Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH3:32])[CH:26]=2)=[CH:10][CH:9]=1.Br[CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C>[Si:37]([O:36][CH2:35][CH2:34][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:15]2[N:14]([C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=3)[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:26][C:27]=1[CH3:32])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1OCCO[Si](C)(C)C(C)(C)C
Yield: 103.6 %

Procedure:
K2CO3 (0.131 g, 0.95 mmol) was added to a solution of 3-(4-chlorophenyl)-2-(4-hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.230 g, 0.63 mmol) in DMF (15 mL) and stirred for 30 min. (2-Bromoethoxy)(tert-butyl)dimethylsilane (0.16 mL, 0.76 mmol) was added and the reaction was heated to reflux temperature for 3 hours, and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, and then brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford 2-(4-(2-(tert-Butyldimethylsilyloxy)ethoxy)-3-methylphenyl)-3-(4-chlorophenyl)quinazolin-4(3H)-one (0.340 g, quantitative).
Reaction SMILES: [Mg].C(Br)C.C([Mg]Br)C.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C:15]([NH:18][C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[C:20]=1[C:28]([O-])=[O:29])(=[O:17])[CH3:16]>O1CCCC1>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[NH:9][C:28]([C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:19]=1[NH:18][C:15]([CH3:16])=[O:17])=[O:29]
Reactant: Nc1cccs1
Reactant: CC(=O)Nc1sc2ccccc2c1C(=O)[O-]
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CC(=O)Nc1sc2ccccc2c1C(=O)Nc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g of magnesium curlings and 30 ml of anhydrous tetrahydrofuran are initially introduced into a sulfonation flask and 13.5 g of ethyl bromide are added in order to prepare ethyl-magnesium bromide. After the magnesium has dissolved, 6.1 g of 2-aminothiophen, dissolved in 60 ml of absolute tetrahydrofuran, are added dropwise and the mixture is stirred for one hour at room temperature and then refluxed for a further 15 minutes. 8 g of . . . 2-acetamido-benzo[b]thiophen-3-carboxylate, dissolved in 100 ml of absolute tetrahydrofuran, are then added dropwise at room temperature. The mixture is then refluxed for 15 minutes and stirred for a further 15 minutes at room temperature, the reaction solution is evaporated in vacuo, dilute hydrochloric acid is added to the evaporation residue and the mixture is extracted twice with chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated to dryness in vacuo. Crude N-(2-thienyl)-2-acetamino-benzo[b]thiophen-3-carboxamide is obtained and this can be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[NH:13][C:12](=O)[C:11]3=[CH:15][CH:16]=[CH:17][N:10]3[N:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:21])=O.CN(C)C1C=CC=CC=1>>[Cl:21][C:12]1[C:11]2=[CH:15][CH:16]=[CH:17][N:10]2[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nn2cccc12
Solvent: CN(C)c1ccccc1
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2cccn2n1
Temperature: 110 °C
Yield: 56 %

Procedure:
2-(5-Chloro-2-fluoro-phenyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (60 mg, 0.228 mmole) was added to phosphorous oxychloride (1 ml). 57 microliters N,N-dimethylaniline (catalyst) were added and heated to 110° C. overnight. The excess phosphorous oxychloride was removed under vacuum, and the residue was treated with ice, and the product extracted with chloroform. The chloroform extract was dried over sodium sulfate (anh.) and the solvent was removed to give crude product. The product was purified by silica gel chromatography eluting with chloroform to give 36 mg of product (yield: 56%).
Reaction SMILES: [CH2:1]([O:9][C:10](=[O:18])[CH:11]([CH:13]([C:15]([OH:17])=[O:16])[OH:14])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:9][C:10](=[O:18])[C@H:11]([C@@H:13]([C:15]([OH:17])=[O:16])[OH:14])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(=O)C(O)C(O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
The tartaric acid - mono - n - octylester is dissolved in tetrahydrofuran and treated with p-vinyl-anilinein presence of N,N'-dicyclohexyl-carbodiimide, D-Tartaric acid - mono - n - octylester (p-vinyl-anilide) is formed in high yields. This product is boiled with tri- (p-vinyl-phenyl)boroxine in benzene in a flask provided with a water separator. In nearly quantitative yield D-tartaric acid - mono - n - octylester - 2,3 -0- (p-vinyl-phenyl-boranate)- (p-vinylanilide) is formed.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]2[N:7]=[CH:8][C:9]([NH2:10])=[C:3]12.Cl[C:12]1[N:17]=[C:16]([NH:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][NH:18][C:16]1[C:15]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:13]=[C:12]([NH:10][C:9]2[CH:8]=[N:7][N:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]=23)[N:17]=1
Reactant: CN1CCn2ncc(N)c21
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: CNc1nc(Nc2cnn3c2N(C)CC3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 13.8 %

