Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:15][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CN(C)C(=O)N(OC(=O)Oc1ccccc1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3,3-dimethylurea (12.5 grams; 0.05 mol) in isopropyl alcohol (40 ml), and pyridine (6 ml) are charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl chloroformate (7.8 grams; 0.05 mol) is added to the flask, with stirring, at a temperature of about 10° to 15°C. After the addition is completed, the reaction mixture is stirred for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture is poured onto ice and the precipitate is recovered by filtration and is dried. The dried precipitate is recrystallized to yield 1-(3,4-dichlorophenyl)-1-phenoxycarbonyloxy-3,3-dimethylurea.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.Br.[Br:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[Br:8][CH2:9][CH2:10][CH2:11][NH:12][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: NCCCBr
Reactant: C=C1CC(=O)O1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCBr
Reaction time: 1 h

Procedure:
Diketene (1.22 mL, 15.7 mmol 1.50 equiv) was added at room temperature to a stirred mixture of 3-bromopropylamine hydrobromide (2.30 g, 10.5 mmol, 1.00 equiv) and triethylamine (1.46 mL, 10.5 mmol, 1.00 equiv) in anhydrous THF (20 mL) under argon, and stirring was continued at room temperature for 1 hour. The solvent was removed and the residue was purified by flash chromatography (SiO2, MeOH—CH2Cl2 0:1 to 1:18) to afford a light yellow oil, 2.10 g (90%), which was characterized spectroscopically.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.N1C=CC=[CH:13][CH:12]=1.C(B1OB(C=C)OB(C=C)O1)=C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH:12]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1)=[CH2:13]
Reactant: c1ccncc1
Reactant: COC(=O)c1cc(Br)c[nH]1
Agent: [Fe+2]
Agent: [Pd]
Agent: C=CB1OB(C=C)OB(C=C)O1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
Degas, by purging with nitrogen for 10 minutes, a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (2.0 g, 9.8 mmoles), triethenylboroxin pyridine (1.3 equiv; 3.1 g, 12.7 mmoles), and potassium carbonate (3 equiv; 4.1 g, 29.4 mmoles) in a mixture of 1,4-dioxane (20 mL) and water (10 mL). Add tris(dibenzylideneacetonyl)bis-palladium (Pd2(dba)3) (0.01 equiv; 0.0925 g, 98.0 μmoles) and 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf) (0.03 equiv; 0.0853 g, 294.1 μmoles) and heat at 95° C. for 3 h. Cool to room temperature then partition between water (50 mL) and a 1:1 mixture of hexanes/diethyl ether (100 mL). The organic layer is washed with water (2×50 mL) then brine. Dry over Na2SO4, filter and evaporate to give methyl 4-ethenyl-1H-pyrrole-2-carboxylate as a straw colored oil (1.5 g). Use without further purification. 1H-NMR (CDCl3), δ: 8.90 (1H, br. s), 7.02 (1H, m), 6.95 (1H, m), 6.56 (1H, q) 5.48 (1H, dd), 5.05 (1H, dd), 3.86 (3H, s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C)C=O>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([C:51]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:52])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N(Cc2cnn(C(=O)C3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) in dimethylformamide (5 mL) were added triethylamine (0.23 mL) and cyclohexanecarbonyl chloride (0.22 mL), and the mixture was stirred at room temperature for one day. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-{[1-(cyclohexylcarbonyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g). By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclohexanecarbonyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.23 g) was obtained.