Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[N:16][N:17]([C:2]2[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:18]=1
Reactant: Clc1cn[nH]c1
Reactant: COC(=O)c1cnc(F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-n2cc(Cl)cn2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (800 mg, 4.73 mmol, Step-1 of Amine-36), 4-chloro-1H-pyrazole (509 mg, 4.97 mmol), and cesium carbonate (3.08 g, 9.46 mmol) in DMF (16 mL) stirred at 60° C. for 1 hour. After cooling to rt, the mixture is diluted with EtOAc (150 mL) and washed with water (100 mL×3). The organic phase is filtered through silica gel, and the filtrate is concentrated to give 1.19 g (>99% yield) of the title compound as white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[NH2:10][OH:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[NH:7]=[C:6]1[C:5]([CH3:9])([CH3:8])[CH2:4][CH2:3][CH2:2][N:10]1[OH:11]
Reactant: CC(C)(C#N)CCCCl
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCCN(O)C1=N
Temperature: 25 °C
Reaction time: 1 h
Yield: 140.6 %

Procedure:
A solution of intermediate 8, 5-chloro-2,2-dimethylpentanenitrile, (725 mg, 5.0 mmol) and 50% aqueous NH2OH (1.0 g, 15 mmol; Aldrich) in ethanol (1.5 mL) was stirred at room temperature for 5 days, and then treated with Na2CO3 (265 mg, 2.5 mmol). The mixture was stirred at room temperature for 1 h, and concentrated in vacuo to provide 1.0 g of the title compound as crude brown oily solid. 1H NMR (DMSO-d6, 500 MHz) δ ppm: 1.29 (6H, s, Me), 1.59 (2H, m, CH2), 1.85 (2H, m, CH2), 3.62 (2H, t, J=6 Hz, NCH2); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 18.23, 26.63, 33.57, 35.09, 51.85, 162.76.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[C:24]([N+]([O-])=O)[C:21]=1[C:22]#[N:23]>C(OCC)(=O)C>[Br:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[C:24]([F:1])[C:21]=1[C:22]#[N:23]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(Br)c1OC
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C#N)c(Br)c1OC
Temperature: 25 °C
Yield: 85 %

Procedure:
A partially dried solution of tetrabutylammonium flouride (24 ml, 1M in THF stored over 4A sieves) was added to 2-bromo-3,4-dimethoxy-6-nitrobenzonitrile (prepared according to step (c), 1.73 g, 6.02 mmol) with stirring at room temperature. After 1 hour ethyl acetate was added and the mixture washed with 1M aqueous HCl (50 ml). The aqueous wash was extracted with ethyl acetate (50 ml) and the combined organics then washed with aqueous NaHCO3 (50 ml) before being dried over MgSO4 and concentrated in vacuo. The crude residue was recrystallised from toluene:tert-butylmethylether (1:1) to give 1.34 g of the subtitle product (85%).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Br:29]Br>CN(C=O)C>[Br:29][CH:9]([CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:16])([F:1])[CH2:7][CH2:6]1)[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: O=C(CCC1CCC(F)(F)CC1)C(F)(F)F
Reactant: BrBr
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
4-(4,4-Difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (100 mg, 0.410 mmol) obtained in step 1 was dissolved in DMF (1.0 mL). Under ice-cooled condition, triethylamine (0.110 mL, 0.788 mmol) and chlorotrimethylsilane (0.0570 mL, 0.450 mmol) were added, and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was extracted with hexane after adding saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (1.0 mL). Under ice-cooled condition, bromine (73.0 mg, 0.456 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL) after adding a saturated sodium hydrogen carbonate aqueous solution and sodium thiosulfate aqueous solution. