Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[O:25]=[C:23]1[NH:15][C:14]2[CH:13]=[CH:12][C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][C:2]=2[NH:1]1
Reactant: CCOC(=O)COc1ccc(N)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a stirred solution of ethyl 2-(3,4-diaminophenoxy)acetate (144 mg, 0.685 mmol) in dry CHCl3 (5 mL) at 0° C., pyridine (0.083 mL, 1.027 mmol) and triphosgene (203 mg, 0.685 mmol) were added and allowed to stir at room temperature for two hours. Completion of the reaction was monitored by LCMS. Solvent was removed under vacuum. Water was added to the residue. The solid which formed was filtered and dried to afford crude ethyl 2-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (85 mg, 75% by LCMS) which was used in the next step without further purification. 1H NMR: 400 MHZ, DMSO-d6: δ 1.22 (t, J=7.20 Hz, 3H), 4.18 (q, J=7.20 Hz, 2H), 4.70 (s, 2H), 6.52 (t, J=2.40 Hz, 2H), 6.81 (d, J=9.20 Hz, 1H), 10.40 (s, 1H), 10.51 (s, 1H). LCMS: RT 1.16 min. LCMS (ES-API), m/z 237.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Li].Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:22])=[O:21]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:21])=[O:22]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)c(F)c1
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.5 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 2.34 g, 9.35 mmol, 0.95 eq) was suspended in THF (20 ml) and stirred at 0° C. for 10 minutes. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 19.5 ml, 20 mmol, 2.0 eq) was added dropwise maintaining the temperature below 30° C. and the reaction mixture stirred for a further 30 minutes. A solution of 4-(chlorosulfonyl)-3-fluorobenzoic acid (Preparation 9, 2.35 g, 9.85 mmol, 1 eq) in THF (15 ml) was added dropwise maintaining the reaction temperature below 30° C. and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with brine (10 ml), extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was slurried in t-butylmethyl ether and stirred at room temperature for 72 hours. The resulting solid was collected by filtration to yield the title compound as a beige solid (744 mg, 1.64 mmol, 17%).
Reaction SMILES: [ClH:1].C1C=C[C:5]2N(O)N=[N:8][C:6]=2C=1.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=C[C:24]([N:27]2[CH2:32]CC3(CCNCC3)C[CH2:28]2)=[CH:23][CH:22]=1>C1COCC1.C(Cl)Cl>[CH3:5][CH2:6][N:8]=[C:26]=[N:21][CH2:22][CH2:23][CH2:24][N:27]([CH3:28])[CH3:32].[ClH:1]
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN=C=NCCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (939 mg, 4.9 mmol), HOBT (660 mg, 4.9 mmol) and DIPEA (2.2 ml, 12.69 mmol) were added to a solution of the product just obtained in step 4 (1 g, 3.2 mmol) in THF (20 ml). The reaction mixture was stirred at 25° C. for 30 min, a solution of 3-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane (3.2 mmol, 1 eq.) in THF (20 ml) was then added and the mixture was stirred further at 25° C. for 12 h. The reaction mixture was diluted with methylene chloride and washed with sat. NH4Cl solution and NaHCO3 solution. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[CH:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[I:1][CH2:2][C:3]1[N:4]=[C:35]([C:34]2[CH:33]=[CH:32][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:38][CH:37]=2)[O:36][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-isopropylbenzaldehyde gave 4-iodomethyl-2-(4 isopropylphenyl)-5-methyloxazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22](N(OC)C)=[O:23])[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[CH3:21][C@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])[C:22](=[O:23])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 4 h

Procedure:
