was added, followed by additional 5-chloropicolinic acid (2.5 mg, 0.015 mmol) and additional 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (4.3 mg, 0.015 mmol). After 14 h, the reaction was taken up in EtOAc (75 mL). The organic phase was washed with half-saturated NaHCO3 (2×10 mL), then with saturated brine (10 mL), dried over MgSO4 and concentrated. The residue was purified by preparative TLC, using 12.5% MeOH-dcm to afford (S)—N-(2′-amino-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (3.5 mg, 0.0083 mmol). MS (m/z) 422 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 9.88 (s, 1H), 8.57 (s, 1H), 8.27 (m, 2H), 7.89 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=7.4 Hz), 7.76 (m, 2H), 7.32 (d, 1H, J=8.4 Hz), 7.20 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 1.98 (m, 1H), 1.93 (m, 1H).