Procedure:
A mixture of 1-methyl-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-7-amine (91 mg, 0.66 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (90 mg, 0.44 mmol), cesium carbonate (287 mg, 0.88 mmol), palladium acetate (2 mg, 0.009) and Brettphos (7 mg, 0.013 mmol) in 1,4-dioxane (1.5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction tube was sealed and the mixture was heated to 100° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (5 mL) and washed with water (2×5 mL). The aqueous washes were combined and extracted with EtOAc (5 mL). The organic extracts were combined and filtered through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (19 mg, 14%). 1H NMR (400 MHz, DMSO) δ 8.64† (br s, 1H), 8.32* (br s, 1H), 8.05 (s, 1H), 7.30† (br s, 1H), 7.11* (br s, 1H), 6.91 (s, 1H), 4.06 (t, J=7.6 Hz, 2H), 3.65 (t, J=7.6 Hz, 2H), 2.86 (d, J=4.4 Hz, 3H), 2.69 (s, 3H)†and * refer to different rotamers (arbitrarily assigned). LC-MS (Method C): m/z=314 (M+H)+, 2.78 min, 98.7% purity.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([Cl:27])[N:19]=1>C(#N)C>[Cl:27][C:20]1[N:19]=[C:18]([NH:16][C:15]2[C:10]([O:9][CH3:8])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: COc1ncccc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ncccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 14.1 %

Procedure:
Triethylamine (6.5 mL, 46.6 mmol) was added to a solution of 2-methoxypyridin-3-amine (1.0 g, 8.1 mmol) and 2,6-dichloro-3-nitropyridine (1.62 g, 8.4 mmol) in acetonitrile (30 mL) and the resulting mixture was stirred at ambient temperature for 5 days and then at 50° C. for 24 h. The precipitate formed was filtered, washed with acetonitrile and dried in vacuo. The solid was then treated with tetrahydrofuran, filtered, washed with more tetrahydrofuran and the combined filtrate and washings were concentrated to dryness under reduced pressure to yield the title compound (0.32 g, 11%) as an orange solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([O:19][C@@H:20]([C@H:22]3[CH2:26][NH:25][C:24](=[O:27])[CH2:23]3)[CH3:21])[CH:10]=2)O1.Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[F:37][C:36]([F:39])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([O:19][C@@H:20]([C@H:22]3[CH2:26][NH:25][C:24](=[O:27])[CH2:23]3)[CH3:21])[CH:10]=2)=[N:31][CH:32]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncccc12)[C@H]1CNC(=O)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(-c2ccc(C(F)(F)F)cn2)cc2ncccc12)[C@H]1CNC(=O)C1
Yield: 62.1 %

Procedure:
500 mg (R)-4-{(R)-1-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one (325 mg 2-Bromo-5-trifluoromethyl-pyridine, 46 mg Bis(triphenylphosphine)palladium(II) chloride, 1.96 mL 2N aqueous sodium carbonate and 10 mL DMF were heated at 80° C. for 18 hours. The reaction was partitioned between DCM and NaHCO3 (sat aq) then the organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC using a Hept/EtOAc/MeOH gradient to give 326 mg of (R)-4-{(R)-1-[7-(5-Trifluoromethyl-pyridin-2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1
Reactant: OC(c1cccc(Cl)c1)c1ccc2c(c1)Cc1ccccc1-2
Reactant: c1c[nH]cn1
Product: Clc1cccc(C(c2ccc3c(c2)Cc2ccccc2-3)n2ccnc2)c1

