Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=[O:24])C>O1CCCC1.O.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([OH:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OCC(C)(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetyl-4-(2-phenylallyloxy)piperidine (4.0 g.) in dry tetrahydrofuran (60 ml.) was added dropwise to a stirred solution of mercuric acetate (6.35 g.) in water (60 ml.) and the solution stirred at room temperature for one hour. Sodium hydroxide solution (40 ml., 3 N) and sodium borohydride (0.75 g.) in sodium hydroxide solution (40 ml., 3 N) were then added dropwise to the stirred solution at 0° C. The grey suspension was stirred at 0° C. for one hour, glacial acetic acid was added to pH 6, then the suspension filtered and the filtrate extracted with chloroform (3×150 ml.). The combined chloroform extracts were dried (Na2SO4) and evaporated in vacuo to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (2.1 g.). This product in methanol (30 ml.) and sodium hydroxide solution (20 ml., 5 N) was heated under reflux for 4 hours. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3×20 ml.), dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g.) as an oil. A sample was characterized as the oxalate salt which recrystallized from ethyl acetate and had an m.p. of 132°-134° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:7]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:8])([O-:3])=[O:2].[CH2:18]=[O:19].Cl.[OH-:21].[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:7]([CH:9]([CH2:10][OH:12])[CH2:13][C:18]([OH:21])=[O:19])=[O:8])([O-:3])=[O:2]
Reactant: CC(C(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [OH-]
Reactant: C=O
Agent: Cl
Agent: [Na+]
Product: O=C(O)CC(CO)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
25 g of 3-nitro-4-chloro-benzoyl-propionic acid are stirred together with 25 ml of a 35% formaldehyde solution and 220 ml of 0.5N sodium hydroxide solution for 16 hours at room temperature. The reaction mixture is adjusted with 2N hydrochloric acid to pH 3, and is extracted with ethyl acetate. The ethyl acetate phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The 3-(3-nitro-4-chlorobenzoyl)-3-hydroxymethyl-propionic acid obtained as residue is refluxed together with 9 ml of hydrazine hydrate and 800 ml of ethanol for 5 hours. The reaction mixture is afterwards concentrated by evaporation, and the residue is stirred together with 170 ml of dimethyl sulfoxide, 10 ml of morpholine and 15 ml of diisopropylethylamine for 3 hours at 80° C. The reaction mixture is subsequently concentrated under high vacuum in a rotary evaporator, and the residue is refluxed in 90 ml of methylene chloride for 30 minutes. The product which crystallises out on cooling of the reaction mixture with stirring to 0° C. is 6-(3-nitro-4-morpholino-phenyl)-5-hydroxymethyl-4,5-dihydro-3(2H)-pyridazinone, m.p. 210°-213° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)C(C(O)=O)[C:9]2=[O:20]>CN(C)C=O.ClCCl>[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)[CH:1]([C:2]([Cl:4])=[O:3])[C:9]2=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (4.1 mL, 46.9 mmol) was added dropwise to a solution of (1S,4S)-3-camphorcarboxylic acid (Intermediate 24; 4.0 g, 20.4 mmol) and N,N-dimethylformamide (3 drops) in dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then at room temperature for 1.5 h. The solvent was evaporated, and the residue was co-evaporated three times with dichloromethane and then dried under high vacuum to give crude (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride as an orange-brown oil. The crude acid chloride was dissolved in dichloromethane (52 mL) at 0° C., and triethylamine (6.5 mL, 46.8 mmol) and N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 2.29 g, 15.7 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min and then at ˜50° C. for 2 h. The reaction mixture was cooled and partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were dried (sodium sulfate), filtered and evaporated to give crude N-methyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (6.15 g, 93%) which was used directly in the next step.
Reaction SMILES: [Si]([O:8]/[N:9]=[C:10]1\[NH:11][C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[Br:29])[CH2:13][C:14]2[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([CH3:20])[C:19]\1=2)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.O>O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([CH3:20])[C:19]2=[C:14]([CH2:13][C@H:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[Br:29])[NH:11]/[C:10]/2=[N:9]\[OH:8])[N:15]=1
Reactant: Cc1nc(N)nc2c1/C(=N/O[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of ((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-tert-butyldimethylsilyloxime (105a, 384 mg, 0.8 mmol) in dioxane (2 mL) was added 1:9 TFA-H2O and the reaction mixture stirred at rt for 2 h. The resultant sold was filtered and washed with dioxane. The resultant solid was dried to afford (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydro pyrido[4,3-d]pyrimidin-5(6H)-one oxime (105b, 206 mg, 70%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.56 (s, 3H) 2.83 (dd, J=15.92, 4.55 Hz, 1H) 3.17 (dd, J=16.04, 5.94 Hz, 1H) 4.90 (q, J=4.97 Hz, 1H) 7.20 (d, J=1.52 Hz, 1H) 7.21-7.23 (m, 1H) 7.57 (ddd, J=8.34, 1.64, 1.39 Hz, 1H) 9.82 (s, 1H). MS (ES) [M+H] calculated for C14H14BrFN5O, 366.03; found 366.20.
Reaction SMILES: Br[CH:2](C)[C:3](=[O:15])[CH:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:5].[C:17](=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28]([OH:30])[CH:27]=[CH:26][CH:25]=1.O>CC(C)=O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][C:4]([CH3:5])([CH3:17])[C:3](=[O:15])[CH2:2][O:30][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:23])[N:29]=2)=[CH:13][CH:12]=1
Reactant: Oc1cccc(Cl)n1
Reactant: O=C([O-])[O-]
Reactant: CC(Br)C(=O)C(C)OCc1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(OCc1ccc(Cl)cc1)C(=O)COc1cccc(Cl)n1
Yield: 88.9 %

