Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:36]([O:43][C:44]1[CH:45]=[C:46]([Cl:53])[C:47]([CH2:51]Br)=[C:48]([Cl:50])[CH:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH2:36]([O:43][C:44]1[CH:45]=[C:46]([Cl:53])[C:47]([CH2:51][N:15]2[CH2:16][CH2:17][CH:13]([N:10]3[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:12][CH2:11]3)[C:14]2=[O:18])=[C:48]([Cl:50])[CH:49]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: CC(C)(C)[Si](OC1CCN(C2CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCN(C2CCN(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
Treat a −78° C. solution of 3-[4-(tert-butyl-diphenyl-silanyloxy)-piperidin-1-yl]-pyrrolidin-2-one (0.25 g, 0.59 mmol) in THF (6 mL) with a 1.6 M n-butyl lithium in hexanes (0.37 mL, 0.59 mmol) and stir at −78° C. for 10 minutes under N2. Treat the reaction with 5-benzyloxy-2-bromomethyl-1,3-dichloro-benzene (0.204 g, 0.59 mmol), warm to room temperature, and stir for 16 hours under N2. Re-cool the reaction to −78° C., treat with 1.6 M n-butyl lithium in hexanes (0.37 mL, 0.59 mmol), warm to room temperature, and stir for 2 hours. Quench the reaction with water and extract with ethyl acetate. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 50 to 100% ethyl acetate in hexanes gradient to afford 0.263 g (65%) of the titled product. Rf=0.18 (3/1 ethyl acetate/hexanes). ES MS (m/z): 687 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:19]1[NH:23][C:22](=[O:24])[O:21][N:20]=1.ClC1C=CC2C(=CC=C(O)C=2)N=1.C(C1C=CC(B(O)O)=C([F:48])C=1)#N>>[F:48][C:7]1[CH:2]=[C:3]([C:19]2[NH:23][C:22](=[O:24])[O:21][N:20]=2)[CH:4]=[CH:5][C:6]=1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]=1
Reactant: O=c1[nH]c(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2F)no1
Reactant: N#Cc1ccc(B(O)O)c(F)c1
Agent: Oc1ccc2nc(Cl)ccc2c1
Product: O=c1[nH]c(-c2ccc(-c3ccc4cc(O)ccc4n3)c(F)c2)no1

Procedure:
Followed procedure described for Compound 20 in Example 20 starting from 2-chloroquinolin-6-ol (Intermediate 2) and 4-cyano-2-fluorophenylboronic acid. 1H NMR (DMSO-d6, 300 MHz): δ 10.22 (1H, s), 8.27-8.33 (2H, m), 7.97 (1H, d, J=9 Hz), 7.77-7.82 (2H, m), 7.39 (1H, dd, J=3, 9 Hz), 7.21 (1H, d, J=3 Hz) ppm. MS (ESI): m/z 324.0 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=1)=[O:10].Cl.C(C(NCCCN(C)C)=N)C.ON1C2C=CC=CC=2N=N1.[F:48][C:49]([F:59])([F:58])[C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>CN(C=O)C.C(N(CC)CC)C>[F:48][C:49]([F:58])([F:59])[C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH:53][C:21]([C:14]1[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=[C:12]([NH:11][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:25])([F:24])[F:1])=[O:10])[CH:13]=1)=[O:23]
Reactant: O=C(Nc1cc2c(c(C(=O)O)c1)OCC2)c1ccccc1C(F)(F)F
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc2c(c(C(=O)NCc3ccccc3C(F)(F)F)c1)OCC2)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxylic acid (35 mg) in DMF (2 mL), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine hydrochloride (23 mg), 1-hydroxybenzotriazol (23 mg) and triethylamine (17 μL) were added. Under ice-cooling, to the mixture was added 2-(trifluoromethyl)benzylamine (15 μL), and it was stirred at room temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was washed with n-hexane/ethyl acetate (1:1) and collected by filtration to obtain the titled compound (43 mg) as colorless powder. MS (ESI+) m/z 509 (M+H)+, Rt=2.31 minutes (method A)
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([NH2:6])=[O:5].[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:18][C@@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[C:4]([NH2:6])=[O:5]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)C(=O)C(N)=O
Product: C[C@@H](N=C(C(N)=O)C(C)(C)C)c1ccccc1
Yield: 66.7 %