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (73.8 mg, yield 56%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[C:28]([F:37])[CH:27]=2)[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[N+:38]([O-])=O)C1C=CC=CC=1.[H][H].CCOC(C)=O>C1COCC1.[Pd]>[NH2:38][C:10]1[CH:11]=[CH:12][C:13]([C:15]([NH:17][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[C:28]([F:37])[CH:27]=2)[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:16])=[N:14][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1O

Procedure:
To a stirred mixture of (S)-6-(benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-nitropicolinamide (800 mg, 0.0014 mol) in THF (8 mL), was added 10% Pd/C (800 mg, Aldrich). The reaction mixture was stirred under hydrogen atmosphere in the form of hydrogen bladder (˜20-22 PSI) for 12 h at room temperature. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was filtered through Celite® brand filter agent, the filtrate dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 9.13 (d, J=6 Hz, 1H), 8.46 (d, J=4 Hz, 1H), 7.79 (t, J=9.2 Hz, 1H), 7.57-7.46 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.08 (br. s., 1H), 6.62 (d, J=7.6 Hz, 1H), 6.40 (br. s., 1H), 5.83 (br. s., 2H). MS (ESI, positive ion) m/z: 440.9 (M+H).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:7]([CH2:8][CH2:9][CH2:10][N:16]1[CH2:17][CH2:18][C:13]([OH:12])([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:15]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCOc1ccccc1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cnc3ccccc3c2)CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 0.112 gm (0.7 mMol) 3-chloropropyl phenyl ether, 0.150 gm (0.7 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, and 0.136 gm (1.5 mMol) potassium carbonate in 5 mL acetonitrile was heated to reflux for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 25:2 dichloromethane:methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.142 gm (60%) of 1-(3-phenoxyprop-1-yl)-4-hydroxy-4-(quinolin-3-yl)piperidine as a light yellow, viscous oil. The oil was converted to the oxalate salt to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:37][CH2:38][C:39]1[N:40]=[CH:41][NH:42][CH:43]=1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:37][CH2:38][C:39]2[N:40]=[CH:41][NH:42][CH:43]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCc1c[nH]cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chlorothiophene-2-carboxylic acid 1-5 (1.10 g, 6.76 mmol) and TEA (2.0 mL, 14.4 mmol) in DMF (12 mL), BOP (3.30 g, 7.45 mmol) was added. After being mixed for 5 min, the solution was added to the compound 4-aminomethylimidazole II-2 prepared above (0.604 g, 6.22 mmol) in a round bottom flask. The mixture was then stirred at room temperature overnight. It was purified by HPLC to give 5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (1.52 g). MS 242.0 and 244.0 (M+H, Cl pattern).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)C=CC=CC=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:24]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:16][CH2:15]2)=[O:23])[CH:27]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from 1-benzo[1,3]dioxol-5-ylmethyl-piperazine and pyridin-3-yl-carbamic acid phenyl ester in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.44-8.43 (m, 1H), 8.19-8.17 (m, 1H), 7.98-7.95 (m, 1H), 7.18-7.16 (m, 1H), 6.83-6.80 (m, 2H), 6.70 (s, 1H), 5.89 (s, 2H), 3.55-3.52 (m, 4H), 3.47 (s, 2H), 2.51-2.48 (m, 4H).
