Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH2:14][C:15]2[C:16]([CH:25]=1)=[C:17]1[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1.[Li].[Cl:27][Si:28](Cl)([CH3:30])[CH3:29]>CCOCC>[Cl:27][Si:28]([CH:14]1[C:15]2=[CH:24][CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]2[CH:25]=[C:13]1[CH3:12])([CH3:30])[CH3:29]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2c(ccc3ccccc23)C1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(ccc3ccccc23)C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 1.6 M n-BuLi solution in hexane (7.5 mL, 12 mmol) was added at −50° C. to a solution of 2-methyl-3H-cyclopenta[a]naphthalene (2.14 g, MW=180.25, 11.9 mmol) in 50 mL of ether. The resulting suspension was allowed to warm to room temperature and stirred for 45 min at the same temperature. Then the lithium suspension was cooled again to −70° C. and added of dichlorodimethylsilane (18 mmol, 2.2 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The precipitate of lithium chloride was filtered, the filtrate was evaporated off to dryness and dried in vacuo. Yield 3.14 g (97%).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][NH:4]1.[H][H]>C(O)C.[Pd]>[ClH:1].[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5][NH:4]1
Reactant: [H][H]
Reactant: CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1NCCc2ccc(N)cc21

Procedure:
A suspension of 1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.75 mmol) in ethanol (100 ml) and a catalytic quantity of 10% Pd-C was hydrogenated until no more hydrogen was taken up. The catalyst was filtered off, the solvent was concentrated to a small volume, ether was added and the precipitated solid was collected and dried: 1.39 g (78%), MS (M+H)+ 163.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:21]1[CH:22]2[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]2)[CH2:20]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol), (R)-quinuclidin-3-ol (0.51 g, 3.98 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.64 g, 4.78 mmol), and DCC (0.98 g, 4.78 mmol) was stirred at RT overnight. Then THF was removed by vacuum, and the residue was partitioned between EtOAc and 2M K2CO3. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to obtain (R)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-2-phenylacetate (612 mg; 43% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:19][O+](C)C>C(#N)C>[F:14][B-:15]([F:18])([F:17])[F:16].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N+:5]([CH3:19])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Cc1cc(Cl)c2cc(Cl)ccc2[n+]1C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
The starting material may be prepared as follows. Powdered 4,6-dichloro-2-methylquinoline (254 mg.) was added to a stirred solution of trimethyloxonium tetrafluoroborate (177 mg.) in acetonitrile (1 ml.), and stirring was continued overnight. The solvent was evaporated and the residue was triturated with ether to give 4,6-dichloro-1,2-dimethylquinolinium tetrafluoroborate (296 mg.). N.m.r. in solvent A: 3.07(s, 3H); 4.44(s, 3H); 7.9-8.8(complex, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2cc(F)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(Cl)nccc2c1
Yield: 32.4 %

Procedure:
To a solution of 6-fluoroisoquinoline N-oxide (3 g, 18 mmol) in CHCl3 (50 mL) is added phosphorus oxychloride (5 mL, 54 mmol). The reaction mixture is refluxed for 2 h. The reaction mixture is poured into ice, and the pH is brought to pH 8-9 with 5 M NaOH. The aqueous phase is extracted with CH2Cl2 (3×). The combined organic layers are dried over MgSO4, and evaporated. Purification of the crude product by Biotage column eluted with 0-30% EtOAc/hexanes afforded 1.06 g (35%) of 1-chloro-6-fluoro-isoquinoline. LC/MS m/z=182 [M+H]+.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.Cl>>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:18]([C:17]([F:22])([F:21])[F:16])=[N:15][C:10]=3[CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(c1ccc(N)c(N)c1)n1ccnc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: CC(c1ccc2[nH]c(C(F)(F)F)nc2c1)n1ccnc1
Reaction time: 6 h
Yield: 69.3 %

Procedure:
A mixture of 3.6 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-1,2-benzenediamine, 5 parts of trifluoroacetic acid and 100 parts of a hydrochloric acid solution 4N was stirred for 6 hours at reflux temperature. The reaction mixture was concentrated and the concentrate was dissolved in 50 parts of water. The mixture was made alkaline with sodium hydrogen carbonate and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was concentrated. The concentrate was crystallized from 20 parts of ethyl acetate. The product was filtered off and dried, yielding 3.4 parts (69.3%) of 5-[1-(1H-imidazol-1-yl)ethyl]-2-(trifluoromethyl)-1-H-benzimidazole; mp. 164.6° C. (compound 64).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10]OS(C)(=O)=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]2([CH3:30])[CH3:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH2:25][C:24]2([CH3:30])[CH3:29])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Reactant: COc1ccc(CN2CCNCC2(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(Cc3ccc([N+](=O)[O-])cn3)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A mixture of methanesulfonic acid 5-nitro-pyridin-2-ylmethyl ester (Step 112.3) (0.5 g, 2.16 mmol), 1-(4-methoxy-benzyl)-2,2-dimethyl-piperazine (Step 108.2) (0.655 g, 2.8 mmol, 1.3 equiv), cesium carbonate (0.845 g, 2.6 mmol, 1.2 equiv), and DMF (4 ml) was stirred for 5 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by by silica gel column chromatography (DCM→DCM/MeOH, 99:1) to provide 0.642 g of the title compound as a red solid: ESI-MS: 371.2 [M+H]+; tR=3.18 min (System 1); TLC: Rf=0.44 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19]([C:21]([OH:26])([CH2:24][CH3:25])[C:22]#[CH:23])[CH3:20]>C(NCC)C.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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:20]#[C:19][C:21]([CH2:24][CH3:25])([OH:26])[CH2:22][CH3:23])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: C#CC(O)(CC)CC
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCC(O)(C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2)CC
Reaction time: 0.5 h

