Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([N:5]([CH2:15][C:16]1([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:2]([F:1])([F:33])[C:3]([N:5]([CH2:15][C:16]1([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1,4-dicarboxylate (150 mg, 0.310 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 aqueous solution, extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give 110 mg of product as oil. MS: (M+H)+=385.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.37-1.67 (m, 4H), 2.11-2.32 (m, 2H), 2.42 (ddd, J=10.17, 6.51, 3.54 Hz, 1H), 2.57 (m, J=12.60, 12.60, 5.87, 2.78 Hz, 2H), 2.90-3.07 (m, 2H), 3.17 (dt, J=7.45, 3.60 Hz, 1H), 3.52-3.58 (m, 3H), 3.70-3.84 (m, 2H), 7.10 (d, J=7.07 Hz, 2H), 7.19-7.26 (m, 1H), 7.28-7.35 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]([OH:27])=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CCOCC>[CH2:28]([NH:35][C:25](=[O:27])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Yield: 89.3 %

Procedure:
5 g (13.14 mmol) of Nα-benzyloxycarbonyl-Nε-tert.-butoxycarbonyl-L-lysine in 30 cm3 of dry DMF and 1.41 g (13.14 mmol) of benzylamine are condensed in the presence of 2.01 g (13.14 mmol) of hydroxybenzotriazole in 10 cm3 of dry DMF and 2.98 g (14.54 mmol) of dicyclohexylcarbodiimide in 10 cm3 of dry DMF. A pasty solid is obtained after treatment under the same conditions as for the preparation of the compound (5). This solid is covered with ether to give a precipitate of N-benzyl-Nα-benzyloxycarbonyl-Nε-tert.-butoxycarbonyl-L-lysinamide (5.51 g; 89%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([CH:6]=[O:7])[CH2:3]1.I[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[N:23]1[C:36]2C(=CC=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.[Cu]I>[CH:33]1([N:34]2[CH2:26][CH2:25][CH2:24][N:23]([C:6]([N:4]3[CH2:5][CH:2]([O:1][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[CH2:3]3)=[O:7])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30]1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: COc1ccc(I)cc1
Reactant: O=CN1CC(O)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 100 °C
Yield: 187.8 %

Procedure:
To a stirred suspension of 4-cyclobutyl-[1,4]diazepan-1-yl)-(3-hydroxy-azetidin-1-yl)-methanone (50 mg, 0.197 mmol) in toluene (2 ml) was added 4-iodoanisole (69 mg, 0.296 mmol), Cs2CO3 (128 mg, 0.394 mmol), CuI (3.7 mg, 0.0197 mmol) and 1,10-phenanthroline (7.1 mg, 0.04 mmol). The resulting mixture was heated at 100° C. overnight, then cooled to RT and filtered through a plug of silica gel, eluting with EtOAc. The filtrate was concentrated in vacuo and the residue purified by FCC [silica, eluting with DCM/MeOH/NH3; 90:10:1] to provide the title compound as colourless oil (27 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)=[C:5]([N+:19]([O-])=O)[CH:4]=1.[H][H]>C(O)C.[Pd]>[NH2:19][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=1
Reactant: COc1ccc(Nc2ccc([N+](=O)[O-])nc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Nc2ccc(N)nc2)c(N)c1

Procedure:
To a solution of (4-Methoxy-2-nitro-phenyl)-(6-nitro-pyridin-3-yl)-amine (1.5 g, 1.55 mmol) in ethanol (50 ml) was added Pd/C (0.05 g) under N2. The mixture was shaken under a positive pressure of hydrogen at 5° C. for 4 h. After removal of the catalyst by filtration, the filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The crude product, N5-(2-Amino-4-methoxy-phenyl)-pyridine-2,5-diamine, thus obtained was used directly for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:31][CH:28]3[CH2:30][CH2:29]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCC3CC3)nc3cc(Cl)ccc23)CC1
Yield: 31.8 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and cyclopropylmethylamine (360 μL, 4.0 mmol) are treated according to method E yielding 53 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(cyclopropylmethylamino)quinoline. 47 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (19 μL) and triethylamine (140 μL).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.[BH3-]C#N.[Na+]>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][CH:28]=1
Reactant: C1CCNC1
Reactant: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
A mixture of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 uL) and pyrrolidine (1.05 g, 15 mmol) in acetonitrile (7 mL) was stirred at room temperature for 4 hr. To this mixture was added NaCNBH3 (36 mg, 0.67 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 4 hr. Upon removal of solvents under reduced pressure, the residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give the title compound as a white solid (21 mg, yield 22%). LC-MS (ESI) m/z: 427 (M+1)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][N:13]([CH2:36][C:37]1[N:38]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:39]=[CH:40][N:41]=1)[C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21](C(OCC1C=CC=CC=1)=O)[CH2:20][CH2:19]2)=[O:15]>[C].[Pd]>[CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][N:13]([CH2:36][C:37]1[N:38]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:39]=[CH:40][N:41]=1)[C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][NH:21][CH2:20][CH2:19]2)=[O:15]
Reactant: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Product: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc2c(c1)CCNC2

