Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[Cl:12][S:13]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:9]([NH2:11])=[O:10])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: NC(=O)COc1ccccc1
Solvent: ClCCl
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.0 g of 2-(phenoxy)acetamide was dissolved in 10 ml of dichloromethane and 6 ml of chlorosulfonic acid was slowly added at 0 ° C. The reaction mixture was stirred at room temperature for 10 hr. Dichloromethane was evaporated under reduced pressure. Residual material was poured on chopped ice. Solid was collected by filtration and dried in vacuo. 3.9 g of product was obtained. M.P. 166-171° C. (decomposition)
Reaction SMILES: [CH:1]1([C:4]#[C:5][NH:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH2:3]C1.[C:14]1(C)C=CC=CC=1>[Cl-].[Na+].O>[CH:4]1([C:5]2[NH:6][C:7]3[C:8]([CH:14]=2)=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[CH2:1][CH2:3]1
Reactant: Cc1ccccc1
Reactant: Fc1ccc(NC#CC2CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2[nH]c(C3CC3)cc2c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-cyclopropylethynyl-4-fluoro-phenylamine (0.80 g, 4.5 mmol) in PhMe (16 mL) is treated with InBr3 (80 mg, 0.23 mmol) and stirred at 110° C. for 0.5 h. The mixture is then poured over brine (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-25% EtOAc in heptane to afford 2-cyclopropyl-5-fluoro-1H-indole (610 mg, 78%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.88 (s, NH, 1H), 7.12 (m, 2H), 6.83 (m, 1H), 6.09 (s, 1H), 1.90 (m, 1H), 0.95 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](O)=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.CC1C([N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])=C(C=CC=1)C(Cl)=O>C(N(CC)CC)C.ClCCCl>[CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:26]3[C:30](=[O:31])[CH:29]=[CH:28][C:27]3=[O:32])=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3]([N:26]2[C:27](=[O:32])[CH:28]=[CH:29][C:30]2=[O:31])[CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1N1C(=O)C=CC1=O
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1C=CC(=O)N1c1ccc(Cc2ccc(N3C(=O)C=CC3=O)cc2)cc1

Procedure:
A 6.0 g quantity of 4,4′-dihydroxydiphenylmethane is dissolved in a solution of 12.6 ml of triethylamine in 50 ml of 1,2-dichloroethane in a 250 ml flask. To the solution is slowly added a solution of 15.5 g of methyl maleimidobenzoyl chloride in 50 ml of 1,2-dichloroethane. The mixture is allowed to react at room temperature for 16 hr. The reaction mixture is precipitated in water, filtered under reduced pressure, washed sequentially with water and ethanol, and dried at 60° C. under vacuum for 48 hr, yielding the bismaleimide compound of Formula 20m.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:24][CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:32](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:32][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[N:15]=[C:16]([NH:24][CH2:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:17]=2[CH2:23]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
N2-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (49 mg, 0.12 mmol) was dissolved in methanol (3 mL). Acetic acid (6.69 μL, 0.12 mmol) was added followed by formaldehyde (8.70 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (7.34 mg, 0.12 mmol) was added. After 1 h the solvent was evaporated under reduced pressure, the crude purified twice by preparative HPLC (acidic system) yielding 6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (16.40 mg, 32.4%). MS (ES+) m/z 434.3 (M+H)+
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:24]([O:26]C(C)(C)C)=O)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C[Si]([N:42]=C=O)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:42][C:24]([N:17]1[CH2:18][C@@H:19]([C:20]([O:22][CH3:23])=[O:21])[C@H:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:16]1)=[O:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(C(N)=O)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-1-(1,1-dimethylethoxycarbonyl)-4-(methoxycarbonyl)pyrrolidine (419 mg, 1.0 mmol) in 2 mL of CH2Cl2 at 0° C. was added 2.3 mL of trifluoroacetic acid. The solution was stirred for 12 hr at room temperature, and concentrated to an oil. The oil was dissolved in 2 mL of CH2Cl2 and 4-dimethylaminopyridine 366 mg, 3.0 mmol) was added. To this solution at 0° C. was added trimethylsilylisocyanate (1.15 g, 10.0 mmol). The bath was removed and the resulting mixture was allowed to stir for 60 hr. After dilution with CH2Cl2, the reaction mixture was washed with 1M H3PO4 and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (9:1, CH2Cl2 :methanol) provided a foam. Crystallization with diisopropyl ether afforded trans-1-aminocarbonyl-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine as a white solid (243 mg, 67%), m.p. 127°-129° C. Anal. Calcd for C19H26N2O5 : C, 62.97; H, 7.23; N, 7.73. Found: C, 63.07; H, 7.20; N, 7.76.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:42][N:43]1[C:48]([CH3:50])([CH3:49])[CH2:47][CH:46]([NH2:51])[CH2:45][C:44]1([CH3:53])[CH3:52]>C1COCC1.CC#N>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([NH:51][CH:46]4[CH2:45][C:44]([CH3:52])([CH3:53])[N:43]([CH3:42])[C:48]([CH3:50])([CH3:49])[CH2:47]4)=[O:15])=[CH:16][CH:17]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc3ccc(Cl)cc3[nH]2)cc1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3nc4ccc(Cl)cc4[nH]3)cc2)CC1(C)C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A mixture of 4-(5-chlorobenzimidazol-2-yl)benzoic acid (0.5 g, 1.63 mmol), 1-hydroxybenzotriazole (0.242 g, 1.79 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.34 g, 1.89 mmol) in THF (15 ml) was heated for 1 h at 35–40° C. 1,2,2,6,6-Pentamethyl-4-aminopiperidine (0.333 g, 1.96 mmol) in THF (3 ml) was added dropwise and the reaction was left 1 h at 60° C. After cooling, the solvent was removed under reduced pressure and the residue was treated with 2N NaOH (15 ml) and extracted with ethyl acetate (20 ml). the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give a residue that was treated with CH3CN. The suspension was stirred for 1 h, filtered and dried at 50° C. to give 0.35 g of the title compound (yield 50.5%) as a yellow solid, mp>250° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@@:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:22][C@:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)NCCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CC[C@@](C)(O)C(=O)NCCO)=C(C)C1=O
Yield: 92.4 %