Procedure:
Using α-(9H-fluoren-2-yl)-3-chlorobenzyl alcohol and imidazole as starting compounds, the process of Example 1 was repeated to obtain 1-[3-chloro-α-(9H-fluoren-2-yl)benzyl]-1H-imidazole.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:36])[CH:34]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([C:47]([F:49])([F:50])[F:48])(=[O:46])=[O:45])=[CH:42][CH:43]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:53][CH:54]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A solution of triphenylphosphine (206 mg, 0.785 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (140 mg, 0.785 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (250 mg, 0.710 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (271 mg, 1.57 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded the pure N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (226 mg, 63%) as a yellow foam: mp 130–132° C.; EI-HRMS m/e calcd for C20H20BrF3N2O3S (M+) 504.0330, found 504.0325.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29]CC5C=CC=CC=5)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[BrH:39]>C(O)(=O)C>[BrH:39].[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:37])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(OCc3ccccc3)cn2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(O)cn2)cc1
Yield: 62 %

Procedure:
To a stirred solution of N-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)benzoyl]amino}benzamide (1.0 g, 1.97 mmol) in glacial acetic acid (10 mL) was added a solution of HBr (48% in acetic acid, 30 mL). After 6 hours at 25° C. the solution was diluted with etlher (100 mL) and the resultant precipitate filtered off and dried to give the title compound as a pale yellow solid (610 mg, 62%); NMR SIpectirum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.84 (m, 1H), 5.36 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.78-7.84 (m, 3H), 8.00 (d, 2H), 8.36 (m, 2H), 9.86 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:3]1[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(=O)N(C)OC)c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cn(-c2cccc(-c3cnn(C)c3)c2F)nc(C(=O)N(C)OC)c1=O
Yield: 69 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (500 mg, 1.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (295 mg, 1.42 mmol), Na2CO3 (302 mg, 2.85 mmol) and Pd(PPh3)4 (74.5 mg, 0.0645 mmol) in DME (11.4 mL) and water (2.9 mL) was heated to reflux for 15 h under Ar. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography on basic silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title compound (345 mg, 69% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.25 (3H, s), 3.59 (3H, s), 3.80 (3H, s), 3.90 (3H, s), 7.35-7.44 (1H, m), 7.50-7.59 (1H, m), 7.84-7.94 (1H, m), 7.97 (1H, s), 8.23 (1H, d, J=2.5 Hz), 8.58 (1H, s).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8](OCC)=[O:9])[N:6]=1.[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:13])[CH2:8][OH:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(Br)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC(O)c1csc(Br)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.3 %

