Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>O>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: CNc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CN(c1ccc(O)cc1)c1ncc([N+](=O)[O-])s1

Procedure:
A mixture of 2-bromo-5-nitrothiazole (4.18 g), 4-(N-methylamino)phenol and water (50 ml) was heated under reflux for a period of 18 hours. The cooled solution was neutralised with aqueous potassium hydrogen carbonate and extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate and the solvent removed by distillation under reduced pressure to give 4-[N-methyl-N-(5-nitro-2-thiazolyl)amino]phenol (2.51 g) as an oil. The pmr spectrum of the compound was consistent with the assigned structure (CDCl3 ; chemical shift δ ppm): 3.55, s, 3H; 5.85, br.s, 1H; 7.15, m, 4H; 8.20, s, 1H.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cc(CO)cc(OS(C)(=O)=O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(CBr)cc(OS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)-5-[(methylsulfonyl)oxy]benzoate (0.284 g, 0.939 mmol) in DCM (5 mL) was added triphenylphosphine (0.370 g, 1.41 mmol) and carbon tetrabromide (0.467 g, 1.41 mmol). After 2 hours, reaction mixture was concentrated in vacuo and purified by flash chromatography (25 g silica, 0-20% EtOAc/hexanes) to give 0.21 g (61%) of tert-butyl 3-(bromomethyl)-5-[(methylsulfonyl)oxy]benzoate. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 4.50 (s, 2H), 3.20 (s, 3H), 1.60 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:24][C:25]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:28]([C:25]1([NH:24][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:11][C:10]([CH3:23])([CH3:22])[C:9]4[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[CH:7][CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:27][CH2:26]1)([OH:30])=[O:29]
Reactant: NC1(C(=O)O)CC1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(C(=O)O)cccc21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (374 mg, 1.0 mmol), copper(I) iodide (57 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309 mg, 3.0 mmol) and potassium carbonate (415 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (228 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 381.0.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]1(=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCCl>[C:8]([CH:16]1[C:15](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:24])(=[O:10])[CH3:9]
Reactant: O=C1CC(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Yield: 63 %

Procedure:
A mixture of 4-dimethylaminopyridine (664 mg, 5.44 mmol), triethylamine (7.6 ml 54.56 mmol), acetic anhydride (6.2 ml, 65.48 mmol in dry 1,2-dichloroethane (60,ml) was stirred at −20° C. and a solution of 1,3-indanedione (7.96 g, 54.56 mmol) in 1,2-dichloroethane was added dropwise in 1.5 h. The reaction mixture was stirred for 30 min, then washed with 10% hydrochloric acid (80 ml) and twice with water (80 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from methyl-tert-butylether (50 ml) to give 2-acetyl-1,3-indanedione 38(6.5 g 63%). Rf 0.27 (hexane-ethylacetate-acetic acid 20-5-0.5) MS C11H8O3 m/z (%) 189 [M+H]+ (100), 166 (72), 104 (20).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22]Br)=[N:19][C:18]=2[CH:24]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]([NH2:12])=[O:11])[C:4]([F:9])=[CH:5][CH:6]=3)=[N:19][C:18]=2[CH:24]=1
Reactant: BrCc1nc2cc(Br)ccc2s1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Yield: 81 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 5-bromo-2-(bromomethyl)-1,3-benzothiazole, according to Method B, scheme 2. Yield 81%, mp 244-246° C., HPLC-MS (method 1): m/z 399, 401 [M+H]+, Rt=3.98 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:15][NH:16][CH3:17]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([N:16]([CH3:17])[CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
To a solution of 5-Chloro-2-nitro-benzenesulfonyl chloride (2.0 g, 0.0078 mol) (Lebegue, N.; Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard, P.; Leonce, S.; Pierre, A.; Chavatte, P.; Berthelot, P. J. Med. Chem. (2005), 48(23), 7363-7373) in Tetrahydrofuran (10 mL, 0.1 mol) was added 2.0 M of Dimethylamine in Tetrahydrofuran (7.8 mL). The mixture was stirred for 18 hours. The mixture was evaporated and water was added then agitated until a solid precipitated. The solid was filtered and dried. 5-Chloro-N,N-dimethyl-2-nitro-benzenesulfonamide isolated as yellow solid (1.87 g, 90%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].Cl.[NH2:12][C:13]([NH2:15])=[NH:14]>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:4]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:12]=[C:13]([NH2:15])[N:14]=1
Reactant: N=C(N)N
Reactant: N#Cc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(-c2ccccn2)nc(-c2ccccn2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.0 g (approximately 60% dispersion in paraffin oil, about 25 mmol) of sodium hydride is added in portions to a mixture of 5.21 g (50 mmol) of 2-cyanopyridine and 2.39 g (25 mmol) of guanidine hydrochloride in 100 ml of dimethyl sulfoxide. Stirring is carried out for 2 hours at room temperature, and then for 23 hours at 75° C. The mixture is cooled and poured into 100 ml of ice-water and filtered, yielding 4,6-di-pyrid-2-yl-[1,3,5]triazin-2-ylamine in the form of a white solid after drying in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28]C)=[O:27].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCOc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E)-6-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (76.0 g) in methanol (300 ml) was added 1N aqueous sodium hydroxide (300 ml). After 11/2 hours the solution was diluted with water, washed twice with ether, then acidified with dilute hydrochloric acid. The acidified solution was extracted with ether, and the extract was dried and evaporated to give (E)-6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy -7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 77°-82° C. (etherhexane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 73 (303 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to get 271 mg (68%) of white solids. M.P. 228° C. 1H NMR (DMSO-d6): δ 3.56 (s, 3H), 3.64 (m, 4H), 3.94 (m, 4H), 6.65 (m, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.79 (dd, J=1.9, 9.0 Hz, 1H), 7.86 (m, 2H). EIMS m/z 419 (M+23). Anal. (C20H17ClN4O3) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1cccc(OC)c1
Product: CCOC(=O)C=C(c1cccc(OC)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 90 %