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)=[CH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][C@H:48]1[C:53]([F:55])([F:54])[CH2:52][CH2:51][CH2:50][C@H:49]1[NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:59]([O:58][C:57](=[O:63])[NH:56][C@@H:49]1[CH2:50][CH2:51][CH2:52][C:53]([F:55])([F:54])[C@@H:48]1[NH:47][C:8]([C:6]1[S:7][C:3]([CH:1]=[CH2:2])=[C:4]([C:11]2[N:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:5]=1)=[O:10])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: C=Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acid (105 mg, 0.387 mmol) and BOP (257 mg, 0.581 mmol) in DMF (5.2 mL) was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (145 mg, 0.581 mmol) followed by diisopropylethyl amine (0.169 mL, 0.968 mmol). The mixture was allowed to stir at room temperature for 18 h. After the reaction was complete, water was added and the aqueous layer extracted with ethyl acetate (×3). The organic layers were combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography giving the title compound as an orange solid. LRMS (APCI) calc'd for (C24H27F2N5O3S) [M+H]+, 504.2. found 504.1.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C:27]1[O:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][N:31]=1)=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][C:27]1[O:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][N:31]=1
Reactant: CC(C)(C)c1cnc(C=O)o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cnc(C=C(Br)Br)o1
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a stirred solution of carbon tetrabromide (24.0 g, 72.4 mmole) in methylene chloride (200 mL) at 5-10 deg C. under argon atmosphere was added triphenylphosphine (37.0 g, 141 mmole) in portions. The reaction mixture was stirred for 5 min and treated with a solution of 2-formyl-5-t-butyloxazole in methylene chloride (60 mL). The reaction mixture was stirred at room temperature for 2 hours, while a white solid precipitated out of the solution. The solid was filtered off, the filtrate concentrated and purified (silica gel, EtOAc/hexane 1:4) to give 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene as a pale solid (9.13 g, 39 %).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:24]=3)[C:19](=O)[N:18]2[CH3:31])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Na+]>C1COCC1>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH:27]([CH3:28])[CH3:29])=[CH:23][CH:24]=3)[CH2:19][N:18]2[CH3:31])=[CH:15][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)c1ccc2c(c1)C(=O)N(C)C(c1ccc(C(C)(C)C)cc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc2c(c1)CN(C)C(c1ccc(C(C)(C)C)cc1)C2
Yield: 93.4 %

Procedure:
To 30 ml of a suspension containing 0.58 g of lithium aluminum hydride in THF, 20 ml of a solution containing 2.57 g of 3-(4-tert-butylphenyl)-7-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-one in THF was added and the resulting mixture was heated to reflux for 15 hours. After the reaction, 0.58 g of water, 0.58 g of 15% aqueous sodium hydroxide solution and 1.8 g of water were sequentially added in the order mentioned while cooling the mixture in ice and the generated precipitates were removed by filtration. After drying the filtrate over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1 v/v) to obtain 2.30 g of 3-(4-tert-butylphenyl)-7-isopropyl-2-methyl-l,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:15][CH:16]=O>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[CH:16][N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: O=CCCl
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2ccnc12
Reaction time: 21 h
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (Example 1, METHOD B, Step 1, 2.0 g, 9.92 mmol) and chloroacetaldehyde (1.2 mL, 10.91 mmol) in methanol (100 mL) was refluxed for 135 min. A further chloroacetaldehyde (1.2 mL, 10.91 mmol) was added and refluxing continued over 21 hours. The solvent was evaporated and the resulting solid co-evaporated with methanol (75 mL×2) prior to drying under vacuum, giving 2.62 g of crude material. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (96.5:3.5:0.5 to 93:7:1) to give 1.52 g (68%) of the title compound as an off white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:29]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.[C:36]([O:44][C@@H:45]([C@H:49]([O:53][C:54](=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:50]([OH:52])=[O:51])[C:46]([OH:48])=[O:47])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC(O)C.C(#N)C>[C:54]([O:53][C@@H:49]([C@H:45]([O:44][C:36](=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:46]([OH:48])=[O:47])[C:50]([OH:52])=[O:51])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:29]=[C:14]3[C@H:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CC(C)O
Solvent: CC#N
