Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[K+].[CH2:7]([S:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[NH:14][CH2:13][CH2:12]1)=[O:10])[CH3:8].N.[CH3:26][S:27]([OH:30])(=[O:29])=[O:28]>C(O)(=O)C.C(OCC)(=O)C.C(O)(C)C>[CH3:26][S:27]([OH:30])(=[O:29])=[O:28].[NH:5]=[C:4]1[N:14]2[C:15]3[C:20]([CH:11]([S:9]([CH2:7][CH3:8])=[O:10])[CH2:12][CH2:13]2)=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=3[S:3]1
Reactant: CCS(=O)C1CCNc2ccc(C(F)(F)F)cc21
Reactant: N#C[S-]
Agent: BrBr
Agent: CS(=O)(=O)O
Agent: N
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCS(=O)C1CCn2c(=N)sc3cc(C(F)(F)F)cc1c32
Reaction time: 0.17 h

Procedure:
A solution of 0.25 g of bromine in 2 ml of acetic acid is poured dropwise into a solution, kept under argon and at around 17° C., of 0.42 g of potassium thiocyanate in 5 ml of acetic acid and the suspension obtained is stirred for 10 minutes before adding thereto a solution of 0.4 g of 4-ethylsulphinyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinoline in 1 ml of acetic acid. The reaction mixture is stirred for 16 hours at a temperature close to 20° C. and then poured over a cold aqueous solution of aqueous ammonia and ethyl acetate. The organic extract separated is washed with distilled water, then with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa). The product obtained (0.35 g) is dissolved in ethyl acetate and then 0.55 ml of about 1.94 M methanesulphonic acid in isopropanol is added. The precipitate is separated by filtration, washed with ethyl acetate and dried under reduced pressure at a temperature of 50° C. 0.3 g of 2-imino-6-ethylsulphinyl-8-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo[5,4,3-ij]quinoline methanesulphonate is thus obtained in the form of a cream-coloured soli d m elting at 220° C. with decomposition [Analysis C14H17F3N2O4S3, % calculated C: 39.06, H: 3.98, F: 13.24, N: 6.51, O: 14.87, S: 22.34, % found C: 38.37, H: 4.21, F: 12.27, N: 6.48, S: 22.22].
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)C>C(O)C.C1COCC1>[Br:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH2:7][CH2:6][OH:5])[S:9][C:10]=2[CH:16]=1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCCc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of sodium borohydride (1.11 g, 29.3 mmol) in ethanol (10 mL) at room temperature was added a solution of the (6-bromo-benzothiazol-2-yl)-acetic acid ethyl ester (2.2 g, 7.3 mmol) in THF (25 mL) at 23-28° C. The mixture was stirred at room temperature for 15 hr, cooled to 3° C. and quenched with 20 mL water at 3-5° C. The product was extracted with 40 mL methylene chloride, washed with 20 mL 15% NaCl and concentrated to crude oil. The crude product was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give the pure 2-(6-Bromo-benzothiazol-2-yl)-ethanol: 1H NMR (CDCl3, 400 MHz) δ 3.30 (t, 2H, J=6 Hz), 4.11 (t, 2H, J=6 Hz), 7.54 (dd, 1H, J=5, 2 Hz), 7.78 (d, 1H, J=5 Hz), 7.95 (d, 1H, J=2 Hz). 13C NMR (CDCl3, 400 MHz) δ 36.7, 60.8, 118.3, 123.3, 129.2, 136.1, 151.3, 169.5; (DCl/NH3) m/z 258, 260 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH:21]([CH2:23][CH2:24][CH2:25][CH3:26])[OH:22])[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH3:27]I>>[CH3:27][O:22][CH:21]([C:15]1[N:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[C:4]([NH2:3])[C:13]=2[N:14]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CI
Reactant: CCCCC(O)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Agent: [H-]
Agent: [Na+]
Product: CCCCC(OC)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Reaction time: 2 h
Yield: 16 %

Procedure:
Sodium hydride (0.32 g; 10.1 mmol) was added to a suspension of 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g; 9.2 mmol, Example 60) and the resulting mixture was stirred for about 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was added to the mixture and stirring was continued overnight. Thin layer chromatography indicated that the reaction was incomplete so sodium hydride (0.25 g) was added followed two hours later by methyl iodide (1 mL). The reaction was stirred for several additional hours then quenched with water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under vacuum to provide an oil. The oil was purified by silica gel chromatography (1-3% methanol in methylene chloride as eluent) to provide 0.5 g of a solid, m.p. 125-128° C. Analysis: Calculated: C, 70.55; H, 8.3; %N, 16.5; Found: C, 70.2; H, 8.3; N, 16.0.
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].CI.[C:19](=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN1CCCC1=O
Product: CCCCN(CCCC)c1cccc(OC)c1
Temperature: 60 °C
Yield: 48.7 %

