Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].Cl[CH2:32][P:33](=[O:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:32][P:33]([CH3:35])([CH3:34])=[O:36])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cnn(C3CCN(CP(C)(C)=O)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Yield: 42.7 %

Procedure:
A mixture of 3-(1-(2,6-dichloro-3-fluoro-phenyl)ethoxy)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-amine (6 mg, 0.013 mmol), chloromethyl-dimethyl-phosphine oxide (100 mg, 0.79 mmol), and potassium carbonate (0.2 g) in DMF (5 mL) was heated to 80° C. overnight. The solid was removed and the residue was purified by HPLC (water/methanol, 10˜100%) to give the title compound as an off-white solid (3 mg, 40%); ESMS: m/z 540 (M+H)+.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(O[Cl:18])(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([Cl:18])[CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)(C)OCl
Reactant: CCC(C)Oc1ccc(O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)Oc1ccc(O)c(Cl)c1
Yield: 88.1 %

Procedure:
To a solution of 5.0 g of 4-sec-butoxyphenol in 50 ml of carbon tetrachloride, there was added dropwise 3.27 g of t-butylhypochlorite with vigorously stirring and ice-cooling. After completion of the addition, the reaction mixture was stirred at room temperature for 5 hours and concentrated, followed by addition of 200 ml of ethyl acetate. The obtained solution was washed with an agueous solution of 5% wt. sodium dicarbonate, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.32 g of 4-sec-butoxy-2-chlorophenol. Yield. 88%. nD23.5 1.5312.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[O:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([C:22]3[O:21][N:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=4)[N:23]=3)[CH2:25]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1cccc(-c2noc(C3CCCNC3)n2)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCCC(c2nc(-c3cccc(F)c3)no2)C1
Yield: 50 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 4-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (already prepared before in the Example 9). Yield: 50% (yellow oil); Mp=86-89° C. (beige powder); Rf=0.28 (DCM/MeOH:98/2); LCMS (Tr): 4.88 min (Method C); MS (ES+) gave m/z: 370.3; 1H-NMR (CDCl3), δ (ppm): 8.05-7.90 (m, 2H), 7.30-7.23 (m, 2H), 7.25-7.15 (m, 3H), 7.00 (m, 1H), 3.65-3.32 (m, 4H), 2.53 (m, H), 1.86-1.45 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([S:22][CH3:23])[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9]2.[OH-].[Na+].Cl>C(O)C.O>[C:16]([C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH:4]([S:22][CH3:23])[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=2)#[CH:17]
Reactant: COC(=O)C(Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of Methylsulfanyl-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetic acid methyl ester (5 g) in ethanol (50 ml), a 2 M solution of sodium hydroxide in water (9.74 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-could water (200 ml) and acidified with a 2 M solution of hydrochloric acid in water (9.74 ml). The precipitate was filtered off and washed with water to give (3-Ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid as yellowish solid (3.53 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(N(CC)CC)C>CS(C)=O>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:12]([C:11]([O:15][CH3:16])=[O:14])[S:13][C:2]=2[CH:9]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(F)cc2s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give 6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([F:16])[CH2:12][CH2:11]1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([C:27]1[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12][CH:13]([F:16])[CH2:14][CH2:15]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:17][C:18](=[O:20])[CH3:19])=[CH:3][C:2]=2[N:1]=1)([CH3:26])([CH3:23])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)CC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Amino-4-{[(4-fluorocyclohexyl)methyl]amino}phenyl)acetamide (300 mg, 1.07 mmol) and DMAP (25 mg, 0.214 mmol) were dissolved in DCM (10 mL). Trimethylacetyl chloride (0.145 mL, 1.18 mmol) was added dropwise and the solution was stirred at rt for 1 h. The solution washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The residue was dissolved in 5 mL of AcOH and was heated at 150° C. for 2.5 h using a Personal Chemistry microwave apparatus. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using acetone/hexane (2:1) as eluent. Yield: 196 mg (53%). 1H NMR (400 MHz, CDCl3) δ 1.14-1.25 (m, 2 H), 1.37-1.45 (m, 1 H), 1.43-1.51 (m, 1 H), 1.54-1.57 (m, 9 H), 1.70-1.78 (m, 2 H), 1.70-1.77 (m, 1 H), 2.02-2.08 (m, 1 H), 2.10-2.17 (m, 1 H), 2.19-2.21 (m, 3 H), 4.12-4.19 (m, 2 H), 4.53-4.90 (m, 1 H), 7.21-7.29 (m, 1 H), 7.30 (s, 1 H), 7.50-7.57 (m, 1 H), 7.64-7.67 (m, 1 H).
Reaction SMILES: N#N.Cl[C:4]1[N:5]=[N+:6]([O-:20])[C:7]2[CH:16]=[C:15]3[C:11]([CH2:12][CH:13]([N:17]([CH3:19])[CH3:18])[CH2:14]3)=[CH:10][C:8]=2[N:9]=1.[Sn](CC)(CC)(CC)[CH2:22][CH3:23]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:17]([CH3:19])[CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:7]3[N+:6]([O-:20])=[N:5][C:4]([CH2:22][CH3:23])=[N:9][C:8]=3[CH:10]=2)[CH2:14]1
Reactant: CN(C)C1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Reactant: CC[Sn](CC)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Temperature: 85 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
Pd(PPh3)4 (240 mg, 0.21 mmol) was added to a N2-purged, stirred solution of chloride 112 (550 mg, 1.9 mmol) and SnEt4 (800 mg, 3.4 mmol) in DME (55 mL), and the mixture stirred at 85° C. under N2 for 16 h. The mixture was cooled, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 115 (250 mg, 47%) as an unstable brown solid: 1H NMR δ 8.23 (s, 1H, H-9), 7.73 (s, 1H, H-5), 3.04-3.33 (m, 5H, H-6, H-7, H-8) 3.02 (q, J=7.6 Hz, 2H, CH2), 2.35 [s, 6H, N(CH3)2], 1.43 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.2, 152.2, 147.6, 146.3, 132.4, 122.9, 114.6, 67.6, 43.8 (2), 38.0, 37.6, 30.6, 12.3; HRMS calcd for C14H18N4O (M+) m/z 258.1481, found 258.1473.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[CH:40][N:39]([CH3:42])[C:38](=[O:43])[CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[CH:41]=[CH:40][N:39]([CH3:42])[C:38](=[O:43])[CH:37]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 50.9 %