Product: COc1nc(/C=C/c2nc3n(n2)CCC[C@H]3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1

Procedure:
2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.208 mmol) was dissolved in the mixture of 2-propanol (1.6 mL) and acetonitrile (2.0 mL) at 45° C., and the solution of (2S,3S)-2,3-bis(benzoyloxy)succinic acid (D-DBTA) (89.5 mg, 0.250 mmol) in acetonitrile (1.6 mL) was added. Traces of seed crystal of the title compound which was obtained by the method similar to this step was added to the solution at 33° C., and the mixture was stirred at room temperature for 18 hours. The solids were collected by filtration, washed with acectonitrile/2-propanol=2/1 (0.5 mL) and dried at 50° C. under the reduced pressure to obtain the title compound (62.3 mg, 35.7% yield, 90.7% de). The title compound (50.7 mg, 90.7% de) was suspended in acectonitrile/2-propanol=1/1 (0.5 mL), and the mixture was stirred at 80° C. for 25 minutes, and then stirred at room temperature for 15 hours. The solids were collected by filtration and dried at 50° C. under the reduced pressure to obtain the title compound (35.9 mg, 70.8% yield, 98.1% de)
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].FC1(F)CCNC1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][Cl:31])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: FC1(F)CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCl)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 20.9 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (50 mg, 0.108 mmol), 3,3-difluoropyrrolidine hydrochloride (78 mg, 0.54 mmol, 5.0 eq), triethylamine (77 mg, 0.76 mmol, 7.0 eq), and sodium iodide (3.3 mg, 0.022 mmol, 0.2 eq) in anhydrous DMF (1.0 mL) was stirred at 50° C. for 6 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in MeOH (3 mL) and purified using HPLC (RT=10.16 min) to give a colorless oil. Crystallization from DCM/hexane afforded 9.4 mg (20.8%) of the byproduct as a white solid. 1H-NMR (CD3OD) 8.35 (s, 1H), 7.82 (s, 1H), 7.81 (d, 1H), 7.64 (s, 1H), 7.36 to 7.30 (m, 5H), 7.23 (d, 1H), 6.62 (s, 1H), 5.66 (s, 2H), 3.64 (t, 2H), 3.14 (t, 2H), 226 to 2.22 (m, 2H); LC-MS [M+H]+=417/419, RT=2.91 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[N:24]([CH3:25])[C:23]([CH3:26])=[N:22][CH:21]=3)([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[C:75]([N:77](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][N:24]1[C:20]([C:12]([OH:13])([C:14]2[N:18]([CH3:19])[N:17]=[N:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=2)=[C:2]3[C:75]#[N:77])=[CH:21][N:22]=[C:23]1[CH3:26]
Reactant: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(C#N)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (370 mg, 0.66 mmol, Example 80A), zinc cyanide (147 mg, 1.26 mmol), X-phos (64.5 mg, 0.14 mmol), zinc powder (12 mg, 0.19 mmol) tris(dibenzylideneacetone)dipalladium (0), (Pd2(dba)3, 98 mg, 0.11 mmol) were added to a large microwave vial, then DMA (8 mL, degassed with argon) was added and the vial was sealed and evacuated. The mixture was heated to 125° C. in an aluminum heating mantle (for how long?). The mixture was filtered through a Celite® pad while still warm, rinsed with EtOAc-MeOH (10:1) and concentrated under vacuum providing a brown oil. The crude material was purified by RP-HPLC to give the title compound as an off white solid. MS m/e 548.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.42 (apparent d, 8.1 Hz, 3H), 7.3-7.4 (m, 1H) 6.41 (s, 1H), 4.41-4.26 (m, 2H), 4.10 (s, 3H), 3.90 (s, 3H), 3.64 (s, 3H), 2.58 (s, 3H). The racemic material was separated into its individual enantiomers using the following conditions: Chiralpak IA SFC column (5 u), 85% hexane: 15% EtOH (containing 0.2% Et3N) to provide the two enantiomers. The first eluting enantiomer was Example 81B and the second eluting enantiomer was Example 81C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.C[NH:40]CCNC.C(=O)(OC(C)(C)C)N.O>O1CCOCC1.[Cu]I.C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:9]([N:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[C:10]3[C:2]([NH2:40])=[N:3]2)=[CH:36][CH:35]=1
Reactant: CNCCNC
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: [Cu]I
Agent: CC(C)(C)OC(N)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2nc(N)c3c(N4CCNCC4)c(-c4ccccc4)cnc32)cc1
