Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:63]([C:52]1[C:51]([NH:50][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:56][CH:55]=[CH:54][C:53]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(=[O:64])[NH2:65]
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.4 g, 10 mmol) in DCM (40 mL) was added HATU (5.3 g, 14 mmol) and DIPEA (3.6 mL, 28 mmol) and the reaction mixture was stirred at room temperature for 1 h. 3-Aminobiphenyl-2-carboxamide (from Example 218) (1.5 g, 7.07 mmol) was added and the resulting mixture stirred for an additional 16 h. The reaction mixture was washed with water, the organic portion dried, filtered and concentrated under reduced pressure. The resulting residue was purified by ISCO chromatography (50% ethyl acetate in hexanes) to yield tert-butyl 4-(2-carbamoylbiphenyl-3-ylcarbamoyl)piperidine-1-carboxylate (1.0 g, 22% yield) as a white solid. LCMS Method T: retention time 1.71 min; [M+1]=423.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1csc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1csc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 45%). 1H NMR (400 MHz, CDCl3) δ 8.53 (t, J=1.4 Hz, 1H), 8.27-8.24 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.09-8.06 (dt, J=7.6 Hz, 1.6 Hz, 1H), 7.94-7.90 (m, 2H), 7.70 (m, 1H), 7.63-7.59 (t, J=7.8 Hz, 1H), 7.09-7.05 (m, 3H), 3.91-3.86 (m, 2H), 3.16-3.13 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O2S: 462.08. found: 463.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)[CH3:2].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17])[CH3:2]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCN1C(=O)c2ccccc2C1=O
Yield: 87.4 %

Procedure:
This compound was prepared according to the procedure used to prepare 1,3-dihydro-1,3-dioxo-2H-isoindoleoctanoic acid ethyl ester. Thus, a mixture of 62.3 g (0.265 mole) of 6-bromohexanoic acid ethyl ester (ethyl 6-bromocapronate, 95%, Fluka) and 52.4 g (0.277 mole) of potassium phthalimide (98%, Aldrich) in 200 mL of dimethylformamide gave 67 g (87%) of crude title compound as a viscous oil. A 2.0 g sample of this oil was purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:10; flow rate 200 mL/min). Fractions containing title compound were combined and the solvents evaporated under reduced pressure to give 1.9 g (95% recovery) of colorless liquid.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:30](O)=[O:31])[N:28]=1)=[O:22]>>[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:30]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[NH:15][N:14]=[N:13][CH:12]=4)[CH2:7][S:8][C@H:3]23)=[O:31])[N:28]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Yield: 67.7 %

Procedure:
7-Amino-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.7 g.) and 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) were treated in a similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 mL dichloromethane is cooled in an ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 mL dichloromethane are added followed by 9.8 mL triethylamine and 0.5 g 4-dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 mL dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulfate. After the solvent has been removed, the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=3)[CH:20]=[CH:19][C:18]=2[F:33])[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.CO[CH:38](OC)[N:39]([CH3:41])[CH3:40]>CN(C)C=O>[CH3:38][N:39]([CH3:41])/[CH:40]=[CH:29]/[C:27]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([F:33])=[C:17]([CH:22]=2)[CH2:16][N:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6](=[O:7])[C:5]2[CH:34]=[CH:35][C:2]([F:1])=[CH:3][CH:4]=2)[CH:28]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(-c2ccc(F)c(CN(CCN3CCCC3)C(=O)c3ccc(F)cc3)c2)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(-c2ccc(F)c(CN(CCN3CCCC3)C(=O)c3ccc(F)cc3)c2)ncc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 72.4 %

Procedure:
4-Fluoro-N-[2-fluoro-5-(4-methyl-5-nitro-pyridin-2-yl)-benzyl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide (prepared according to example 20, 600 mg, 1.25 mmol) in 15 mL of dimethylformamide was treated with dimethylformamide dimethyl acetal (0.23 mL, 1.68 mmol), and the resulting mixture was heated at 80° C. for 5 h. The mixture was allowed to cool and the volatiles were removed. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to give an oil. The above process was repeated to give 485 mg of product.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=1>CN(C)C=O>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:60]=[C:61]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2nc3ccccc3[nH]2)c1
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: COc1cccc2cc(C(=O)Nc3cccc(-c4nc5ccccc5[nH]4)c3)c(=O)oc12
Temperature: 25 °C