Procedure:
The procedure described under n) was carried out using 5.0 g of 3,3-dimethyl-2-oxo-butyramide and 10.0 g of (R)-1-phenylethylamine. After a single crystallization from hexane there were isolated 6.0 g (67%) of (R)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of melting point 100°-101° C. [α]=+61.4 (c=0.8, CHCl3).
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].B(F)(F)F.[CH3:23]COCC.[N+](=C)=[N-]>C(Cl)Cl>[CH3:1][C@@:2]1([O:18][CH3:23])[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(O)[C@H](C)O1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Product: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(OC)[C@H](C)O1
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 1 g (3.7 mmoles) of methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (II-A) in 10 ml of dry methylene dichloride was treated at -70° with 0.05 ml of boron trifluoride etherate. While maintaining the temperature at -70°, an excess of diazomethane dissolved in methylene dichloride was added until a faint yellow color persisted. After 60 minutes at -70°, a white solid (polymethylene) was removed by filtration, and the filtrate was washed successively with 10% sodium bicarbonate solution and with water, after which it was dried with anhydrous magnesium sulfate. The residue which was obtained by evaporation was chromatographed on a silica-gel column. Elution with a 95:5 chloroform:acetone mixture gave pure methyl 2,3,6-trideoxy-4-C-methyl-4-O-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (II-B, 0.68 g, 65%) as a syrup; [α]D =-129° (c=1.1 in CHCl3); mass spectrum m/e 285 (M+). The pmr spectrum (CDCl3) showed absorptions at 1.22 (s, CH3 -C-4), 1.28 (d, CH3 -C-5), 3.33 and 3.48 (two s, --OCH3) and 4.77δ (broad s, C-1-H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[O:15][CH2:14][CH2:13][O:4]1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 5 h
Yield: 98.9 %

Procedure:
2-bromo-1-(4'-methoxy-phenyl)-ethanone (20 g, 87 mmol), ethylene glycol (54 g, 870 mmol), para-toluenesulfonic acid hydrate (1.7 g, 8.7 mmol) and benzene (50 ml) are heated and stirred together for 5 h in a flask beneath a Dean-Stark trap. The reaction mixture is added dropwise to a well stirred saturated sodium carbonate solution (0.4 l) and extracted with ethyl ether (3×70 ml). The combined organic extract is washed with a 2% sodium hydrogen carbonate solution, dried (Na2CO3) and filtered. The solvent is evaporated under reduced pressure to give 2-bromomethyl-2-(4'-methoxy-phenyl)-1,3-dioxolane (23.5 g, 86 mmol; yield: 99%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Na+].[F:20][CH:21]([F:23])Cl>O>[F:20][CH:21]([F:23])[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: FC(F)Cl
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(OC(F)F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 43.0 g of 3-methyl-2-nitrophenol, 250 ml of p-dioxane, 150 ml of water, and 75 ml of 50% sodium hydroxide solution at 70° C. was added gaseous difluorochloromethane at a steady rate. The pH of the reaction was checked periodically. If the pH became acidic, 30 to 40 ml of 50% sodium hydroxide solution was added. After six hours of heating, the flow of the difluorochloromethane was halted and the reaction allowed to cool to room temperature. After standing overnight the reaction solution was poured onto a mixture of 50 g of ice and 250 ml of water and extracted with two 450 ml portions of ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and concentrated. The resulting brown liquid was dried in a vacuum oven at 45° C. overnight to yield 53.3 g of the desired intermediate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[CH:21](=[O:25])[CH2:22][CH2:23][CH3:24]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC=O
Reactant: Brc1cccc(Br)n1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCC(O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of 2,6-dibromopyridine (1.00 g, 4.22 mmol) in THF (40 mL) was cooled to −78° C. (dry-ice/acetone bath) and treated with nBuLi (2.64 mL of a 1.6M solution in hexanes, 4.22 mmol) drop-wise over 10 minutes under nitrogen. After 30 minutes at this temperature the pale yellow/green solution was treated with butyraldehyde (400 μL, 4.44 mmol) drop-wise over 5 minutes and the resulting orange/red solution stirred at this temperature for 1 hour. The solution was then allowed to warm slowly to 0° C. (ice/water bath) over 20 minutes and was then quenched by the drop-wise addition of aqueous HCl (2M, 4 mL). The resulting pale yellow solution was reduced to an oil, partitioned between EtOAc (100 mL) and aqueous HCl (2M, 100 mL), and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (150 mL), brine (150 mL), dried (MgSO4), filtered and reduced to an orange/yellow oil. Purification by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 2:1) afforded the title compound (626 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.57 ml of trans-crotonoyl chloride in 6 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid recrystallized from n-butanol to give 0.69 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(E)-2-butenamide: mp=153-160° C., mass spectrum (m/e): M+H 383, 385.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][NH2:29]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: COc1ccc(CN)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2I)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-iodobenzoic acid (1-1, 500 mg, 1.529 mmol, 1.0 equiv) in dichloromethane (8 mL) was added catalytic DMF (0.012 mL, 0.153 mmol, 0.1 equiv) and oxalyl chloride (0.161 mL, 1.835 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred for 1 hour and concentrated. The crude residue was dissolved in dichloromethane (15 mL) and to the reaction was added 3,4-dimethoxybenzylamine (281 mg, 1.682 mmol, 1.2 equiv), and TEA (0.682 mL, 4.59 mmol, 3.0 equiv) at 0° C. After stirring for 10 min, the mixture was removed from the cold bath, diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in hexanes) to afford the product (1-2) as a tan solid. ESI+ MS [M+H]− C16H15BrINO3: 476.9 found, 476.1 required.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Product: NC(Cc1cc(Br)c(OCc2ccccc2F)c(Br)c1)C(=O)O
Yield: 10 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 1-bromomethyl-2-fluorobenzene and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 10% yield of 2-amino-3-[3,5-dibromo-4-(2-fluorobenzyloxy)phenyl]propionic acid. LC/MS (electrospray): m/z 446 (M−1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]7[CH2:64][CH2:63][CH2:62][CH2:61]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](NC(=O)OC5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsi-lyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with cyclopentyl chloroformate (7.3 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and cyclopentyl chloroformate (7.3 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.30 min.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.CN([CH:16]=[O:17])C.Cl>C(OCC)C>[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:16]=[O:17]
Reactant: CN(C)C=O
Reactant: COc1ccsc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1C=O

