Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O-:21])=[O:20])[CH2:15][CH2:14]1.[OH-:22].[K+]>CC(O)(C)C>[NH2:12][C:11]([C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[C:5]2[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:20])[CH2:17][CH2:18]1)=[O:22]
Reactant: [OH-]
Reactant: N#Cc1cc(Br)cc2c(C3CCN(C(=O)[O-])CC3)n[nH]c12
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Yield: 191.5 %

Procedure:
To 4-(5-bromo-7-cyano-1H-indazol-3-yl)-1-piperidine-carboxylate (0.30 g, 0.74 mmols) in 2-methyl-2-propanol (30 mL) was added KOH (0.45 g, 7.4 mmol). The reaction mixture was heated at reflux overnight. After cooling, the solvent was evaporated and the residue was redissovled in ethyl acetate (150 mL) and filtered through a pad of silica gel to give the title compound (300 mg) as a yellow solid (99%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][Si](C(C)(C)C)(C)C)=[CH:24][CH:23]=2)[C:18]([N+:36]([O-:38])=[O:37])=[CH:17][N:16]=1.O>CN(C=O)C>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]2[C:18]([N+:36]([O-:38])=[O:37])=[CH:17][N:16]=[C:15]([O:11][C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:20]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cc(Cl)ncc2[N+](=O)[O-])cc1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Yield: 33.6 %

Procedure:
A solution of 3-acetamidophenol (10.8 g, 72 mmol) in DMF (50 mL) was added dropwise to a slurry of NaH (60% in oil, 2.88 g, 72 mmol) over 1 h. A solution of the product from Step 1 (13.7 g, 36.0 mmol) in DMF (50 mL) was added and the resulting mixture was heated to 60° C. overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4), filtered and the filtrate was concentrated to give an oil which was purified by chromatography (10-100% EtOAc in hexanes) to give the title compound (4.6 g, 34%) as an orange solid. MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [CH:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([O:29]C3CCCCO3)[CH3:28])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]([C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:18][CH:17]=2)=[N:12][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC=Cc1cnc(-c2ccc(CCCCCC(C)OC3CCCCO3)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCCC=Cc1cnc(-c2ccc(CCCCCC(C)O)cc2)nc1

Procedure:
In a reactor equipped with a stirrer and a thermometer., 5-nonenyl-2-[4-(6-tetrahydropyranyloxy-1-heptyl)phenyl]-pyrimidine, p-toluenesulfonic acid and methanol are charged and reacted at room temperature for 2 hours. Then, the reaction mixture is extracted with toluene and the extract is washed with water and evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography to obtain 5-nonenyl-2-[4-(6-hydroxy-1-heptyl)phenyl]pyrimidine
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Product: CC(C)COC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and isobutyl chloroformate by using the same method as in Example 107.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[NH2:31][CH2:32][C:33]([N:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH2:44][O:45][C:46]2[C:54]3[N:53]=[C:52]([O:55][CH3:56])[N:51]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[C:50]=3[CH:49]=[CH:48][CH:47]=2)[C:38]=1[Cl:64])[CH3:36])=[O:34].O>CN(C=O)C>[Cl:64][C:38]1[C:39]([CH2:44][O:45][C:46]2[C:54]3[N:53]=[C:52]([O:55][CH3:56])[N:51]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=1[N:35]([CH3:36])[C:33](=[O:34])[CH2:32][NH:31][C:18]([CH:15]1[CH2:16][CH2:17][N:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH2:14]1)=[O:20]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(C(=O)O)C2)C1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCN(C(=O)OC(C)(C)C)C5)C4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
A solution of 1′-(tert-butoxycarbonyl)-[1,3′-bipyrrolidine]-3-carboxylic acid (0.5 g, 1.0 mmol) in anhydrous DMF (20 ml) was treated with HOBT (Hydroxybenzotriazole) (0.21 g, 1.52 mmol), EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), hydrochloride (0.24 g, 1.27 mmol) then 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.50 g, 1.0 mmol) and the mixture was stirred at room temperature overnight. The reaction was treated with water (100 mL) and the resulting precipitate was filtered. The aqueous mixture was treated with aqueous saturated sodium bicarbonate (100 mL), extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give a white solid, 0.62 g that was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford tert-butyl 3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)carbamoyl)-[1,3′-bipyrrolidine]-1′-carboxylate as a white solid, 0.41 g (53%), that was pure by LC/MS (+ESI) m/z 766 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8](=[O:34])[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=2[CH3:26])[CH:12]=[CH:11][C:10]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>[Pd].CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8](=[O:34])[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:17]([CH3:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCOC(=O)c1cc(Oc2c(C)cc([N+](=O)[O-])cc2C)ccc1OCOCCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOCOC(=O)c1cc(Oc2c(C)cc(N)cc2C)ccc1OCOCCOC
Reaction time: 3 h

