Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[N:52]1([CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH:58]2[NH2:63])[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([NH:63][CH:58]2[CH:57]([N:52]3[CH2:53][CH2:54][CH2:55][CH2:56]3)[CH2:62][CH2:61][O:60][CH2:59]2)=[O:8])[CH2:2][CH2:3]1
Reactant: NC1COCCC1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1COCCC1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J, 118 mg, 0.513 mmol) was dissolved in 2.5 mL dimethylformamide. N,N-Diisopropyl ethyl amine (338 mg, 2.62 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (195 mg, 0.513 mmol) were added. After 10 minutes of stirring at room temperature trans-(4-pyrrolidin-1-yl-tetrahydro-pyran-3-ylamine dihydrochloride (intermediate 1,187 mg, 0.769 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate/triethylamine 1:0:0→10:10:1) yielded the title compound as a white solid (121 mg, 62%), MS: m/e=383.3 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[C:37]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccc(C#N)c2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3-cyanophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H19N2O3 (M+H): 359.1390. Found 359.1394
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:5]([CH3:9])[C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].B1([C:31]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][CH:32]=2)OC(C)(C)C(C)(C)O1.C(O)C>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O>[CH3:37][C:34]1([CH3:38])[CH2:35][CH2:36][C:31]([C:2]2[C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:4][N:5]([CH3:9])[C:6]=2[CH:7]=[O:8])=[CH:32][CH2:33]1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cn1nc(-c2ccccc2)c(Br)c1C=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(-c2ccccc2)c(C2=CCC(C)(C)CC2)c1C=O
Temperature: 95 °C
Yield: 80.7 %

Procedure:
A solution of 4-bromo-1-methyl-3-phenyl-1H-pyrazole-5-carbaldehyde (1c) (150 mg, 0.57 mmol), sodium carbonate (240 mg, 2.26 mmol), and 4,4-(dimethylcyclohexene-1-yl)boronic acid pinacol ester (174 mg, 0.74 mmol) in a mixture of toluene (0.8 mL), ethanol (0.3 mL) and water (0.3 mL) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphosphine) (32.7 mg, 0.028 mmol) was added and the reaction mixture was heated at 95° C. overnight. The solution was concentrated in vacuo. Water (3 mL) was added to the residue. The aqueous layer was extracted with ethyl acetate (2×5 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide 4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazole-5-carbaldehyde (1d) (135 mg, 0.46 mmol, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8](Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22](B2CC(C)(C)C(C)(C)C2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2CC(C)(C)C(C)(C)C2)CC1
Reactant: CCOC(=O)c1csc(Br)c1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1csc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Yield: 56.3 %

Procedure:
2-Bromothiophene-4-carboxylic acid ethyl ester (1.0 g, 5.26 mmol) and 4-(3,3,4,4-tetramethyl-borolan-1-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.26 mmol) were dissolved in DME (40 mL), IMS (20 mL) and water (10 mL). Palladium tetrakis-triphenylphoshine (0.53 mmol) and caesium carbonate (7.9 mmol) were then added and the mixture heated to 120° C. for 20 minutes using microwave radiation. The solvent was then evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a clear oil (1.0 g). LCMS m/z 238.06 [M+H]+ RT=4.33min (Analytical Method 4).
Reaction SMILES: [C:1]([N:4]1[C:17]2[CH:16]=[C:15]([O:18][CH3:19])[C:14]([O:20]C(=O)C)=[C:13]([Br:24])[C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([O:25][CH3:26])[CH:9]=2)(=[O:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([N:4]1[C:17]2[CH:16]=[C:15]([O:18][CH3:19])[C:14]([OH:20])=[C:13]([Br:24])[C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([O:25][CH3:26])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(OC(C)=O)c1Br)N2C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 10-acetyl-3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine (2.0 g) in methanol (40 ml) and 1N aqueous sodium hydroxide solution (40 ml) was stirred at room temperature for 5 hours. The mixture was then made slightly acidic with 1N aqueous HCl and after 15 minutes the crude product was filtered. Crystallization from ethyl acetate afforded the pure title compund (600 mg), m.p.: dec 235° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:13][C:12]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:26])[N:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])=[CH:13][C:12]=1[CH3:25])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1NC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a 0° C. solution of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-carbamic acid benzyl ester (18 g, 48.5 mmol) in DMF (100 mL) is added sodium hydride (60% dispersion in oil, 2.3 g, 58 mmol) portionwise. The reaction mixture is stirred at room temperature for 30 minutes, followed by the addition of iodomethane (8.2 g, 58 mmol). The mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure to give a residue, which is partitioned between EtOAc (100 mL) and water (100 mL). The organic phase is washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give [4-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-carbamic acid benzyl ester as oil (14.0 g, 75%). LC-ES/MS: 386.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.O>CC(N(C)C)=O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1nc(Cl)cc(Nc2cc(C)ccc2NC(=O)OC(C)(C)C)n1
Temperature: 100 °C
Reaction time: 7 h
Yield: 51.2 %