Procedure:
3-Methoxy-2-thiophenecarboxadlehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane)(Aldrich), without cooling, to a solution of 3-methoxythiophene (1 g,8.8 mmol) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was gently heated at reflux for 2 h at which time the organolithium compound was transferred, via cannula, to a solution of DMF (23 mmol) in diethyl ether (5 mL) which was cooled in an ice bath. The reaction was stirred at room temperature for 14 h, at which time 1N HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3×25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to yield 3-methoxy-2-thiophenecarboxaldehyde as a pale, yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added to ethynylmagnesium chloride (Aldrich) according to Method A above to yield 3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. (Yield 151 mg, 0.9 mmol).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[CH2:11]1[O:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C@@H:9]1[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: O=Cc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: O=C1O[C@H]([C@@H]2COC(c3ccccc3)O2)C(O)=C1O
Reaction time: 1 h

Procedure:
Ascorbic acid (89.2 g.) was slurried in 400 ml. of p-dioxane, 200 g. of zinc chloride were added slowly and the resulting mixture was stirred for one hour. Next, 100 ml. (104 g.) of benzaldehyde were added. This reaction mixture was stirred at ambient temperature for about 24 hours and was then extracted with 500 ml. of ethyl acetate. The ethyl acetate extract was itself extracted with three portions of saturated aqueous sodium chloride. The ethyl acetate solution was dried and the dried solution treated with activated charcoal and then filtered through cellulose. Concentration of the filtrate caused 5,6-O-benzylidene-L-ascorbic acid to crystallize.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>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>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25](O)=[O:26])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1)#[N:2].ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[O:54]=[C:52]1[NH:51][CH2:50][CH2:47][N:49]([C:25]([C:16]2[CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([CH:8]=[C:7]([O:9][C:10]([F:12])([F:13])[F:11])[CH:6]=3)[C:1]#[N:2])[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=2)=[O:26])[CH2:53]1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Agent: O=C1CNCCN1
Product: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
30 mg (0.08 mmol) of the compound of Example 58A is reacted analogously to the synthesis of the compound of Example 1 with 9 mg (0.09 mmol) of 2-oxopiperazine. 30 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)=[CH:18][C:17]=2[Br:41])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([NH2:33])=[NH:25])=[CH:18][C:17]=2[Br:41])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1ccc(OCCCOS(=O)(=O)c2ccc(Br)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCc1ccc(OCCCOS(=O)(=O)c2ccc(Br)cc2)c(Br)c1
Reaction time: 4 h

Procedure:
A 25 mL round bottom flask was charged with Compound 4 (3.00 g, 4.15 mmol) then CH2Cl2 (6 mL), and the resulting suspension stirred until complete dissolution was observed. Trifluoroacetic acid (6 mL, 78.3 mmol) was then added and the mixture stirred an additional 4 h. All volatiles were then removed, and the residue treated with EtOAc (20 mL). The resulting mixture was stirred at room temperature for 3 h, during which time a white solid precipitated. The solids were collected on a sintered glass funnel of medium porosity then exhaustively washed with EtOAc (20 mL) and dried to constant weight (2.5 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.54 (m, 4H), 7.4 (d, 1H), 7.15 (m, 1H), 6.9 (d, 1H), 4.15 (m, 4H), 3.86 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]([NH:17][NH2:18])=O)[CH2:14][CH2:13]1.O.C([O-])(O)=O.[Na+]>O=P(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:3]([C:4]2[O:6][C:15]([CH:12]3[CH2:14][CH2:13]3)=[N:17][N:18]=2)[C:2]([NH2:1])=[N:10][CH:9]=1
Reactant: NNC(=O)C1CC1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Temperature: 0 °C
Yield: 95.4 %

Procedure:
A solution of 2-amino-5-bromo-nicotinic acid (300 mg, 1.38 mmol) and cyclopropanecarboxylic acid hydrazide (300 mg, 3.0 mmol) in POCl3 (30.0 mL,) was stirred for 18 h at 65° C. The reaction mixture was distilled under reduced pressure to obtain a residue, which was cooled to 0° C. by adding iced water and neutralizing with saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous Na2SO4 and evaporated to afford 370 mg of crude 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 15% EtOAc in petroleum ether to afford the title compound as a pale yellow solid used without further purification.