Procedure:
Ethyl (2-bromo-1,3-thiazol-4-yl)(oxo)acetate (3.07 g, 11.6 mmol) synthesized in Example (9a) was dissolved in methanol (100 mL), and cooled to 0° C. Sodium borohydride (1.32 g, 34.9 mmol) was added in small portions, and stirring was carried out at 0° C. for 1.5 hours, followed by stirring at room temperature for further 2 hours. Dilute hydrochloric acid (1M, 100 mL) was added, and the solution was separated with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-80%) to afford the desired compound (1.10 g, yield 42%) as a yellow oil.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.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.[NH2:72][C@H:73]1[C@@H:76]([CH2:77][N:78]2[N:82]=[C:81]([CH2:83][OH:84])[CH:80]=[N:79]2)[NH:75][C:74]1=[O:85]>C(Cl)Cl.CN(C=O)C>[C:35]([O:34][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])[CH2:18][CH2:19]2)/[C:23]([NH:72][C@@H:73]2[C:74](=[O:85])[NH:75][C@@H:76]2[CH2:77][N:78]2[N:82]=[C:81]([CH2:83][OH:84])[CH:80]=[N:79]2)=[O:24])[N:27]=1)=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
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
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CO)n2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (2.5 g, 4.43 mmol) in DCM (78 mL) and DMF (15 ml) at 0° C. was added DIPEA (1.2 ml, 7.00 mmol), HATU (1.9 g, 5.13 mmol), and (3S,4R)-3-amino-4-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)azetidin-2-one (0.92 g, 4.67 mmol). After stirring at 0° C. for 1 h, the reaction mixture was diluted with DCM, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-5%), affording the title compound (2.5 g, 75%). LCMS: R=0.98 min, m/z=717.3 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([CH:22]=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:23])[CH2:24][CH3:25])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CC[Mg]Br
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (3.00 g, 8.67 mmol) in tetrahydrofuran (25 mL) was added dropwise ethylmagnesium bromide (3.0 M solution in diethyl ether, 3.4 mL, 10.4 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by methanol, and the mixture was neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (2.95 g, 7.84 mmol, 90%).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].Br[C-:7]1C=CC=[CH:8]1.[C-:12]1([Br:17])[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:18].[C:19]1([P:25]([Cl:27])Cl)[CH:24]=[CH:23][CH:22]=[CH:21]C=1.ClP>C1COCC1>[C:5]1([C-:21]2[CH:22]=[CH:23][CH:24]=[C:19]2[PH:25][Cl:27])[CH:8]=[CH:7][CH:2]=[CH:3][CH:4]=1.[Br:17][C-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:18]
Reactant: ClP(Cl)c1ccccc1
Reactant: [Li]CCCC
Agent: [Fe+2]
Agent: Br[c-]1cccc1
Agent: PCl
Solvent: C1CCOC1
Product: ClPc1ccc[c-]1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
14.5 ml (23.2 mmol) of n-BuLi (1.6 M in hexane) are added dropwise to a solution of 8 g (23.2 mmol) of 1,1′-dibromoferrocene in 30 ml of THF at a temperature of <−30° C. The mixture is stirred for another 30 minutes at this temperature. It is then cooled to −78° C. and 3.15 ml (23.2 mmol) of phenyldichlorophosphine are added dropwise at such a rate that the temperature does not exceed −60° C. After stirring at −78° C. for a further 10 minutes, the temperature is allowed to rise to room temperature and the mixture is stirred for another one hour. This gives a suspension of the monochlorophosphine X1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c2) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[C:5](=[O:15])[N:4]([CH3:16])[N:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[C:20]([N:25]([CH3:27])[NH2:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C(O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[N:26][N:25]([CH3:27])[C:20]2[C:19]([C:18]([F:29])([F:28])[F:17])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5](=[O:15])[N:4]([CH3:16])[N:3]=1
Reactant: CN(N)c1ncccc1C(F)(F)F
Reactant: Cn1nc(Cl)n(-c2ccccc2C=O)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(N=Cc1ccccc1-n1c(Cl)nn(C)c1=O)c1ncccc1C(F)(F)F
Temperature: 50 °C

Procedure:
The title compound of Step A (0.20 g, 0.80 mmol) was dissolved in absolute ethanol (7 mL) and a solution of 1-[3-(trifluoromethyl)pyridin-2-yl]-1-methylhydrazine in ethanol (3 mL) was added followed by 3 drops of glacial acetic acid. The mixture was warmed to 50° C. for 1 h, cooled to room temperature and then diluted with aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated to give 0.38 g of the title compound of Step B as a yellow solid. 1H NMR (300 MHz. CDCl3): δ 8.42 (d.1H. J=5 Hz), 8.16 (d,1H, J=8 Hz), 8.01 (d,1H, J=8 Hz), 7.51 (t,1H, J=8 Hz), 7.42 (t,1H), J=8 Hz), 7.35 (s,1H), 7.21 (d,1H, J=8 Hz), 7.03 (dd,1H, J=8, 5 Hz), 3.56 (s,6H).