Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1c(=O)sc2cnc(N)nc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 88 (0.22 g, 0.44 mmol) in THF (5 mL) in a plastic vial was added HF/pyridine (0.70 mL). The reaction was stirred for 2 h, concentrated and purified by flash column chromatography (silica, MeOH/CHCl3: gradient=5-10%) to afford 0.17 g (100%) of the title compound as a white solid: mp 109-111° C.; 1H (400 MHz, d6-DMSO) δ 8.37 (s, 1H), 6.91 (s, 2H), 6.00 (m, 2H), 5.48 (t, J=6.0 Hz, 1H), 4.91 (t, J=6.0 Hz, 1H), 4.04 (dd, J=10.4, 6.0 Hz, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H); MS (+)-ES [M+H]+ m/z 385.3. Elemental Analysis calc'd for C14H16N4O7S.0.5 CH3OH.0.2 CHCl3: C, 41.61; H, 4.32; N, 13.21; S 7.56. Found: C, 41.73; H, 4.29; N, 12.86; S, 7.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6]Cl.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6][S:14][C:13](=[NH:12])[NH2:15]
Reactant: NC(N)=S
Reactant: ClCCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: N=C(N)SCCc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenethyl chloride (0.8 g., 0.004 mol.) and thiourea (0.26 g., 0.0035 mol.) in 25 ml. of ethanol were refluxed for two days. The mixture was concentrated and the residue treated with ether to give a solid which was recrystallized from acetone to yield carbamimidothioic acid 3,4-dichlorophenethyl ester, m.p. 135°-139° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)=[O:4].[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:23][C:7]1[N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:8]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
N,5-Dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.079 g, 0.25 mmol) was dissolved in DMF (1.5 ml) in a vial. N-Bromosuccinimide (0.066 g, 0.38 mmol) was added. The vial was sealed and heated with stirring to 50° C. for 90 minutes. The crude mixture was added dropwise to water (20 ml) under magnetic stirring. The precipitate was isolated by filtration to give 0.078 g (80%) of 6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C@@H:9]1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C@@H:9]1[CH2:23][F:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)N(Cc2ccccc2)CC12CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CF)N(Cc2ccccc2)CC12CC2
Reaction time: 20 h
Yield: 90 %

Procedure:
A dichloromethane (8 ml) solution of the compound (360 mg, 1.08 mmol) obtained in Step 6 above was cooled to −78° C. Subsequently, bis(2-methoxyethyl)aminosulfur trifluoride (0.26 ml, 1.41 mmol) was added dropwise and the resulting mixture was gradually heated and stirred for 20 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography [ethyl acetate:n-hexane=1:10 (v/v)] to give the title compound (325 mg, 90%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][O:23][CH2:24][CH2:25]I>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([N:13]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: ICCOCCI
Reactant: COc1ccc(N)c2oc(N)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2oc(N)nc12
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To a stirred solution of 800 mg (4.47 mmol) 4-methoxy-benzooxazole-2,7-diamine in 40 ml DMF at room temperature were added 2.47 g (17.9 mmol) potassium carbonate and 2.18 g (6.70 mmol) 1-iodo-2-(2-iodo-ethoxy)-ethane and the mixture heated at 60° C. for 48 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane, then 10/90 methanol/dichloromethane) afforded 585 mg (53%) 4-methoxy-7-morpholin-4-yl-benzooxazol-2-ylamine as a light brown solid. ES-MS m/e (%): 250 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([CH2:11][N:12]4[C:20](=[O:21])[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]4=[O:22])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][C:4]12[CH2:10][CH:8]3[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38]#[N:39])=[O:32])([CH2:3]1)[CH:6]([CH2:7]3)[CH2:5]2
Reactant: NC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.4 g, 0.98 mmol) and K2CO3 (0.54 g, 3.92 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.18 g) in 43% yield. m/z (M+1) 433; 1H NMR (CDCl3) 300 MHz δ 7.90-7.80 (m, 2H), 7.75-7.65 (m, 2-H), 4.86-4.72 (m, 1H), 3.72-3.38 (m, 2H), 3.60 (s, 2H), 3.40 (s, 2H), 2.40-2.05 (m, 7H), 1.90-1.78 (m, 2H), 1.70-1.40 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:24]([F:26])[F:25])=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH2:13][CH2:14]2)[C:5]([NH2:21])=[CH:4][C:3]=1[CH:24]([F:26])[F:25]
Reactant: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A stirred suspension of N-[5-chloro-4-(difluoromethyl)-2-nitrophenyl]-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D97, 330 mg, 0.84 mmol) in ethanol (20 ml) at room temperature under argon was treated with Raney Nickel (20 mg) followed by dropwise addition of hydrazine hydrate (0.25 ml, 8.0 mmol). The mixture was maintained at room temperature for 30 minutes, then heated at 45° C. for 1 hr. The mixture was filtered through a pad of Kieselguhr and the filtrate concentrated under vacuum to leave the title compound as a yellow solid (180 mg of ˜88% purity, 59% yield).
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]([CH3:21])[NH:18][N:17]=3)[CH2:15][C@@:9]1([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:10]([O:22][C@H:23]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=1)[CH2:24][O:25][CH3:26])[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd].C(O)(=O)C>[F:35][C:33]([F:34])([F:36])[C:31]1[CH:32]=[C:27]([C@@H:23]([O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:15][C@H:14]3[C:16]2[NH:20][N:19]([CH3:21])[NH:18][N:17]=2)[CH2:24][O:25][CH3:26])[CH:28]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:30]=1
Reactant: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C3=NNN(C)N3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC[C@H](O[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2C1=NNN(C)N1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-methoxyethoxy}-6-(2-methyl-1H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 200; 0.03 g, 0.05 mmol), palladium, 5% on carbon (20 mg) and acetic acid (0.5 ml) were placed on the Parr™ apparatus for 2 hours. The mixture was filtered using a Whatman™ 0.2·m filter and concentrated in vacuo. The residue was taken into dichloromethane and washed with NaHCO3 and the phases separated using a bond elute cartridge. The organics were concentrated in vacuo and the title compound isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]([OH:12])[CH:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:14]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc3c(N)ncnn23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(C(O)c2ccc3c(N)ncnn23)C1
Temperature: 78 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl 3-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]azetidine-1-carboxylate (1.35 g, 4.25 mmol) in EtOH (25 mL) was added sodium borohydride (644 mg, 17.01 mmol). The mixture was stirred at 78° C. for 2 h. The reaction was quenched with the addition of H2O (20 mL). The resulting solid was removed by filtration and the filtrate was extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated to dryness to afford 1.0 g (74%) of the desired product. ES-MS m/z 320.16 [M+H]+, HPLC RT (min) 2.02.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[O:17]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:22][CH:19]2[CH2:20][CH2:21][O:17][CH2:18]2)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:15])([F:14])[F:16]
Reactant: O=CC1CCOC1
Reactant: NCCc1ccc(F)c(OCC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(CCNCC2CCOC2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A mixture of 500 mg (2.1 mmol) of 2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethylamine, 210 mg (2.1 mmol) of tetrahydrofuran-3-carbaldehyde and 2 g of 4 Å molecular sieves in 30 ml of dry dichloromethane was stirred at room temperature for 30 minutes. 630 mg (2.9 mmol) of NaBH(OAc)3 were added portionwise. The reaction mixture was stirred for 4 hours at room temperature. An aqueous 5% solution of NaHCO3 was added and the product was extracted with dichloromethane. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3 100:9:0.5 v:v:v). 300 mg (44% yield) of the title compound were isolated as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=2)[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[O:11])=[C:4]([N+:25]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:25][C:4]1[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)=[O:11]
Reactant: O=C(Nc1cccc(O)c1)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Nc1cc(Cl)ccc1Oc1cccc(C(=O)Nc2cccc(O)c2)c1
Yield: 77 %

