Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:22])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:4]([C:7](OC)=[O:8])[S:5][CH:6]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:22])[CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1O[C@@H](C)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](CNC(=O)OC(C)(C)C)Oc1c(Br)csc1CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-bromo-3-{(1S)-2-[(tert-butoxycarbonyl)amino]-1-methylethoxy}thiophene-2-carboxylate (15.36 g) in THF-MeOH (5:1, 180 mL) was added 8 N aqueous sodium hydroxide solution (7.5 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction solution was cooled to room temperature, neutralized with 6 N hydrochloric acid (10 mL), and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution (250 ml) of the residue in THF were added isobutyl chloroformate (5.6 mL) and triethylamine (6.5 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was filtered, a solution (10 ml) of sodium borohydride (4.42 g) in water was added to the filtrate, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give the title compound (12.82 g, 90%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:33][C:32]3[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1ccc(CBr)cc1F
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 27 step D from methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4-difluorobenzyl bromide, and was isolated as white solid after reverse phase chromatography (46%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.98 (s, 9H), 2.43 (s, 3H), 3.66 (s, 3H), 5.45 (s, 1H), 5.68-5.86 (m, 2H), 6.06 (d, J=2.8 Hz, 1H), 6.97-7.05 (m, 2H), 7.05-7.15 (m, 2H), 7.25-7.31 (m, 2H), 7.31-7.38 (m, 1H), 7.49-7.59 (m, 1H); LCMS (m/z) ES+=495 (M+1).
Reaction SMILES: [SH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([OH:11])=O)=[C:6]([OH:8])[N:7]=1.C(N(CC)CC)C.S(Cl)([Cl:21])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(Cl)Cl>[SH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([Cl:21])=[O:11])=[C:6]([OH:8])[N:7]=1
Reactant: O=C(O)c1nnc(S)nc1O
Reactant: O=S(Cl)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)c1nnc(S)nc1O

Procedure:
In a similar manner to that of Example 1-4), 3-mercapto-5-hydroxy-1,2,4-triazine-6-carbonyl chloride, which was prepared from 3-mercapto-5-hydroxy-1,2,4-triazine-6-carboxylic acid (1.73 g), triethylamine (1.0 g), dimethyllformamide (30 ml) and thionyl chloride (1.19 g), was treated with a mixture of 7-(D-2-phenylglycinamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (4.0 g) and bis(trimethylsilyl) acetamide (6.4 g) in methylene chloride (40 ml). Thus obtained reaction mixture was worked up in a similar manner to that of Example 1--1) to give power (870 mg) of 7-[D-2-(3-mercapto-5-hydroxy-1,2,4-triazine-6-carboxamido)-2-phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, mp 175° to 179° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[C:9]1(/[CH:15]=[CH:16]/B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>CN(C=O)C>[CH:16](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cc(Br)co1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CN(C)C=O
Product: O=Cc1cc(/C=C/c2ccccc2)co1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and trans-phenylvinyl-boronic acid (1.4 g, 9.4 mmol, 1.5 equiv) using the conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in DMF (25 mL). The resulting residue was purified via ISCO Companion (0-30% EtOAc/heptane) and preparative HPLC using the Chromeleon purification system (0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min)) afforded a clean product, retention time of product: 3.4-3.6 min. Amount of (E)-4-styrylfuran-2-carbaldehyde isolated: 89.1 mg (7% yield). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.62 (d, J=0.59 Hz, 1H), 7.91 (s, 1H), 7.63 (d, J=0.63 Hz, 1H), 7.50-7.55 (m, 2H), 7.35-7.42 (m, 2H), 7.26-7.32 (m, 1H), 7.08 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([Zn]CC)C.ClCI>C(OCC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]2[CH:15]1[CH2:16]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Zn]CC
Reactant: O=C(OCc1ccccc1)N1C=CCC1
Agent: ClCI
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC2CC21
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a cold (0° C.) solution of 2,3-dihydro-pyrrole-1-carboxylic acid benzyl ester (example 4, step 5, 300 mg, 1.0 eq.) in diethyl ether was slowly added a solution of diethylzinc in hexanes (1M, 7 mL, 4.75 eq.), followed by chloroiodomethane (1.1 mL, 10 eq.). The reaction mixture was stirred 3 h at 0° C., allowed to warm up to room temperature and stirred an additional 3 h. The reaction mixture was partitioned between an aqueous solution of ammonium chloride and diethyl ether. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, dried over sodium sulphate and evaporated in vacuo and purified on silica, eluting with a 1:1 to 1:3 gradient of cyclohexane/dichloromethane, to yield 160 mg (50%) of the desired product as colourless oil. MS (m/e): 218.5 (MH+, 100%)
