Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH:8]1([N:11]2[C:15]3[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][N:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])[C:15]4[N:11]([CH:8]5[CH2:9][CH2:10]5)[CH:12]=[N:13][C:14]=4[CH:19]=3)=[N:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:2])[CH3:3]
Reactant: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2ccc(-c3cc(O[C@H](C)[C@H]4CNC(=O)C4)c4c(c3)ncn4C3CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the TFA salt of (R)-4-((R)-1-((1-cyclopropyl-5-(5-(piperazin-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (45 mg, 0.1 mmol) in DCM (1 mL) and TEA (0.07 mL, 0.5 mmol) was added acetic anhydride (0.014 mL, 0.15 mmol). The reaction was stirred at rt for 2 h. The mixture was then concentrated and purified by prep-HPLC (MeCN:water gradient; TFA modified) to give (R)-4-((R)-1-((5-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: 3.59 as a TFA salt. The salt was then converted to the free base by treatment with MP carbonate resin.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCCCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 mmol) was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 mmol) and sodium triacetoxyborohydride (13.8 g, 65 mmol). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 mmol) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) and the layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-aminooctane (14.6 g, 88%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11]C23C=CC=CC2C(NC3=O)=O)=[CH:4][CH:3]=1.O.[NH2:29]N>C1COCC1.CCO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][NH2:29])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C1NC(=O)C2(Cc3cccc(COc4ccc(Cl)cc4)c3)C=CC=CC12
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cccc(COc2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
2-[3-(4-Chloro-phenoxymethyl)-benzyl]-phthalimide (345 mg, 0.91 mmol) and hydrazine hydrate (0.27 mL, 4.5 mmol) were dissolved in THF (2.5 mL) and EtOH (2.5 mL). The mixture was heated to reflux for 17 h, cooled to r.t. and evaporated to dryness. The residue was suspended in THF (6 mL). The precipitate was filtered and washed with THF (4×3 mL). The filtrate was evaporated to dryness to give the title compound, pure enough for further reactions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[N:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[N:7]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)n1
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [6-(2-oxo-propylsulfanyl)-pyridin-2-yl]-acetic acid ethyl ester and 3-chloro-2-fluorophenylhydrazine hydrochloride.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:20]([NH:30][C@H:31]([C:35]([CH:7]([OH:8])[C@H:6]1[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3][C@@H:2]1[F:1])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)C(O)[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Reaction time: 72 h

Procedure:
To a solution of 2′,3′—dideoxy-3′—fluoroguanosine (810 mg, 3 mmole) and 4-dimethylaminopyridine (73 mg, 0.6 mmole), N-CBz-L-valine (1.5 g, 6 mmole) and 1-hydroxybenzotriazole (810 mg, 6 mmole) in DMF (20 ml) was added DCC (1.36 g, 6.6 mmole). After 72 h, the reaction mixture was filtered and concentrated in vacuo. 5′-(N-CBz-L-valyl)-2′,3′-dideoxy-3′-fluoroguanosine was isolated by silica gel column chromatography (1.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[C:5]2[O:20][C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=3[C:6]=2[CH:7]=1.[C:22]1([S:28]([O-:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>>[Cl:21][C:4]1[C:5]2[O:20][C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=3[C:6]=2[CH:7]=[C:2]([S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CCOC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2CC1
Agent: [Na+]
Product: CCOC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CC1
Yield: 62 %

Procedure:
The product of step D and sodium benzenesulfinate were coupled using the procedure of Example 29 step C. Purification by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) afforded ethyl 7-chloro-9-(phenylsulfonyl)-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (35 mg, 62%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.00-7.92. (m, 3H), 7.80 (s, 1H), 7.62-7.48 (m, 3H), 4.20 (q, J=7.1 Hz, 2H), 3.80-3.68 (m, 4H), 3.22-3.11 (m, 2H), 2.96-2.82 (m, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1(=[O:16])N[C:13](=[O:15])[CH2:12][CH2:11]1.N.O>ClCCl>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[C:13](=[O:15])[CH2:12][CH2:11][C:10]1=[O:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C1CCC(=O)N1
Agent: N
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)N1C(=O)CCC1=O
Reaction time: 2 h
Yield: 119.6 %