Procedure:
31 g (0.1 mol) of 1-bromo-3-(4-chlorobenzyloxy)-methyl-2-butanone in 200 ml of acetone are heated under reflux with 14 g (0.1 mol) of potassium carbonate and 13 g (0.1 mol) of 6-chloro-2-hydroxypyridine for 6 hours. Thereafter, the reaction mixture is poured into water and extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated. 31.5 g (89% of theory) of 3-(4-chlorobenzyloxy)-1-(6-chloropyridin-2-yloxy)-3-methyl-2-butanone are obtained as a light-coloured oil. ##STR14##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6]2.[CH2:16]([OH:20])[CH2:17][CH2:18]O.[C:21]([O:24][CH2:25][CH3:26])(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C>[OH:20][C:16]1[CH:17]=[CH:18][C:12]([C:3]([C:4]2[CH:26]=[C:25]([O:24][CH3:21])[CH:7]=[CH:6][C:5]=2[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[O:2])=[CH:11][CH:10]=1
Reactant: OCCCO
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: CCOC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6-methoxynaphthalen-2-yl)boronic acid in diethyl ether (60 ml) was added 1,3-propanediol (2.3 ml), the solution was stirred for 15 minutes at room temperature, then ethyl acetate (70 ml) was added thereto followed by stirring for 10 minutes at room temperature. To the reaction mixture was added anhydrous magnesium sulfate, the solution was stirred, then insoluble material was removed by filtration, the solvent was evaporated in vacuo. To the total amount of the resulting 2-(6-methoxynaphthalen-2-yl)[1.3.2]dioxaborinane crude product were sequentially added (2-bromo-5-methoxyphenyl)[4-(4-nitrobenzyloxy)phenyl]methanone (6.9 g), cesium carbonate (10.2 g), N,N-dimethylformamide (80 ml) and tetrakis(triphenylphosphine)palladium(0) (900 mg), and the solution was stirred for 10.5 hours at 80° C. Ethyl acetate and water were added thereto, insoluble material was removed by filtration, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (brown foam) (4.1 g).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1([CH:16]([OH:18])O)[C:10](C)=[CH:11][CH:12]=[CH:13][CH:14]=1.CS(O)(=O)=O.C[C:25](C)=[O:26]>O>[CH:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1.[OH:18][CH2:16][C:9]1[CH:14]=[CH:13][C:12]([CH2:25][OH:26])=[CH:11][CH:10]=1
Reactant: CC(C)=O
Reactant: Cc1ccccc1C(O)O
Agent: CS(=O)(=O)O
Agent: Cc1ccc(O)cc1
Solvent: O
Product: OCc1ccc(CO)cc1
Reaction time: 2 h

Procedure:
p-Cresol in an amount of 38.4 g (0.36 mole) and 35.0 g (0.25 mole) of xylene-α,α-diol were dissolved with heating, followed by addition of 0.15 g of methanesulfonic acid at 90° to 100° C. The reaction was carried out at 90° to 100° C. for 2 hours with stirring. After cooling, 100 ml of acetone was poured into the reaction solution. After dissolving, the reaction solution was poured into 2000 ml of water and stirred. After allowed to stand, a supernatant was removed by decantation. The residue was dissolved in 100 ml of acetone, followed by pouring into 2000 ml of water and stirring. After allowed to stand, a supernatant was removed by decantation. The residue was dried under reduced pressure to give 65.0 g of pale yellowish powdered crystals of p-cresol/1,4-dihydroxymethylbenzene polycondensate. Mw was about 6,700 and the degree of dispersion was 3.50 (GPC method, polystyrene standard).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>C(#N)C(C)C>[CH2:7]([O:14][C@H:6]1[C@H:2]([OH:1])[CH2:3][O:4][CH2:5]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: C1OCC2OC12
Agent: CC(C)C#N
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O[C@@H]1COC[C@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a flask fitted with a condenser and nitrogen inlet was added 3,4-epoxytetrahydrofuran (20 g, 0.23 mol), isobutyronitrile (100 ml, 5 vol), benzyl alcohol (124 g, 1.15 mol, 5 eq.) and finally magnesium perchlorate (10.3 g, 0.046 mol, 0.2 eq). The solution was heated at 100° C. for 24 hours. After cooling to room temperature, the reaction was quenched with water (1000 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×400 mL). After drying the organic phases over MgSO4, filtering and concentrating in vacuo, the trans-3-benzyloxy-4-hydroxytetrahydrofuran was isolated by column chromatography to give 29 g (66% yield) of a clear colorless liquid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:23]=[CH2:24])[CH:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 80 °C
Yield: 97.7 %