Procedure:
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) and 4-bromo-1-methylpyridin-2(1H)-one (30 mg, 0.16 mmol), Pd(Ph3P)2Cl2 (10 mg), and aq. Cs2CO3 solution (4 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. When the reaction was over, the mixture was washed with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, 51%). 1H NMR (CDCl3): δ=1.35 (m, 1H), 1.47 (d, 3H), 1.63 (m, 2H), 1.94 (m, 2H), 2.18 (m, 1H), 2.39 (m, 2H), 2.86 (m, 1H), 3.51 (m, 5H), 5.63 (m, 1H), 6.31 (m, 1H), 6.70 (m, 1H), 6.91 (m, 2H), 7.20-7.32 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:20][C:19](=[O:21])[CH:18]([C:11]1[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:22]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-benzyloxy4-nitrophenyl)propionic acid(1.89 g), methanol(30 mL) and concentrated sulphuric acid(1 mL) was heated at reflux for 3 h, cooled to ambient temperature and the mixture was extracted with ether. The extract washed with brine, dried and evaporated to dryness to give methyl-2-(3-benzyloxy-4-nitrophenyl)propionate(1.8 g). [m/e316(MH+)].
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C@H]1N(C)CCN(C2CCCC[C@@]2(C(C2C=CC=C(OC(F)(F)F)C=2)C)O)C1)C.Cl.Cl.[CH2:34]([CH:36]1[NH:41][CH2:40][CH2:39][N:38]([CH2:42][C@@H:43]([C:55]2([OH:61])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:54])([F:53])[F:52])[CH:45]=2)[CH2:37]1)[CH3:35]>>[ClH:1].[ClH:1].[CH2:34]([C@H:36]1[N:41]([CH3:3])[CH2:40][CH2:39][N:38]([CH2:42][C@@H:43]([C:55]2([OH:61])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:53])([F:54])[F:52])[CH:45]=2)[CH2:37]1)[CH3:35]
Reactant: CCC1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CCN1
Reactant: CC[C@@H]1CN(C2CCCC[C@]2(O)C(C)c2cccc(OC(F)(F)F)c2)CCN1C
Agent: Cl
Product: CC[C@@H]1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CCN1C

