Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C:8]([CH3:13])([C:10](O)=[O:11])[CH3:9])=[O:6])[CH3:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.O.S(O)(O)(=O)=O.O[NH:64][C:65]([NH2:67])=[NH:66]>CN(C=O)C>[C:2]([O:4][C:5](=[O:6])[NH:7][C:8]([C:10]1[O:11][N:66]=[C:65]([NH2:67])[N:64]=1)([CH3:13])[CH3:9])([CH3:14])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N=C(N)NO
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(N)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a colorless solution of N-[(1,1-dimethylethoxy)carbonyl]-2-methyl-alanine (CAN 30992-29-1; 1.0 g, 4.92 mmol) in DMF (24 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (3.07 g, 5.9 mmol) and DIEA (1.72 mL, 4.9 mmol), and the resulting pale yellow solution was stirred under argon for 30 minutes at room temperature. This mixture was added dropwise over 40 minutes to a suspension of hydroxyguanidine sulfate monohydrate (3.93 g, 14.8 mmol), DIEA (2.6 mL, 7.4 mmol), and molecular sieves (4 Å, 2 g) in DMF (35 mL) under argon, the temperature not exceeding 25° C. Once addition was complete another 2 g of molecular sieves was added and the reaction mixture (pale yellow suspension) was stirred for 1.5 hours under argon at room temperature then stirred at 130° C. for 20 hours. After cooling to room temperature the mixture was filtered through Celite®. The filtrate was concentrated in vacuo (HV pump) and the residue was stirred vigorously with 2-methoxy-2-methylpropane (40 mL) and 1N NaOH (40 mL) for 20 h. Phases were separated; the aqueous phase was washed with 2-methoxy-2-methylpropane (2×10 mL). Combined organic extracts were washed with water, then dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 50 g, 0% to 100% EtOAc in hexanes) to give the title compound (106 mg, 8.9%), which was used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([CH:14]([NH2:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][CH2:12][CH2:13]3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCN(C3CC3)CC2)CCC1
Product: NC(c1ccccc1)C1(N2CCN(C3CC3)CC2)CCC1

Procedure:
The title compound, yellow liquid, MS: m/e=286.2 [(M+H)+], was prepared in accordance with the general method or intermediate B from 1-(4-cyclopropyl-piperazin-1-yl)-cyclobutanecarbonitrile (intermediate V) and phenyllithium.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:12][S:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1OS(C)(=O)=O
Reaction time: 20 h
Yield: 92.8 %

Procedure:
A solution of methyl salicylate (200 g, 1310 mmoles) and methanesulfonyl chloride (210 g, 1830 mmoles) in toluene (600 ml), cooled at 5÷10° C. and under inert atmosphere (nitrogen), is slowly added (about 1 hour) with triethylamine (192 g, 1900 mmoles). The mixture is stirred for 20 hours, then poured into water (1500 ml) and the phases are separated. The aqueous phase is extracted twice with 250 ml of toluene. The combined organic phases are washed twice with 250 ml of water, dried over sodium sulfate, then evaporated under vacuum to a residue which is recrystallized from isopropanol (590 ml) to yield methyl 2-(methanesulfonyloxy)benzoate (280 g, 99.8% purity, 89% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.CO[N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(N(CC)CC)C.C(O)[CH2:36][OH:37]>>[CH3:36][O:37][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: CON1CCN(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: OCCO
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
A suspension of p-nitrobenzyl chloride (2.58 g, 15 mM), p-methoxyphenylpiperazine dihydrochloride (3.97 g, 15 mM) and triethylamine (4.55 g, 30 mM) in 25 ml of ethylene glycol is heated at 80° C. for 1 hour under nitrogen. The resulting mixture is quenched with cold water, neutralized with 10% aqueous sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over sodium sulfate and concentrated to a yellow solid. This, after recrystallization from ethyl acetate, gives 4 g (81%) of 1-(4-methoxyphenyl)-4-[ (4-nitrophenyl)-methyl ]piperazine of melting point 130° -132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[CH:15])=[CH:4][CH:3]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:20]=[N:21][NH:22][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccccc1-c1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2-c2c[nH]nn2)cc1
Yield: 44 %

