Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18].C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[N:14][O:18][NH2:17])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C=NON)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
In a mixture of 21.2 ml of t-butanol and 2.1 ml of water were dissolved 4.3 g of 4-cyanobenzoic t-butyl ester, 1.84 g of hydroxylamine hydrochloride and 2.31 g of sodium hydrogencarbonate. The solution was stirred for 2 hours at 80° C. To the reaction mixture was added water, and the mixture was subjected to extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate=1/1), followed by crystallization from hexane to afford 4.41 g of the titled compound as colorless needles.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Cl:29])[C:20]=2[F:30])=[CH:11][C:10]=1[C:43]([CH3:46])([CH3:45])[CH3:44])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:17]([CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([Cl:29])[C:20]=2[F:30])=[CH:38][CH:37]=1)([CH3:40])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(O)c(C(C)(C)C)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Yield: 82.9 %

Procedure:
A solution of 182 mg of N-[2-(4-benzyloxy-3-tert-butyl-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide (0.278 mmol) in 15 ml ethyl acetate were hydrogenated over 100 mg Pd/C-5%. After completion of the reaction the suspension was filtered off and concentrated in vacuo. The resulting residue was purified by flash column chromatography (Heptane/AcOEt:90/10) to yield 130 mg of a colorless viscous oil. MS (ISP) 564 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11]([F:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:15]([O-])(=O)=O.[Na+]>Cl.O>[N+:1]([C:4]1[CH:10]=[C:9]([S:11]([F:14])(=[O:12])=[O:13])[CH:8]=[C:7]([Cl:15])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(S(=O)(=O)F)cc1[N+](=O)[O-]
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(Cl)cc(S(=O)(=O)F)cc1[N+](=O)[O-]
Yield: 177.7 %

Procedure:
2-Nitro-4-fluorosulphonylaniline (10 g) was dispersed in 30% HCl (63.6 g), cooled to 0°-5° C. and sodium chlorate (2 g) dissolved in water (3.6 g) added dropwise ensuring maintaining the temperature at 0°-5° C. After 30 minutes reaction mixture drowned onto ice and precipitate collected, washed with water and suction dried to yield 8.5 g of 2-Nitro-4-fluorosulphonyl-6-chloroaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:20]>>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:4]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)c1cccnc1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2cc(F)c(F)cc2C(=O)c2cccnc2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-Amino-4,5-difluoro-phenyl)-pyridin-3-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 484 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[NH:11][C:10]([CH3:27])=[C:9]2[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:39]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]([CH3:39])[C:10]([CH3:27])=[C:9]2[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)OCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCC[Si](C)(C)C)=C(C)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCC[Si](C)(C)C)=C(C)N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
277 mg (0.53 mmol) of 5-(3-phenyl-2-propene-1-yl) 3-(2-trimethylsilylethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was dissolved in N,N-dimethylformamide. 40 mg (1.0 mmol) of sodium hydride (60%, oily) was added to the obtained solution. Then 0.05 ml (0.8 mmol) of methyl iodide was added to the resultant mixture, and they were stirred at room temperature for 2 hours. N,N-dimethylformamide was evaporated under reduced pressure. Water was added to the residue. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.CO.C(N)CN>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(c1cncc(Br)c1)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 71.4 %

Procedure:
The 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.220 g, 0.000419 mol) in DCM (9.0 mL, 0.14 mol) and TFA (9.0 mL, 0.12 mol) was stirred at room temperature for 1 hour. The reaction was concentrated in to give a residue. This crude intermediate was dissolved in methanol (12 mL, 0.30 mol) and ethylenediamine (0.2 mL, 0.003 mol) and was stirred overnight at room temperature. The reaction was concentrated in vacuo to give the crude product which was purified by preparative HPLC eluting with a water:ACN gradient buffered with ammonium hydroxide (pH=10) to give 3-(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as an amorphous white powder (118 mg, 71.36%). LCMS (M+1)+: 394, 396, 1H NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 8.98 (s, 1H), 7.0 (s, 1H), 6.50 (m, 2H), 8.50 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H), 6.98 (s, 1H), 6.21 (m, 1H), 3.90 (m, 1H), 3.70 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:40]([CH:42]3[CH2:44][CH2:43]3)[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[N:28][C:29]=1Br>>[NH2:23][C:24]1[C:29]([C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)=[N:28][C:27]([C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:39])(=[O:38])[N:40]([CH:42]3[CH2:43][CH2:44]3)[CH3:41])=[CH:33][CH:32]=2)=[CH:26][N:25]=1
Reactant: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CNC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CNC(=O)N1CCc2cc(-c3nc(-c4ccc(S(=O)(=O)N(C)C5CC5)cc4)cnc3N)ccc21
Yield: 28.1 %

