Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[CH2:41]([Li])CCC.CI>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH:25]([C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)[CH3:41])[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(C(=O)OC)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.200 g, 0.346 mmol) and tetrahydrofuran (2 mL). The solution was cooled to −78° C. and a 1.83 M solution of n-butyl lithium in hexanes (0.23 g, 0.41 mmol) was added. The reaction was stirred at −78° C. for 45 min, then methyl iodide (0.026 mL, 0.41 mmol) was added and the reaction was warmed to 0° C. and stirred for 90 min. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give crude product. Purification by silica gel chromatography using 20% ethyl acetate/hexanes, followed by 70% ether/hexanes as eluent afforded the desired methylated product. MS m/z 593 (M++H); 1H NMR (CDCl3) δ7.85 (bs, 1H), 7.8 (bs, 2H), 7.05 (bs, 1H), 6.5 (bs, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 1.65 (d, 1.5H, J=7Hz), 1.05 (d, 1.5H, J=7.0Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2].C(ON=O)(C)(C)C.[ClH:31].CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:31])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 50 °C

Procedure:
steps 4 and 5—A suspension of 44a (16.1 g, 37 mmol), Fe powder (8.2 g, 148 mmol, Fisher, electrolytically deposited), and NH4Cl (8.0 g, 148 mmol) in absolute ethanol (700 mL) and H2O (180 mL) was heated to reflux for 4 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with chloroform (2×150 mL). The filtrate was washed with aqueous NaHCO3, water, and brine and dried (K2CO3), filtered and the volatiles removed to afford 14.0 g of [4-amino-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44b). The aniline 44b (9.7 g, 24.1 mmol) was dissolved in anhydrous MeCN (100 mL) under nitrogen. This solution was added slowly to a mixture of tert-butyl-nitrite (7.1 mL, 60.3 mmol, assay 90%) and CuCl2 (6.5 g, 48.2 mmol) that had been prepared under nitrogen and warmed to 50° C. The reaction temperature was maintained at 50° C. for 15 min, cooled to 0° C. and poured into 5% aqueous HCl solution (80 mL) and Et2O (150 mL). The mixture was extracted with EtOAc (3×150 mL), the combined extracts were washed with brine and dried (MgSO4), filtered and the volatiles were removed. The residual oil was purified by flash SiO2 chromatography eluting with EtOAc/hexanes (0% to 10% EtOAc) to afford 6.25 g of [4-chloro-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44c) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10]Cl)[S:7][C:6]=1[CH3:12].[C-:14]#[N:15].[K+].C(Cl)(Cl)Cl.[Na+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10][C:14]#[N:15])[S:7][C:6]=1[CH3:12]
Reactant: COC(=O)Cc1cc(CCl)sc1C
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(CC#N)sc1C
Temperature: 50 °C
Yield: 43.4 %

Procedure:
A solution of (5-chloromethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (2.6 g, 12.1 mmol) and potassium cyanide (1.7 g, 25.4 mmol) in DMF (33 mL) is stirred for 14 h at room temperature then warmed to 50° C. for 0.5 h. After cooling, the mixture is poured into a mixture of CHCl3 and saturated aq NaCl and extracted with CHCl3. The combined extracts are washed with saturated aq NaCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography (silica gel, 10-50% ethyl acetate in heptane) to give (5-cyanomethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (1.1 g, 43.4%): 1H NMR (CDCl3, 300 MHz) δ 6.83 (s, 1 H), 3.80 (s, 2 H), 3.70 (s, 3 H), 3.50 (s, 2 H), 2.38 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20](OCC)=[O:21])[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2.Cl.[NH2:26][OH:27].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20]([NH:26][OH:27])=[O:21])[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2
Reactant: NO
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2cc3c(=O)[nH]c(C(=O)NO)nc3nc2cc1OC
Temperature: 95 °C
Yield: 74 %

Procedure:
Ethyl 7,8-dimethoxypyrimido-[4,5-b]quinolin-4(3H)-one-2-carboxylate (200 mg., 6.08 millimoles) is added to a solution of hydroxylamine hydrochloride (69 mg., 100 millimoles) and triethylamine (100 mg., 100 millimiles) in absolute ethanol (50 ml.). The mixture is heated at 95° C. overnight in a bomb and then cooled. The insoluble yellow solid is filtered off, washed with hot ethanol and dried to provide 143 mg. (74%) of the title product. M.P. 337° C. (dec.).
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][N:22]1[C:26](=[O:27])[CH2:25][NH:24][C:23]1=[O:28])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][N:22]1[C:26](=[O:27])[CH2:25][NH:24][C:23]1=[O:28])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:7])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.7 %