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.050 g, 0.23 mmol) and HATU (0.095 g, 0.25 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-benzimidazol-2-yl)-benzenamine (0.048 g, 0.23 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 1541F: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[N:21]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:32][CH:29]2[CH2:30][CH2:31][N:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2cccnn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3cccnn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 31.1 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.240 g, 0.80 mmol), 1-pyridazin-3-ylpiperidin-4-amine (0.257 g, 1.02 mmol) and TEA (0.324 g, 3.2 mmol), was dissolved in dry DMF (10 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried (MgSO4), filtered and evaporated and the residue was purified by silica gel column chromatography using EtOAc as eluant, to give the title compound (0.110 g, 31%). 1H NMR (500 MHz, CDCl3): δ 8.55-8.52 (m, 1H), 7.55-7.50 (m, 2H), 7.47-7.42 (m, 3H), 7.19-7.14 (m, 1H), 6.85-6.82 (m, 1H), 5.21 (d, 1H), 4.17-4.11 (m, 2H), 3.22-3.13 (m, 1H), 2.60-2.52 (m, 2H), 1.80-1.73 (m, 2H), 1.72 (s, 9H), 1.42-1.32 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.5, 143.1, 133.8, 131.6, 129.9, 128.7, 127.4, 125, 112.8, 107.2, 61.6, 50.1, 43.6, 31.7, 27.5; Mass Spectrum: M−H+ 442.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]1=[O:22])=O)(C)(C)C.[ClH:23]>C(O)C>[ClH:23].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]1=[O:22]
Reactant: CCOC(=O)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN1CCCC[C@H](N)C1=O
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of 49 (3.143 g, 0.0100 mole) in 20 mL of ethanol at 0° C. was added 12N HCl in ethanol (27.0 mL, 0.32 mol) in one portion. The solution was stirred at 0° for 5 min and then allowed to stir at ambient temperature for one hr. The solvent was evaporated, anhydrous acetonitrile (100 mL) was added and the solvent was reevaporated. The residue was pumped at <1 mm Hg on a vacuum pump for 20 hrs to afford 2.410 g (96% yield) of product 50 as a pale yellow foam. TLC (silica gel; CH2Cl2, methanol, conc. NH4OH: 25, 5, 1): Rf=0.63.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:29])[CH:17]([CH3:28])[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[C:21]([F:27])[CH:20]=1)C>>[F:25][C:23]1[CH:24]=[C:19]([CH2:18][CH:17]([CH3:28])[C:16]([OH:29])=[O:15])[CH:20]=[C:21]([F:27])[C:22]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCSc1ncccc1CCl
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Product: CCCSc1ncccc1COc1c(F)cc(CC(C)C(=O)O)cc1F
Yield: 69.9 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (35 mg, 0.15 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.04 g, 68%).
Reaction SMILES: C(OC(NCC1C=C(NC(=O)COC2C=CC([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=CC=2)C=CC=1)=O)C1C=CC=CC=1.[Si:60]([O:67][CH:68]([CH3:79])[CH2:69][C:70]1[CH:75]=[CH:74][C:73](B(O)O)=[CH:72][CH:71]=1)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>>[C:48]([O:47][C:45]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:56])[CH3:57])=[O:53])[C:40]1[C:41]2[C:36](=[CH:35][C:34]([NH:33][CH:29]([C:73]3[CH:74]=[CH:75][C:70]([CH2:69][CH:68]([O:67][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:61])[CH3:62])[CH3:79])=[CH:71][CH:72]=3)[C:30]([OH:32])=[O:31])=[CH:43][CH:42]=2)[CH:37]=[CH:38][N:39]=1)=[O:46])([CH3:50])([CH3:51])[CH3:49]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Reactant: CC(Cc1ccc(B(O)O)cc1)O[Si](C)(C)C(C)(C)C
Product: CC(Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc1)O[Si](C)(C)C(C)(C)C
Yield: 65 %