Reaction SMILES: [CH2:1]([C@:8]1([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C@:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[CH2:10][C@@H:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CNCC[C@@]1(O)Cc1ccccc1
Reactant: ClCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@@]1(O)Cc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 0.2 g (1.0 mmol) (3R,4R) and (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine in 10 ml DMF were added 297 mg (1.0 mmol) 1-benzyloxy-4-(2-chloro-ethoxy)-benzene and 0.2 g (1.5 mmol) K2CO3 and the reaction mixture was heated to 90° C. for 16 hours. After the addition of water, the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 551 mg (100%, ˜80% purity) (3R,4R) and (3S,4S)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH3:28]>[Zn].CCOC(C)=O>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:8][C:9]2[CH:10]=[C:11]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])=[O:38])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(N)c1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(CNC(=O)OC(C)(C)C)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirring toluene solution (100 mL) of (3-Amino-4-nitrophenyl)methyl-carbamic acid, 1,1-dimethylethyl ester (1.10 g, 4.12 mmol) were added 4-ethoxyphenylacetyl chloride (980 mg, 1.2 eq) and zinc dust (400 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution was stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 2:1/hex:EtOAc on silica gel to yield the desired product [3-[[(4-Ethoxyphenyl)acetyl]amino]-4-nitrophenyl]methyl-carbamic acid, 1,1-dimethylethyl ester (1.18 g, 67% yield); 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.11 (d, J=9.2 Hz, 1H), 7.22 (m, 3H), 6.93 (d, J=9.2 Hz, 2H), 4.40 (m, 2H), 3.75 (s, 2H), 3.33 (s, 3H), 1.50 (s, 9H), 1.42 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>CO.C(#N)C>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N#CCCCCn1cnc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CO
Solvent: CC#N
Product: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
This nitrile (3.6 g.) in MeOH (80 ml.) and acetonitrile (5 ml.) was treated with mercuric oxide (3.06 g.) and methanolic ammonia (15 ml.). After stirring for 1.5 hours the black suspension was filtered through diatomaceous earth and the filtrates evaporated to give a white solid. The solid was washed with ether and filtered to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (2.87 g.) as a white solid, m.p. 200°-201° after recrystallisation from EtOH.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C1CCc2cc(F)ccc2N1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(F)ccc32)CC1
Reaction time: 20 h
Yield: 70.2 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79) (0.090 g, 0.37 mmol), 4-butylpiperidine (0.078 g, 0.55 mmol), KI (0.091 g, 0.55 mmol), and K2CO3 (0.076 g, 0.55 mmol) in MeCN and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc) to give the title compound (92LH81) (0.090 g, 70%). 1H NMR (CD3OD) δ 7.19-7.15 (m, 1H), 6.99-6.97 (m, 2H), 3.97 (t, J=6.4 Hz, CH2), 2.90-2.87 (m, 4H), 2.59 (t, J=7.6 Hz, CH2), 2.38 (t, J=7.6 Hz, CH2); 1.96-1.78 (m, 4H), 1.67 (d, J=9.6 Hz, 2H), 1.29-1.22 (m, 9H), 0.90-0.88 (m, 3H); 13C NMR (CD3OD) δ 172.1, 160.0 (d, J=241.8 Hz), 136.7 (d, J=2.3 Hz), 130.6 (d, J=7.7 Hz), 117.8 (d, J=8.1 Hz), 115.9 (d, J=23.1 Hz), 114.6 (d, J=22.7 Hz), 57.0, 55.0, 41.6, 37.4, 36.9, 33.1, 32.4, 30.1, 26.2, 25.5, 23.9, 14.4; HPLC-MS (ammonium acetate) [M+H+]=347.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:11]=1[NH2:23].[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:23]=[C:25]([CH3:27])[C:24](=[O:28])[N:16]([C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CC[C@H](COC)Nc1ncnc(-c2ccc(OC)cc2Cl)c1N
Solvent: CCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3Cl)ncnc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.20 g, 0.60 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.68 ml, 6.0 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 5.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one (Example 571a). 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (s, 1 H), 7.41 (d, J=8.79 Hz, 1 H), 7.05 (d, J=2.56 Hz, 1 H), 6.93 (dd, J=8.79, 2.56 Hz, 1 H), 3.87 (s, 3 H), 3.73 (m, 2 H), 3.29 (s, 3 H), 2.63 (m, 2H), 2.49 (s, 3 H), 2.10 (m, 2 H), 0.87 (t, J=7.51 Hz, 3 H). MS (AP) 389.3 [(M+H)+, 100].