Procedure:
A solution of 2.52 g (13.1 mmol) of 4-methyl-2'-ethynyl-1,1'-biphenyl in 18 mL of trimethylsilyl azide under a nitrogen atmosphere was heated at 120° C. for 72 hours. The volume was reduced by distillation at atmosphere pressure. The residue was dissolved in methylene chloride. The organic layer was washed with water (3×) dried over magnesium sulfate, filtered and evaporated under vacuum to yield 3.1 g of crude product which was purified over silica gel, eluting with hexane/ethyl acetate (3:1) to yield 1.35 g (5.77 mmol, 44%) of the product. FAB-MS: calculated for C15H13N3 235; found 237. 1H NMR (400 MHz, CDCl3): 2.38 (s, 3H), 7.0 (s, 1H), 7.20 (dd, 4H), 7.40 (m, 3H), 7.80 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]([NH:9][CH3:10])=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=O)[CH:16]=[N:17][CH:18]=1.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[N:9]([CH3:10])[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:11]=2)[CH:16]=[N:17][CH:18]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CNc1ccc(OC)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)nc(-c1cncc(Br)c1)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-N1-methyl-benzene-1,2-diamine (34; 0.5 g, 0.00328 mol) and 5-bromo-pyridine-3-carbaldehyde (0.61 g, 0.00328 mol) in DMF (10 ml) and H2O (4 ml) was added OXONE® monopersulphate (2.42 g, 0.00394 mol). Reaction mass was stirred at room temperature for 3 h. The reaction mixture was basified with 10% K2CO3 solution to pH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 2-(5-bromo-pyridin-3-yl)-5-methoxy-1-methyl-1H-benzoimidazole (35).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[Cl:23][C:24]1[S:25][C:26]([Cl:33])=[CH:27][C:28]=1[S:29](Cl)(=[O:31])=[O:30]>>[ClH:23].[Cl:23][C:24]1[S:25][C:26]([Cl:33])=[CH:27][C:28]=1[S:29]([N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Product: Cl
Product: O=S(=O)(c1cc(Cl)sc1Cl)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 2,5-dichloro-3-thienylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.24 (br, 1 H), 7.78 (d, J=5 Hz, 1 H), 7.72 (s, 1 H), 7.57 (d, J=8 Hz, 1 H), 7.29 (t, J=8 Hz, 1 H), 7.01 (d, J=5 Hz, 1 H), 6.86 (d, J=8 Hz, 1 H), 3.31 (m, 8 H). MS (ESI+) for m/z 416 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].[Cl:3][C:4]1[C:5]([N:16]([CH2:21][CH3:22])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:6]([CH:12]=[CH:13][C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:3][C:4]1[C:5]([N:16]([CH2:21][CH3:22])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:6]([CH:12]=[CH:13][C:14]=1[S:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CS
Reactant: CCOC(=O)c1ccc(F)c(Cl)c1N(CC)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC)c(Cl)c1N(CC)S(C)(=O)=O
Temperature: -10 °C

Procedure:
A solution of methanethiol (4 ml) in dry DMF was added to a mixture of ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoate (7.4 g) and anhydrous potassium carbonate (4.71 g) in DMF at -40° C. The mixture was maintained at -10° C. for 1 hour, then warmed to ambient temperature over 2.5 hours. Water was added and the mixture extracted with ether, washed with brine solution then water, dried (anhydrous magnesium sulphate) and the solvent evaporated to give ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)benzoate (8.3 g) as a white powder, m.p. 109-110.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O-:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[Na].[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[CH:16][C:15]=1[NH:14][C:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=1)=[O:10]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: CSc1ncc(C(=O)[O-])c(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 4-amino-2-methylsulfanyl-5-pyrimidinecarboxylate in a sodium salt form (1.28 g, 6.2 mmol), N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (1.82 g, 6.2 mmol), and DIEA (3.22 mL, 18.5 mmol) in DMF is added HATU (2.82 g, 7.42 mmol), and the mixture is stirred for 1 h at room temperature. The reaction mixture is diluted with EtOAc and washed with 5% aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution, and brine. The organic layer is dried over MgSO4 and concentrated in reduced pressure. The crude product is crystallized from MeOH to give 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide (1.79 g, 61%) as a white solid.
Reaction SMILES: BrC1C=CC([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])CC[CH2:31][CH2:30]2)=CC=1.[Br:41][C:42]1[CH:43]=[C:44]([CH:66]=[CH:67][CH:68]=1)CNC1C(N)=CC(OCC2C=CC3C(=CC=CC=3)N=2)=CC=1.[CH3:69]C1(C)[C@@H]2[C@H]1C(=O)OC2=O>>[Br:41][C:42]1[CH:68]=[C:67]([CH:66]=[CH:44][CH:43]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[CH:28]1[CH:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:30]1([CH3:31])[CH3:69]
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: CCOC(=O)C1C(c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C

