Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][OH:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.CN(C)C=O.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>O>[CH3:1][C@H:2]([CH2:8][CH2:9][O:10][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C[C@H](C)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@H](C)CCO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 37 g. (0.253 m) of methyl 3-(R)-methyl-5-hydroxypentanoate and 37 g. (0.543 m) of imidazole in 500 ml. of dimethylformamide was added 37 g. (0.249 m) of t-butyldimethylsilyl chloride and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted (4×100 ml.) with ether. The combined extracts were washed with 10% hydrochloric acid, a saturated sodium bicarbonate solution, water and a brine solution, and dried over magnesium sulfate. Removal of the solvent gave 121.88 g. of crude product which, on distillation, gave 107.12 g. of pure product, b.p. 80°-81° C./0.4 torr.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:21](Cl)(=[O:23])=[O:22])([O-:11])=[O:10]>N1C=CC=CC=1>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:21]([O:8][N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])(=[O:23])=[O:22])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: [O-][n+]1ccccc1O
Solvent: c1ccncc1
Product: O=c1ccccn1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 31 %

Procedure:
2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (1.32 g, 5.0 mmol) in 40 mL of pyridine to afford PZBG-1d in 31% yield (0.48 g, 1.4 mmol). 1H NMR (500 MHz, CDCl3) δ=8.96 (d, J=2.3 Hz, 1H), 8.42 (dd, J1=9.2 Hz, J2=2.3 Hz, 1H), 7.68 (dd, J1=6.9 Hz, J2=1.7 Hz, 1H), 7.50 (dt, J1=7.5 Hz, J2=2.3 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.82 (dd, J1=9.2 Hz, J2=1.8 Hz, 1H), 6.35 (dt, J1=6.9 Hz, J2=1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ=157.0, 155.6, 140.5, 135.1, 129.6, 124.0, 122.9, 116.0, 106.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylsulfonyl)-phenylboronic acid following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[CH3:37][CH:38]([CH3:43])[CH2:39][C:40](Cl)=[O:41]>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:40](=[O:41])[CH2:39][CH:38]([CH3:43])[CH3:37])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: CC(C)CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-E1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and 3-methylbutanoyl chloride were converted to l-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6Hpyrazolo[3,4-c]pyridin-6-yl)-3-methylbutan-1-one as a white solid (37 mg, 63%): mp 184-188° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.13-13.11 (m, 0.25H), 12.87-12.84 (m, 0.75H), 7.79-7.70 (m, 1H), 7.51-7.49 (m, 1H), 4.89-4.86 (m, 1H), 4.67-4.57 (m, 3H), 3.67-3.64 (m, 2H), 3.15-3.13 (m, 2H), 2.79-2.77 (m, 1H), 2.68-2.64 (m, 2H), 2.55-2.51 (m, 1H, partially merged with DMSO peak), 2.02 (pent, J=7.0 Hz, 1H), 1.76-1.70 (m, 4H), 1.26 (t, J=7.0 Hz, 1H), 0.92-0.90 (m, 6H); ESI MS m/z 499 [M+H]+.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:13][CH:12]=4)([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:22]=[C:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:14]1[CH:15]=[CH:16][C:11]([C:4]23[CH2:10][CH:8]4[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]#[N:39])=[O:32])([CH2:3]2)[CH:6]([CH2:7]4)[CH2:5]3)=[CH:12][CH:13]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a stirred solution of 1-[4-(3-aminotricyclo[3.3.1.03,7]non-1-yl)phenyl]pyrrolidin-2-one obtained in step II (0.36 g, 1.2 mmol) in DMSO (4.8 mL) at an ice bath temperature under nitrogen atmosphere was added K2CO3 (0.48 g, 3.6 mmol) followed by addition of (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.21 g, 1.2 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 the title compound (2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.26 g) in 50% yield. M.R: 254-256° C.; m/z (M+1) 433; 1H NMR (300 MHz, CDCl3) δ: 7.54 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.30-4.20 (m, 1H), 4.06-4.18 (m, 2H), 3.87 (t, J=7.0 Hz, 1H), 3.80-3.50 (m, 4H), 2.64 (t, J=7.8 Hz, 2H), 2.58-1.60 (m, 18H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH:19]OC)=[CH:4][CH:3]=1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:18]=[CH:19][C:4]=2[CH:3]=1
Reactant: COC=Cc1ccccc1-c1ccc(Br)c2ccccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cc2ccc3ccccc3c2c2ccccc12
Yield: 15 %

