Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27]([OH:30])[CH:28]=[CH2:29]>>[CH2:27]([O:30][C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1)[CH:28]=[CH2:29]
Reactant: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 8 h

Procedure:
To a suspension of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (I-13A-1a; 30 mg, 0.08 mmol) in allyl alcohol (0.8 ml) was added NaH (60% dispersion in oil, 2 mg, 0.08 mmol). After stirring overnight, the reaction was concentrated and purified on a Chromatotron using methylene chloride as eluant to give product 13A-1 (12 mg, 38%) as a solid: +ESI MS (M+1) 396.4; 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=5.4 Hz, 1H), 7.53–7.40 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 6.68 (d, J=5.4 Hz, 1H), 6.20 (ddt, J=17.0, 10.4, 5.8 Hz, 1H), 5.64–5.58 (m, 1H), 5.45–5.41 (m, 1H), 5.10–5.08 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+]>CN(C)C=O>[C:24]([O:27][CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CBr)nc2s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To 10.5 g of 3,4-dihydro-2-bromomethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 100 ml of dimethylformamide and 6.0 g of sodium acetate, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured onto water, and the mixture was extracted with ethyl acetate, washed with water and concentrated to give 8.7 g of the residue. This residue was purified by silica gel column chromatography to give 5.3 g of an oily substance, which was crystallized from ethanol to afford 3.4 g of the title compound, m.p. 192.5°-194° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][CH:20]([CH3:24])[CH2:21]2)[C@H:17]1[CH:25]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(=O)OCC.CCCCCCC>[C:9]([O:13][C:14]([N:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][CH:20]([CH3:24])[CH2:21]2)[C@H:17]1[CH2:25][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](C=O)[C@H]2C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Product: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CNCc3ccccc3)[C@H]2C1
Reaction time: 16 h

Procedure:
Benzylamine (0.155 mL, 1.75 eq) was added to a solution of (1S,2S,5R)-2-formyl-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (206 mg, 1 eq) in chloroform (6 mL). After 15 min the mixture was treated with NaBH(OAc)3 (173 mg, 1 eq), and stirred for 16 h. The reaction mixture was poured into a sat. aq. NaHCO3 solution. The layers were separated and the aq. layer was extracted twice with chloroform. The combined org. extracts were washed with sat. NaHCO3 solution, dried over anh. MgSO4, filtered and concentrated in vacuo to give a crude yellow oil. FC (EA/n-heptane: 3/7 to 7/3) gave the title compound as a colourless oil
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:18][N:17]=1)[CH2:14][CH3:15]>CN(C=O)C.O>[N:1]1([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:18][N:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCC(Br)c1ccc(-c2cccc(OC)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(-c2cccc(OC)c2)cn1)n1ccnc1
Temperature: 50 °C
Yield: 12 %

Procedure:
To a solution of imidazole (0.2 g, 2.9 mmol) in DMF (5 mL) was added potassium carbonate (0.4 g, 2.9 mmol) and 2-(1-bromopropyl)-5-(3-methoxyphenyl)pyridine under nitrogen and the reaction was heated to 50° C. for 3 h. The contents were cooled to rt, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The layers were separated, the organic layer was washed with brine solution (2×30 mL), dried over sodium sulphate and distilled off to get the crude product. The product was purified by preparative TLC (2000μ; pure ethyl acetate) to provide 2-(1-(1H-imidazol-1-yl)propyl)-5-(3-methoxyphenyl)pyridine (50 mg, 12% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.09 (d, 1H), 7.81 (s, 1H), 7.40 (m, 2H), 7.36 (s, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.89 (s, 1H), 5.37 (q, 1H), 3.80 (s, 3H), 2.25 (m, 2H), 0.82 (t, 3H); LC-MS m/z calcd for [M+H]+ 294.15. found 294.2.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:10](=[O:11])[C:9]([C:12]3[N:16]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[C:8]([CH3:25])[N:7]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:6]2=[O:36])[CH2:2]1.[CH2:37]=O>>[CH3:25][C:8]1[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)[C:6](=[O:36])[N:5]([CH:3]2[CH2:2][N:1]([CH3:37])[CH2:4]2)[C:10](=[O:11])[C:9]=1[C:12]1[N:16]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=[CH:14][CH:13]=1
Reactant: C=O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C2CNC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C2CN(C)C2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
The intended compound was obtained by using 4-(5-(3-(azetidin-3-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 112) and formaldehyde according to the similar reaction and treatment method to those described in Example 69.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:31][C@H:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:5][C:6]([F:30])=[C:7]([S:9]([N:12](CC2C=CC(OC)=CC=2OC)[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:8]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:4]([O:31][C@H:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:5][C:6]([F:30])=[C:7]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C#N)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1C#N
Yield: 89.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-cyano-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (32.3 mg, 0.0545 mmol) prepared in Example 62d, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (21.5 mg, 89%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([N:31]([CH3:39])[C@@H:32]([CH:36]([CH3:38])[CH3:37])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH3:39])[CH:36]([CH3:38])[CH3:37])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyric acid to yield (3aR,4S,7aR)-4-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryloxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((S)-3-methyl-2-methylamino-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=5.490 min; HPLC Method I
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.O1CCN([C:20](=[O:30])[C@H:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:22])CC1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:30])[C@H:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:22])=[N:3][CH:4]=1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
2,5-dibromopyridine (5 g, 21.1 mmol) was dissolved in dried toluene (100 mL), cooled to −78° C., to which n-butyl lithium (9 mL, 22.5 mmol, 2.5 M solution in n-hexane) was added dropwise. The mixture was allowed to react at −78° C. for 2 hrs, and then the solution of (2R)-1-morpholino-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-one (7.7 g, 31.6 mmol) in toluene was added dropwise and allowed to react at −78° C. for 5 hrs. The reaction was monitored by TLC (petroleum ether). After the reaction completed, the reaction was quenched by adding saturated solution of ammonium chloride. The mixture was raised to room temperature and diluted with water. The toluene layer was separated and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then dried by rotary dryer. Column chromatography (petroleum ether) afforded 4.1 g of pale yellow solid (compound 1a), yield 62%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=1)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[CH3:22][O:21][C:19](=[O:20])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:14]=1
Reactant: COC(=O)c1cccc([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cccc([C@H]2CCCN2)c1

