Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[OH-:22].[NH4+]>>[CH3:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]([NH2:15])=[O:22])=[CH:9][C:8]=1[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1
Reactant: Cc1nc(-c2cc(C#N)c(=O)[nH]c2C)cs1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nc(-c2cc(C(N)=O)c(=O)[nH]c2C)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold stirred 150 ml portion of concentrated sulfuric acid was added over a 5 minute period 64.2 g of finely powdered 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile and the resulting mixture was stirred in an ice bath for 30 minutes and then allowed to stand at room temperature overnight. The reaction mixture was poured onto ice (800 ml beaker half filled) and then neutralized by adding aqueous ammonium hydroxide solution. The tan solid that separated was collected, washed with water, recrystallized from dimethylformamide and dried in an oven at 90° C. for 2 days to produce 59.2 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide, m.p. >300° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[N:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)sc2ccc(F)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A suspension of 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.5 g) and 4-pyridineboronic acid (0.197 g) in 1,2-dimethoxyethane (6 ml), ethanol (2 ml) and 2 M aqueous sodium carbonate solution (4.0 ml) was degassed 3-4 times to remove oxygen, then tetrakis(triphenylphosphine)palladium (0.065 g) was added. The reaction mixture was stirred at 80° C. for 3 h, quenched with ice/water, and extracted with ethyl acetate. The organic layers were washed, dried and concentrated. The residue was chromatographed over silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.35 g) as a yellowish solid. MS (ISP): 467.3 (M+H)+
Reaction SMILES: C(O)C.NC1C(=O)C2C(C)=CC(C)=CC=2OC=1.[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:20]=1[C:21]([OH:31])=[CH:22][C:23](=[O:30])[O:24]2.[N+:32]([O-])([OH:34])=[O:33]>C(O)(=O)C>[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:20]=1[C:21]([OH:31])=[C:22]([N+:32]([O-:34])=[O:33])[C:23](=[O:30])[O:24]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c2c(O)cc(=O)oc2c1
Agent: Cc1cc(C)c2c(=O)c(N)coc2c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c2c(O)c([N+](=O)[O-])c(=O)oc2c1

Procedure:
5,7-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyrane with a melting point of 186°-187° (from ethanol) can be prepared in a manner analogous to that described in Example 1, using 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyrane as the starting material. The starting material can be obtained, for example, using 5,7-dimethyl-4-hydroxy-coumarin as the starting material, by reacting the latter with nitric acid in acetic acid at 80° to give 5,7-dimethyl-4-hydroxy-3-nitro-coumarin, treating this compound for 24 hours with sodium hydroxide solution and subsequently acidifying, with decarboxylation, to give 4,6-dimethyl-2-hydroxy-β-nitro-acetophenone, analogously to the process described in J. Am. Chem. Soc. 67, 99 (1945), and also reacting the latter compound with the mixed anhydride of formic acid and acetic acid to give 5,7-dimethyl-3-nitro-4-oxo-4H-1-benzopyrane with a melting point of 120°-125° and reducing this compound with sodium dithionite to give 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyrane (melting point 120°-121°), analogously to the process described in Tetrahedron Letters 1976, 719, and purifying this product via the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc21
Reactant: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCCc2c(-c3cc4c(cc3Cl)N(C)C(=O)CC4)cncc21
Yield: 40 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 7-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-10) and (rac)-ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide (intermediate B-4) were used to give the title compound as a white solid in 40% yield. MS: 434.2 (M+H)+.
Reaction SMILES: B(F)(F)F.CCOCC.N[C:11]1[CH:12]=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[C:14]([CH3:17])=[N:15][CH:16]=1.COCCOC.N(OC(C)(C)C)=O.[C:47]([O:50]C(=O)C)(=[O:49])[CH3:48]>CCCCC>[C:47]([O:50][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[CH:12]=1)(=[O:49])[CH3:48]
Reactant: Cc1ncc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCC
Solvent: COCCOC
Solvent: CCOCC
Product: CC(=O)Oc1cnc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a flask containing boron trifluoride etherate (0.100 mL, 0.789 mmol) at −15° C. (brine/ice bath) was added a solution of N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (119.1 mg, 0.3741 mmol) in 1,2-dimethoxyethane (1.0 mL, 9.6 mmol). tert-Butyl nitrite (67.0 uL, 0.563 mmol) was then added dropwise and the reaction mixture was stirred at −15° C. for one hour. 3 mL pentane was added and the mixture stirred for 5 minutes. The pentane layer was decanted, and the remaining oil was then dissolved in acetic anhydride (0.60 mL, 6.4 mmol) and stirred at 100° C. for 1.5 hours. The solvent was evaporated in vacuo, and the residue was suspended in 2M aqueous Na2CO3 and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate. This material was dissolved in tetrahydrofuran (3 mL, 40 mmol) and 1.0 M of lithium hydroxide in Water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then neutralized with 10% aqueous citric acid and extracted 3× with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 30-100% ethyl acetate in dichloromethane) followed by reverse phase HPLC to yield 3.3 mg (3%) of N-(7-(5-hydroxy-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.237, M+H=320.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.7 Hz, 1H), 7.04 (s, 1H), 2.33 (s, 3H), 2.14-2.03 (m, 1H), 0.91-0.78 (m, 4H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry tetrahydrofuran (45 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) was cooled to −78° C. and then treated dropwise with a 2.5M solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellow reaction mixture was stirred at −78° C. for 20 min and then slowly treated with a solution of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15 min period. The reaction mixture turned deep purple (almost black) in color. The reaction mixture was then stirred at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at −78° C. and then allowed to warm to 25° C. where it was stirred for 48 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (50 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining residue was diluted with ethyl acetate (150 mL) and water (50 mL). The organic phase was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C15H18ClNO4 (M+) 311.0924, found 311.0927.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH2:5][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(F)c1N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(F)c2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.4 %