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])=[C:8]([CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12]CS([O-])(=O)=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([OH:31])=[O:30].C(=O)([O-])O.[Na+]>O>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([O:31][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH3:18])=[C:7]([F:6])[F:19])=[O:30]
Reactant: CC(CCCCCS(=O)(=O)[O-])=C(F)F
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1cc2ccccc2[nH]1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To 20 ml of N,N-dimethylformamide were dissolved 1.50 g (6.6 mmol) of 6,6-difluoro-5-methyl-5-hexenylmethanesulfonate and 1.30 g (8.1 mmol) of 1H-indole-2-carboxylicacid, followed by the addition of 1.40 g (17 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 1.70 g (yield: 88%) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:30])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:17]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:30][C:20]1[CH:19]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:1]=2)[CH:15]=[C:14]([CH3:13])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 145 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4,6-difluoro-benzamide (0.80 g, 4.60 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.14 g, 4.60 mmol) in N,N-dimethylacetamide (60 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.25 g, 6.9 mmol) and p-toluenesulfonic acid monohydrate (3.50 g, 18.4 mmol). The reaction mixture was stirred at 145° C. for 16 hours under nitrogen atmosphere, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (50 mL) was added, followed by saturated aqueous sodium bicarbonate solution (15 mL). The mixture was extracted with CH2Cl2 (2×100 mL) and washed with water. The organic phase was evaporated and the residue was washed with hexane/ether (90:10, 100 mL). The solid was filtered and dried under vacuum to give the title compound as a brown solid. Yield: 1.48 g (80%). MP 234-235° C. 1H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 7.90 (s, 1H), 7.32 (m, 2H), 3.91 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.55 (s, 4H), 2.31 (s, 6H), 1.70 (s, 4H).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([CH2:10][Cl:11])[N:4]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15]>>[NH2:2][C:3]1[N:4]=[C:5]([CH2:10][Cl:11])[CH:6]=[C:7]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[N:8]=1
Reactant: Nc1nc(Cl)cc(CCl)n1
Reactant: OCC(F)(F)F
Agent: [Na]
Product: Nc1nc(CCl)cc(OCC(F)(F)F)n1
Reaction time: 24 h

Procedure:
0.23 Parts of sodium metal was added to 10 parts of 2,2,2-trifluoroethanol with stirring and ice-bath cooling. The mixture was then stirred for several hours at room temperature until the sodium dissolved. This solution was added dropwise, over 30 minutes, to a stirred suspension of 1.78 parts of 2-amino-4-chloro-6-chloromethyl-pyrimidine in 25 parts of 2,2,2-trifluoro-ethanol and the resulting mixture was stirred at 60° C. for 18 hours. A further 0.1 parts of sodium was dissolved in 10 parts of 2,2,2-trifluoroethanol and added to the reaction mixture. Stirring at 60° C. was continued for a further 24 hours then the reaction mixture was cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4) and evaporated. The crude product was purified by chromatography on silica (Merck Kieselgel 60 using a 50:50 mixture of ether and 40°-60° petroleum ether as eluent followed by recrystallisation from a mixture of 60°-80° petroleum ether and ethyl acetate to give 2-amino-4-chloromethyl-6-(2,2,2-trifluoroethoxy)pyrimidine m.p. 77°-78° C.
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5](=[O:23])[CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5](=[O:23])[CH2:4]1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1CC(=O)N1CC(=O)CCCCCCCc1ccccc1
Solvent: ClCCl
Product: CS(=O)C1CC(=O)N1CC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-methylthio-1-(9-phenyl-2-oxononyl)azetidin-2-one (0.993 g, 2.98 mmol) in dry dichloromethane (90 ml) was cooled to -50° C. and mCPBA (0.95 g, 2.58 mmol) in dry dichloromethane (50 ml) was added dropwise over 30 minutes, then stirred for 90 minutes at room temperature. This was washed with dil Na2SO3, dil NaHCO3 and water (×2), dried (MgSO4)and evaporated to a solid (1.09 g). This was purified by flash chromatography on silica gel eluted with petroleum ether/ethyl acetate 1 ethanol to give 4-methylsulphinyl-1-(9-phenyl-2-oxononyl)azetidin-2-one (Example 5) as a white waxy solid (0.718 g, 69%).