Procedure:
8.93 g (25 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 24 hours with 3.03 g (27 mmol) of 3-ethyl-1-pentyn-3-ol, 100 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 60 ml of diethylamine. A further 0.87 g (7.7 mmol) of 3-ethyl-1-pentyn-3-ol as well as 50 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 50 mg of copper(I) iodide were added thereto and the mixture was stirred at the boiling temperature for 0.5 hour. The reaction mixture was subsequently evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After decolorizing the crude product with active charcoal and crystallization from ethyl acetate there was obtained 8-fluoro-3-(3-ethyl-3-hydroxy-1-pentynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 135° -136°.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH:30]=[CH:29]1>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:30]3[C:31](=[O:32])[O:33][C:28](=[O:34])[C:29]3=[CH:3]2)=[CH:6][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2c1cc1cc(OCc3ccccc3)ccc1c2-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the alcohol (112 g) from Step 1 in toluene (1.1 L) was added maleic anhydride (150 g). The reaction mixture was heated to reflux for 24 hours. After cooling to room temperature, the toluene was evaporated. The residue was triturated in EtOAc at 0° C., filtered and washed with Et2O to afford the title product as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH3:26])=[N:20]2.CS(C)=O>O>[CH3:26][C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:23]([F:25])=[CH:24][C:15]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:20]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(F)cc(F)cc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(N3CCNCC3)cc(F)cc2n1
Temperature: 120 °C
Yield: 20.7 %

Procedure:
A stirred mixture of piperazine (20 g), potassium carbonate (32 g), 5,7-difluoro-2-methylquinoline hydrochloride (WO2002034754, 20 g) and dimethylsulfoxide (390 mL) was heated to 120° C. for 15 hours. The mixture was cooled to room temperature, diluted with water (600 mL) and extracted with 6×500 mL portions of a mixture of DCM-ether (15:85). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (sodium sulfate) and the solvent was partially evaporated under vacuum. The precipitate formed during the evaporation was filtered-off, washed with ether (50 mL) and dried under vacuum to give the title compound (4.7 g, 21%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[CH3:13][O:14][C@@H:15]([CH3:18])[CH2:16][OH:17].[OH-].[Li+]>>[CH3:13][O:14][C@@H:15]([CH3:18])[CH2:16][O:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CO[C@@H](C)CO
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: CO[C@@H](C)COc1ccc(C(=O)O)cn1
Temperature: 75 °C
Yield: 67 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 67% yield starting from ethyl 6-chloronicotinate and (s)-(+)-2-methoxypropanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 75° C. for 3 h. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, CD3OD) δ ppm 8.77 (d, 1 H), 8.21 (dd, 1 H), 6.87 (d, 1 H), 4.27-4.40 (m, 2 H), 3.69-3.81 (m, 1 H), 3.42 (s, 3 H), 1.24 (d, 3 H); MS (ESI) m/z 212[M+H+], m/z 210 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: Cc1cccc(O)c1N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: Cc1cccc(O)c1NC(=O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-3-methylphenol (283 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:10]1[N:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:4]=2)[N:9]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CSc1nncc(-c2ccc(F)c(-c3cccnc3)c2)n1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4cccnc4)c3)n2)c(F)c1