Procedure:
A 50 mL round-bottom flask was charged with 3-fluoro-2-(morpholin-4-yl)benzaldehyde (0.500 g, 2.39 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (404 mg, 2.17 mmol, 0.91 equiv), dichloromethane (10 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (1.38 g, 6.51 mmol, 2.72 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with dichloromethane. The resulting mixture was washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.00 g (crude) of tert-butyl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5].C1(C)C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1>C1COCC1>[CH2:3]([N:7]1[C:12]2=[CH:25][NH:26][CH:27]=[C:11]2[C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)Cn1ccc(=O)n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Temperature: 25 °C

Procedure:
Sodium hydride (95%, 1.74 g, 69 mmol) is suspended in 20 mL of anhydrous THF, and then a mixture of 1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (approx. 23 mmol) and p-toluenesulfonylmethyl isocyanide (97%, 7.0 g, 35 mmol) in 20 mL of anhydrous THF is added dropwise over 80 minutes at 0° C. The mixture is stirred at room temperature for an hour after the completion of the addition, and then carefully quenched with water. The mixture is diluted with 50 mL of saturated NaHCO3, and then extracted with CH2Cl2 five times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is evaporated to dryness under reduced pressure to give product as light brown solids, which is used for the next reaction without further purification. MS (ESI) m/z 222.2 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:31])[C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1.[C:32]1(=[O:42])[C:36]2([CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:35][C:34](=O)[O:33]1>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=3)[C:34]([CH2:35][C:36]3([C:32]([OH:42])=[O:33])[CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:31][C:15]=2[CH:14]=1
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Solvent: CC#N
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 80 °C

Procedure:
To a 10 mL round bottomed flask, equipped with a reflux condenser, were added 4-(quinolin-2-ylmethoxy)-N1-(4-(trifluoromethyl)benzyl)benzene-1,2-diamine (53 mg, 0.12 mmol), 2-oxaspiro[4.4]nonane-1,3-dione (19 mg, 0.12 mmol) and acetonitrile (1.3 mL). The flask was heated to 80° C. for 72 hours. The mixture was concentrated and the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N). The mixture was then heated to 80° C. until the starting material had been consumed. The reaction mixture was cooled to RT, concentrated to dryness and the resulting residue was dissolved in THF (3.4 mL) and methanol (3.4 mL). To this solution was added LiOH (3.6 mL, 1 M aq.) and the reaction was monitored by LCMS until the ester was consumed. The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc. The aqueous layer was further extracted with EtOAc (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C32H28F3N3O3, 559.21; m/z found, 5602 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58-7.44 (m, 3H), 7.35 (s, 1H), 7.14-6.85 (m, 4H), 5.32 (s, 4H), 3.04 (s, 2H), 2.43-2.14 (m, 2H), 1.75-1.31 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:20][O-].[Na+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:20])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: C[O-]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C(=O)c2cn(C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of compound 1 was dissolved in 30 ml of dimethylformamide and the solution was stirred at room temperature. 258 mg of sodium methoxide was added to the solution, followed by stirring for 30 minutes. Then,678 mg of methyl iodide was added dropwise to the solution and the reaction was continued for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, followed by addition of ethyl acetate and washing with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The obtained crude product was recrystallized from ethanol to give 3-(p-methoxybenzoyl)-N-methylindole (compound 8) in the form of white platy crystals. (Yield: 94%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-:10].[Na+].[CH3:12][OH:13]>>[Br:1][C:2]1[C:3]([C:8]([O:13][CH3:12])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Br
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COC(=O)c1ncccc1Br
Temperature: 0 °C
Yield: 80.5 %

