Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]2[CH:20]=[C:21](Br)[S:22][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.Cl>C(O)C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]2[S:22][C:21]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:9]1=2
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)c1cc2sc(Br)cc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2sc(-c3cccs3)cc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
Tetrakis-(triphenylphosphine)palladium (0) (20 mg) was added to a degassed solution of ethyl4-(3,4-dichlorobenzyl)-2-bromothieno[3,2-b]pyrrole-5-carboxylate (0.1 g) and thiophene-2-boronic acid (34 mg) in ethanol (1 ml), toluene (1 ml) and aqueous potassium carbonate (2N, 1 ml), and the reaction stirred at 80° C. under an argon atmosphere for 6 hours. The reaction was cooled, poured into 2N HCl and extracted with ether. Combined organic extracts were cried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using isohexane to isohexane-25% ethyl acetate as eluent to give the product as a pale yellow crystalline solid (77 mg, 77%), M/z (+) 435 (MH+), 276, 204, 159, 127.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>CCOCC>[Br:18][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of 24.8 g. (0.127 mol.) of m-trifluoromethylacetophenone in 20 ml. of anhydrous ether was added with cooling and stirring 0.15 g. of anhydrous aluminum chloride and 20.2 g. (0.127 mol.) of bromine. The reaction mixture was concentrated in vacuo and the residue was distilled to give α-bromo-m-trifluoromethylacetophenone, b.p. 135°-140° (20mm.).
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[CH:28]=5)[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:49]N(C)CCN>>[CH3:2][N:3]([CH3:49])[CH2:4][CH2:5][NH:1][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)n4ccnc4)CC3)c2c1
Reactant: CN(C)CCN
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)NCCN(C)C)CC3)c2c1

Procedure:
60 mg 1H-1-imidazolyl{4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]piperazin-1-yl)methanone obtained in Example 195 and 1 mL N,N-dimethylethylene diamine were reacted in the same manner as in Example 196, to give 29 mg of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23]C(=O)OC(C)(C)C)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C([O-])([O-])=O.[K+].[K+]>>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][NH:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23][S:15]([CH3:16])(=[O:32])=[O:31])=[CH:22][C:16]=3[S:15](=[O:31])(=[O:32])[N:14]=2)[C:3]1=[O:33])[CH3:45]
Reactant: CCOC(=O)CBr
Reactant: CC(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CNC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
Follow same procedure as Example 18D, treating the product of Example 18C with ethyl bromoacetate (5.7μL, 0.05 mmol) and K2CO3 (6.8 mg, 0.05 mmol). 1H NMR (d6-DMSO) δ 13.81 (s, 1H), 9.98 (s, 1H), 8.16, 8.13 (d, 1H), 7.85, 7.83 (d, 1H), 7.69-7.43 (m, 4H), 7.38, 7.35 (d, 1H), 4.15-4.00 (q, 2H), 3.44, 3.38, 3.23, 3.17 (dd, 1H), 3.02 (s, 3H), 2.32-2.16 (m, 1H), 2.15-2.01 (m, 1H), 1.38-1.21 (m, 2H) 1.21-1.09 (t, 3H), 1.09-0.93 (m, 1H), 0.73-0.62 (q, 6H), 0.55-0.42 (m, 1H); MS (ESI) m/z 605 (M+H+).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]([CH3:20])([CH3:19])[CH3:18])/[C:5]1=[O:21])(=O)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:17]([C:16]1[O:15][CH:14]=[N:13][C:12]=1/[CH:11]=[C:6]1/[C:5](=[O:21])[NH:4]/[C:9](=[CH:27]\[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)/[C:8](=[O:10])[NH:7]/1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)N1CC(=O)N/C(=C\c2ncoc2C(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=c2\[nH]c(=O)/c(=C/c3ncoc3C(C)(C)C)[nH]c2=O)c1