Procedure:
In 70 ml of 1-methyl-2-pyrrolidone were dissolved 10.0 g (45.18 mmol) of 3-(dibutylamino)phenol and 12.8 g (90.18 mmol) of methyl iodide. To this mixture was added 18.7 g (135.3 mmol) of anhydrous potassium carbonate and the mixture was stirred with heating at 60° C. for 6 hours. After the reaction mixture was poured into 350 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 5.2 g of a colorless oily matter (yield: 48.7%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[S:47][C:25]2[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[O:38][C@H:39]3[CH2:44][CH2:43][C@H:42]([O:45][CH3:46])[CH2:41][CH2:40]3)[C:24]=2[C:23]=1[CH3:48])=[O:21].[NH:49]1[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50]1.C(O)(=O)C>C(Cl)Cl>[OH:54][CH:51]1[CH2:52][CH2:53][N:49]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[S:47][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[O:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([O:45][CH3:46])[CH2:41][CH2:40]4)[C:24]=3[C:23]=2[CH3:48])=[O:21])[CH2:50]1
Reactant: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCC=O)c(C)c23)CC1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCCN4CCC(O)C4)c(C)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.155 g sodium triacetoxyborohydride were added to a solution of the 0.21 g 4-[4-fluoro-2-(trans-4-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (3-oxo-propyl)-amide and 43 μl 3-pyrrolidinol in methylene chloride followed by addition of 49 μl acetic acid. The mixture was stirred at rt overnight, diluted with methylene chloride and then washed with 10% aq. K2CO3. The mixture was passed through a hydrophobic frit. The filtrate was evaporated and purified by chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][CH:8]([OH:18])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH:8]([OH:18])[CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: OC(CCl)CNc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: OC(CNc1ccc(Cl)cc1)Cn1ccnc1