Procedure:
The same procedure as a series of reactions of Example 2 was carried out, except that the compound 12 was used in place of the compound 1 and 10% palladium carbon was used in place of 20% palladium hydroxide carbon, to obtain the title compound having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:45])[CH2:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[O:35])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21](COCC[Si](C)(C)C)[CH:22]=3)[S:17][C:10]=12>C(O)(C(F)(F)F)=O>[NH:21]1[CH:22]=[C:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:31][C:32](=[O:45])[CH2:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[O:35])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:19]=[CH:20]1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(COCC[Si](C)(C)C)cn4)sc23)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4c[nH]cn4)sc23)c(F)c1
Yield: 113.3 %

Procedure:
A solution of 105 (42 mg, 0.0648 mmol) in TFA (1 ml) was stirred at RT for 30 mins. The TFA was removed by evaporation and then 4N HCl in dioxane (0.5 ml) was added and the mixture was concentrated to dryness. The residual solid was triturated with diethyl ether to afford title compound 102 (38 mg, 100% yield). MS (m/z): 518.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCN(S(C)(=O)=O)C3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 4-(3-amino-6-(1-(methylsulfonyl)piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (60 mg, 0.147 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (400 μL, 0.400 mmol). The reaction mixture was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to ˜3 to 4 with 2 N HCl, and the product was extracted with ethyl acetate. The organic layer was separated from water and washed with brine, dried over sodium sulfate, filtered off, and evaporated to provide the crude product, which was taken to the next step without further purification. LCMS (m/z): 395.1 (MH+), 0.573 min.
Reaction SMILES: [Te:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>C(Cl)(Cl)(Cl)Cl>[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Te:1]([Cl:5])([Cl:3])[Cl:2])=[CH:14][CH:13]=1)=[O:9]
Reactant: Cl[Te](Cl)(Cl)Cl
Reactant: COC(=O)COc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1ccc([Te](Cl)(Cl)Cl)cc1
Yield: 96.1 %

Procedure:
Tellurium tetrachloride (11.36 g, 0.042 mol) and methyl phenoxy acetate (21.00 g, 0.127 mol) were refluxed in carbon tetrachloride (175 ml) for 18 h. The reaction solution was filtered while still hot, the filtrate cooled in an ice bath and the resulting solid filtered to afford p-methoxycarbonylmethoxyphenyltellurium trichloride (16.11 g, 96%) δ(CDCl3 /DMSO d6) 8.38 (2H,d,9Hz), 6.90 (2H,d,9 Hz), 4.67 (2H,s), and 3.77 (3H,s). No attempt was made to purify this compound and it was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][CH:14]([F:29])[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:24][CH2:23][C@H:22]([OH:25])[C:21]2=[O:26])=[CH:17][CH:16]=1>ClCCl.O>[CH3:8][S:9]([O:25][C@H:22]1[CH2:23][CH2:24][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH:14]([F:13])[F:29])=[CH:28][CH:27]=2)[C:21]1=[O:26])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@@H](O)CCN1Cc1ccc(C(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Triethylamine (0.319 mL, 2.29 mmol) and methansulfonyl chloride (0.131 mL, 1.68 mmol) was added to a stirred solution of (S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, 1.53 mmol, intermediate L) in dichloromethane (7.63 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel column chromatography (0-100% EtOAc). The pure fractions were combined and concentrated in vacuo to afford the desired product (322 mg, 66% yield) as a white solid: LC-MS (M+H)+ 320.1; 1H NMR (500 MHz, chloroform-d) δ 7.53 (d, J=7.9 Hz, 2H), 7.38-7.33 (m, 2H), 6.67 (br. t, J=1.0 Hz, 1H), 5.27 (dd, J=8.2, 7.5 Hz, 1H), 4.60-4.49 (m, 2H), 3.41-3.35 (m, 1H), 3.33 (s, 3H), 3.27 (dt, J=9.9, 7.3 Hz, 1H), 2.64-2.55 (m, 1H), 2.27 (ddt, J=13.9, 8.9, 7.1 Hz, 1H).
Reaction SMILES: CO.[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1.[OH-].[K+]>O>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: COC(=O)CCOCCc1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To methanol (5 mL) solution of 5.00 g of methyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added water (5 mL) solution of 1.27 g of potassium hydroxide, which was then stirred at room temperature for 2 hours. This reaction mixture was distilled off under reduced pressure, to which were added 30 mL of toluene and 30 mL of water. The pH was adjusted to 1.0 with 5 mL of 6 mol/L hydrochloric acid. The organic layer was separated, followed by distilling off the solvent under reduced pressure. Thereto were added 11 mL of toluene and 30 mL of cyclohexane. The precipitate was collected by filtration to provide 4.51 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid as white solid form.
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1.C[O-].[Na+].[OH-].[Na+]>CO>[O:2]=[C:3]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[S:4]1
Reactant: COc1ncc(C(=O)O)s1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(=O)s1
Temperature: 25 °C