Procedure:
15.6 ml (0.075 mole) of hexamethyldisilazane were added dropwise over a few minutes to a refluxing suspension of 9.90 g (0.1 mole) of succinimide and 0.24 g (0.5 mmole) of di-4-nitrophenyl N-4-toluenesulfonyl-phosphoramidate in 50 ml of dichloromethane and a stream of nitrogen was led over the reaction mixture to pass the ammonia evolved into water. The progress of the reaction was established by titration of the ammonia evolved and it was found that after refluxing for 1.5 hours, the production of ammonia was completed. 90% of the theoretical amount of ammonia had been evolved and refluxing was continued for another 2 hours. Then the solvent was removed by distillation at normal pressure and fractionation under reduced pressure yielded 15.36 g (89.8%) of N-trimethylsilylsuccinimide boiling at 118°-119° C. at 18 mm Hg and nD 25=1.4745.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[OH:12][C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21](=O)[CH3:22].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:28][O:27][C:25]([CH2:24][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:22])=[C:13]([OH:12])[CH:14]=1)=[O:26]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)c(O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(O)c1
Yield: 57.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.07 g of methyl 3-hydroxy-4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 34), 70 ml of dry benzene, 60 ml of absolute methanol and 1.7 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 2.62 g of the title compound were obtained as crystals, melting at 68° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:3]1[S:11]([CH3:14])(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([SH:31])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.[H-].[Na+]>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([S:31][C@H:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH:3][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:1])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-n2ncc3cc(S)ccc32)cc1
Reactant: C[C@@H]1[C@@H](c2ccccc2)N1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](NS(C)(=O)=O)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To (2R,3R)-2-methyl-1-(methylsulfonyl)-3-phenylaziridine (38a, 0.03 g, 0.14 mmol) in THF (4 ml) was added 1-(4-Fluorophenyl)-1H-indazole-5-thiol (37c, 0.038 g, 0.16 mmol) and sodium hydride (5.11 mg, 0.21 mmol) on an ice bath with stirring. The ice bath was removed and the mixture was stirren at room temperature over night. The solvent was removed and the mixture was purified on HPLC. Yield 0.007 g (11%).
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-])=O.[OH-].[Na+]>CO>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]2[CH:8]=[C:7]([CH:26]=[CH:25][CH:24]=2)[NH2:4])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C

Procedure:
Tin (II) chloride (13.6 g (60 mmole)) is added to a solution of 4-(3-Nitro-phenoxymethyl)-biphenyl (4.6 g, 15 mmole) in 120 ml methanol. The reaction mixture is refluxed for 12 hr. The reaction is cooled to room temperature, 4 N of NaOH solution is added with stirring to adjust pH=8. The resulting mixture is filtered through a plug of CELITE, the filtrate concentrated and taken up in ethyl acetate. The organic layer is washed with brine and dried over Na2SO4, and concentrated. The resulting solid is washed with little methanol to yield 3-(Biphenyl-4-ylmethoxy)-aniline as a yellow solid. MS: 276(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+].Cl>C(OC)(C)(C)C>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:14][C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[C:2]([F:1])[CH:3]=1)=[O:15]
Reactant: CC(=O)c1ccc(-c2cscn2)c(F)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)c(F)c1
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of 1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (666 mg, 3.01 mmol), ethyl trifluoroacetate (470 mg, 3.31 mmol) in t-butylmethylether (40 ml) was added sodium methoxide (28 wt. % solution in methanol; 0.8 ml, 3.6 mmol) over 5 minutes, and the mixture was stirred for 20 hours. The mixture was made neutral by addition of 2N HCl aqueous solution, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (1.06 g, 99% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCN2C(=NCCC2)CC1.[CH2:56]([O:58][C:59](=[O:61])C)C>CO.C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:59]([O:58][CH3:56])=[O:61])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CCOC(C)=O
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 110 °C