Procedure:
In an analogous manner to Example 24, 1-{(1S)-2-[(3R)-3-ethyl-4-methylpiperazin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethylcyclohexanol dihydrochloride was prepared from 1-{(1S)-2-(3-ethylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (See Example 350). HRMS: calcd for C22H33F3N2O2+H+, 415.25669; found (ESI, [M+H]+), 415.2563.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([CH2:30][CH:31]=[CH2:32])=[CH:20][C:21]4[N:26]([CH3:27])[C:25](=[O:28])[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][Si](C=[N+]=[N-])(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]1([CH2:30][C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:29][C:22]3[O:23][CH2:24][C:25](=[O:28])[N:26]([CH3:27])[C:21]=3[CH:20]=2)[CH2:34][CH2:32]1
Reactant: C=CCc1cc2c(nc1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc1)OCC(=O)N2C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(CC3CC3)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 50 ml 3 necks round-bottomed flask was tert-butyl(1-(4-(7-allyl-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (52 mg, 0.116 mmol), palladium acetate (32 mg, 0.180 mmol) in diethyl ether (5 ml) to give a yellow solution at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0° C. and trimethylsilyldiazomethane (2 ml) was added via a plastic syringe. The reaction mixture was left stirring at 0° C. for 10 minutes and warmed up to room temperature overnight.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of ethyl bromodifluoroacetate (1.1 equiv.) and 2-bromopyridine (1 equiv.) in DMSO was added copper bronze (2.2 equiv.) and the mixture was heated to 50° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. A solution of potassium dihydrogen phosphate was added and the mixture stirred for 30 minutes before filtering. The copper salts were washed with ethyl acetate and the organic layer was washed with water. Solvent evaporation and purification by flash column chromatography on silica gel (diethyl ether-hexane) gave the title compound as a colorless oil in 82% yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:21][N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2Cl)[CH2:11][CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:32]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]([O:21][N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[NH2:32])[CH2:11][CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)ncnc21)OCC
Solvent: CCO
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 9-[1-(t-butyldimethylsilyloxymethyl)-3-(diethoxyphosphoryl)propoxy]-6-chloropurine (0.30 g) in ethanol (10 ml) saturated with ammonia gas was heated in a sealed vessel at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature overnight, the ethanol evaporated under reduced pressure and the residue chromatographed on silica gel using dichloro-methane-methanol (98:2) as eluant. Starting material (0.06 g) was recovered and the eluant was changed to dichloromethane-methanol (95:5) to afford the title compound (0.10 g, 43%) as an oil. 1H NMR: δH ((CD3)2)2SO) 0.00, 0.61 (6H, 2 x s, SiMe2). 0.81 (9H, s, SiBut), 1.20 (6H, t, J=7Hz, (OCH2CH3)2), 1.7-2.2 (4H, m, --CH2CH2P), 3.82 (2H, d, J=4.1 H, CH2OSi), 4.0 (4H, m, (OCH2CH3)2), 4.44 (1H, m, OCHCH2), 7.35 (2H, s, D2O exchangeable, N2), 8.3 (1H, s), 8.27 (1H, s). Found: C, 47.82; H, 7.61; N, 14.41%. C19H36N5O5SiP requires: C, 48.16; H, 7.66; N, 14.79%. m/z: C19H36N5O5SiP requires: 473.2221. Observed: 473.2219.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].O[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:23][CH:22]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1)OCC
Temperature: 25 °C
Yield: 65.3 %

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) (0.71 g; 2.97 mmole) dissolved in dichloromethane (5 ml) was added to a mixture of N-[4-(2-hydroxyethyl)phenyl]isobutyramide (0.5 g; 2.47 mmole), azodicarbonyl dipiperidine (0.75 g; 2.97 mmole) and triphenylphosphine (0.78 g; 2.97 mmole) in dichloromethane (15 ml). After stirring at room temperature over night the reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using heptane:ethyl acetate (gradient 3:1 to 1:1) as eluant to give 0.69 g (yield 65%) of 2-ethoxy-3-{4-[2-(4-isobutyrylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH:7]1([O:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([CH2:21][OH:22])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[K+].C([OH:28])(C)C>O>[CH:7]1([O:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([C:21]([OH:28])=[O:22])[CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)O
Reactant: COc1cnc(CO)cc1OC1CCCC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cnc(C(=O)O)cc1OC1CCCC1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Solid potassium permanganate (5.87 g) is added portionwise during 30 minutes to a suspension of 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (4.0 g) in water (100 mL) at 50±5° C. When the addition is complete the mixture is heated at 70±5° C. for 45 min and then cooled to room temperature. A solution of potassium hydroxide (1.95 g) in water (50 mL) is added followed by sufficient isopropanol to react with excess potassium permanganate. After stirring for 10 minutes the mixture is filtered through diatomaceous earth and the filtrate concentrated to ˜70 mL. The solution is acidified to pH 2 with concentrated aqueous hydrochloric acid and extracted with chloroform. After drying (MgSO4) the extracts are evaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.5 g) as a white solid, m.p. 184-5° C. [1Hnmr in D6-DMSO shifts relative to Me4Si: 1.55-1.79, 6H, m; 1.95, 2H, m; 3.92, 3H, s; 5.00, 1H, m; 7.59, 1H, s; 8.24, 1H, s.].
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:37][CH2:36][C:29]2([C:33](=[O:34])[NH:32][C:31](=[O:35])[CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][C:29]2([C:33](=[O:34])[N:32]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[C:31](=[O:35])[CH2:30]2)[CH2:36][CH2:37]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NC2=O
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.0 g, 3.25 mmol) and 1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.82 g, 3.42 mmol) are dissolved in DMF (15 ml) and potassium carbonate (0.58 g, 4.23 mmol) is added to the solution. The reaction mixture is stirred at room temperature for 15 h and quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. Chromatography on silica gel (eluent; n-hexane:ethyl acetate=2:1) gives 1.56 g of desired 2-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester in 97% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[N:28][CH:29]=1)#[N:23]>>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:12][N:11]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH2:35][CH2:34]2)=[O:37])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an orange oil. MS m/e: 524.3 [M]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10](O)[C:5]=2[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3]1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(N2CCCC2)c2c(O)c(-c3ccccc3)nnc21
Product: Cn1nc(N2CCCC2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 60 °C

Procedure:
A suspension of 1-methyl-5-phenyl-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c]pyridazin-4-ol (117 mg) in POCl3 (1.9 mL) was heated to 60° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The layers were separated and the aqueous was extracted with CH2Cl2, the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to give the title compound (81 mg).