Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O-])([O-])=[O:6].[K+].[K+].[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:22].Cl>O>[Cl:11][C:12]1[C:17]([C:18]([F:20])([F:21])[F:19])=[C:16]([CH:15]=[CH:14][C:13]=1[OH:22])[CH:5]=[O:6]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(O)c(Cl)c1C(F)(F)F
Yield: 11.7 %

Procedure:
Chloroform (6.7 g, 2.0 eq.) was added dropwise to a stirred mixture of Ca(OH)2 (8.95 g, 120 mmol.), K2CO3 (13.5 g, 98 mmol.), 2-chloro-3-(trifluoromethyl)phenol (50. g, 22 mmol.), and H2O (50 mL) at 60°-70° over 2 hours. The reaction mixture was cooled, and acidified with conc. HCl. The product was extracted into EtOAc and dried over Na2SO4. Solvent was evaporated, the crude product was separated and purified through a silica column, eluting with hexane and EtOAc (3:2) to give 580 mg (10%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].CC([N-]C(C)C)C.Cl[C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reactant: Nc1ccc(I)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)cn(C)c1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To the stirred solution of 2-fluoro-4-iodoaniline (470 mg, 1.94 mmol) in dry THF (4 mL) cooled to −78° C., was added LDA (2M in THF) (1.35 mL, 2.70 mmol). After vigorous stirring for 10 minutes at this temperature, a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (160 mg, 0.792 mmol) dissolved in dry THF (8 mL) was added dropwise through a syringe. The dry-ice bath was removed after 1 hour, and the reaction was stirred for 16 hours at room temperature At this time, LC/MS indicated 23% of the title product and 33% of unreacted chloride in the reaction mixture. The same reaction mixture was continued to stir at room temperature for additional 24 hours. The mixture was then re-cooled to −78° C. under a dry-ice/acetone bath. Additional LDA (1.35 mL, 2.70 mmol) (2M in THF) was added to the reaction mixture and slowly warmed to room temperature in 16 hours until LC/MS showed the consumption of chloride material. The mixture was cooled to −5° C., and aqueous HCl (1N) (15 mL) was added. The solution was extracted with EtOAc (15 mL×3). The combined organic layers was dried (MgSO4) and concentrated to give a residue which was triturated with DCM to give a solid. The title compound was used for the next reaction without further purification. (165 mg, 52% yield). MW m/z: 403.13 (MW+1), 401.18 (MW−1). 1H NMR (DMSO-d6, 300 Hz): δ ppm 13.26 (s, br, 1H), 9.08 (s, 1H), 8.48 (s, 1H), 7.62 (d, J=10.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 6.49 (t, J=8.7 Hz, 1H), 3.48 (s, 3H), 1.58 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:13][CH2:14][OH:15]>O>[OH:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc(OCCO)cc1

Procedure:
A mixture of 4-hydroxybenzaldehyde (45.5 g), sodium hydroxide (15 g) and 2-chloroethanol (30 g, 25 ml) was heated at reflux in water (200 ml) for 7 hours. The mixture was cooled and extracted with dichloromethane (200 ml). The dichloromethane solution was washed with sodium hydroxide solution (2M, 2×150 ml), brine (150 ml), dried (MgSO4) and evaporated to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[CH2:4][C@@H:3]1[OH:10].[C:11]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:18][CH:19]([C:27](=[O:28])[NH:1][CH:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[CH2:4][CH:3]1[OH:10])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H]1c2ccsc2C[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1c2ccsc2CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the racemic cis-4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-5-ol (17.5 g, 0.112 mol) in dry DMF (400 mL) was added Boc-L-phenylalanin (30.51 g, 0.115 mol) HOBT (15.6 g, 0.115 mol) and EDAC (22.0 g, 0.115 mol). To the stirred mixture was added TEA (16 mL, 0.115 mol) and the mixture was stirred at room temperature overnight. The mixture was added to 5% citric acid and extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogen carbonate (two times). The organic phase was dried with sodium sulphate and evaporated under reduced pressure. Yield: 43 g=95%
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH:4][CH2:13][CH:14]=[O:15]
Reactant: COCc1ccc(C)c(N)c1
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCc1ccc(C)c(NCC=O)c1
Temperature: 150 °C