Procedure:
The product from Example 174b (1.0 g, 2.6 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.71 g, 84%).
Reaction SMILES: C(O[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:48])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:25][C:24]=3[F:47])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=O.C([Si]([O:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([O:73][CH2:74][CH:75]2[CH2:77][O:76]2)[CH:68]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:47][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:77][C@H:75]([OH:76])[CH2:74][O:73][C:69]3[CH:70]=[CH:71][CH:72]=[C:67]([OH:66])[CH:68]=3)=[CH:12][CH:11]=2)[CH2:19][CH2:18]1)=[O:48]
Reactant: CC(C)(C)[Si](Oc1cccc(OCC2CO2)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNOC=O)cc3)CC2)c(F)c1)(c1ccccc1)c1ccccc1
Product: O=C(NCc1ccc(O)cc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(O)c3)cc2)CC1
Yield: 18.9 %

Procedure:
[2-(4-{1-[4-(tert-Butyl-dipheny-silanyloxy)-2-fluoro-benzylcarbamoyl]-piperidin-4-ylamino}-phenyl)-ethyl]-amino formate (1.05 g, 1.59 mmol) was reacted with tert-butyl-(3-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.642 g, 1.59 mmol) according to Procedure G to give the title compound (0.290 g, 0.3 mmol).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][N+:14]([O-])=C(C)[CH:12]=1)[CH3:9]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:12]=[C:11]([O:10][CH2:8][CH3:9])[C:16]([CH3:17])=[CH:15][N:14]=1)(=[O:7])[CH3:6]
Reactant: CCOc1cc(C)[n+]([O-])cc1C
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOc1cc(COC(C)=O)ncc1C