Procedure:
The title compound was prepared using similar methods to those for ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate using N1-(3-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine and cis-6,6-dimethyl-3-oxa-bicyclo[3.1.0]hexane-2,4-dione. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.1 [M+H]+.
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:30](C(O)=O)[CH2:31][CH2:32][C:33](=[O:35])[NH2:34].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.CN(C=O)C>[NH:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:30]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:31][CH2:32][C:33](=[O:35])[NH2:34]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reaction time: 0.17 h

Procedure:
In 10 ml of trifluoroacetic acid is dissolved 0.80 g of BOC-Gly-MePhe-NHNHCSNH2, and the solution is shaken for 10 minutes, concentrated, treated with ether and filtered to obtain a powder. This powder is dissolved in 10 ml of DMF, and after ice-cooling, the solution is neutralized with 10 ml of DMF and 0.05 g BOC-(D)-Gln-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 20 hours. The precipitated DCU is filtered off, the solvent distilled off and the residue dissolved in n-butanol. The solution is washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is treated with ether and filtered to obtain a powder. Yield 0.73 g; m.p. 120°-123° C.; [α]D24 -46.0° (c=1.0, DMF); Rf1 0.18.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][C@@H:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[OH:12].[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:12][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][NH:2][CH2:37][C@H:35]([OH:36])[C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[O:34])[O:31][CH2:32][C:33]=2[C:25]=1[CH3:24]
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN2CCCCC2CN)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNCC2CCCCN2C[C@H](O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[2-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)piperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(1R)-2-[2-(Aminomethyl)piperidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 6] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[F:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:24]=2)=[CH:28][CH:27]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1nc(-c2cn3c(n2)-c2cc(-c4ccc(F)nc4)ccc2OCC3)n(C(C)C)n1
Yield: 39 %

Procedure:
10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with 6-fluoropyridin-3-ylboronic acid to give 10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.121 g, 39%). 1H NMR (500 MHz, DMSO) δ 8.67 (d, J=2.4, 1H), 8.52 (d, J=2.6, 1H), 8.25 (td, J=8.2, 2.7, 1H), 7.92 (s, 1H), 7.68 (dd, J=8.5, 2.5, 1H), 7.31 (dd, J=8.4, 2.8, 1H), 7.19 (d, J=8.5, 1H), 5.69 (dt, J=13.3, 6.6, 1H), 4.56 (s, 4H), 2.26 (s, 3H), 1.47 (d, J=6.6, 6H). MS (ESI(+)): m/z 405.2 (M+H)
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH:11]=[C:10]1[O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([NH2:37])(=[O:36])=[O:35]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:20][C:10]1[C:9](=[O:8])[C:18]2[C:13]([C:12](=[N:37][S:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH:11]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)COC1=CC(=O)c2ccccc2C1=O
Reactant: NS(=O)(=O)c1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
triethyl amine (0.12 ml, 0.88 mmol) was added in the mixture of tert-Butyl 2-(1,4-dioxo-1,4-dihydronaphthalen-2-yloxy)acetate (7c, 0.115 g, 0.4 mmol) and thiophene-2-sulfonamide (0.078 g, 0.48 mmol) in anhydrous DCM (4 ml), followed by adding TiCl4.2THF. The reaction mixture was heated with μW at 60° C. for 20 min. and poured into EtOAC, then filtered with celite. The filtrate was concentrated under reduce pressure and purified by flash chromatography to give compound 8d as a yellow solid, 22%, m.p.=153-155° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH3:7])[CH2:5][OH:6].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>>[CH3:21][O:22][CH2:23][O:6][CH2:5][C@@H:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8]
Reactant: COCCl
Reactant: COC(=O)[C@H](C)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC[C@@H](C)C(=O)OC
Temperature: -78 °C
Yield: 87.2 %