Reaction SMILES: N#N.CO[N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]1[NH:7][C:8](=[O:22])[C:9]2[N:10]=[CH:11][N:12]([CH2:15][CH2:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])[C:13]=2[N:14]=1.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>N1C=CC=CC=1>[C:42]([O:21][CH2:20][CH:17]([CH2:18][O:19][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:8](=[O:22])[NH:7][C:6]([NH2:5])=[N:14][C:13]1=2)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: CON(c1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC(CCn1cnc2c(=O)[nH]c(N)nc21)COC(=O)C(C)(C)C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a solution of N2 -monomethoxytrityl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.47 g, 0.9 mmol) in pyridine (4.5 ml) was added pivalyl chloride (0.55 ml, 4.5 mmol) and the solution was stirred for 45 minutes. The mixture was precipitated in water (45 ml) and the resulting precipitate was stirred in 80% acetic acid (10 ml) at 80° for 20 minutes. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroformmethanol (10:1) to afford 9-(4-pivalyloxy-3-pivalyloxymethylbut-1-yl)guanine (0.22 g, 58%), m.p. 225°-237° C.; νmax (KBr) 3430, 2980, 1730, 1690, and 1620 cm-1 ; δH [(CD3)2SO] 1.11 (18 H, s, 2×C(CH3)3), 1.81 (2 H, q, J 6.8 Hz, 2'-H), 1.93 (1 H, m, 3'-H), 4.0-4.1 (6 H, m, 1'-H and 2×4'-H), 6.38 (2 H, s, 2-NH2), 7.69 (1 H, s, 8-H), and 10.58 (1 H, br.s, 1-H); (Found: C, 56.58; H, 7.26; N, 16.14%; C20H31N5O5 requires: C, 56.99; H, 7.41; N, 16.62%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=O.Cl.[CH3:12][O:13][NH2:14].C(N(CC)CC)C>CO>[CH3:12][O:13][N:14]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of 4-iodo acetophenone (2.0 g, 8.13 mmol) in methanol (25 ml), O-methyl hydroxyl amine hydrochloride (0.7 g, 8.94 mmole) was added followed by triethyl amine (0.904 g, 8.94 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. Reaction mixture was concentrated under vacuum, residual mass was diluted with water (50 ml) and aq. layer was extracted with ethyl acetate (3×30 ml). Organic layer was washed with water (2×30 ml) followed by brine solution, dried over anhydrous sodium sulfate and evaporated to obtain 2.17 g (97% of theory) of 1-(4-iodo-phenyl)-ethanone O-methyl-oxime.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[S:26][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]3[CH:8]=[CH:7][S:26][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(CNc2ncnc3sc(Cl)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sccc23)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 6-chloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1cccc2[nH]ccc12
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4[nH]ccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 98.3 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.20 g, 0.48 mmol) obtained in Example 19, step 4 and 4-aminoindole (0.128 g, 0.97 mmol), the title compound (0.240 g, 98%) was obtained.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:46]=[CH:45][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][C@@H:27]([S:42][S:43][CH3:44])[CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31]([OH:33])=[O:32])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][C@@H:27]([S:42][S:43][CH3:44])[CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:31]([O:33][CH2:2][C:1]#[N:4])=[O:32])=[O:24])=[CH:45][CH:46]=1)=[N+:15]=[N-:16]
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Reaction time: 4.5 h
Yield: 89.5 %

Procedure:
N,N-Diisopropylethylamine (51 μL, 0.291 mmol) and subsequently bromoacetonitrile (92 μL, 1.321 mmol) were added to a solution of (2S,5S)-6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoic acid (Compound tk8) (132 mg, 0.264 mmol) in acetonitrile (0.4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 4.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (2S,5S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk9) (127.3 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].S(=O)(=O)(O)O.[I:24]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([I:24])[CH:13]=2)=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