Procedure:
5-[4-Fluoro-3-(pyridin-3-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine was coupled to 2,4-difluorophenylboronic acid by the method of Example 2 to give 3-(2,4-difluorophenyl)-5-[4-fluoro-3-(pyridin-3-yl)phenyl]-[1,2,4]triazine as a yellow solid: δH (400 MHz, CDCl3) 7.00-7.12 (2H, m), 7.42 (2H, m), 7.96 (1H, dd, J 2.0, 7.8 Hz), 8.27-8.36 (2H, m), 8.42 (1H, dd, J 2.5, 7.2 Hz), 8.70 (1H, s), 8.89 (1H, s), 9.66 (1H, s); m/z (ES+) 365.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>>[F:25][C:24]([F:26])([F:27])[C@@H:23]([C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1)[OH:28]
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Product: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (5.01 g) (described in example 133, step 3) and (1R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (9.07 g) (synthesis described in J. Org. Chem. 2009, 74, 1605-1610) as a white solid (4.9 g). MS (m/e): 386.1[MH+].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:23][C:24]1[C:32]([I:33])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=1)[N:6]2[CH2:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:15][CH2:14][CH2:13][CH2:12][N:6]1[C:5]([CH2:23][C:24]2[C:32]([I:33])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)=[N:4][C:3]2[C:7]1=[N:8][C:9]([F:11])=[N:10][C:2]=2[NH2:1]
Reactant: CC(C)(C)OC(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (3.3 g, 8 mmol) in DMF (50 mL) was added t-butyl (3-bromopropyl)carbamate (9.6 g, 40 mmol) and Cs2CO3 (5.26 g, 16 mmol). The resulting mixture was stirred at room temperature for 1 day. The reaction mixture was condensed and purified by flash chromatography to yield t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate as white solid (3.1 g, 66%). The solution of t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate (1.9 g, 3.3 mmol) in the mixture of TFA/CH2Cl2 (10 mL/2 mL) was stirred at room temperature for 2 hrs. The reaction mixture was condensed, purified by flash chromatography to yield 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine as yellow solid (1.4 g, 89%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.28 (s, 1H), 6.70 (s, 1H), 5.98 (s, 2H), 4.21 (s, 2H), 4.13 (t, J=7.1 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 1.89 (m, 2H); 13C NMR (150 MHz, CDCl3/MeOH-d4): δ 160.8, 159.4, 157.8, 153.7, 152.1, 150.4, 149.4, 132.4, 120.1, 117.2, 111.3, 103.4, 89.8, 41.7, 40.4, 39.3, 33.6; HRMS (ESI) m/z [M+H]+ calcd. for C16H17IFN6O2, 471.0436. found 471.0442.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:18][C:17]=1[F:35])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:18][C:17]([F:35])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(O[C@H]2CCCC[C@H]2n2ccnc2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(O[C@H]2CCCC[C@@H]2n2ccnc2)cc1F
Yield: 104.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (340 mg, 0.610 mmol) prepared in Example 13a, trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (292 mg, 67%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](O)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:28]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C29H26N4O, 446.56; m/z found, 447.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH3:6]>C(N(CC)CC)C.ClCCl>[C:5]([NH:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:2][CH3:1])=[O:4])(=[O:7])[CH3:6]
Reactant: CN=C=O
Reactant: CC(=O)NNc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N(NC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.7-g (0.1-mol) sample of methyl isocyanate was added dropwise to a solution of 15.0 g (0.1 mol) 1-acetyl-2-phenyl-hydrazine and 2 drops triethylamine in 200 ml dichloromethane. The resulting reaction mixture was stirred for 2 hours at about 25° C., refluxed for about 16 hours and evaporated under reduced pressure to give 21 g of crude 1-acetyl-2-phenyl-4-methyl semicarbazide, as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1cccnc1C(=O)O

Procedure:
A mixture of 2,3-pyridinedicarboxylic anhydride (9.0 g, 60.36 mmol) in 75 mL of fluorobenzene is warmed and stirred mechanically while AlCl3 (17.7 g, 0.132 mol) is added portionwise from a powder addition funnel over 20 m. The resulting mixture is heated to reflux for 24 hours, then allowed to cool and the excess fluorobenzene decanted. Quenching of the residue with ice water and 5% aqueous HCl generates a solid which is filtered and washed with hot H2O. The combined filtrates are evaporated to a final volume of ca. 250 mL, then heated to boiling and treated with a hot solution of 15% aqueous CuSO4 solution to precipitate a blue solid. The suspension is filtered and the resulting solid resuspended in H2O (75 mL) and treated with a stream of H2S gas until the initial blue color of the suspension subsides and is replaced by a black suspension. The solid is filtered with the aid of Celite and the filtrate evaporated to produce a tan solid which is recrystallized from H2O to obtain 3-(4-fluorobenzoyl)pyridine-2-carboxylic acid. M.P. 153.5°-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:34][C:32]1=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[O:34][C:32]1([C:14]1[S:13][C:12]2[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=3)=[CH:8][CH:9]=[CH:10][C:11]=2[CH:15]=1)[OH:33])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(Cc2cccc3ccsc23)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cccc3cc(C4(O)O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)sc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 7-(4-methylbenzyl)benzo[b]thiophene (0.57 g) in tetrahydrofuran (10 mL) was added n-butyllithium (2.71 mol/L tetrahydrofuran solution, 0.88 mL) at −78° C. under an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes and a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (1.2 g) in tetrahydrofuran (5 mL) was added to the mixture. The reaction mixture was warmed to 0° C. and stirred for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.2 g).