Procedure:
(R)-3-Hydroxy-2-methyl-propionic acid methyl ester (8.60 g, 0.0728 mol) was dissolved in methylene chloride (200 mL, 3 mol), followed by N,N-diisopropylethylamine (25.4 mL, 0.146 mol). The reaction mixture was then cooled to −78° C., and chloromethyl methyl ether (9.48 mL, 0.0874 mol) was added dropwise. The reaction mixture was then allowed to warm up gradually over for 5 hours to 23° C., and quenched with Na2CO3 (sat). Organic layer was separated, and washed with water, brine, and then dried over Na2SO4. The to crude mixture was purified via chromatography (SiO2, 120 g, 0-30% ethyl acetate/hexanes) to give 10.3 g clear liquid product (87%). 1H NMR (CHLOROFORM-d) δ: 4.61 (s, 2H), 3.71 (m, 4H), 3.58 (dd, J=9.5, 5.5 Hz, 1H), 3.35 (s, 3H), 2.77 (m, 1H), 1.19 (d, J=7.0 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1Cl)C.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][SH:18])[CH3:14].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:15][C:16]([C:17]1[S:18][C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[OH:12])=[O:19])[CH3:14]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1ccncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cnccc2c1O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
To a cooled (5° C.) stirred solution of 3-chloro-isonicotinic acid ethyl ester (1.11 g, 6.0 mmol) and mercapto-acetic acid ethyl ester (1.8 ml, 16.7 mmol) in anhydrous DMF (20 ml), under an argon atmosphere, was added sodium hydride (15.6 mmol, 60% dispersion in oil, 622 mg) in portions over 20 minutes. Stirring was continued at 5° C. for 20 minutes, followed by 18 hours at room temperature. The reaction mixture was then quenched by the addition of water (5 ml), acidified by the addition of acetic acid (1 ml), and subsequently concentrated to provide a residue. The residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The organic phase was isolated, dried over sodium sulphate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to 30:70) to afford the title compound as a yellow solid (1.33 g, 99%). LCMS (method B): RT=2.57 min, M+H+=224.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[CH2:4][NH2:5].[C:13]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:20]=1)([O:15][CH3:16])=[O:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:13]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:5][CH2:4][CH:3]([O:2][CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)=[CH:23][CH:24]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(CN)c1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(CCNCC(OC)c2cccc(Cl)c2)cc1
Temperature: 55 °C

Procedure:
A mixture of 2-methoxy-2-(3-chlorophenyl)ethanamine (1.81 g), 2-(4-carbomethoxymethoxyphenyl)-1-(p-toluenesulphonyloxy)ethane (4.0 g) and triethylamine (4 ml) in dimethyl sulphoxide (50 ml) was heated at 55° C. After 24 h the solution was poured into saturated sodium carbonate solution and the aqueous layer extracted with dichloromethane. The organic extract was separated, dried and evaporated. Chromatography over silica gel (eluting with 2% methanol-dichloromethane) gave N-[2-(4-carbomethoxymethoxyphenyl)ethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine which was converted into the title compound, mp 167°-169° C. (ethyl acetate-hexane) by an analogous procedure to that described in Example 4.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[C:6]=1[C:7]#[N:8]>C1COCC1.CCOC(C)=O>[Cl:16][C:9]1[C:6]([C:7]#[N:8])=[C:5]([NH:3][CH2:1][CH3:2])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of ethylamine in THF (2 M, 13.8 mL, 27.6 mmol) was added slowly to a solution of 2,6-dichloro-3-nitrobenzonitrile (3.0 g, 13.8 mmol) in THF (30 mL) at −5° C. After 1.5 h, the solution was diluted with EtOAc (150 mL) and washed with 0.5 N HCl and brine. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (8:1:1 hexanes/CHCl3/EtOAc) gave 2.57 g (82%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (br s, 1H), 8.30 (d, 1H, J=8.8 Hz), 6.78 (d, 1H, J=8.4 Hz), 3.89-3.97 (m, 2H), 1.41 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C9H8N3O2Cl, 226, 228; found 226, 228.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27](C(O)=O)=[CH:28][CH:29]=[CH:30][CH:31]=1.[NH3:35]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[C@H:9]([C:16]([NH2:35])=[O:18])[CH2:10]1
Reactant: Cc1ccccc1-c1ccccc1C(=O)O
Reactant: N
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(N)=O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]carboxylic acid, and ammonia (0.5M in dioxane), the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=352.