Procedure:
The title compound was synthesized from (3-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 90% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.45-6.68 (m, 9H), 6.49 (m, 2H), 6.23 (s, 1H), 4.37 (m, 2H), 4.13 (q, 2H, J=7.2 Hz), 3.76 (t, 2H, J=5.2 Hz), 3.68 (s, 2.1H), 3.58 (s, 0.9H), 3.20 (m, 2H), 2.73 (t, 2H, J=6.8 Hz), 1.90 (m, 2H), 1.51 (s, 9H), 1.26 (t, 2.1H, J=7.2 Hz), 1.13 (t, 0.9H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+1); found 498.4.
Reaction SMILES: Br[CH:2](Cl)[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].C([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH:32](C(N)=O)[CH2:31]1)=O)(C)(C)C>CN(C)C=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:33]1[CH2:34][CH2:35][N:30]([CH:28]=[O:27])[CH2:31][CH2:32]1
Reactant: Cc1cccc(C)c1NC(=O)C(Cl)Br
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C=O)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromo,chloro-N-(2,6-dimethylphenyl)acetamide (V: 24.2 g, 0.10 mol), anhydrous sodium carbonate (15.9 g, 0.15 mol), sodium iodide (0.10 g) and 1-piperazine carboxaldehyde (IV: 10.3 mL, 0.10 mol) in anhydrous dimethylformamide (200 mL) was heated to 85° C. for 6 h before it was cooled, suction-filtered and concentrated down in vacuo. The residue was then dissolved in a minimal amount of hot 5% methanol in ethyl acetate. After 2 h at ambient temperature, the mixture was suction-filtered and the filtrate was concentrated down once again to yield a grey-colored solid which was recrystallized from ethyl acetate. There the Formula III compound was isolated 17.95 g (65%) as a white solid, m.p. 139°-140° C.; 1H NMR (300 MHz, CDCl3) δ 8.50 (br s, 1H), 7.99 (s, 1H), 7.25-7.03 (m, 3H), 3.59-5.56 (m, 2H), 3.42-3.39 (m, 2H), 3.17 (s, 2H), 2.66-2.59 (m, 4H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl3) ppm 167.96, 160.96, 135.18, 133.67, 128.53, 127.55, 61.89, 54.28, 53.21, 45.69, 40.07, 18.83; IR (KBr) 3432, 3274, 2958, 1672, 1506, 1446, 1436, 1148, 1020, 1008, 788 cm-1 ; MS m/z calc'd for C15H22N3O2 276.1712, found 276.1709.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[N:10][CH:11]=1.[CH3:21]O>>[OH:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:17][CH3:21])=[O:16])=[N:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cccc(-c2ncc(O)cn2)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
32.7 ml (445 mmol) of thionyl chloride are added to a suspension of 88.0 g (366 mmol) of 3-(5-hydroxypyrimidin-2-yl)benzoic acid in 1.4 l of methanol, and the mixture is heated at 80° C. for 2 hours. 20 ml (276 mmol) of thionyl chloride and, after 2 hours, a further 10 ml (138 mmol) of thionyl chloride are then added. After each addition, the reaction mixture is stirred at 80° C. for 2 hours. The reaction mixture is evaporated to a volume of about 300 ml in vacuo. The precipitate formed is filtered off and dried in vacuo: methyl 3-(5-hydroxypyrimidin-2-yl)benzoate as brownish crystals; m.p. 219-223°; ESI 231 (M+H); HPLC: Rt.=2.58 min (method A).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH:43]1[CH2:45][CH2:44]1.C(OCC)(=O)C>C(#N)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:42][CH:43]5[CH2:45][CH2:44]5)[CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrCC1CC1
Reactant: Oc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1cc(OCC2CC2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (400 mg, 0.88 mmol) in acetonitrile (80 mL) was added cesium carbonate (315 mg, 0.97 mmol) and (bromomethyl)-cyclopropane (0.26 mL, 2.64 mmol). The reaction mixture was heated at reflux for 6 hours. After the reaction was cooled to room temperature, ethyl acetate was added and the organic phase was washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by purification with silica gel chromatography (3:2 hexanes/ethyl acetate) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (320 mg, 71%) as yellow solid. 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.78 (d, 1H), 7.33 (m, 2H), 7.18 (m, 2H), 6.98 (m, 1H), 6.30 (d, 1H), 6.02 (m, 2H), 5.08 (d, 1), 4.35 (m, 1H), 3.99 (m, 1H), 3.80 (d, 2H), 2.014 (m, 4H), 1.83–1.55 (m, 12H), 1.22 (m, 1H), 0.61 (m, 2H), 0.35 (m, 2H). MS m/z 509 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].ClCCl.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(N(CC)CC)C>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH2:3][O:4][Si:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(CO)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO[Si](C)(C)C)CO[Si](C)(C)C
Temperature: 0 °C