Temperature: 75 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
A mixture of tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.55 g, 2.4780 mmol, see Example 9), CuI (0.47 g, 2.48 mmol), N1,N2-dimethylethane-1,2-diamine (0.53 ml, 4.96 mmol) and tert-butyl carbamate (2.90 g, 24.78 mmol) in dioxane (50 mL) was stirred at 75° C. (oil bath) for 6 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the organic layer was separated, washed with saturated ammonium chloride, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give 1-(4-methoxybenzyl)-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (1.00 g, 97%) as a solid. This solid was dissolved in DCM (20 mL), and TFA (4.77 mL, 62.0 mmol) was added. The reaction was stirred at room temperature for 4 hours. The solvent was removed. The residue was partitioned between saturated NaHCO3 (30 mL) and DCM (40 mL). The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo to give 1-(4-methoxybenzyl)-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (1.00 g, 97%) as a solid. LCMS (APCI+) m/z 415(M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][CH:17]([NH:19][CH3:20])[CH3:18])[CH2:12][C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:18][CH:17]1[N:19]([CH3:20])[C:13](=[O:14])[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16]1
Reactant: CNC(C)CN(CC(=O)O)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)OCc2ccccc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[(benzyloxy)carbonyl]-N-[2-(methylamino)propyl]glycine (2.42 g, 8.63 mmol) in DMF (40 mL) was treated with EDC (1.66 g, 8.63 mmol) and stirred at room temperature overnight. The reaction was diluted with EtOAc and washed once each with aqueous 1N HCl, saturated aqueous NaHCO3, and brine. The combined aqueous layers were extracted once with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was subjected to column chromatography eluting with a gradient of 50-100% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]([CH2:18][CH2:19][OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[O:11]([CH2:18][CH:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCOc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
At −78° C., a solution of dimethylsulphoxide (5.11 ml, 72 mmol) in DCM (50 ml) was added dropwise to a solution of oxalyl chloride (6.12 ml, 72 mmol) in DCM (150 ml). The reaction mixture was stirred for 10 min at −78° C. A solution of 2-phenoxyethanol (10.0 g, 72 mmol) in DCM (70 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 10 min. A solution of triethylamine (50 ml, 360 mmol) in DCM (50 ml) was added dropwise. The reaction mixture was stirred for 10 min at −78° C. It was warmed to room temperature. The reaction mixture was washed with a 10% aqueous solution of sodium hydrogensulphate (2×200 ml) and subsequently with brine (2×200 ml). It was dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (1:3) as eluent, to give 2.73 g of phenoxyacetaldehyde.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([CH3:30])=[CH:25][C:24]=1[C:31]1[CH:35]=[C:34]([O:36][CH:37]([F:39])[F:38])[N:33]([CH3:40])[N:32]=1.C(OC)(C)(C)C>C(#N)C>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([CH3:30])=[CH:25][C:24]=1[C:31]1[C:35]([F:21])=[C:34]([O:36][CH:37]([F:38])[F:39])[N:33]([CH3:40])[N:32]=1
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
46.3 g (131 mmol) of Selectfluor™ were added to a solution of 40.2 g (131 mmol) of 3-(2,4-dichloro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 0.5 l of acetonitrile. After the mixture had been stirred for 12 hours at room temperature, it was heated for a further hour at reflux temperature. Thereafter, three batches of 6.9 g (20 mmol) of Selectfluor™ were added to the reaction mixture, a little at a time, and the mixture was heated in each case for one hour at reflux temperature. The resulting mixture was subsequently treated with 0.5 l of methyl tert-butyl ether. The organic phase was washed with water, saturated aqueous sodium hydrogen carbonate solution and again with water, then dried over magnesium sulfate and finally concentrated. The crude product was purified by means of silica gel chromatography (eluent:hexane/ethyl acetate=9:1). Yield: 20.3 g.