Procedure:
A reaction vessel was charged with 180 g of 1-bromo-4-[2-(2-methoxyvinyl)phenyl]naphthalene and 1.0 L of dichloromethane. 25 mL of methanesulfonic acid was added to the mixture at room temperature with stirring. The mixture was stirred at room temperature for 8 hours. After completion of the reaction, 1 L of a 10% potassium carbonate aqueous solution was added to the mixture. After removing the aqueous phase, the organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The residue was purified by silica gel column chromatography to obtain 24.4 g of the target 5-bromobenzo[c]phenanthrene (yield: 15%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:16]=2)=[O:14])[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:24][C:19]1[C:18]2=[C:17]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:29]=4)[CH:16]=[C:15]([C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[O:14])[N:23]2[N:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 12 h
Yield: 77.8 %

Procedure:
The product from Step 3 (0.51 g, 0.94 mmol) was dissolved in THF (15 mL) and HCl in dioxane (4N, 2.34 mL) was added. The mixture was stirred for 12 hours and then concentrated. The residue was suspended in EtOAc, sonicated for 10 min and the white solid was filtered. The solid was partitioned between NaHCO3 saturated solution and i-PrOH/CHCl3 (1:2) mixture. The organic layer was separated and washed with brine, dried over Na2SO4 filtered and concentrated to provide 320 mg (78%) of the title compound. 1H-NMR (CD3OD-d4) 8.41-8.39 (m, 1H), 8.05 (s, 1H), 7.87 (dd, 1H), 7.71-7.69 (m, 1H), 7.70 (s, 1H), 7.37-7.29, (m, 5 H), 7.24 (dd, 1 H), 5.67 (s, 1 H), 4.39-4.31 (m, 1 H), 3.28-3.21 (m, 2 H), 3.12-2.96 (m, 2 H), 2.25-2.07 (m, 2 H); LC-MS [M+H]+=438.4, RT=2.52 min.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1

Procedure:
As described in Example 44, 8.14 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with p-trifluoromethylphenol to give 7.7 g of off-white crystals. Recrystallization from methanol gives the product as white crystals, mp 83°-84° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:39]#[N:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-:42].OO>CO>[Si:1]([O:8][C@@H:9]([C:39](=[O:42])[NH2:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)O[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
A 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]-2-cyanoethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (2.2 g, 3.75 mmol, 1.00 equiv) in 20 mL of methanol was added LiOH (315 mg), followed by addition of H2O2 (30%, 3 mL) via syringe at 0° C. with vigorous stirring. The resulting solution was stirred for 3 h at 20° C. The reaction was then quenched by the addition of 50 mL of saturated aqueous Na2SO3, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with 2×30 mL of brine, and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) to afford the desired tert-butyl N-(4-[[(3R)-3-[(2R)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (0.7 g) as a white solid. MS: m/z 605 (M+H)+, 627 (M+Na)+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[S:9][N:8]=1.[ClH:19].[CH3:20][O:21][C:22]1[C:30]2[O:29][C:28](C)(C)C[C:26]=2[C:25]([C:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH:39]=[CH:40][CH2:41]3)[C:36](=[O:43])[N:35]([C:44]3[CH:49]=[CH:48][C:47]([C:50](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:51])=[CH:46][CH:45]=3)[N:34]=2)=[CH:24][CH:23]=1>>[ClH:19].[CH3:28][O:29][C:30]1[CH:26]=[C:25]([C:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH:39]=[CH:40][CH2:41]3)[C:36](=[O:43])[N:35]([C:44]3[CH:45]=[CH:46][C:47]([C:50]([N:15]4[CH2:16][CH2:17][N:12]([C:10]5[S:9][N:8]=[C:7]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=6[CH3:18])[N:11]=5)[CH2:13][CH2:14]4)=[O:51])=[CH:48][CH:49]=3)[N:34]=2)[CH:24]=[CH:23][C:22]=1[O:21][CH3:20]
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: Cc1ccccc1-c1nsc(N2CCNCC2)n1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5nc(-c6ccccc6C)ns5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A1 and 1-(3-o-tolyl-1,2,4-thiadiazol-5-yl)-piperazine as described for compound 8. M.p. 115–118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH2:28])=[CH:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH:28][C:11]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=3)[O:10][N:9]=2)=[O:13])=[CH:18]1
Reactant: NCCc1coc2ccccc12
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1coc2ccccc12)c1cc(Cc2cccc(F)c2)on1
Yield: 8.5 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g, 0.257 mmol), 2-(benzofuran-3-yl)ethanamine (0.042 g; 0.260 mmol), HATU (0.108 g; 0.285 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (method 2) to yield 0.008 g (9%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH:22]([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C(C)C)cc1
Yield: 4.9 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.007 g).
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:47])[NH:9][C@@H:10]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:11]([OH:39])[CH2:12][N:13]([CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][C:35]#[N:36])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:4][O:3][CH2:2]1>CO>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:47])[NH:9][C@@H:10]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:11]([OH:39])[CH2:12][N:13]([CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][C:35]#[N:36])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:4][O:3][CH2:2]1
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 115.8 %