Procedure:
2-Methyl-5-methoxymethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[C:22]([F:25])=[N:23][CH:24]=1.C([O-])(=O)C.[K+].O>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:22]([F:25])=[N:23][CH:24]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cc(Cl)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.979 mmol) and 5-chloro-2-fluoropyridin-3-ylboronic acid (1.388 g, 7.91 mmol) (Combi-Blocks, Inc., San Diego, Calif.) in THF (25 ml) were added to a 100 mL round-bottomed flask. Potassium acetate (0.583 g, 5.94 mmol) was added to the mixture, followed by water (1 mL). The mixture was evacuated, then backfilled with Nitrogen gas. Then bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.050 g) (Aldrich, St. Louis, Mo.) was added into the mixture. The mixture was evacuated, then backfilled with nitrogen gas. The flask was fitted with a reflux condenser, then placed into a pre-heated (90° C.) oil bath and allowed to stir under inert atmosphere for 2 h. The progress of the reaction was monitored by LCMS, which showed mostly desired product. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with CH2Cl2 (3×25 mL). The organic extracts were washed with satd aqueous Na2CO3 (1×20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 1% to 40% EtOAc in CH2Cl2, to give 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.502 g, 1.443 mmol, 73.0% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.37-8.45 (m, 1H); 8.27-8.33 (m, 2H); 5.79-5.92 (m, 1H); 4.14-4.26 (m, 1H); 3.74-3.91 (m, 1H); 2.89 (s, 3H); 1.96-2.25 (m, 3H); 1.63-1.91 (m, 3H). m/z (ESI, +ve) 348 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:31]=[C:30]([C:38](O)=O)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[N:31]=[C:30]([C:38]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH3:16]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.05 g, 18%). MS (ISP) 560.0 [(M+H)+]; mp 227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[N:10]([C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[C:11]=S>>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:11]([NH:10][C@H:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)[NH:1][C:2]=2[CH:3]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: S=C=N[C@@H]1CCCc2ccccc21
Product: Cc1ccc2nc(N[C@@H]3CCCc4ccccc43)[nH]c2c1

Procedure:
The title compound was prepared from 3,4-diaminotoluene and (R)-1-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base (off-white solid, mp 91-93° C.). MS(ES+) m/z 278 ([M+1]+, 100).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH:3]2[CH2:4][O:1][CH2:2]2)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: NC1COC1
Solvent: CO
Solvent: CC#N
Product: FC(F)(F)COCc1cc(NC2COC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A solution of oxetan-3-amine (77 mg, 1.06 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (92 mg, 0.35 mmol) in acetonitrile (2 mL). The mixture stirred at rt overnight. The mixture was separated by preparative chromatography to give the title compound (58 mg, 55%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 50 °C
Yield: 63.3 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate, (0.2 g, 0.571 mmol) and anhydrous potassium carbonate (0.316 g, 2.284 mmol) in DMF (2.5 ml) was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.152 g, 0.685 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and then extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. DMSO:MeOH (1:1) was added to the residue and the resulting precipitate was collected by filtration, washed with methanol and dried in vacuo to give the title compound as a white solid (136 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3ccccc3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (490 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionic acid (430 mg, yield: 94%) was obtained. This was recrystallized from acetone-hexane. Melting point: 115–116° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH2:29][O:30][CH2:31][CH3:32])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 94-111, trans-2-phenyl-1-cyclopropanecarbonyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 422.2564.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-])=O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OC)(C)(C)C.[Pd]>[C:12]1([NH:18][C:19](=[O:20])[NH:1][C:4]2[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Pd]
Solvent: COC(C)(C)C
Product: O=C(Nc1ccccc1)Nc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off. 24 g (200 mmol) of phenyl isocyanate were added to the filtrate at 15° C. with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 43 g (89%).
Reaction SMILES: [NH:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH3:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[C:2]([CH3:4])=[O:3].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[NH:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH3:17])=[O:16])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH2:7][CH2:6]1)[C:2]([CH3:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)CCN2NC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(NC(C)=O)CC2
Yield: 62.8 %