Procedure:
A mixture of the title A compound, 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxy-ethoxymethoxy)benzoic acid 2-methoxyethoxymethyl ester (3.2 g, 6.68 mmol) and palladium on activated carbon (10 wt. %; 320 mg) in 50 mL of EtOAc is stirred under hydrogen atmosphere (H2, 1 atm) for 3 h. The catalyst is removed by vacuum filtration through celite, washed with EtOAc, and the combined filtrate and washings are concentrated and dried under vacuum to give 5-(4-amino-2,6-dimethylphenoxy)-2-(2-methoxyethoxymethoxy)benzoic acid 2-methoxy-ethoxymethyl ester: NMR (CDCl3) 2.07 (s, 6H), 3.37 (s, 3H), 3.40 (s, 3H), 3.52-3.62 (m, 4H), 3.83-3.92 (m, 4H), 5.26 (s, 2H), 5.52 (s, 2H), 6.60 (s, 2H), 6.80 (dd, 1H, J=8.3, 3), 7.13 (d, 1H, J=8.3), 7.24 (d, 1H, J=3).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])(=O)C.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>>[S:11]([O:4][CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CC(=O)OC1CCOC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OC2CCOC2=O)cc1

Procedure:
reacting enantiopure (S) or (R) α-hydroxy-γ-butyrolactone with tosyl chloride to give enantiopure (S) or (R) α-tosyloxy-γ-butyrolactone (Step 5);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O[CH:8]=1.CC(O)=O.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1>O>[C:23]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:15])[CH:5]=[C:6]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:22]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: COc1coc(-c2ccccc2)cc1=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cn(-c2cccc(-c3ccccc3)c2)c(-c2ccccc2)cc1=O
Temperature: 130 °C
Yield: 44 %

Procedure:
To a solution of 5-methoxy-2-phenyl-4H-pyran-4-one (35 mg, 0.17 mmol) in a 1:1 mixture of AcOH:water (0.6 mL) was added 3-aminobiphenyl (59 mg, 0.35 mmol). The reaction vessel was sealed and heated at 130° C. for 3 h before being cooled to room temperature and purified by reversed phase HPLC (2 cm×5 cm CI 8, acetonitrile-water gradient, 0.05% TFA added) to provide (44%) 1-(biphenyl-3-yl)-5-methoxy-2-phenylpyridin-4(1H)-one. LC/MS (M+H)+ 354.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:4]([NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:3].[CH:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[C:32](O)[CH:31]=1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[NH:1]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:2]([C:4]([NH:6][C@H:7]([C:20]([O:22][C:32]1[CH:31]=[CH:30][C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=1)=[O:21])[CH2:8][CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:5])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-L-Ala-L-Glu(OBzl)-OH (40.5 g, 0.1 mol) was dissolved in 300 ml of EtOAc and combined with 17 g (0.12 mol) of p-nitrophenol. The reaction was kept at 0° C. for 1 hour. DCC (24.7 g, 0.12 mol) was then added. The reaction was stirred for 1 hour at 0° C. and for 4 hours at room temperature. The precipitate of DCU was filtered off and the solvent was evaporated in vacuum. The residual oil was then dissolved in ether. The precipitate was filtered off and washed with ether and hexane. The yield was 35 g (64%). Rf=0.7 (CHCl3:Et-Ac:MeOH=6:3:1).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17]C)=[O:16])=[CH:12][CH:13]=2)[N:8]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:21][N:20]=2)[CH:7]=1>O.C1COCC1>[CH3:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[N:8]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:21][N:20]=2)[CH:7]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4ccccn4)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.837 g, 19.94 mmol, 3 eq) was added to a solution of 244a) (2.5 g, 6.64 mmol, 1 eq) in water/THF (1:1, 40 mL) and the reaction mixture was stirred for 16 h at room temperature. The solvents were removed under reduced pressure and the residue was dissolved in water (100 mL), washed with ether (50 mL) and acidified with 2N hydrogen chloride solution. The aqueous phase was then extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with water and brine (50 mL), dried over sodium sulfate, and evaporated. White solid. Yield: 1.5 g (63% of theory)
Reaction SMILES: C[O:2][C:3]1([CH3:18])[CH2:8][CH2:7][C:6]2[C:9]([CH3:17])=[C:10]([O:15][CH3:16])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1.CC(C)=O.Cl>O>[CH3:16][O:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([CH3:18])([OH:2])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:17]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(OC)O2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(O)O2

Procedure:
A mixture of 84.3 g (0.337 mole) of rac.-2,6-dimethoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran, 370 ml of acetone, 300 ml of water, and 2.5 ml of conc. hydrochloric acid was distilled until the distillate temperature reached 90° C. After being cooled, the mixture was diluted with water and extracted three times with ether. The ether extracts were combined, washed with saturated brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from aqueous acetone giving rac.-6-methoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol as an off-white solid, in crops of 34.6 g (43.5%) and 11.1 g (13.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[H-].[Na+].[NH2:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([N:30]2[CH2:54][CH2:53][C:33]3([CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH:35]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:34]3)[CH2:32][CH2:31]2)[N:24]=1>C1COCC1>[NH2:22][C:23]1[N:28]=[C:27]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[C:9]([F:12])([F:11])[F:10])[N:26]=[C:25]([N:30]2[CH2:54][CH2:53][C:33]3([CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[CH:35]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:34]3)[CH2:32][CH2:31]2)[N:24]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(N)nc(Cl)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(CCN(c3nc(N)nc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (380 mg, 1.3 mmol) in 10 mL of THF was added NaH (60 mg, 1.4 mmol) and the reaction was stirred at RT for 30 min. After this time, 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 1, Example 39a) (570 mg, 1.2 mmol) was added and the reaction was heated to 50° C. for 12 h. After this time, the reaction was cooled to RT, quenched with methanol and concentrated in vacuo. Normal phase silica gel chromatography (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CO>[NH:27]([C:28]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:2][CH2:3]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCNCC2)C1
Reactant: O=C=Nc1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccccc3)CC2)C1
Yield: 80.5 %