Procedure:
4,6-Dichloro-2-(methylsulfanyl)pyrimidine (50 mg) and tert-butyl (2-amino-4-methylphenyl)carbamate (57 mg) were dissolved in dimethylacetamide (250 μL), and N,N-diisopropyl ethylamine (69 μL) was added thereto, followed by stirring at 100° C. for 7 hours. After the completion of the reaction, the mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain a desired compound tert-butyl (2-{[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-4-methylphenyl)carbamate (50 mg) as a white powder.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[N:13][CH:14]=2)O1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([O:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:34]=2[N:35]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:40]1[CH2:39][CH2:38][CH:37]([O:36][C:33]2[C:34]3[N:35]=[C:26]([C:9]4[CH:10]=[C:11]([NH:15][C:16](=[O:23])[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=[N:13][CH:14]=4)[CH:27]=[CH:28][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:42][CH2:41]1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cncc(NC(=O)c3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide (Intermediate 13) (0.07 g, 0.216 mmol), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.063 g, 0.238 mmol), 1N aq. sodium bicarbonate (0.432 ml, 0.432 mmol) and PdCl2(dppf)-CH2Cl2 (0.018 g, 0.022 mmol) in dioxane (1.08 ml) was subjected to microwave irradiation for 1 hour at 110° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (only EtOAc) to give N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzamide (0.058 g, 63%) as a pink solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.04-2.11 (2H, m), 2.23-2.27 (2H, m), 3.67-3.73 (2H, m), 4.10-4.15 (2H, m), 5.63-5.70 (1H, m), 7.53-7.56 (2H, m), 7.60-7.63 (1H, m), 7.94 (2H, d, J=7.2 Hz), 8.12 (1H, brs), 8.29 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.83 (1H, s), 8.91 (1H, d, J=2.8 Hz), 9.01 (1H, t, J=2.2 Hz), 9.20 (1H, d, J=2.0 Hz). m/z=428.2 [M+1]+.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[C-:16]#[N:17].[K+]>C(O)C.O>[C:16]([CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15])#[N:17]
Reactant: COc1cc2c(cc1OC)C(=O)C(Br)C2
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(C#N)C2
Yield: 44.4 %

Procedure:
2-Bromo-5,6-dimethoxy-indan-1-one (69.1 g) was suspended in ethanol (1,200 ml) and added to a solution of potassium cyanide (70.4 g) in water (2,200 ml). The reaction mixture was heated at reflux for 1 hour and then the ethanol was distilled off. The dark solution was cooled, stirred and carefully neutralised with hydrochloric acid (5M, 120 ml) in a well ventilated hood. The organic extracts were combined, washed with brine, dried over magnesium sulphate, filtered, then concentrated to low volume under reduced pressure. The residual liquid was filtered through a column of coarse silica (0.2-0.5 mm, Merck, 300 g) and the column was eluted with dichloromethane. The appropriate fractions were combined and evaporated to dryness to give 2-Cyano-5,6-dimethoxy-indan-1-one (24.6 g). A portion crystallised from dichloromethane: ether; m.p. 177°-179° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:4][N:3]=1.[S:41]1[C:45]2[CH:46]=[CH:47][C:48]([NH2:50])=[CH:49][C:44]=2[N:43]=[CH:42]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(Cl)Cl>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:50][C:48]3[CH:47]=[CH:46][C:45]4[S:41][CH:42]=[N:43][C:44]=4[CH:49]=3)=[N:3][CH:4]=[C:5]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:6]=2)[N:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2Nc2ccc3scnc3c2)n1
Temperature: -20 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
A mixture of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.500 g, 0.918 mmol) and benzo[d]thiazol-5-amine (0.276 g, 1.836 mmol) in THF (10 mL) was cooled to −20° C. and treated dropwise with 1.0 M lithium bis(trimethylsilyl)amide in THF (3.21 mL, 3.21 mmol). The mixture was allowed to slowly warm to ambient temperature while stirring under inert atmosphere for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CHCl3 (3×50 mL). The combined organic extracts were dried over Na2SO4. The solution was filtered and concentrated to give the crude product as a tan solid. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (80 gram) eluting with a gradient of 10% to 100% EtOAc in hexane over 30 minutes, followed by a gradient of 1-20% MeOH/DCM over 25 min to give the bis-PMB protected material (0.437 g) as a tan oil. This was treated with a mixture of trifluoroacetic acid (1.8 mL, 23.36 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) and the resulting solution was heated at 70° C. 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. The mixture was dissolved in DCM (10 mL) and allowed to stir 5 min, then sodium carbonate (2.5 grams) was slowly added to the mixture and allowed to stir vigorously for 20 min. The solid was collected by filtration and rinsed with dichloromethane (2×30 mL) followed by water (3×20 mL). The solid was dried to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.155 g, 0.357 mmol, 38.9% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 12.25 (s, 1H); 9.36 (s, 1H); 8.91 (s, 1H); 8.76 (s, 1H); 8.33 (s, 1H); 8.06 (d, J=8.80 Hz, 1H); 7.94 (s, 1H); 7.80 (s, 2H); 3.58 (s, 4H); 3.46 (s, 2H); 2.44-2.54 (m, 3H); 2.39 (s, 4H). m/z (ESI, +ve ion) 435 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:31])[C:15]=1[C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][N:22]=2)[CH:20]=1>O.C1COCC1.CO>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:31])[C:15]=1[C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=2)[CH:20]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
A solution of lithium hydroxide monohydrate (63 mg, 1.49 mmol) in water (3.0 mL) was added dropwise to a suspension of methyl 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinate (282 mg, 0.745 mmol) in THF (6.0 mL) and methanol (1 mL). The reaction mixture was then stirred at room temperature for 1.5 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (244 mg, 90%) as a white solid. MS: m/e=363.3 [M−H]−.
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[N:5]=1>C(OC(=O)C)(=O)C>[CH3:3][C:4]1[C:9]([Cl:1])=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[N:5]=1
Reactant: ClCl
Reactant: Cc1cc(C)[nH]c(=O)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(=O)[nH]c(C)c1Cl
Reaction time: 1 h