Procedure:
A solution of 0.783 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in 20 ml of dichloromethane was treated with 10 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 4 hours and evaporated. Traces of trifluoroacetic acid were removed by the three-fold addition and evaporation of toluene to give 0.805 g of (E)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([OH:29])(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23]>CN1CCCC1=O.C(OCC)(=O)C>[C:20]([OH:29])(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Nn1cc(Cl)c2ccccc21
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C(O)c1ccccc1O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1cn(Nc2ccncc2)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of crude 3-chloro-1H-indol-1-amine (65.5 g) and 4-chloropyridine hydrochloride (45 g) in 1-methyl-2-pyrrolidinone (250 ml) was stirred at 60° C. for eight hours. The cooled reaction mixture was quenched into 5% aqueous sodium hydroxide, extracted into toluene, dried and concentrated to give an oil. A portion of this oil was dissolved in ethyl acetate. Salicylic acid (1.2 eq) was added to precipitate the salt. The solid was collected at room temperature and dried. This solid was recrystallized with a charcoal treatment from methanol and oven dried (75° C., house vacuum) overnight to yield 10.9 g of the title compound as a solid, m.p. 185°-186° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([OH:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@@H:24]([OH:26])[CH3:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Product: C[C@H](O)Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Cl.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([S:3][CH2:2][N:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]2=[O:20])=[CH:5][CH:6]=1
Reactant: OCc1ccc(SCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1CSc1ccc(CO)cc1

Procedure:
4-(Chloromethylthio) benzyl alcohol (see Preparation 17) (5 mmol) in CH2Cl2 (2 ml) was added dropwise with stirring to a solution prepared from 5-chloropyrimidin-2-one hydrochloride (4 mmol) and triethylamine (8 mmol) in CH2Cl2 (20 ml). The resultant mixture was heated under reflux for 24 hours. The solvent was then distilled off, the residue triturated with water, dried (MgSO4), triturated with ether and the residual material recrystallized from ethanol/Pet. ether. Yield 0.17 g (15%). 1H NMR (DMSO-d6, δ) 4.50 (CH2O), 5.22 (CH2S), 7.22 (Ph), 8.03 or 8.50 (H-4, H-6, J3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]=[C:11]=[S:12].[CH3:13][CH:14]([NH2:17])[CH2:15][CH3:16].Cl[CH2:19][C:20](O)=[O:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]=[C:11]1[N:17]([CH:14]([CH2:15][CH3:16])[CH3:13])[C:20](=[O:21])[CH2:19][S:12]1
Reactant: S=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCC(C)N
Reactant: O=C(O)CCl
Product: CCC(C)N1C(=O)CSC1=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
2,4,6-Trichlorophenyl isothiocyanate was reacted with 2-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2,4,6-trichlorophenylimino)-3-(2-butyl)-1,3-thiazolidin-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]([CH3:9])[C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[N:18](C(OC(C)(C)C)=O)[C:17](=[O:26])[O:16][C:15]([CH3:28])([CH3:27])[C:14]=2[CH:29]=1.[O-]CC.[Na+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]([CH3:9])[C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[NH:18][C:17](=[O:26])[O:16][C:15]([CH3:27])([CH3:28])[C:14]=2[CH:29]=1
Reactant: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 80 °C
Yield: 54.2 %

Procedure:
A solution of tert-butyl 6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate (1 eq, 0.4 g, 0.87 mmol) in THF was added to a solution of sodium ethoxide (3 eq, 0.18 g, 2.6 mmol) in ethanol (10 mL). The solution was heated at 80° C. for 1 hour, then cooled to room temperature, and concentrated in vacuo. The residue was dissolved in THF (10 mL) and 4N HCl (10 mL) was added. After heating to 60° C. for 16 hours the solution was cooled, poured into water and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, 4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.17 g, 54%) was obtained by crystallization from 20% ethyl acetate/hexane. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 3.62 (s, 3H), 7.02 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.35 (dd, 1H, J=1.3, 8.2 Hz), 7.40 (s, 1H), 10.47 (s, 1H). MS (ESI (−)) m/z 358/360 (M−H)−. Anal. calcd for C16H14N3O2Br, C, 53.4, H, 3.92, N, 11.7. Found, C, 52.6, H, 3.82, N, 11.2.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>ClC(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCOc1ccncc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCCOc1ccncc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 122.1 %