Procedure:
tert-Butyl (3S)-3-(piperazin-1-ylmethyl)piperidine-1-carboxylate (3.5 g) and phenyl isocyanate (1.62 g) were stirred in toluene (50 ml) at room temperature for 20 h. The solvent was then concentrated in-vacuo to afford a white solid. The solid was dissolved in methanol and passed through an SCX2 column. The SCX2 column was then flushed with 5% ammonia in methanol solution. The solution was collected and the solvent removed under reduced pressure. The resultant solid was re-crystalised from EtOAc and isoHexane, to afford the desired product as a white solid (4 g).
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:2]([C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=3[Cl:36])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Temperature: 100 °C
Yield: 51.5 %

Procedure:
To a degassed solution of 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (8.0 mg, 0.041 mmol) and K2CO3 (8.5 mg, 0.061 mmol) in 1,4-dioxane (0.3 mL) and H2O (0.1 mL) was added Pd(PPh3)4 (2.3 mg, 0.002 mmol) under argon at 20° C. The reaction mixture was heated at 100° C. for 2 h under argon, then allowed to cool to 20° C. The reaction was concentrated in vacuo, and the residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 5.5 mg (55%) of the title compound as a white solid. LC/MS (method B): retention time=2.03 min, [M+H]+=533.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.CC([O-])=O.[Na+].Br[CH2:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]2[CH:16]=[C:17]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:9][C:4]=2[N:3]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2cc3c(O)nc(N)nc3[nH]2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2,6-diaminopyrimidin-4-ol (1 g, 7.93 mmol) and NaOAc (0.846 g, 10.31 mmol) in water (180 mL) was heated to 100° C. for 20 minutes. To this was added a suspension of 4-(2-bromoacetyl)benzonitrile (2.2 gm, 8.73 mmol) [prepared according to procedure mentioned in J. Med. Chem., 2011, 54(12), 4042-4056] in MeOH (25 mL) and heated overnight at 100° C. After completion of reaction, the reaction mixture was cooled to 0° C. Resultant solid product was filtered off and dried under reduced pressure to provide title compound XI-10-I (1.2 g, 100%). LCMS: m/z 252 (M+1)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:31][C:28]1[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:26][C:25]([NH:24][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:30][N:29]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 4, 0.0895 g, 0.286 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, Step 2, 0.0772 g, 0.348 mmol) in THF (1 mL) in 5 mL microwave vial, LiHMDS (1.14 mL, 1.14 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding saturated aqueous sodium chloride (0.2 mL). The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken into THF (5 mL) and 5N HCl (1 mL) was added. The yellow mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The pure fractions were collected and lyophilized to afford N-(2-chloro-5-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (TFA salt, 0.0185 g, 11% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1H) 9.79 (d, J=7.63 Hz, 1H) 9.67 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (s, 1H) 8.50 (d, J=2.54Hz, 1H) 8.41 (dd, J=4.69, 1.96 Hz, 1H) 7.14 (dd, J=7.92, 4.79 Hz, 1H) 3.13-3.18 (m, 3H) 2.86-2.90 (m, 3H). Note: one proton was missing from the NMR spectrum. m/z (ESI, positive ion): 430.9 (M+H)+ as parent ion.
Reaction SMILES: O1CCN(C[CH2:8][NH:9][C:10](=[O:56])[CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:16]=[C:17]([CH:53]=[CH:54][CH:55]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:22]=2[C:33]2[CH:34]=[C:35]([CH:50]=[CH:51][N:52]=2)[C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[O:37])=[O:19])CC1.[CH3:57][O:58][CH2:59]CN>>[CH3:57][O:58][CH2:59][CH2:8][NH:9][C:10](=[O:56])[CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:53]=[CH:54][CH:55]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:23][C:22]=1[C:33]1[CH:34]=[C:35]([CH:50]=[CH:51][N:52]=1)[C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=1)=[O:37])=[O:19]
Reactant: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Reactant: COCCN
Product: COCCNC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared using the procedure described for the preparation of 2-(2-(3-(((3-((2-morpholinoethyl)amino)-3-oxopropyl)thio)methyl)benzamido)-5-(piperidin-1-yl)-phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 4.16, using 2-methoxyethylamine in place of 2-morpholinoethylamine MS (ES, m/z): 734 [M+H]+