Procedure:
To a stifling solution of (R)-2-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (830 mg, 2.582 mmol) in methylene chloride (30 mL) at room temperature add 4 M HCl in dioxane solution (12.91 mL, 51.64 mmol) and stir the reaction at ambient temp for 18 h. Concentrate the solution in vacuo at 35° C. to remove most solvent. Dilute and stir the dioxane suspension of solids with Et2O (50 mL) and hexane (50 mL). Filter the solid washing with Et2O then hexane and dry in vacuo under P2O5 to give (R)-3-pyrrolidin-2-yl-benzoic acid methyl ester HCl as a solid (577 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: CC1=COc2ccccc2C(=O)N1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=COc2ccccc2C(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2.0 g of 3-methyl-4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 120 ml of dimethylformamide, then 548 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was stirred at room temperature for 1 hour, then 4.1 ml (3 equivalents) of 1,4-dibromobutane was added and the mixture was stirred for 3 hours. Ice water was added to the reaction solution and extraction was performed with ethyl acetate. The ethyl acetate extract was washed with saline, then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.0 g of the above-identified compound (yield 84%).
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([CH3:13])[CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19].C(O)C.Cl>[Cl-].[Zn+2].[Cl-].O>[O:19]=[C:18]1[O:1][C:2]2=[N:11][C:10]3[N:9]([CH3:12])[CH2:8][CH2:7][CH:6]([CH3:13])[C:5]=3[CH:4]=[C:3]2[C:16]([C:15]([F:25])([F:24])[F:14])=[CH:17]1
Reactant: CC1CCN(C)c2nc(O)ccc21
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: CC1CCN(C)c2nc3oc(=O)cc(C(F)(F)F)c3cc21

Procedure:
The following procedure is typical of that used to prepare the various azacoumarins. 7-Hydroxy-1,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (0.19 g.), 1.2 ml. of ethyl trifluoroacetoacetate, 50 mg. of anhydrous zinc chloride, and 10 ml. of absolute ethanol were refluxed for 40 hours. The cooled solution was poured with stirring into 50 ml. of water plus 3 ml. of hydrochloric acid; the yellow precipitate was filtered, washed with water, and dried (0.31 g., 95%). Solvent used for recrystallization, melting point, fluorescence data and analytical data are summarized in the table below. The 1H nmr spectral data (deuteriochloroform, 100 MHz) on the analogous 6,8,9-trimethyl derivative are: δ1.37 (d, 6H, CH3CH), 1.47 (m,1H, H7b), 2.10 (dt, 1H, H7a,J=13 Hz, J=4 Hz), 2.80 (m, 1H, H6), 3.20 (s, 3H, NCH3), 3.70 (m, 1H, H8), 6.38 (s, 1H, H3), 7.41 (q, 1H, H5, JH5 --CF3 =~1.5 Hz).
Reaction SMILES: C[O:2][C:3](=[O:15])[C@@:4]([O:13][CH3:14])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+].Cl>CO>[CH3:14][O:13][C@:4]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:15])=[O:2]
Reactant: COC(=O)[C@@](C)(Cc1ccccc1)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CO[C@](C)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.69 g of (R)-2-methoxy-2-methyl-3-phenyl-propionic acid methyl ester are dissolved in 40 ml of methanol. 40 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 2.5 hours at room temperature. The reaction mixture is neutralised with 1M HCl and concentrated by evaporation. The residue is purified by flash chromatography (SiO2 60F) to provide the title compound as a yellow oil. Rf=0.70 (35:13:5 dichloromethane-methanol-acetic acid).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:28]([CH3:29])[CH3:27])[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: CN(C)c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and dimethylamine (33% aqueous solution); δH (CDCl3) 9.00 (1H,s), 8.52 (1H,s), 7.59 (2H,d), 7.40 (4H,m), 7.23 (1H,s), 7.13 (2H,d), 6.35 (1H,s), 5.10 (2H,s), 3.20 (6H,s); m/z (M+1)+395.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C@H:10]([NH2:12])[CH3:11])[CH:6]=[N:5]1.CC1N(C[C:20]([F:23])([F:22])[F:21])N=CC=1C(=O)C>>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:4]([CH2:3][C:20]([F:23])([F:22])[F:21])[N:5]=[CH:6][C:7]=1[CH:10]([NH2:12])[CH3:11]
Reactant: Cc1c([C@@H](C)N)cnn1C
Reactant: CC(=O)c1cnn(CC(F)(F)F)c1C
Agent: Cl
Product: Cc1c(C(C)N)cnn1CC(F)(F)F
Yield: 99 %