To a stirred mixture of isopropylmagnesium chloride-lithium chloride complex (14% wt 1 M solution, 726 mg, 5 mmol, 5 ml) and THF (5 ml) was added 1-bromo-4-(trifluoromethyl)benzene (1.125 g, 5 mmol) under argon. The stirring was continued at r.t. for 4 h. A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (232 mg, 1 mmol) in THF (10 ml) was added dropwise, and the stirring was continued overnight at r.t. Then the reaction mixture was quenched with sat. aq. NH4Cl (20 ml), and stirring was continued for 30 min. The layers were separated, the aqueous layer extracted with ethyl acetate (20 ml). The combined organic extracts were dried over Na2SO4, and the solvent was evaporated to give yellow partly crystalline product. Purification by flash chromatography on silica gel with n-heptane/ethyl acetate afforded colourless solid, 260 mg (82%).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH:34]([CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1)=O.O>C1COCC1>[F:30][C:27]1[CH:26]=[C:5]([CH:6]=[CH:34][CH:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:4]=[C:3]([F:2])[C:28]=1[F:29]
Reactant: O=CC1CCC(=O)CC1
Reactant: Fc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(F)c1F
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(C=Cc2cc(F)c(F)c(F)c2)CC1
Yield: 70.5 %

Procedure:
A suspension of 3,4,5-trifluorobenzyltriphenylphosphonium bromide (234 g) in THF (500 ml) was stirred in a nitrogen gas stream, followed by adding sodium methoxide (32.4 g) little by little at room temperature, stirring the reaction solution at room temperature for one hour, dropwise adding a solution of 4-formylcyclohexanone (50 g) in THF (250 ml), stirring the mixture at room temperature for 2 hours, adding it to water (1 l) extracting with ethyl acetate (1 1), washing the organic layer with water, drying over anhydrous MgSO4, concentrating the solvent under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethenyl)cyclohexanone (71 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]#N)[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16].[S-2].[Na+].[Na+].[CH3:25][N:26]([CH3:36])[C:27]([C:29]1[CH:34]=[CH:33]C(I)=[CH:31][CH:30]=1)=[O:28]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]2[CH:33]=[CH:34][C:29]([C:27](=[O:28])[N:26]([CH3:36])[CH3:25])=[CH:30][CH:31]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16]
Reactant: C[C@@](O)(C(=O)Nc1ccc(SC#N)c(Cl)c1Cl)C(F)(F)F
Reactant: CN(C)C(=O)c1ccc(I)cc1
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cc1
Temperature: 50 °C

Procedure:
(R)-N[2,3-Dichloro-4-thiocyanatophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 39) (0.5 g) as a solution in DMF was treated with a solution of sodium sulphide (403 mg) in water (2 ml) and the mixture was heated at 50° C. for 1 hour. The reaction mixture was then treated with a solution of N,N-dimethylcarbamoyl-4-iodobenzene (0.455 g) in DMF (5 ml), followed by cuprous oxide (0.121 g). The reaction mixture was heated at 150° C. for 4.5 hours under an argon atmosphere. The reaction mixture was quenched with water (100 ml), and DCM was added (100 ml) and the mixture was filtered through diatomaceous earth. The aqueous layer was separated and washed with DCM (3×50 ml). The organic extracts were combined and dried. The volatile material was removed by evaporation, and the product was purified by chromatography using a Mega Bond Elut column (20 g silica) eluting with 0-5% MeOH/DCM to yield the title compound as a white solid. (0.53 g) 80%. NMR: 1.60 (s, 3H), 2.95 (d, 6H), 7.30 (d, 1H); 7.30-7.50 (m, 4H), 7.85 (s, 1H), 7.90 (d, 1H), 9.90 (s, 1H); m/z: 479.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[C:8]2[S:9][C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11](COC)[C:7]=2[CH:6]=[CH:5][N:4]=1.C[OH:28]>Cl>[OH:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[C:8]2[S:9][C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:28])[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: COCc1c(-c2ccccc2)sc2c(C(O)c3ccccc3)nccc12
Reactant: CO
Agent: Cl
Product: Oc1c(-c2ccccc2)sc2c(C(O)c3ccccc3)nccc12
Yield: 93 %

Procedure:
A solution of 0.61 g (1.8 mmol) of 7-(hydroxyphenylmethyl)-3-methoxymethyl-2-phenyl-6-azabenzo[b]thiophene in 2.7 mL of 2M HCl and 2.7 mL of methanol was heated at reflux for 30 minutes. The solution was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to afford 0.50 g (93%) of white solid, m.p. 214°-215° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[OH:10])=[CH:4][C:3]=1[CH3:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:16]=[C:15]([Cl:25])[C:14]=1[F:26].Cl([Na])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:20][C:19]([C:17]3[CH:16]=[C:15]([Cl:25])[C:14]([F:26])=[C:13]([Cl:12])[CH:18]=3)([C:21]([F:24])([F:23])[F:22])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: Cc1cc(/C=N/O)ccc1Br