Procedure:
0.6 g of 2,2-dimethyl-1,3-propandiol was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, thereto was added 2.09 ml of triethyl amine, followed by the addition of 1.76 ml of trimethylsilyl chloride. The mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.23 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH:26](=O)[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>COCCOCCOC>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccco1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Solvent: COCCOCCOC
Product: CC(=O)Nc1ccc(Sc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: The mixture of 2 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid, 1 g of furfural and 20 ml of diethyleneglycol dimethyl ether is heated to 105° for 22 hours while stirring under nitrogen. It is evaporated under reduced pressure, the residue taken up in 75 ml of ethanol and 1 g of sodium borohydride is added portionwise while stirring at room temperature under nitrogen. After stirring overnight, 75 ml of water are added and the mixture is filtered. The filtrate is concentrated under reduced pressure, the concentrate acidified with concentrated hydrochloricacid and the precipitate formed filtered off, to yield the 4-(4-acetamidophenylmercapto)-3-furfurylamino-5-sulfamoylbenzoic acid.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][C:6]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:22]=[N:21]1.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:5][C:6]([C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:7]1)#[N:2]
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Yield: 17.2 %

Procedure:
Diisopropyl 3-(cyanomethylene)cyclobutane-1,1-dicarboxylate (2.65 g, 0.00999 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1 g, 0.003 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 0.003 mol) was added under N2. The mixture was heated at 50° C. overnight. The reaction was concentrated and purified with Combiflash (silica gel, 0-50% EtOAc/Hex) to give the desired product (0.3 g) as colorless oil. LCMS calculated for C29H41N6O5Si(M+H): 581.3; Found: 581.4.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCOCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 93.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-morpholin-4-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (28 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:31])[N:12]([CH2:14][CH2:15][NH:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO>[C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:31])[N:12]([CH2:14][CH2:15][N:16]([CH2:17][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:38])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(CNCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1cccc(CN(C)CCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of ethyl {3-[({2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethyl}amino)methyl]phenoxy}acetate (90 mg) in EtOH (3 mL) was added sodium triacetoxyborohydride (326 mg) at ambient temperature and the resulting mixture was stirred at ambient temperature for 18 hours. And then the reaction mixture was evaporated in vacuo and partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=20:1) to give ethyl (3-{[{2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethyl}(methyl)amino]methyl}phenoxy)acetate (61.9 mg) as a colorless oil.