Procedure:
To a solution of 4 (50 mg, 0.17 mmol) in DMF (4 mL) was added 3-methoxybenzaldehyde (31.4 μL, 0.26 mmol) and the solution was repeatedly evacuated in a short time to remove oxygen and flushed with Ar, followed by the addition of Cs2CO3 (111.9 mg, 0.34 mmol) and the evacuation-flushing process was repeated again. The resultant mixture was heated for 3 h at 85□. After the solvent was removed by evaporation, the residue was AcOEt, washed with water for two times and saturated NaCl for three times, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in 70% MeCN aq and applied to reverse-phase HPLC column (tBondasphere 5C18 100 A, 19×150 mm) and eluted using a linear gradient from 30 to 100% CH3CN in 0.1% TFA aq over 30 min at a flow rate of 12 mL/min, and the desired fraction was collected and concentrated by evaporation to give a 35.3 mg (55.9%) of yellow colored KPU-201. mp 114-116° C.; 1H NMR(300 MHz, CDCl3)δ11.40 (br s, 1H), 8.14 (br s, 1H), 7.88 (s, 1H), 6.96-7.00 (m, 2H), 6.92 (s, 1H), 6.88 (s, 1H), 6.88-6.92 (m, 1H), 3.83 (s,3H), 1.44 (s, 9H); HRMS (El) m/z 367.1538 (M+) (calcd for C20H21N3O4: 367.1532).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]#N)[CH2:28][CH2:27]4)[CH2:23][C:22]=3[CH:34]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:4]([C:3]1[N:7]=[C:32]([N:29]2[CH2:28][CH2:27][CH:26]([CH:24]3[CH2:23][C:22]4[CH:34]=[C:18]([C:15]5[CH:16]=[CH:17][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:13][CH:14]=5)[CH:19]=[CH:20][C:21]=4[O:25]3)[CH2:31][CH2:30]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4O3)CC2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A 0.5 M solution of zinc chloride in tetrahydrofuran (0.78 mL) is diluted with tetrahydrofuran (5 mL) and added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (40 mg) and 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile (100 mg) in ethyl acetate (5 mL). The reaction mixture is stirred at 50° C. for 4 h and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 2 h in a mixture of ethanol (5 mL) and glacial acetic acid (2.5 mL). The solvents are evaporated and the residue is mixed with dichloromethane and 10% aqueous K2CO3 solution. The organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 2): tR=1.12 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8]1)=S.FC1C=C(C=CC=1F)C(N1CCCC(C2C=CC=CC=2)=N1)=S.ClC1C=C(C=CC=1Cl)C(N1CCCC(C2C=CSC=2)=N1)=[O:50].ClC1C=C(C=CC=1Cl)C(N1CCCC(C2SC=CC=2)=N1)=S.ClC1C=C(C=CC=1Cl)C(N1CCCC(C2C=CSC=2)=N1)=S>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8]1)=[O:50]
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Reactant: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccccc2)=N1
Agent: Fc1ccc(C(=S)N2CCCC(c3ccccc3)=N2)cc1F
Agent: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cccs2)=N1
Agent: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccccc2)=N1

Procedure:
1-(3,4-dichlorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine; 1-(3,4-difluorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine; 1-(3-bromo-4-fluorothiobenzoyl)-3-phenyl-1,4,5,6-1tetrahydropyridazine; (R,S)-(3,4-difluorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine; (R,S)-1-(3,4-dichlorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine; (R,S)-1-(3,4-dichlorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine; (R,S)-1-(3,4-difluorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazine 1-(3,4-dichlorobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine and 1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine.
Reaction SMILES: CO[C@H:3]1O[C@H:7]([CH2:9]O)[C@@H:6](O)[C@H:5](O)[C@H:4]1O.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN([CH:37]=[O:38])C>>[C:14]([O:38][C:37]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:9]=[CH:7][CH:6]=[CH:5][CH:4]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1ccc(C(OC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A process of producing compound 6 (methyl-2,3,4-trideoxy-6-O-trityl-4-methylcarboxymethyl-hex-2-enpyranoside) comprising reacting compound 1 (methyl-α-D-glucopyranoside) in the presence of Ph3CCl and 4-Me2Py and DMF to produce compound 2 (6-O-trityl-α-methylglucoside) and reacting compound 2 in the presence of n-Bu2SnO, CH3OH and BzCl, Et3N, THF to produce compound 3 (methyl-2-O-benzoyl-6-O-trityl-α-D-glucopyranoside) and reacting compound 3 in the presence of MsCl and Et3N, CH2Cl2 to produce compound 4 (methyl-2-O-benzoyl-3,4-di-O-methanesulfonyl-6-O-trityl-α-D-glucopyranoside) and reacting compound 4 in the presence of Zn-Cu, DMF and CH3ONa/CH3OH to produce compound 5 (methyl-3,4-dideoxy-6-O-trityl-hex-3-enpyranoside) and reacting compound 5 in the presence of CH3C(OCH3)3, C2H5CO2H while refluxing xylenes to produce the desired compound 6 (methyl-2,3,4-trideoxy-6-O-trityl-4-methylcarboxymethyl-hex-2-enpyranoside).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH2:1]([NH:8][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: O=C1CCCCCO1
Product: CCCCCCCNC(=O)CCCCCO
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of n-heptylamine (1.21 g, 10.5 mmols) and 6-hexanolactone (1.14 g, 10 mmols) was stirred at 100° C. for 3 hours, and then crystallized from ether-hexane to obtain 1.77 g (yield 78%) of N-heptyl-6-hydroxyhexaneamide as colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12]N(C)CCN(C)C.C([Li])CCC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH3:12]
Reactant: CN(C)CCN(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1C(=O)Nc2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 15 h
Yield: 18.2 %