Procedure:
Oxidation as described in protocol B, using 1.49 g (5.11 mmol) of precursor (R)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 6.16 g CAN (11.2 mmol) yielded 1.46 g of (R)-2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a waxy yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>CO>[OH:15][N:14]=[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[NH2:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccc2c(c1)CC(=O)N2
Temperature: 65 °C
Reaction time: 12 h

Procedure:
A mixture of 5-cyanooxindole (5.00 g, 32 mmol) (commercially available from the Combi-Blocks Catalog (Order Number IN-0073), hydroxylamine hydrochloride (4.4 g, 63 mmol), and sodium bicarbonate (11 g, 126 mmol) in 50 mL anhydrous MeOH was heated to 65° C. After 12 hours, the reaction was complete. The mixture was cooled and the suspension was filtered. The resulting solid was washed with 50 mL MeOH. The solid was transferred into a 500 mL round bottom flask and 200 mL distilled water was added. The resulting suspension was sonicated for 5 minutes. Filtration gave the desired compound as an off white solid (5.3 g, 88%). MS (API-ES) m/z (%): 192.0 (100%, M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Cl)ccc2n[nH]cc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)ccc2nn(C)cc12
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of methyl 5-chloro-2H-indazole-4-carboxylate (3.80 g, 18.0 mmol) in ethyl acetate (72 mL) was added trimethyloxonium tetrafluoroborate (3.47 g, 23.5 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (3.20 g, yield 79%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=1[CH2:17][CH:18]([CH3:20])[CH3:19])(=O)=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]=1[CH2:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[CH2:17]([C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][C:15]#[N:16])[CH:11]=[CH:12][C:7]=1[C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[C:26]([CH2:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43][CH:42]=2)[CH:27]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cc1cccc2ccccc12
Reactant: CC(C)Cc1cc(CCC#N)ccc1OS(=O)(=O)C(F)(F)F
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: COCCOC
Product: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1cccc2ccccc12
Temperature: 80 °C
Yield: 88.1 %