Procedure:
To a mixture of 3-bromo-2-cyano-pyridine (13.53 g; 73.93 mmol) in 150 ml of methanol was added 25% NaOH solution (250 ml) and the resulting mixture was refluxed for 3 hours, cooled, and concentrated in vacuo. The residue was dissolved in 350 ml of methanol, cooled to 0° C. 250 ml of methanolic HCl solution was added portionwise, and the mixture was refluxed for 17 hours. The reaction mixture was cooled to 0° C. neutralized with triethylamine, concentrated in vacuo, and the residue partitioned between ethyl acetate (800 ml)/water (300 ml). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 12.85 g (80.5%) of methyl 3-bromo-pyridine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[OH:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:23][C:17]3[CH:18]=[CH:19][C:20]([Br:22])=[CH:21][C:16]=3[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Br)ccc3o2)CC1
Temperature: 55 °C

Procedure:
A mixture of 4-(5-bromo-2-hydroxy-phenylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (70 mg), copper iodide (9 mg), N,N-dimethylformamide (1 mL), triethylamine (100 μL), and Pd(PPh3)2Cl2 (7 mg) is heated under an argon atmosphere to 55° C. for 0.5 h. The reaction mixture is diluted with ice water after cooling to room temperature and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. LC (method 2): tR=1.49 min; Mass spectrum (ESI+): m/z=380, 382 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:33]>O1CCCC1>[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([N:34]([C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH3:33]
Reactant: COC(=O)[C@H](C)NCc1ccc(F)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)N(Cc1ccc(F)cc1)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-propionic acid (37 g, 195 mmol) in dry tetrahydrofuran (250 mL) at 0° C. was added 4-methyl morpholine (21.5 mL, 195 mmol) followed by isobutylchloroformate (25.3 mL, 195 mmol). The reaction was allowed to warm to ambient temperature and stirred for two hours. This was followed by the addition of (S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (43.2 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:56]>O1CCCC1.CC(C)=O>[ClH:56].[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2C1CCNC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 65 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.610 g, 21.49 mmol) in tetrahydrofuran (200 mL) was added rac-tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (6.039 g, 32.25 mmol), triphenylphosphine (11.273 g, 42.98 mmol), and diethyl azodicarboxylate (7.485 g, 6.77 mL, 42.98 mmol). The reaction mixture was stirred at room temperature for 6 days and then concentrated to afford an orange-brown oil. Acetone (100 mL) and 5 N hydrochloric acid (50 mL) were added and the solution was heated at 40° C. for 18 h and then cooled to room temperature. The resulting yellow precipitate was filtered, and the filter cake was washed with diethyl ether and dried to afford rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride as an off-white solid (5.153 g, 65%). RP-HPLC Rt 4.079 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 331 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.S1C=CC=C1B(O)O.O.C(Cl)[Cl:23]>>[Cl:23][C:9]1[S:10][CH:11]=[CH:12][C:8]=1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: ClCCl
Reactant: Clc1ccnc(-c2ccsc2)c1
Agent: OB(O)c1cccs1
Solvent: O
Product: Clc1ccnc(-c2ccsc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-thiophen-3-yl-pyridine (410 mg, 2.1 mmol), prepared as described in Example 26, Step A, using 2-thiopheneboronic acid, in CH2Cl2 (10 mL), was added SO2Cl2 (1 M in CH2Cl2, 3 mL). The resulting mixture was stirred at room temperature for 8 h, then was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated to yield a residue. The residue was purified by preparative TLC (hexanes/EtOAc) to yield 2-(2-chloro-thiophen-3-yl)-4-chloro-pyridine.