Procedure:
Method C was applied to N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxamide (85 mg, 0.28 mmol) and 4-(5-amino-6-bromopyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide (100 mg, 0.26 mmol). The organic layer was decanted then triturated with Et2O to provide 5-(3-amino-6-(4-(N-cyclopropyl-N-methylsulfamoyl)phenyl)pyrazin-2-yl)-N-methylindoline-1-carboxamide as a yellow solid (35 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58-8.66 (m, 1H), 8.20-8.31 (m, 1H), 7.92-7.99 (m, 1H), 7.79-7.88 (m, 2H), 7.47-7.64 (m, 2H), 6.61-6.71 (m, 1H), 6.60-6.65 (m, 1H), 6.58-6.71 (m, 2H), 6.42-6.49 (m, 2H), 3.88-3.98 (m, 2H), 3.13-3.25 (m, 2H), 2.68 (s, 3H), 2.08 (s, 3H), 1.79-1.88 (m, 1H), 0.62-0.81 (m, 4H); MS (EI) m/z=479.1[M+1]+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[C:18]1([CH:24]([C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](B(O)O)=[CH:32][C:31]=3[CH:38]=2)[CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:3]1[CH:4]=[C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)[CH:15]=[CH:16][C:2]=1[C:33]1[O:34][C:30]2[CH:29]=[CH:28][C:27]([CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][CH3:26])=[CH:38][C:31]=2[CH:32]=1
Reactant: CCC(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Product: CCC(c1ccccc1)c1ccc2oc(-c3ccc(CN4CC(C(=O)OC)C4)cc3F)cc2c1

Procedure:
Synthesized according to Scheme B2 and general procedure F using methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (1.76 g, 5.81 mmol) and 5-(1-phenylpropyl)-benzofuran-2-ylboronic acid (1.63 g, 5.81 mmol) to give methyl 1-((3-fluoro-4-(5-(1-phenylpropyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 457.2; Observed: 458.3 (M++1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCc1c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionate (1.16 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.03 g, 94%) of 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:8]([Cl:20])[CH:7]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>O>[C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:8]([Cl:20])[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCCn2ccnc2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OCCn2ccnc2)c(Cl)c1
Yield: 62.5 %

Procedure:
A mixture of 1-[2-(4-ethoxycarbonyl-2-chlorophenoxy)ethyl]imidazole (115 mg) and potassium hydroxide (50 mg) in water (6.25 ml) was heated on a steam bath for 18 hours. The resulting solution was just acidified with acetic acid and evaporated to a small volume. The resulting solid was filtered off, washed with water and crystallised from water to give 1-[2-(4-carboxy-2-chlorophenoxy)ethyl]imidazole (65 mg), m.p. 204° C. Found: C, 53.44; H, 4.15; N, 10.52. C12H11ClN2O3 requires: C, 54.04; H, 4.16; N, 10.51%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(O)c1
Yield: 84.2 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 0.33 g of 3'-hydroxyacetophenone and 0.70 g of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.74 g of the title compound, melting at 133°-135° C., was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:25][C@@:24]3([CH3:26])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][C@H:17]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:18]3[OH:27])[CH2:10][C@@H:9]2[OH:33])[CH2:4][CH2:3]1.[CH3:34][C:35]([CH2:37][C:38]([OH:40])=[O:39])=[O:36].[BH4-].[Na+]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:25][C@@:24]3([CH3:26])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][C@H:17]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:18]3[OH:27])[CH2:10][C@@H:9]2[OH:33])[CH2:4][CH2:3]1.[CH3:34][C:35]([CH2:37][C:38]([OH:40])=[O:39])=[O:36]
Reactant: C[C@]12C[C@H](N3CCC(=O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Agent: CC(=O)CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Yield: 81 %