Procedure:
452 mg (1.35 mmol) 4-(2-Cyanoethyl)-2-isobutylphenyl-trifluormethanesulfonate (6), 637.8 mg (1.70 mmol, 1.26 eq.) 2-(4-Methoxy-3-naphthalen-1-ylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (64) and 236.8 mg (205 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 20 ml DME/EtOH (9+1). To this yellow solution 1.35 ml (2.70 mmol, 2 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 15 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (3+1)) yielded 513.8 mg (1.19 mmol, 87.78%) 3-(2-Isobutyl-4′-methoxy-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)propionitrile (65) as a clear oil. Rf (hexanes/EtOAc (3+1))=0.40. 1H-NMR (500 MHz, CDCl3): δ=0.51 (d, 6H, J=6.62 Hz, 2*CH3), 1.42 (m, 1H, CH), 2.17 (d, 2H, J=7.25 Hz, CH2), 2.56 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.87 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.91 (s, 3H, OCH3), 4.42 (s, 2H, CH2Naphthyl), 6.71 (d, 1H, J=2.21 Hz), 6.94 (m, 3H), 7.00 (d, 1H, J=7.72 Hz), 7.04 (dd, 1H, J1=8.36 Hz, J2=2.36 Hz), 7.22 (m, 1H), 7.35 (m, 1H), 7.41 (m, 2H), 7.69 (d, 1H, J=8.20 Hz), 7.81 (m, 1H), 7.97 (m, 1H). MS (EI): m/z=434 (16), 433 (48), 336 (9), 335 (56), 294 (11), 293 (83), 292 (17), 277 (9), 265 (20), 264 (100), 253 (29). HR-MS (EI): Calcd. for C31H31NO: 433.240564. Found: 433.241264.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[C:12]1[CH2:19][CH:18]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([CH2:16][CH2:17]2)[CH2:14][NH:13]1>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:13]2[C:12](=[O:11])[CH2:19][CH:18]3[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([CH2:16][CH2:17]3)[CH2:14]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)NC2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C(=O)C2
Yield: 78.4 %

Procedure:
Following general N—C coupling procedure 1, 5-Bromo-2-nitropyridine (1 gm, 4.93 mmol) was combined with tert-butyl 4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1.18 gm, 4.93 mmol) which gave tert-butyl 3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1.4 gm) in 78% yield.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[N:59]=[C:58]([N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)[N:57]=[C:56]([C:66]2[CH:67]=[CH:68][C:69]([NH2:72])=[N:70][CH:71]=2)[CH:55]=1.[CH3:73][O:74][C:75]1[N:80]=[CH:79][C:78]([NH2:81])=[CH:77][CH:76]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[NH2:72][C:69]1[N:70]=[CH:71][C:66]([C:56]2[N:57]=[C:58]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[N:59]=[C:54]([NH:81][C:78]3[CH:79]=[N:80][C:75]([O:74][CH3:73])=[CH:76][CH:77]=3)[CH:55]=2)=[CH:67][CH:68]=1
Reactant: Nc1ccc(-c2cc(Cl)nc(N3CCOCC3)n2)cn1
Reactant: COc1ccc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COc1ccc(Nc2cc(-c3ccc(N)nc3)nc(N3CCOCC3)n2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 32.1 %

Procedure:
In a glass pressure vessel, Pd(OAc)2 (2.0 mg, 0.0082 mmol), BINAP (6.4 mg, 0.0102 mmol), cesium carbonate (20.0 mg, 0.0615 mmol) and THF (0.8 mL) were mixed and stirred at room temperature for 1-3 minutes. To the resulting mixture was added 5-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-pyridin-2-ylamine (12.0 mg, 0.041 mmol) followed by 6-methoxypyridin-3-ylamine (10.2 mg, 0.082 mmol). The glass pressure vessel was sealed and stirred at 95° C. for 90 minutes. The reaction mixture was filtered and concentrated under reduced pressure. The product was purified by preparative reverse phase HPLC to give [6-(6-amino-pyridin-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-(6-methoxy-pyridin-3-yl)-amine (5.0 mg, 32%). LC/MS (m/z): 380.1 (MH+), Rt 1.82 minutes.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CC2)s1
Yield: 44 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using cyclopropylamine instead of rac-2-amino-1-butanol, to the title compound (76 mg, 44%) which was obtained as a light yellow solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane). MS: m/e=346.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]4)=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)#[N:27]>CN(C=O)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH:20]5[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]5)=[CH:14][CH:15]=4)[N:10]=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[O:36])=[CH:32][CH:33]=1)#[N:27]
Reactant: c1nc(N2CCNCC2)c2ccc(OCCC3CCCCN3)cc2n1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)N2CCN(c3ncnc4cc(OCCC5CCCCN5)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To DMF solution (2 mL) of 4-piperazinyl-7-(2-piperidylethoxy)quinazoline (from Example 1, Step E, 0.287 g, 0.84 mmol) added DMF solution (2 mL) of 4-cyanophenylisocyanate (0.181 g, 1.26 mmol) and the reaction was stirred at room temperature overnight. The solvent was evaporated and residue purified by RP-EHLC to afford desired product N-(4-cyanophenyl){4-[7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}carboxamide as a white solid (200 mg, 50%). MS (ES) 487(M+H)
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].F[C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]=O>CS(C)=O>[CH3:6][O:5][C:1]([C:2]1[S:3][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[CH:12]=1)=[O:4]
Reactant: COC(=O)CS
Reactant: COc1ccc(F)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(OC)ccc2s1
Yield: 13.8 %