Procedure:
{(1S,2R)-1-Benzyl-3-[(4-cyano-2,2-dimethylbutyl)-(4-benzyloxybenzenesulfonyl)-amino]-2-hydroxypropyl}-carbamic acid [1,3]dioxan-5-yl ester (2.2 mg, 0.003 mmol) was dissolved in methanol (1 mL). Solution was degassed with nitrogen for 5 minutes the 10% Pd/C (2 mg) was added. Reaction was pressurized with H2 (1 ATM) and stirred for 30 minutes. Catalyst removed by filtration and solvent was removed in vacuo leaving 2.0 mg (95%) of product as a colorless residue. MS (ES): 576.2 (M+1), HPLC; tR=10.39 min. (84%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:14]([O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(CO)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCC(=O)N1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To an ice cold solution of 5-Hydroxymethylpyrrolidin-2-one (5 grams, 43.4 mmol) in dichloromethane (174 mL) was added imidazole (6.5 grams, 95.5 mmol), 4-dimethylaminopyridine (530 mg, 4.3 mmol) followed by tert-butyldiphenylsilyl chloride (12.53 grams, 45.57 mmol). The reaction mixture was gradually warmed to room temperature and upon completion of 2 hours, diluted with dichloromethane, washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain title compound of 15.37 grams, as gummy liquid, which was taken up for the next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH3:51])[N:44]=1)CCC>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH3:51])[N:44]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OCC)n1
Product: CCOc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)s2)n1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl (6-ethoxy-2-pyridyl) tin (see WO 00/74681) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 660/662 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (245 mg) was dissolved in tetrahydrofuran (5 ml), added thereto was a solution of sodium hydride (oil, 9 mg) in ethanol (5 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (145 mg) as colorless powder. APCI-Mass m/Z 492/494 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:14]=[C:15]=[S:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2ccccc2N=C=S)c1
Reactant: N
Solvent: CCO
Product: NC(=S)Nc1ccccc1-c1cccc(F)c1

Procedure:
Reaction of 3'-fluoro-2-biphenylylisothiocyanate (11.2 g) with ethanol (50 ml) with 28% aqueous ammonia solution (100 ml) for 24 hours at ambient temperature yielded N-(3'-fluoro-2-biphenylyl)thiourea (m.p. 157°-159° C.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(I)cc12
Product: Clc1ncnc2ccc(I)cc12

Procedure:
6-Iodoquinazolin-4(3H)-one (10 g, 37 mmol) was refluxed in POCl3 (100 mL) overnight. Then POCl3 was removed in vacuo. The residue was dissolved in CH2Cl2 (500 mL). The organic phase was washed with water (100 mL) and dried (MgSO4). Then CH2Cl2 was removed in vacuo and 1404-174 was obtained (5.7 g, 53%): LC-MS: 291 [M+1]+, 1H NMR (CDCl3): δ 7.81 (d, J=9.0 Hz, 1H), 8.21 (dd, J1=9.0 Hz, J2=1.8 Hz, 1H), 8.65 (d, J=1.8 Hz, 1H), 9.06 (s, 1H).
Reaction SMILES: [C:1]1([N:7]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:8][CH:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]([O:12]C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH3:33][NH:32][C:28]1[N:27]=[C:26]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:15]([NH:14][CH:9]([CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:10]([OH:12])=[O:11])=[O:16])=[CH:25][CH:24]=3)[CH:31]=[CH:30][N:29]=1
Reactant: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)OC)ccc3[nH]2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)O)ccc3[nH]2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.4 %

Procedure:
4.0 g of the methyl ester 46 were dissolved in 400 ml of methanol. 40 ml of a 2N aqueous solution of NaOH were added and the whole was stirred at room temperature for 12 h. After the solvents had been evaporated, the residue was dissolved with water and the pH was adjusted to 5 using a saturated solution of NaH2PO4. The resulting precipitate was filtered off and washed with water. This resulted in 1.3 g (yield 93%) of the acid 48.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][CH2:65][N:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:63][CH2:64][CH2:65][N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCN2CCOCC2)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 4-(2-Aminoethyl)morpholine (82 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was recrystallised from DMSO to yield white solid (0.040 g, 62%).