Procedure:
Alternatively, a suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (113 mg, 0.25 mmol), Mo(CO)6 (66 mg, 0.25 mmol), Hermann's palladacycle (trans-di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II), 23 mg) and tri-tert-butylphosphonium tetrafluoroborate (15 mg) in methanol (0.8 mL) and THF (0.8 mL) in a 10 mL microwave vial was treated with DBU (0.11 mL, 0.75 mmol) and immediately sealed. The whole was heated in a microwave at 110° C. for 20 min, cooled to room temperature and diluted with ethylacetate. The crude suspension was filtered through celite and the eluent concentrated to give a residue that was purified by flash column chromatography (10-100% ethylacetate in hexanes) to give 138 as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 7.69-7.49 (m, 7H), 6.57 (m, 1H), 4.22 (m, 2H), 3.85 (s, 3H), 3.23 (s, 3H, obstructed by water), 3.02 (m, 2H). MS: (ESI+) 428.1
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17]([CH:19]1[CH:24]2[CH2:25][CH:21]3[CH:22]([C:23]2=[O:26])[CH:20]13)=O.C(O)(C)C.[OH-].[K+]>O>[O:26]=[C:23]1[CH:22]2[CH:20]3[CH:21]2[CH2:25][CH:24]1[CH:19]3[C:17]1[NH:16][C:3]2[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCn1c(N)c(NC(=O)C2C3CC4C(C3=O)C42)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=O)C53)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
5-Oxo-tricyclo[2.2.1.02,6]heptane-3-carboxylic acid (6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (360 mg) from step 1 was taken in 1:1 isopropanol:water (5 ml) and KOH (84 mg) was added. The reaction mixture was refluxed for one and half-hour. After cooling the reaction mixture to room temperature, iPrOH was removed by rotavap. The aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water and brine and dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Yield (75 mg) Mass (ES+ 343).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([F:21])=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:21][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][CH:5]([CH2:4][NH2:1])[O:6][C:7]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: [N-]=[N+]=NCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 53.2 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31]I)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: C1CCNC1
Product: COc1cc2c(cc1CCCCN1CCCC1)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 2 h
Yield: 75 %

Procedure:
Reaction of the iodide (173) prepared as described in example 312 with pyrrolidine using the procedure described in example 179 except that the reaction conditions were 2 h at room temperature gave (176) (75%) as an orange powder, which was used without further purification, mp 173–178° C. 1H NMR δ [(CD3)2SO] 11.85 (s, 1H), 11.04 (br s, 1H), 8.42 (s, 1H), 7.57 (dd, J=8.0, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.43 (m, 3H), 7.42 (s, 1H), 3.93 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H), 2.11 (s, 6H), 1.63 (m, 2H), 1.47 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH:4]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:3]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:6][NH:5][CH:4]([C:14]([OH:16])=[O:15])[CH2:3]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: CC1(C)CC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNC(C(=O)O)C1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 137e (27 g, 90 mmol) and TFA (100 mL) in DCM (200 mL) was stirred at 20° C. for 16 h. See FIG. 1. The reaction solution was concentrated under reduced pressure to give 4,4-dimethylpyrrolidine-2-carboxylic acid 137f as a brown oil (27 g, TFA salt). 1H NMR (400 MHz, CDCl3): δ 12.08 (br s, 2H), 9.56 (br s, 1H), 7.77 (br s, 1H), 4.52 (s, 1H), 3.20 (s, 2H), 2.30-2.24 (m, 1H), 2.00-1.94 (m, 1H), 1.17 (s, 6H).
Reaction SMILES: [H][H].[C:3]1([C:9](=[N:19]O)[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([CH:9]([NH2:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: ON=C(CCCc1ccncc1)c1ccccc1
Product: NC(CCCc1ccncc1)c1ccccc1
Yield: 88.4 %

Procedure:
Using deprotection method A under 4.1 bar (60 psig) of hydrogen, 1-phenyl-4-(pyridin-4-yl)butan-1-one oxime (1.6 g, 6.5 mmol) afforded 1.3 g (87%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:15]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (63 mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture was heated to 140° C. and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with a mixed solvent (25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (112 mg) as pale-yellow powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[NH3:23]>CO.[Pd]>[NH2:23][CH2:17][C:14]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:22])([F:21])[F:20])[CH:4]=2)=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N
Agent: [Pd]
Solvent: CO
Product: N#Cc1cc(CN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a suspension of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-formylbenzonitrile (1.0 g, 3.07 mmol) and ammonia (10 mL, 70.0 mmol) (7M in MeOH) in methanol (50 mL), was added Pd/C (0.327 g, 3.07 mmol). The reaction mixture was stirred at rt overnight under H2 atmosphere, filtered and concentrated. Purification via MDAP afforded the title compound (500 mg). LC-MS (ESI): m/z 327 [M+H]+; 2.49 min (ret time).