Procedure:
To a solution of methyl thioglycolate (0.647 mL, 7.14 mmol, 1.1 eq.) in 14 mL of DMSO was added NaH 50% (0.405 g, 10.1 mmol, 1.56 eq.) and the mixture was stirred for 5 Min., before 2-fluoro-5-methoxybenzaldehyde (1.00 g, 6.49 mmol) was added (strongly exothermic). When the internal temperature had reached again 25° C., the reaction mixture was poured onto crashed ice and the precipitate filtered off and dried to obtain 0.199 g of the title compound as off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12>CCO.[Pd]>[NH:8]1[C:7]2=[CH:2][N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: Clc1nccc2cc[nH]c12
Agent: [Pd]
Solvent: CCO
Product: c1cc2cc[nH]c2cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Hydrogenation of 7-chloro-1H-pyrrolo[2,3-c]pyridine (10 mmol) was carried out in the presence of Pd—C (10%) in EtOH (50 mL). After stirred at room temperature for 20 hrs, the mixture was filtered through a pad of celite 521. The residue was washed with EtOH several times. The filtrate was evaporated to yield 1H-pyrrolo[2,3-c]pyridine as brown oil. MS (ESI+) m/z 119.0657 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:11]1[N:19]=[C:18]([CH2:20][CH2:21][C:22]2([CH3:30])[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][O:23]2)[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH3:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.C([O-])(=O)C.[Na+]>O.C(O)(=O)C.CO.C1COCC1>[CH2:3]([N:10]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:11]1[N:19]=[C:18]([CH2:20][CH2:21][C:22]2([CH3:30])[O:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][O:27]2)[N:17]=[C:16]2[C:12]=1[N:13]=[C:14]([Br:1])[N:15]2[CH3:31])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc(CCC3(C)OCC(C)(C)CO3)nc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Br)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(CCC3(C)OCC(C)(C)CO3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (0.89 ml, 17.5 mmol) was added dropwise at 0° C. to a solution of dibenzyl-{9-methyl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}-amine (1.7 g, 3.50 mmol) in 20 ml of a mixture of MeOH/THF (1/1) and acetate buffer pH=4 (10 ml). The latter was obtained dissolving 4 g of sodium acetate in 100 ml of water and by adjusting to pH 4 through addition of glacial acetic acid. The reaction was stirred at RT for two hours. Excess of bromine was quenched by addition of sodium metabisulphite and the reaction was brought to pH 8 by addition of a saturated solution of Na2CO3. The organic solvents were evaporated under reduced pressure, to give a solid that was filtered and used without any further purification in the next step.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:42]Cl>CN(C=O)C.CCOCC.Cl>[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:42][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:34])([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[C:4]([OH:3])=[O:35])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: Cc1ccc(CCl)cc1C
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccc(C(F)(F)F)cc4)C(=O)O)cc3)N(C)C2=O)cc1C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.06 mL of 3,4-dimethylbenzyl chloride is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 ml). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 54 mg (56%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.6 Hz), 7.16 (d, 1H, J=8.6 Hz), 7.10 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 6.99-6.94 (m, 3H), 6.75 (d, 2H, J=8.4 Hz), 4.33, 4.25 (ABq, 2H, J=14.8 Hz), 4.07 (bs, 1H), 3.97-3.93 (m, 2H), 3.70-3.65 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.32, 3.16 (ABq, 2H, J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.85 (s, 3H), 2.28-2.20 (m, 1H), 2.22 (s, 3H), 1.96-1.88 (m, 1H), 1.50 (s, 3H). HRMS (ES+) m/z exact mass calcd for C32H36N2O5F3 (m+1) 585.2576, found 585.2578.