Procedure:
Reaction of imidazole and N-(3-chloro-2-hydroxypropyl)-4-chloroaniline [Current Sci. (India) 4, 142-4 (1959)] yields 1-[3-(4-chloroanilino)-2-hydroxypropyl]-imidazole, M.P. 123°-125° C., which is in turn reacted with 2,4-dichlorobenzyl chloride to yield 1-[3-(4-chloroanilino)-2-(2,4-dichlorobenzyloxy)-propyl]-imidazole; M.P. of oxalate salt is 134°-135° C.; M.P. of hydrochloride salt is 161°-163° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C2C(=NC=CC=2)C=C1>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][NH:42][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:43][CH:44]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NCc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cnc2cc[nH]c2c1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-quinoline carboxylic acid (100 mg, 0.577 mmol) in tetrahydrofuran (50 mL) was added N,N′-dicyclohexylcarbodiimide (1.90 g, 11.7 mmol), and the solution was stirred at room temperature for 1 hour. Then, to this solution was added a solution of 4-benzyloxybenzylamine described in Preparation Example 1 (2.49 g, 11.7 mmol) in tetrahydrofuran (5 mL), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (4.31 g, quantitatively) was obtained as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([S:20][CH3:21])=[CH:15][N:14]=1>C(Cl)Cl>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([S:20]([CH3:21])=[O:9])=[CH:15][N:14]=1
Reactant: CSc1cnc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cnc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
8.9 g (0.052 mol) of m-chloroperbenzoic acid were added, a little at a time, to a suspension of 10 g (0.052 mol) of 2,3-dichloro-5-methylthiopyridine in 60 ml of methylene chloride. After the mixture had been stirred for 2 hours at approximately 20° C., a further 0.9 g (5 mmol) of m-chloroperbenzoic acid was added. The mixture was subsequently refluxed for a further 2 hours. After cooling, the solids were separated off, whereupon the organic phase was washed once with sodium hydrogen sulfite, once with sodium hydrogen carbonate and once with water. After the mixture had been dried over sodium sulfate, it was concentrated. The crude product which was obtained as a red oil was purified by means of flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate=1:1). Yield: 6.3 g (58%) as a brown oil; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=2.9 (s, CH3); 8.4 and 8.7 (2×d, pyr H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:5][C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(=O)=O.CC(C)=O.[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1>[NH:5]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[C@H:4]([CH:3]=[O:2])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)C[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
Fmoc-Leucine methyl ester (35 g, 134 mmoles) in dry toluene (250 ml) under N2 is cooled with dry ice/acetone, and 150 ml of 25 % di-isobutyl-aluminum hydride in toluene are added over 30 mins. The mixture is stirred for 20 min in a bath of dry ice/acetone after the addition of the di-isobutyl aluminum hydride, then methanol (15 ml) is added cautiously. The mixture is poured into 1000 ml ice-cold water, shaken and filtered. The toluene is separated and the aqueous phase re-extracted with ether (3×300 ml). Toluene and ether extracts are combined and dried over Na2SO4. The resulting oil is passed rapidly though a silica gel column (3×50 cm) in 1500 ml 15% EtOAc/petrol. The Fmoc-Leu-CHO is obtained as a solid (27.6 g).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N>N1C=CC=CC=1.O>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
A suspension of cytidine (9.72 g, 40.0 mmol) in pyridine (200 ml) was added to trimethylchlorosilane (25.6 ml, 200 mmol). After 15 minutes of stirring, benzoyl chloride (23.2 ml, 200 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was then cooled on an ice bath, and water (40 ml) was added. Five minutes later, 28% aqueous ammonia (40 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Then, the solvent was distilled off under reduced pressure, and acetone was added to precipitate a white solid. The precipitate was filtered off and recrystallized from water to give N4-benzoylcytidine (13.3 g, 96%). The N4-benzoylcytidine (13.0 g, 37.4 mmol), triphenylphosphine (28.0 g, 107 mmol) and lithium azide (13.0 g, 266 mmol) were suspended in dried DMA, and carbon tetrabromide (35.5 g, 107 mmol) was added to the suspension. After 3 hours of stirring at room temperature, ethyl acetate (1500 ml) was added, and the mixture was washed with water and a saturated aqueous solution of sodium chloride (1000 ml each). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give 5′-azido-5′-deoxy-N4-benzoylcytidine (12.4 g, yield 89%). A solution of 5′-azido-5′-deoxy-N4-benzoylcytidine (10.0 g, 26.9 mmol) in methanol-DMF (1:1 v/v, 100 ml) was vigorously stirred with 10% palladium-on-carbon (about 1.0 g) in a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 5′-amino-5′-deoxy-N4-benzoylcyridine (9.04 g, yield 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([O:44]C)=[O:43])[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([OH:44])=[O:43])[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)O
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Methyl 4-(4-(4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate (510 mg, 0.82 mmol) in 10 ml of DMA was added 0.8 g of LiOH in 10 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 under vacuum to afford 363 mg (73%) of the title product. 1H NMR (DMF-d7) 10.31 (s, 1H), 10.18 (s, 1H), 10.11 (s, 1H), 9.10 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.10 (s, 1H), 3.98 (s, 1H), 3.95 (s, 1H), 3.93 (s, 1H), 1.47 (s, 9H); 13C NMR 162.16, 160.05, 159.90, 157.20, 154.31, 137.88, 135.35, 124.56, 124.39, 123.51, 123.09, 121.76, 120.09, 119.83, 118.96, 115.32, 109.53, 105.58, 102.27, 79.32, 38.13, 36.02, 35.81, 34.88, 28.79; MS m/z− 606.2 (M−H).
Reaction SMILES: I[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[Cl:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:27]([O:30][CH3:31])=[N:28][CH:29]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[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.C(Cl)(Cl)Cl.[Pd].[Pd].C(O)CCC>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:27]([O:30][CH3:31])=[N:28][CH:29]=1
Reactant: COc1ncc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)Nc1cnn(COCC[Si](C)(C)C)c1I
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: COc1ncc(Cl)cc1-c1c(NC(=O)OC(C)(C)C)cnn1COCC[Si](C)(C)C
Temperature: 80 °C
Reaction time: 15 h
Yield: 52.5 %