Procedure:
The title compound was prepared in >99% yield by the same process as described for (R)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanamine dihydrochloride (Amine 2) using 1-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethanone (Step A6A) as a starting material. 1H NMR (300 MHz, DMSO-d6) δ 1.49 (3H, d, J=6.0 Hz), 2.32 (3H, s), 4.29-4.33 (1H, m), 5.07 (1H, d, J=9.0 Hz), 5.13 (1H, d, J=9.0 Hz), 7.72 (1H, s), 8.34 (3H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1.Cl([O-])=[O:15].[Na+].S(=O)(=O)(O)N.CCOC(C)=O>CC(C)=O.Cl.FC(F)(F)C1C=CC([C@@H](C2C(C(F)(F)F)=CC=CN=2)N)=CC=1>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([C:9]([OH:15])=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(C=O)cc1[N+](=O)[O-]
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: NS(=O)(=O)O
Agent: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cnc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-methoxy-4-nitropicolinaldehyde (4 g, 0.02 mol) in acetone and water (1:1,100 mL) was added sodium chlorite (5.9 g, 0.065 mol, spectrochem, india) and sulfamic acid (6.3 g, 0.065 mol, Rankem, India) and the reaction mixture was stirred for 1 h at rt. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion, the reaction mixture was concentrated to get a white precipitate which was filtered and dried to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.6 (brs, 1H) 8.90 (s, 1H), 8.41 (s, 1H), 4.15 (s, 3H). MS (ESI, positive ion) m/z: 197.8 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 290 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: C[O:2][CH:3]([O:10]C)[C@@H:4]1[O:9][CH2:8][CH2:7][C@H:5]1[OH:6].[H][H]>O>[OH:6][C@@H:5]1[CH2:7][CH2:8][O:9][C@H:4]1[CH:3]([OH:10])[OH:2]
Reactant: COC(OC)[C@@H]1OCC[C@H]1O
Reactant: [H][H]
Solvent: O
Product: OC(O)[C@@H]1OCC[C@H]1O
Temperature: 95 °C
Yield: 14.4 %

Procedure:
A mixture of 9.25 g of product from Example 172, 15 ml of water and 1.5 g of DOWEX-50W-X8(100-200 mesh, hydrogen form) is heated at 95° C. for 4 hours. The reaction mixture is cooled to room temperature, filtered and the residue washed with water. The filtrate is treated with toluene and concentrated in vacuo to give 1.1 g of the desired product as a stickyyellow oil.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:25]([N+:26]([O-])=O)=[C:24]([CH3:29])[CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.[Zn]>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of zinc (40.2 g), THF (50 ml) and acetic acid (100 ml) was added slowly a solution of N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine (13.75 g) in THF (150 ml), and the obtained mixture was stirred at room temperature for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (8.77 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[F:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:27]=[CH:26][C:25]=1[OH:37]>CN1C(=O)CCC1>[F:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:27]=[CH:26][C:25]=1[O:37][C:8]1[C:9]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1
Reactant: CC(=O)N1CCC(c2nccnc2Cl)CC1
Reactant: Oc1ccc(Nc2ccccn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2F)CC1
Temperature: 120 °C

Procedure:
To a mixture of cesium carbonate (1.11 g, 3.41 mmol), 1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone (0.336 g, 1.40 mmol), and 2-fluoro-4-(pyridin-2-ylamino)phenol (0.547 g, 2.68 mmol) was added NMP (3 mL). The reaction mixture was degassed and heated to 120° C. for 1.5 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (40% to 100% EtOAc in hexanes) gave 1-(4-(3-(2-fluoro-4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a white solid. MS (ESI, pos. ion) m/z: 408.2 (M+1). IC50 (uM) 0.008056.