Procedure:
20 ml of acetic anhydride were added dropwise at room temperature to a solution of 7.8 g of 4-ethoxy-2,5-dimethylpyridine 1-oxide in 30 ml of chloroform. After boiling under reflux for 3 hours the solution was evaporated, the residue was dissolved in 50 ml of toluene and again evaporated. The residue was taken up in 50 ml of ethyl acetate, whereupon the solution was extracted three times with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 50 g of silica gel with ether and there was obtained (4-ethoxy-5-methyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.[Si:16]([O:23][CH2:24][C@:25]1([CH3:34])[S:31][CH2:30][CH2:29][N:28]=[C:27](SC)[CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:28]4[CH2:29][CH2:30][S:31][C@:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:34])[CH2:26][C:27]4=[N:14][N:13]=3)[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1
Reactant: NNC(=O)C1(c2ccc(Br)cc2F)CC1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of the compound (2.00 g, 7.32 mmol) obtained in Example 14-4) and the compound (2.57 g, 8.06 mmol) obtained in Example 4-1) in n-butanol (40 mL) was stirred at 140° C. for 8 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.86 g, quant.) as a yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH:32]([S:35]([NH2:38])(=[O:37])=[O:36])([CH3:34])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][NH:38][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CC(C)S(N)(=O)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C(C)C)C2CC2)C1=O

Procedure:
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A, 59.3 mg, 0.129 mmol;) and isopropyl sulfonamide (48.7 mg, 0.395 mmol) were coupled by the procedure as described in Example 202, Step C to form the title compound isolated after silica gel chromatography as an off-white solid. MS (ESI) m/z=563 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]2[C:22]3[N:23]=[C:24]([CH2:30][CH2:31][CH2:32]O)[N:25]([CH2:26][O:27][CH2:28][CH3:29])[C:21]=3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:5]1([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13]2[C:22]3[N:23]=[C:24]([CH2:30][CH2:31][CH2:32][Cl:3])[N:25]([CH2:26][O:27][CH2:28][CH3:29])[C:21]=3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCOCn1c(CCCO)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCn1c(CCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Yield: 95.4 %

Procedure:
Thionyl chloride (5 mL, 68 mmole) was added to N,N-bis(phenylmethyl)-2-(3-hydroxypropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1 g, 2.1 mmole) and the reaction mixture was stirred rapidly until thin layer chromatography (silica gel, 10% ethyl acetate in methylene chloride v/v) indicated that the reaction was complete. The reaction mixture was diluted with methylene chloride then neutralized with 10% sodium hydroxide and sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10-30% ethyl acetate in hexanes v/v) to provide 1 g of N,N-bis(phenylmethyl)-2-(3-chloropropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18](=[O:19])[C:17]2([CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[O:19]=[C:18]1[C:17]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[N:16]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:15][N:14]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reaction time: 16 h
Yield: 102.7 %

Procedure:
A solution of benzyl 3-(2-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.86 g, 3.44 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (360 mg, 20%/wt) and the resulting mixture was hydrogenated at atmospheric pressure for 16 h. The reaction was filtered over Celite and the filtrate was concentrated and dried in vacuo to afford the title compound as a white foam (1.44 g, 96.4%); 1H NMR (400 MHz, DMSO-d6): δ 1.49 (s, 9H); 1.71 (d, 2H, J=13.2 Hz); 2.41-2.49 (m, 2H); 2.84-2.88 (m, 2H); 3.08-3.13 (m, 2H); 5.07 (s, 2H); 6.78 (t, 1H, J=7.2 and 7.6 Hz); 6.98 (s, 1H); 7.00 (s, 1H); 7.23-7.27 (m, 2H); 7.46-7.49 (m, 1H); 7.60 (dd, 1H, J=1.2 and 1.6 Hz); 7.65-7.69 (m, 1H); 7.77 (dd, 1H, J=1.2 and 1.6 Hz); MS for C24H29N3O3 m/z 408.22 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]2=[CH:11][C:12](=O)[CH:13]=[CH2:14].CC[O:18]CC>C[O-].[Na+].[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][C:13](=[O:18])[CH3:14]
Reactant: C=CC(=O)C=C1C(C)(C)CCC2OC12C
Reactant: CCOCC
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C=CC1=C(C)C(O)CCC1(C)C
Reaction time: 0.5 h

Procedure:
Retro-ionone (1.9 g) was added to a solution of m-chloroperbenzoic acid (2.2 g) dissolved in dichloromethane. This resulted in an exothermic reaction (~40°). After cooling, the mixture was washed with an aqueous sodium carbonate solution dried over MgSO4 and taken to dryness to yield the epoxide, the 1-(2,6,6-Trimethyl-2,3-epoxy-1-cyclohexylidene)-buten-2-one. This epoxide (~2 g) was dissolved in a solution of methanolic sodium methoxide (1.4 Molar; 20 ml) and left at RT for 1/2 hour (instant color change and probably complete reaction). Dilution with ether followed by a brine washing yielded 1-(2,6,6,-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-1-butene, upon chromatography over silica gel.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]2[N:32]=[C:31]3[NH:33][N:34]=[C:35]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([S:42][CH3:43])[N:37]=4)[C:30]3=[CH:29][N:28]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl.CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]2[N:32]=[C:31]3[NH:33][N:34]=[C:35]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([S:42]([CH3:43])=[O:9])[N:37]=4)[C:30]3=[CH:29][N:28]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
m-CPBA (339 mg, 1.98 mmol) was added slowly to a solution of 4-{[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (from Example 14 supra) (450 mg, 0.99 mmol) in a mixture of dichloromethane and methanol (80 mL, 1:1). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 15 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford 4-{[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 150 mg, 32.3%).