Procedure:
33 g of 1,5-diacetamino-indoline were dissolved at 70° C. in 120 ml of glacial acetic acid and nitrated dropwise with 15 ml of nitric acid (d=1.4). The reaction became vigorous and methanol/ice cooling was used. The precipitated crystals were removed by filtration under suction, dissolved in methylene chloride and washed neutral. After evaporation and crystallization from isopropanol, there were obtained 25 g (62.8% of theory) of 1,5-diacetamino-6-nitro-indoline of melting point 212°-213° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH3:5].BrBr.[NH2:9][C:10]([NH2:12])=[S:11]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:10]([NH2:12])[S:11][CH:5]=1
Reactant: COCC(C)=O
Reactant: NC(N)=S
Agent: BrBr
Solvent: CO
Product: COCc1csc(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
A solution of 1-methoxypropan-2-one (20.3 g, 231 mmol) in 200 mL of MeOH was added to a 250 mL round-bottom flask. The flask was then immersed in an ice-water bath. Br2 was added dropwise to the reaction mixture through an addition funnel. After the addition, the addition funnel was rinsed with 50 mL MeOH, and the reaction mixture was stirred for 20 minutes at 0° C. The ice-water bath was then removed, and the reaction mixture was stirred for two more hours. Thiourea (18 g, 231 mmol) was then added to the reaction mixture, and the reaction was heated at reflux overnight. The reaction was concentrated, and saturated sodium bicarbonate and solid sodium carbonate were used to adjust the pH to 8-9. The resulting mixture was then extracted three times with 200 mL portions of EtOAc. The organic layers were concentrated and then purified by recrystallization to give 4-(methoxymethyl)thiazol-2-amine (11 g, 33% yield over two steps). MS m/z: 145 (M+1).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([Cl:27])[CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([NH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([Cl:27])[CH:18]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
A solution of 2.37 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-amino-2-chlorobenzoate and 1.49 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132°-134° C. M+H=365
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][N:21]1[C:33]2[CH:32]=[CH:31][C:30]([CH:34]=O)=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 429.28 g/mol.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[C:32]([CH3:34])[CH:33]=2)[C:29]#[N:30])=[O:25])=[N:6][C:7]([O:17]CC[Si](C)(C)C)=[N:8][C:9]=1[O:10]CC[Si](C)(C)C)([CH3:3])=[CH2:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:17])[NH:6][C:5]=1[C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:29]#[N:30])=[O:25])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1c(OCC[Si](C)(C)C)nc(OCC[Si](C)(C)C)nc1C(=O)c1cc(C)cc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)c1c(C(=O)c2cc(C)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 3-[5-isopropenyl-2,6-bis-(2-trimethylsilanyl-ethoxy)-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (0.636 g, 1.28 mmol) in dichloromethane (10 mL) at 0° C. was added TFA (2 mL). Reaction mixture was stirred at 0° C. for 30 min, concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/dichloromethane) to give a yellow solid (0.311 g, 82%). 1H NMR (300 MHz, CD3OD): δ 8.11 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 4.91 (s, 1H), 4.75 (s, 1H), 2.49 (s, 3H), 1.82 (s, 3H). Mass spectrum: 296.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:16]([CH3:15])(=[O:18])=[O:17])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 150 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 609 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 20 minutes and then methanesulfonylchloride (1.18 ml) was introduced dropwise via syringe. After 5 minutes the reaction mixture became homogeneous and was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 300 ml of ethyl acetate and was washed with brine. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (ethyl acetate then chloroform-methanol, 95:5 v/v) to yield 1.6 g of the title compound in pure form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.[CH:27]([O:30][C:31](Cl)=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>CN(C=O)C>[CH:27]([O:30][C:31]([N:24]1[CH2:25][CH2:26][CH:22]([NH:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:23]1)=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(NC4CCNC4)ncnc32)c(F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A mixture of [1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl-amine (20 mg, 0.048 mmol), isopropylchloroformate (7.2 μL, 0.52 mmol), and triethylamine (20 μL, 0.144 mmol) in DMF (500 μL) was stirred for 2 hours at room temperature. The reaction was purified by HPLC to afford compound A142 as a white solid (9 mg, 41%). Exact mass calculated for C20H23FN6O4S 462.15 found 463.3 (MH+).