Procedure:
A mixture of tert-butyl 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate (390.7 mg, 0.8892 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid pinacol ester (364.0 mg, 1.350 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (48.5 mg, 0.0468 mmol), S-Phos (74.2 mg, 0.181 mmol), potassium phosphate (597.1 mg, 2.813 mmol), and 1-butanol (10 mL) was degassed with nitrogen and then stirred at 80° C. for 15 hours. The reaction mixture was diluted in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 50% ethyl acetate in heptanes) to yield 212.3 mg (52%) of tert-butyl 5-(5-chloro-2-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylcarbamate. LCMS (ESI) m+H=455.2; 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (s, 1H), 8.33 (s, 1H), 7.79 (d, J=2.6, 1H), 5.22 (s, 2H), 3.85 (s, 3H), 3.35 (t, 2H), 1.38 (s, 9H), 0.70 (t, J=8.1, 2H), −0.10 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:42])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:18]3[N:23]=[C:22]([NH:24][C:25]4[C:26]([C:27](=[O:28])[NH:29][CH3:30])=[CH:31][C:32]([C:36]5[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=5)=[CH:33][C:34]=4[F:35])[C:21]([Cl:42])=[CH:20][N:19]=3)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a yellow solid (128 mg, 58%). m.p.=175-181° C.; LCMS (m/e) 581 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.39 (bs, 1H), 9.27 (s, 1H), 8.64-8.54 (m, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.79-7.65 (m, 2H), 7.31 (s, 1H), 7.19-7.08 (m, 1H), 6.93 (d, 1H, J=8.7 Hz), 3.94-3.79 (m, 2H), 3.89 (s, 3H), 3.74-3.37 (m, 5H), 2.76 (d, 3H, J=4.3 Hz), 1.88-1.76 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13][C:14]([CH2:16]Br)=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[NH2:18][C:19]([NH2:21])=[S:20].[ClH:22]>C(O)CC>[CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13][C:14]3[N:18]=[C:19]([NH2:21])[S:20][CH:16]=3)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[ClH:22]
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: NC(N)=S
Agent: Cl
Solvent: CCCO
Product: Nc1nc(CCN2C(=O)c3ccccc3C2=O)cs1

Procedure:
1-Bromo-4-N-phthalimido-2-butanone (50.0 g, 0.169 mol) and thiourea (25.71 g, 0.338 mol) were mixed with n-propanol (1000 ml) and concentrated hydrochloric acid (100 ml), and the reaction mixture was heated to reflux for 1.5 hour. After cooling, the precipitate was filtered and washed with n-propanol and ether. After air drying, the title product was obtained as a fluffy white solid (37.51 g, 0.121 mol, 72% yield), m.p. 230°-240° (decomp.).
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][CH:3]1[C:16]([O:18][CH3:19])=[O:17].BrN1C(=O)CCC1=O>C1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1N=C(c2ccc([N+](=O)[O-])cc2)OC1C
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: COC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)oc1C
Yield: 68.8 %

Procedure:
The same operation as in Example (96a) was performed using methyl 5-methyl-2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (97b) (1.1 g, 4.16 mmol), α,α-bisisobutyronitrile (33 mg, 0.2 mmol), N-bromosuccinimide (0.78 g, 4.37 mmol) and benzene (20 mL). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1) gave 0.75 g of the title compound as a light yellow solid (69%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[N:24]=[C:23]([C:25]([O-:27])=O)[CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]#[N:30]>>[C:29]([CH2:28][C:25]([C:23]1[N:24]=[C:19]([O:18][CH2:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH:20]=[CH:21][CH:22]=1)=[O:27])#[N:30]
Reactant: O=C([O-])c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
CH3CN addition to 6-((1-((benzyloxy)carbonyl)piperidin-4-yl)methoxy)picolinate following the method described in Example 6 gave benzyl 4-(((6-(2-cyanoacetyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate in which was used in the next step without further purification. Yield (1.53 g, quant).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:28]=[C:13]2[C:14]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:14]1[C:13]2[N:12]([N:11]=[C:10]([NH:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:28]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(N)cn1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Product: COc1ccccc1CNc1cccn2nc(Nc3ccc(C)nc3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-(6-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 6-Methyl-pyridin-3-ylamine (83.90 mg, 0.7758 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (200.00 mg, 0.69268 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (23.23 mg, 9%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 8.74 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.97 (d, J=6.7 Hz, 1H), 7.23 (m, 2H), 7.15 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.87 (t, J=15.1, 7.4 Hz, 1H), 6.75 (t, J=14.1, 7.1 Hz, 1H), 6.32-6.23 (m, 2H), 4.47 (d, J=5.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H). MS=361. (MH)+.