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dichloromethane (10 mL), (E)-N-[(4-bromo-3-methylphenyl)methylidene]hydroxylamine (50 mg, 0.23 mmol, 1.00 equiv), 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (60 mg, 0.23 mmol, 1.00 equiv), chlorosylsodium (5 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3×10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 82 mg (75%) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)=[O:9])[CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (60 mL), obtained as described above for Intermediate 7, step 1 (798 mg; 4.51 mmol) was added dropwise, during a period of 30 minutes, a solution of 5-aminoindazole (Aldrich, 500 mg; 3.76 mmol) and DIEA (1.29 ml; 7.51 mmol) in dry DMF (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. A white precipitate separated from the organic phase. It was filtered and dried in vacuo to afford the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:24]=[C:25]([Cl:28])[C:26]=1[Cl:27].C(=O)([O-])O.[K+]>COCCOC.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:30][C:29]([C:23]3[CH:24]=[C:25]([Cl:28])[C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)([C:31]([F:34])([F:33])[F:32])[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: Cc1ccc(C=NO)cc1Cl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10.5 g of 3-chloro-4-methylbenzaldoxime in 50 mL of 1,2-dimethoxyethane, 9.1 g of N-chlorosuccinimide was added and the resultant mixture was stirred at 70° C. for 2 hours. Next, the reaction mixture was left to be cooled down to room temperature and to the reaction mixture, 17.0 g of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 9.3 g of potassium hydrogen carbonate and 10 mL of water were added, followed by continuing the stirring of the reaction mixture at room temperature further for 16 hours. After the completion of the reaction, the reaction mixture was diluted with 200 mL of ethyl acetate, and the diluted reaction mixture was washed with water (70 mL×1). Subsequently, the washed reaction mixture was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:5) to obtain 26.2 g of the objective substance as a brown resinoid.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[Cl:8][C:7]1[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:10]=2[F:9])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Br
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(-c2ncccc2Cl)c1F
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-3-chloropyridine [96424-68-9] (144 mg, 0.75 mmol) and 2-fluoro-3-nitrophenylboronic acid pinacol ester [1189042-70-3] (200 mg, 0.75 mmol) in dioxane (4 mL) and water (1 mL) was added potassium carbonate (259 mg, 1.87 mmol) and Pd(dppf)Cl2CH2Cl2 adduct (61.2 mg, 0.075 mmol). The solution was heated for 60 min at 120° C. under microwave irradiation. The reaction mixture was diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine, then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (c-hexane/EtOAc 4:1) to give the title compound. MS (LC-MS): 253 [M+H]+; tR (HPLC conditions k): 3.45 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:14]([C:18]1[C:19]([Cl:27])=[C:20]([C:24](O)=[O:25])[N:21]([CH3:23])[N:22]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:24]([C:20]2[N:21]([CH3:23])[N:22]=[C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:19]=2[Cl:27])=[O:25])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6-bromo-3-nitro-pyridin-2-ylamine (750 mg, 3.44 mmol) in THF (20 mL) was treated with NaH (413 mg, 10.3 mmol) at room temperature for 1 h. Simultaneously a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (969 mg, 4.47 mmol, prepared as described in Example B) in DCM (20 mL) was treated with oxalyl chloride (390 μL, 4.47 mmol) and DMF (4 drops) at room temperature for 1 h. The acid chloride solution was concentrated to dryness in vacuo, taken up in THF (10 mL), and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted twice with EtOAc (60 mL, 20 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 1 min, then 1:99 to 3:17 v/v over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 10.48 (br. s., 1H), 8.31 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C14H15BrClN5O3: 416.0 (M+H); Measured: 416.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:34])[CH:15]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:18]=1)[CH3:12].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:34])[CH:15]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1)[CH3:12]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)c2ccccc2)no1)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