Procedure:
N-(1-Adamantylmethyl)-2,5-dichloroisonicotinamide (2.32 g) and tributyl(vinyl)stannane (2.61 g) were stirred together in dry N,N-dimethylformamide (50 mL) at room temperature under nitrogen. The latter was treated with a few crystals of 2,6-ditert-butyl-4-methylphenol and dichloro[bis(triphenylphosphine)]palladium(II) (0.24 g). The reaction mixture was warmed to 80° C. for 4 hours and subsequently cooled to room temperature. The mixture was poured into ethyl acetate (50 mL) and washed with water (2×25 mL) then brine (30 mL). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:dichloromethane (1:20) to afford the sub-titled compound (2.21 g).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C([O-])=O)[CH:14]=[CH:13]3)=[N:7][N:6]=1)(=O)=O.[CH3:22][NH2:23].CCOC(C)=O>CS(C)=O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8]3[S:9][C:5]([NH:23][CH3:22])=[N:6][N:7]=3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3c(ccn3C(=O)[O-])c2)s1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1nnc(-c2ccc3[nH]ccc3c2)s1
Temperature: 110 °C
Yield: 78 %

Procedure:
To a mixture of 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (8 g, 21.11 mmol) in a sealed tube was added methylamine in DMSO (80 mL). The reaction was heated at 110° C. for 1 h and ice-cold water and EtOAc was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 40% EtOAc in Hex) to give 5-(1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (3.8 g, 78%). MS (ESI, pos. ion) m/z: 231 (M+1); 1H-NMR (DMSO-d6, 300 MHz): δ ppm 2.9 (s, 3H), 6.5 (d, 1H) 7.4 (d, 3H) 7.8 (m, 1H), 7.9 (s, 1H), 11.4 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:22]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NC1CCCCC1

Procedure:
102 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 100 g of cyclohexylamine are heated to 137° C. under 4,000 Pa. 59 ml of water and excess cyclohexylamine are distilled off. Distillation of the residue at 162°-163° C. under 10.7 Pa gives 87.6 g (62% of theory) of an oil of nD20 1.5296 and η25 72.8 Pa.s.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:20]3[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
65 mg (0.30 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 95 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH2:25]([O:27]C(=O)CC1C2C(=CC=C(OC)C=2)N(CC2C=CC=CN=2)C=1C)C.NN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH3:25][OH:27]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccn2)c2ccc(OC)cc12
Agent: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccn1
Agent: NN
Product: CO
Yield: 67 %

Procedure:
5-Methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide. Using the method described in Example 1, Part G, 480 mg (1.4 mmol) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid ethyl ester was reacted with 1.4 mL of hydrazine to give on crystallization from MeOH 304 mg (67% yield) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide, mp, 147°-148° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[Br:17])C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[NH:7][CH3:6]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 144B (29.5 g, 92 mmol) in dichloromethane (200 mL) was added trifluoroacetic acid (141 mL, 1831 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried with MgSO4, filtered, and concentrated. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 222 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:30]1([CH:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:9]3[CH:10]=[C:5]([C:4]([F:3])([F:12])[F:13])[CH:6]=[CH:7][C:8]3=[O:11])=[CH:17][CH:18]=2)[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
73.6 mg (1.84 mmol, 60% pure) of sodium hydride were added to 300 mg (1.84 mmol) of 5-(trifluoromethyl)pyridin-2(1H)-one in 2.5 ml of DMF. After 30 min of stirring, 500 mg (1.42 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were added. After a further 2 h of stirring at RT, the reaction mixture was warmed to 40° C. for 1 h. Water and ethyl acetate were then added to the mixture, and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1 to 4:1). This gave 522.0 mg (84.7% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:45]=[N:44]2)[CH2:39][CH2:38]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:46]4[CH:45]=[N:44][N:43]([CH:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][OH:34])[CH2:42][CH2:41]5)[CH:47]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(C3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C4CCN(CCO)CC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (12 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was concentrated. The residue was treated with methanol. After solid was filtered off the filtrate was concentrated. The resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution and stirred at r.t. overnight. Then it was purified with RP-HPLC (pH=10) to afford the desired product (2.5 mg). LCMS (M+H)+:m/z=532.3.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>CN(C=O)C>[N:33]1([C:31]([NH:30][C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:17]3[N:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:6][CH2:7][N:2]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:16]=3)[CH2:25]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added DIEA (190 μL, 1.10 mmol) and then acryloyl chloride (30 mg, 0.33 mmol). The mixture was stirred at RT for 20 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (499), as HCl salt (35 mg). LC-MS (ESI): m/z (M+1) 562.3. UV: λ=258, 329, 337 nm.