4′-Chloro-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 54, 150 mg, 0.55 mmol) was dissolved in acetic acid (5 mL) and concentrated sulphuric acid (0.032 μL) was added followed by N-iodosuccinimide (124 mg, 0.55 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate (50 mL) and water (20 mL). The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 85:15 to give the title compound (167 mg, 0.42 mmol, 76%) as a gum.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].OS(O)(=O)=O.[CH3:17]O>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:17])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO3. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH:16]([C:18]1[N:23]2[N:24]=[CH:25][N:26]=[C:22]2[N:21]=[CH:20][CH:19]=1)[CH3:17]>COCCOC>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:16]([C:18]2[N:23]3[N:24]=[CH:25][N:26]=[C:22]3[N:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(OC(F)(F)F)cc1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 4-trifluoromethoxyphenol (1.78 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2,27 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred for 4 hours at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane to give 7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.69 g, (m.p. 91°-93° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22](=O)[NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[N:40]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1.83 h
Yield: 53.2 %

Procedure:
{1-[2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (192 mg, 0.34 mmol) was dissolved in m-Xylenes (2 mL) and heated at 135° C. Solid ammonium acetate (128 mg, 1.66 mmol) was added and the reaction was stirred at 135° C. After 110 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product {1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol): LCMS-ESI+: calc'd for C22H27BrF3N5O3: 546.4 (M+); Found: 546.0/548.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH3:30])([O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]([C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[C:2]2[CH3:1])[CH3:29])[CH3:25]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(-c2ccc([N+](=O)[O-])cc2)c(C)c2cc(O)ccc21
Product: CCCn1c(-c2ccc([N+](=O)[O-])cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-methyl-2-(4-nitro-phenyl)-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:37](=[NH:39])[NH2:38])[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH2:28]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:39]=[C:37]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[N:38]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: N=C(N)C1(O)C=CC=C(C(F)(F)F)C1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C(F)(F)F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 1. Yield: 60 mg (59% of theory)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](O)(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: CNc1ccccc1
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of N-methylbenzenamine (110 mg, 1.02 mmol) in DCM (3 mL) was successively added at R.T. 4-pentynoic acid (100 mg, 1.02 mmol), HOBT (171mg, 1.12 mmol) and EDCI.HCl (293 mg, 1.53 mmol). The reaction was stirred at R.T. overnight. The reaction was quenched with water. The organic layer was separated and washed with 1M NaHCO3 and water. The solvent was removed under reduced pressure to afford 150 mg N-methyl-N-phenylpent-4-ynamide (Yield: 78%) as an orange oil which cn be used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:2][C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 186.4 %

Procedure:
2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mL DMF. Cesium carbonate (20 g, 2.3 eq) was added to the solution and the resulting reaction mixture was heated at 50° C. for 20 minutes. Benzyl bromide (10 g, 2.1 eq) was added. The resulting reaction mixture was stirred at 50° C. for 1 hour. Then the reaction mixture was poured into 500 mLice-water, the precipitate was collected by filtration, and dried in vacuo to afford 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g). 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mL THF, and 2 N LiOH solution (20 mL) was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed in vacuo, and the residue acidified by the addition of 2N NaHSO4 to pH 3–4. The white precipitate was collected to afford 2-carboxy-4-benzyloxyquinoline (7.2 g), which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:16]1[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=[C:12]([O:11][C:9]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:10])[CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cncs1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morphcline in 100 ml of methylene chloride was cooled to 0° C. and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed successively with 1N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl3, Rf=0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. NMR (CDCl3) δ5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)+ =281.