Procedure:
2β-(4-Oxo-1-piperidinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α,17β-diol-diacetate is reduced by sodium borohydride as described in Example 11 to give the foam-like title compound in a yield of 81%, Rf2 =0.55.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1
Yield: 88.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 4-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (210 mg, 83.7%) as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:31]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]1>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22]([N:31]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]5)=[O:23])[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:29])[CH3:30])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Reactant: OC1CCNC1
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(=O)N2CCC(O)C2)cs1
Temperature: 80 °C

Procedure:
The ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate (Example 20) (100 mg, 0.228 mmol) was dissolved in methanol (10 mL) and to it pyrrolidin-3-ol (0.455 mmol, 2 equiv) was added and heated at 80° C. for 2 h. The reaction mixture was concentrated, the crude obtained was purified on preparative TLC to obtain (2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypyrrolidin-1-yl)methanone. 1H NMR: 400 MHz, DMSO-d6: δ 1.24 (d, J=4.00 Hz, 6H), 1.85-1.86 (m, 3H), 3.46-3.50 (m, 1H), 3.56-3.57 (m, 1H), 3.72-3.73 (m, 1H), 3.90-3.91 (m, 1H), 4.35 (bs, 1H), 5.00-5.01 (m, 1H), 6.18 (s, 1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.95-7.97 (m, 1H), 8.13-8.13 (m, 1H), 8.14-8.18 (m, 1H), 8.52-8.52 (m, 1H), 8.72-8.72 (m, 1H), 9.16 (s, 1H), 9.37 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.883 min; LCMS (ES-API), m/z 481.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.062 min; Purity: 92.2%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:21]=[C:20]([CH3:29])[CH:25]=[CH:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: Cc1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and m-tolylboronic acid to give (6-methoxy-1-m-tolyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:4]=1)#[N:2].CCO.CCOC(C)=O.[H][H]>[Pd].C(N(CC)CC)C>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:4]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(C#N)nc(C)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CN)nc(C)n2)cc1
Yield: 60.9 %

Procedure:
In a PARR reactor, combine palladium (3.6 g, 10% on charcoal, 1-[4-(6-cyano-2-methyl-pyrimidin-4-yl)oxyphenyl]-N-methyl-methanesulfonamide (18 g, 56.5 mmol), EtOH (270 mL), EtOAc (270 mL), and triethylamine (31.5 mL). Seal the PARR reactor and charge it with hydrogen (400 psi); then shake the reactor at room temperature overnight. Open the reactor and filter the contents through CELITE®; wash the CELITE® pad with EtOH (1000 mL); collect the filtrate; and evaporate the solvent to provide the title compound as a brown solid (11.1 g, 43%). MS (m/z): 323 (M+1). Alternative Preparation 4
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:15]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c4) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=P(O)(O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
Phosphoric acid (0.58 ml, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][N:12]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]1B(O)O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:6][C:5]1[C:4]([F:10])=[CH:3][C:2]([C:13]2[N:12]([CH3:11])[C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:8]([F:9])[CH:7]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Nc1cc(F)c(Br)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1c(C#N)ccc1-c1cc(F)c(N)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
4-Bromo-2,5-difluoroaniline (0.1 g, 4.85 mmol), 1-methyl-5-cyano-2-pyrrole-boronic acid (1.3 g, 8.7 mmol), KF (0.93 g, 16 mmol), and Pd2(dba)3 (117 mg, 0.12 mmol) were added to a 50 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. THF (12.1 mL) was added and the mixture was purged with nitrogen for an additional 5 minutes. A solution of tri-t-butylphosphine (10% wt in hexanes) (0.72 mL, 0.24 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 16 hours. The mixture was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification via Isco chromatography (the Redisep® column, silica, gradient 5-100% ethyl acetate in hexane) afforded 5-(4-amino-2,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (0.87 g, 77%).