Procedure:
Thionyl chloride (2.2 ml, 30 mmol) was added slowly to a solution of 4-(3-hydroxypropoxy)pyridine (3.1 g, 20 mmol) in trichloromethane (40 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give 4-(3-chloropropoxy)pyridine hydrochloride (3.81 g, 91%) as a solid. 1H NMR Spectrum: (DMSOd6) 2.22(m, 2H); 3.80(t, 2H); 4.42(t, 2H); 7.55(d, 2H); 8.72(d, 2H) MS-ESI: 172 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine (80 mg, 0.31 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (51 mg, 0.33 mmol) and DIPEA (0.16 mL, 0.93 mmol) in IPA (0.7 mL) was heated in a sealed tube for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to give a pale yellow oil. The residue was taken up in EtOAc and product triturated with cyclohexane. The solid was filtered to afford 348 as an off white solid (31 mg, 26%). LCMS (Method K): RT 3.04 min [M+H]+ 3.75. 1H NMR (DMSO-d6, 400 MHz): δ 8.73 (1H, d, J=2.5 Hz), 8.64 (1H, dd, J=5.0, 1.5 Hz), 8.01-7.98, (1H, m), 7.81 (1H, s), 7.76-7.73 (2H, m), 7.55 (1H, ddd, J=8.0, 5.0, 1.0 Hz), 7.18 (2H, bs), 7.12 (1H, ddd, J=10.0, 9.0, 2.5 Hz), 6.93 (1H, dd, J=7.0, 2.5 Hz), 7.48 (1H, dq, 7.0, 7.0 Hz), 1.55 (3H, d, J=7.0 Hz)
Reaction SMILES: [C:1]([C:3]1([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1(C#N)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide (140 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 4 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc to afford 92 mg (86%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide as a light yellow powder. MS (M+Na)+=454; mp=300-315° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.96 (br. s., 1H), 9.11 (s, 1H), 8.51-8.56 (m, 1H), 8.50 (s, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.67 (dd, J=9.8, 1.9 Hz, 1H), 7.15 (td, J=9.1, 2.3 Hz, 1H), 4.34-4.50 (m, 1H), 4.14 (s, 3H), 1.92-2.14 (m, 3H), 1.63-1.90 (m, 5H), 1.46 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:21])[CH2:19][O:20][CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44][O:39]4)[CH2:16][CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1=COCCC1
Reactant: O=C(CO)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C(COC1CCCCO1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (730 mg) was reacted with 17 mg para-toluenesulfonic acid and 245 μL of 3,4-dihydro-2H-pyran in ethyl acetate overnight to yield 1-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-phenyl acetic acid (10.0 g, 65.72 mmol) in DMF (70 mL) at rt were added Cs2CO3 (47.11 g, 144.5 mmol) and benzyl bromide (17.29 mL, 144.5 mmol). The reaction mixture was stirred overnight at room temperature, heated at 100° C. for 1 h and cooled to rt. The solvent was removed under reduced pressure and poured into H2O. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallization in hexanes to afford (4-benzyloxy-phenyl)acetic acid benzyl ester as a yellow solid. (20.5 g, 94%): 1H NMR (300 MHz, CDCl3): δ 7.25-7.34 (m, 10H), 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 5.50 (s, 2H), 5.12 (s, 2H), 3.61 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([OH:10])[N:4]=1.N([O-])=O.[Na+].C(O)=O.[CH:18]([NH2:20])=O>[Pd]>[NH:4]1[C:5](=[O:10])[C:6]2[NH:20][CH:18]=[N:9][C:7]=2[N:8]=[C:3]1[NH2:2]
Reactant: Nc1cc(O)nc(N)n1
Reactant: NC=O
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
29.0 g (0.2 mol) 2,4-diamino-6-hydroxypyrimidine hydrate was nitrosed with 13.8 g (0.2 mol) sodium nitrite and 10.8 g (0.2 mol) 85% formic acid in 150 ml formamide and the pink-coloured suspension obtained was admixed with a further 42.4 g (0.8 mol) 85% formic acid. After stirring in 1.0 g of a palladium catalyst on active carbon according to example 1, it was heated for 3 hours to 120° C. In this process the suspension became colorless and was subsequently heated for 3 hours to 180° C. while removing a small amount of water by distillation. After cooling to 80° C., 100 ml water was added and the solid was suction filtered. The filter cake was washed twice with 50 ml water and dissolved in 320 ml of a 5% sodium hydroxide solution. The insoluble noble metal catalyst was removed by filtration and the filtrate was stirred for 30 minutes at 50° C. with 3 g active carbon. After separating the active carbon, guanine was precipitated by addition of 20% sulphuric acid to pH 9.0, suction filtered, washed twice with 50 ml water and dried in a vacuum at 80° C. 26.7 g (0.174 mol, 87% of theory) 98.4% pure guanine was obtained in this manner.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[Cl-:1].[CH3:18][N+:19]1[CH:23]=[CH:22][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:20]=1
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: Cn1ccnc1
Product: CCCCCCCCCCCCCCCCn1cc[n+](C)c1
Product: [Cl-]
Reaction time: 4 h

Procedure:
The procedure of Example 1 was repeated with minor changes. 868 g of 1-chlorohexadecane and 570 g of 1-methylimidazole were added into a 2000 ml three-neck round-bottom flask. The reaction temperature was set from 95 to 100° C. After four hours the milk-like solution transferred into homogenous solution. The reaction was continued for three days. Then, the product was washed with ethyl acetate five times and toluene three times. After that, it was dried under vacuum for three days.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromo-3-methoxyphenol (21 g), benzyl bromide (13.5 ml), potassium carbonate (21.4 g) and acetone (200 ml) was stirred at room temperature for 24 h. The insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 20:1) to give 4-benzyloxy-2-methoxybromobenzene (25 g) as an oil.