Procedure:
A solution of chlorine (0.01 mol) in acetic anhydride (100 ml) was added to a solution of 4,6-dimethylpyrimid-2-one (0.008 mol) in acetic anhydride (100 ml) and the solution left at room temperature for 1 hr before the solid precipitate was collected and recrystallised from water; m.p. 235° C. (decomp.)
Reaction SMILES: [CH3:1][CH:2]([CH2:6][O:7][Si](C(C)C)(C(C)C)C(C)C)[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][N:52]1[C:61]2[C:56](=[CH:57][N:58]=[C:59]([CH3:62])[CH:60]=2)[CH:55]=[C:54]([C:63]2[CH:64]=[C:65]([NH:70]/[C:71](/[NH2:74])=[N:72]/O)[CH:66]=[CH:67][C:68]=2[CH3:69])[C:53]1=[O:75].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[OH:7][CH2:6][CH:2]([C:3]1[O:5][N:72]=[C:71]([NH:70][C:65]2[CH:66]=[CH:67][C:68]([CH3:69])=[C:63]([C:54]3[C:53](=[O:75])[N:52]([CH3:51])[C:61]4[C:56]([CH:55]=3)=[CH:57][N:58]=[C:59]([CH3:62])[CH:60]=4)[CH:64]=2)[N:74]=1)[CH3:1]
Reactant: CC(CO[Si](C(C)C)(C(C)C)C(C)C)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)CO)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Methyl-3-(triisopropylsilyloxy)propanoic acid (34 mg, 0.12 mmol), HATU (50 mg, 0.12 mmol), and DIPEA (0.023 mL, 0.12 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (40 mg, 0.118 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling, TBAF (1 ml, 1 M in THF) was added and stirred for 5 h at rt. After filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(1-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A67) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 9.06 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.35 (dd, J=2.4, 8.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.82 (m, 2H), 3.35 (s, 3H), 3.18 (m, 1H), 2.86 (s, 3H), 2.16 (s, 3H), 1.35 (d, J=7.2 Hz, 3H). MS m/z 406.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)c(F)c1
Reaction time: 6 h

Procedure:
A solution of the compound of Example 120A (2.26 g, 10.00 mmol) in ethyl acetate (35 mL) was treated with 10% palladium on carbon (300 mg) followed by hydrogenation under one atmosphere pressure for 6 h. The mixture was filtered through celite and concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@:10]([NH:23][NH:24]C(OC(C)(C)C)=O)([CH3:22])[C:11]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]>ClCCl.FC(F)(F)C(O)=O>[C:15]([CH2:14][O:13][C:11](=[O:12])[C@:10]([NH:23][NH2:24])([CH3:22])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)COC(=O)[C@](C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCC(=O)O
Yield: 58 %

Procedure:
A solution of compound 230 (441 mg, 1 mmol) in 1:1 (v/v) dichloromethane and trifluoroacetic acid was stirred at room temperature for 8 h (monitored by LC/MS). After removing the solvent under reduced pressure at room temperature, the residue was purified by preparative LC/MS technique to afford 165 mg (58%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ1.39 (3H, s), 2.93 (2H, m), 4.56 (1H, d), 4.75 (1H, d), 6.50 (1H, dd), 6.60 (1H, d), 6.67 (1H, d). MS (ESI) m/z 285.26 (M+H+) and 283.13 (M−H−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].[Cl-].C[Zn+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:6]3=[N:7][C:2]([CH3:35])=[CH:3][N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn+]
Solvent: C1CCOC1
Product: Cc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a mixture of 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide (0.204 mmol, 100 mg), potassium carbonate (0.408 mmol, 56.4 mg), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) (0.020 mmol, 14.77 mg) in THF, was added methylzinc chloride (2.041 mmol, 1020 μl) and stirred overnight at 60° C. The reaction was quenched in water, extracted with ethyl acetate. Organic layer was dried and concentrated under reduced pressure. Crude product was purified with HPLC to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide 96l (30 mg, 31%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 2.68 (s, 3H), 7.31 (d, J=8.6 Hz, 1H), 7.62 (m, 2H), 7.76 (d, J=8.6 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.50 (s, 1H), 8.78 (s, 1H), 10.36 (s, 1H), 10.45 (s, 1H). (m/z)=471 (M+H)+.