Procedure:
According to the procedure for the preparation of 66D, 77C (200 mg, 0.68 mmol) afforded 295 mg (65%) of 77D as an off-white solid. MS (ESI) m/z 666.4(M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCCOC
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)methylamine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine as colorless oil, MS: 388 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[C:24]1([CH:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][CH2:32][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=3)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
The compound (1.60 g) prepared in step (a) was dissolved in N,N-dimethylformamide (20 ml). Potassium carbonate (2.79 g) and 3,3-diphenylpropyl bromide (2.82 g) were added to the solution. The mixture was stirred at 70° C. for 8 hr. The reaction solution was extracted with ethyl acetate, followed by washing with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=5:1) to give 2.00 g (71.3%) of ethyl 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzoate.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C@@H:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[I:20]I>C(Cl)Cl>[C:1]([Si:5]([O:6][C@@H:7]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:8]=[CH:9]/[I:20])([CH3:18])[CH3:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: II
Reactant: C#C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](/C=C/I)CCc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A flame dried Schlenk flask, evacuated and purged with nitrogen, was charged with alkyne 88 (1.50 g, 5.46 mmol, 1 eq.). Anhydrous CH2Cl2 (35 ml) was added and the reaction stirred at r.t. Zr(Cp)2HCl (2.82 g, 10.9 mmol, 2 eq.) was added as a solid, in portions. The yellow suspension was stirred at r.t. for 1 h. The resulting yellow solution was cooled to 0° C. and iodine (1.52 g, 6.01 mmol, 1.1 eq.) added as a solid, in one portion. The cooling bath was removed and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was poured into water (100 ml) and extracted with 40/60 petroleum ether (4×50 ml). The combined organic phases were washed with water (100 ml), saturated Na2S2O3 solution (2×100 ml) and brine (100 ml) before being dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with 40/60 petroleum ether. The fractions containing product were combined and washed with saturated Na2S2O3 solution (20 ml), dried (MgSO4), filtered, and concentrated to give the title compound 89 (1.98 g, 90%) as a clear, colourless oil. Analytical data consistent with the literature (Sato, F. et al., EP 1211241 A1, Taisho Pharmaceutical co., LTD (2002)).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CN(C=O)C>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2ncn3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In DMF (4 mL, 0.05 mol) was suspended sodium hydride (47 mg, 0.0012 mol) at 0° C., to which was added a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.200 g, 0.000554 mol) in 2.5 mL DMF. The mixture was stirred at 0° C. for 10 minutes and was added a solution of 6-Chloro-9-(tetrahydropyranyl)purine (0.265 g, 0.00111 mol) (Example 33, step b) in 4 mL DMF. The reaction was stirred at 0° C. for 1 h and warmed to 23° C. overnight. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 5% acetone/toluene) to obtain 271 mg (86.8%).
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[CH:20]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:36][O:35][C:28]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=1[CH:20]([S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COc1ccc(C(O)Cn2ccnc2)c(OC)c1
Reactant: COC(=O)c1ccc(S)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(OC)cc2OC)cc1
Reaction time: 1.5 h
Yield: 40.9 %

Procedure:
10.9 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 766 mg of methyl 4-mercaptobenzoate and 754 mg of 1-[2-hydroxy-2-(2,4-dimethoxyphenyl)ethyl]imidazole, and the resulting mixture was stirred at a temperature between 0° and 5° C. for 1.5 hours. The resulting solution was treated and purified according to the same procedure as described in Example 13, to give 495 mg of the title compound as a colorless oily substance.
Reaction SMILES: [Na+].[I-:2].Cl[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:7]1>CC(=O)CC>[I:2][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:7]1
Reactant: [I-]
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Yield: 95.8 %

Procedure:
Add NaI (1.10 equiv., 30 mg, 0.20 mmol) to bisazaindole 17 (93 mg, 0.182 mmol) in 2-butanone (10 mL). After 16 h of reflux, the reaction mixture is concentrated under vacuum and the residue is dissolved in EtOAc (100 mL), washed with brine, dried (MgSO4) and concentrated, to give 18 (105 mg, 91%) as an ivory-colored solid: TLC (EtOAc at 40%/heptane) Rf=0.08, m/z obs.=604 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=4)=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: FC(F)(F)c1cccc(-c2cnc3c(c2)NCCO3)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(C(F)(F)F)c4)cc32)cc1Br
Yield: 95.9 %

Procedure:
By the same method as in the step c) of Example 45, 7-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (99 mg, 0.35 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (139 mg, 0.42 mmol) and triethylamine (98.5 μl, 0.71 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(3-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (192 mg, 95%).