Procedure:
2-Methoxythiazole-5-carboxylic acid (step 1) (45.5 mg, 0.286 mmol) was solubilised in MeOH (2 ml) and treated with 5.4M NaOMe in MeOH (212 μl, 1.143 mmol) followed by 2M NaOH (572 μl, 1.143 mmol). The reaction mixture was refluxed overnight and after cooling to RT, the solvent was evaporated under reduced pressure. The residue was acidified with 6M aqueous hydrochloric acid and aqueous layer extracted with EtOAc. The organics were combined and dried over MgSO4 (anh) filtered and evaporated under reduced pressure resulting in a pale yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][CH:14]([CH3:24])[CH2:13][C@H:2]1[C:3](=[O:11])[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: O=C1COc2ccccc2N1
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)C[C@@H]1Oc2ccccc2NC1=O
Yield: 77.9 %

Procedure:
4H-Benzo[1,4]oxazin-3-one (2.47 g, 16.5 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (95MF94) (4.01 g, 15.0 mmol) and Cs2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM24-21) (3.92 g, 78%). 1H NMR (CDCl3) δ 7.15-7.11 (m, 1H), 6.99-6.91 (m, 3H), 4.60-4.50 (m, 2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz, 1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz, 1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz, 1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz, 1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11](I)[CH3:12]>C(O)C>[CH2:11]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCI
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSc1ccc(O)cc1

Procedure:
4-(Ethylthio)phenol was prepared as follows. Sixty grams of 4-mercaptophenol were dissolved in 50 milliliters of ethanol. To the solution was added 27 grams of potassium hydroxide dissolved in 150 milliliters of ethanol. Seventy-four grams of ethyl iodide were added at 20° C. to 32° C. over a thirty minute period. The flask contents were stripped to remove the solvent. Benzene was added and the reaction product was water washed. The reaction product was stripped to remove a trace of the 4-mercaptophenol. The product weighed 66 grams.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[OH:16][C@H:14]1[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:10]([O:12][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:11])[CH2:13]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of (4R)-1-(tert-butoxy carbonyl)-4-hydroxy-L-proline in DMF (80 ml) was added 5.4 g of NaHCO3 and 11.1 g of benzyl bromide and the reaction mixture was stirred at 60° C. for 5 hours. Water was added to the reaction solution and the resulting mixture was extracted with EtOAc. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: hexane/EtOAc=1/1 to CHCl3/MeOH=8/1; v/v) to obtain 10.0 g of the title compound (colorless oil).
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].Cl.[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9]([OH:11])=[O:10].[CH2:15](O)[CH3:16]>>[ClH:4].[NH2:6][C@H:7]([C:12]([O:14][CH2:1][CH3:2])=[O:13])[CH2:8][C:9]([O:11][CH2:15][CH3:16])=[O:10]
Reactant: CCO
Reactant: CC(=O)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cl
Product: CCOC(=O)C[C@H](N)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Absolute ethanol (420 ml) was cooled in ice and acetyl chloride (71.4 ml, 1.03 mol) was added dropwise to generate HCl in situ. After the addition, the reaction was stirred for additional 30 minutes. L-Aspartic acid (33.27 g, 0.25 mol) was added in one portion and the solution heated slowly after dissolution to reflux. Refluxing was continued until the reaction was complete (TLC). The reaction mixture was then cooled to 25° C. and the solvent was removed under reduced pressure. Further drying under vacuum gave crude diethyl L-aspartate hydrochloride 2 as a viscous oil which crystallised on standing to a white solid, yield: 60 g (100%). This material was used without further purification. Spectral data for this sample were consistent with those given in the literature1. 13C NMR (75 MHz, d6-DMSO) 169.1, 168.2, 70.0, 60.9, 48.5, 34.2, 14.9 and 13.9.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:43]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:43]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(C)(=O)=O)c3)c2)n1
Yield: 29.4 %

Procedure:
To a stirred and cooled solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-phenylamine (example 307) (0.200 g, 0.493 mmol) in EtOAc (2 mL) and sat. NaHCO3-sol. (1 mL) was added methanesulfonyl chloride (1.0 mL, 13.6 mmol) and the mixture was stirred at 23° C. for 2 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (0.070 g, 29%). MS (ISP) 484.4 [(M+H)+]; mp 196° C.
Reaction SMILES: [Br:1][C:2]1[C:3](C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH3:12].[CH2:14]([I:16])[CH3:15].[C:17](#N)C>>[I-:16].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N+:7]([CH2:14][CH3:15])=[C:6]([CH3:11])[C:5]2([CH3:12])[CH3:17]
Reactant: CC#N
Reactant: CCI
Reactant: Cc1[nH]c2ccc(Br)c(C)c2c1C
Product: CC[N+]1=C(C)C(C)(C)c2cc(Br)ccc21
Product: [I-]
Yield: 87 %

Procedure:
To a 250 mL flask were added bromotrimethylindole 2 (12 g, 50.4 mmol), acetonitrile (25 mL) and ethyl iodide (20 mL). The mixture was heated at reflux under argon for 40 h. The bulk of the volatile components were removed by distillation. The residue was triturated with ether (100 mL) to give a powder. The solid was filtered off, washed with ether (2×50 mL) and dried under high vacuum to afford 3 as a solid (17.3 g, 87%).