Benzoyl chloride (21 μl, 0.18 mmol, 1.0 equivalents) was added in one portion to a solution of 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (1C) (74 mg, 0.20 mmol, 1.1 equivalents) in pyridine (29 μl, 0.36 mmol, 2.0 equivalents) and dichloromethane (2 mL) at 0° C. The reaction was stirred at room temperature for 4 hours then diluted with ethyl acetate (30 mL). The reaction was extracted with 1N hydrochloric acid (30 mL) and brine (30 mL). The organic portion was dried over sodium sulfate and concentrated in vacuo to give the title compound (66 mg, 84%). MS (CI) m/z 442.3 (M+1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O>O1CCCC1>[Br:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2[nH]ccc2c1
Solvent: C1CCOC1
Product: Brc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (15.6 g, 132 mmol) in 400 mL tetrahydrofuran at −40° C. was added a suspension of N-bromosuccinimide in 120 mL tetrahydrofuran. Reaction mixture was warmed to room temperature and allowed to stir for 4 hours. Solid was filtered off. The reaction mixture was quenched with a sodium metabisulfite solution, and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with 1:1 hexane/ethyl acetate and filtered. The filtrate was concentrated and the trituration step was repeated three more times to afford a total of 25 g of the title compound, which was used without further purification. MS (DCI+) m/z 196.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[C:23]([N:27]1[C:31](=[O:32])[CH2:30][CH:29]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][SH:40])=[CH:35][CH:34]=2)[S:28]1(=[O:42])=[O:41])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][S:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([CH:29]4[S:28](=[O:41])(=[O:42])[N:27]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:31](=[O:32])[CH2:30]4)=[CH:38][CH:37]=3)=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CS)cc2)S1(=O)=O
Reactant: COC(=O)c1ccc(-c2ccc(COS(C)(=O)=O)cc2)cc1
Product: COC(=O)c1ccc(-c2ccc(CSCc3ccc(C4CC(=O)N(C(C)(C)C)S4(=O)=O)cc3)cc2)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.35, Step 4, using 4.17-A of Step 1 and 4.15-F of Example 4.15, Step 6 as the starting materials. LCMS found for C29H32NO5S2 (M+H)+: m/z=538.
Reaction SMILES: ClCCl.C(N(CC)CC)C.[C:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]([CH2:22][CH2:23][CH3:24])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:18]=2[CH:33]=1)(=O)[NH2:12]>[Ti](Cl)(Cl)(Cl)Cl.O1CCCC1>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:19]1[C:18]2[CH:33]=[C:14]([C:11]#[N:12])[CH:15]=[CH:16][C:17]=2[N:21]=[C:20]1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1nc2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2ccc(C#N)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Dichloromethane solution (1 molar, 0.14 ml) of titanium tetrachloride and triethylamine (0.36 ml) are added to a tetrahydrofuran solution (4 ml) of 6-carbamoyl-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (200 mg) at 0 ° C., and the solution is stirred for two hours at 20° C. The reaction mixture is separated into layers using ethyl acetate and water. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is developed and purified using column chromatography with ethyl acetate/hexane (1/10˜1/3). The material is re-crystallized using ethyl acetate/hexane and 1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole (140 ing) is obtained. (Colorless crystal) 1H-NMR (CDCl3, δ): 1.05 (3H, t, J=8 Hz), 1.90 (2H, sextet, J=8 Hz), 2.85 (2H, t, J=8 Hz), 5.45 (2H, s), 6.42, (1H, dd, J=1, 8 Hz), 7.15 (1H, dt, J=1, 8 Hz), 7.28 (1H, dt, J=1, 8Hz), 7.48 (1H, s), 7.50 (1H, d, J=10 Hz), 7.54 (1H, dd, J=1, 8 Hz), 7.85 (1H, d, J=10 Hz).