Procedure:
To a 250 mL round-bottom flask, was added 5-bromoindolin-2-one (2 g, 9 mmol), N,N′-tetramethylethylenediamine (4 mL, 28 mmol) and 70 mL of THF. The reaction mixture was cooled to −78° C. 2.5 M n-butyllithium in hexanes (8.4 mL, 21 mmol) was then added slowly to the reaction mixture. The reaction mixture was stirred for 15 hours, 5 mL of saturated NH4Cl solution was added to the reaction mixture, and then the reaction mixture was extracted twice with 30 mL of EtOAc. The combined organic layers were concentrated and purified with silica gel column chromatography, eluting with 0-40% EtOAc/hexane to give 5-bromo-3-methylindolin-2-one (0.37 g, 17% yield). MS m/z: 227 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 24 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.05 g, 0.205 mmol), 2-fluoropyridine-4-boronic acid (0.057 g, 0.4 mmol), sodium carbonate (0.112 g, 1.025 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) in DME:water (3:2, 3 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield the title compound (0.015 g, 24%) as a yellow solid. 1H NMR (CD3OD) δ 8.47 (s, 1H), 8.35-8.33 (d, J=5.29 Hz, 1H), 8.16 (s, 1H), 8.01-8.00 (d, J=5.13 Hz, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.35-7.33 (dd, J=10.33, 1.72 Hz, 1H), 7.29 (d, J=2.95 Hz, 1H), 6.48-6.47 (d, J=2.58 Hz, 1H); MS (API-ES/Positive); m/z: 306 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:11][CH2:12][N:13]([C:17](=[O:18])[CH3:19])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2ncn(C3CCNCC3)c2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cnc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-1-(piperidin-4-yl)-1H-benzo[d]imidazole (50 mg, 0.178 mmol) in DCM (5 mL) in pyridine (5 mL) cooled by an ice-bath was added AcCl (14 mg, 0.178 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvents were removed by concentration and the residue used for next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C>ClCCl.CS(C)=O>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)c1ccc(C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the crude alcohol (1.0 g, 4.5 mmol) in dichloromethane (16.7 mL), dimethylsulfoxide (4.79 mL) and triethylamine (2.28 g, 22.5 mmol) was cooled to 0° C. Sulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions and the mixture stirred at 0° C. for 1 hour. The reaction was then allowed to warm to room temperature and stir for 2 hours. The reaction was quenched with brine and diluted with dichloromethane. The layers were separated and the aqueous was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate. 1H NMR (400 MHz, CDCl3, δ): 8.05-8.17 (m, 2H), 8.04-7.92 (m, 2H), 4.40 (q, J=7.15 Hz, 2H), 2.96 (t, J=7.22 Hz, 2H), 1.86-1.69 (m, 2H), 1.40 (t, J=7.12 Hz, 3H), 1.00 (t, J=7.22 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([O:14][CH3:15])=[O:13].[CH:25]1C=CC=CC=1>O>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:24][CH2:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[OH:9])[CH3:25])=[CH:18][CH:17]=1)([O:14][CH3:15])=[O:13]
Reactant: O=CC(=O)c1cccc(Cl)c1
Reactant: c1ccccc1
Reactant: COC(=O)c1ccc(CCN)cc1
Solvent: O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1
Reaction time: 2 h

Procedure:
3-Chlorophenylglyoxal (1.6 g) and 2-(4-carbomethoxyphenyl)ethanamine (1.8 g) were heated in refluxing benzene (100 ml) under a Dean and Stark head until the theoretical amount of water had been collected. The solvent was replaced with methanol (100 ml) and sodium borohydride (2.5 g) was added portionwise with ice cooling. The mixture was stirred for 2 h, the solvent was evaporated and the residue was paritioned between water (100 ml) and chloroform (100 ml). The dried organic extract was evaporated and crystallised from methanol to give a single diastereoisomer m.p. 94°-96° (0.19 g) (less active diasteroisomer).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH3:25])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:22][C:21]([F:23])([F:24])[O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH2:12][C@@H:11]([NH2:10])[CH3:25])=[CH:19][CH:18]=1
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 72 %

Procedure:
[1-(S)-Methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-carbamic acid benzyl ester (23.9 mmol) was dissolved in ethanol (200 mL) then placed under nitrogen. 10% Palladium on carbon was added (0.5 g) and the mixture was stirred under hydrogen (atmospheric pressure) overnight. When reaction was complete, the mixture was filtered through celite. The celite was washed with ethanol (5×50 mL) then evaporated in vacuo to give a brown oil (4.03 g, 17.21 mmol, 72% yield over 3 steps).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1.[I-].[Na+].[CH2:19]([NH:23][C:24]1[C:25]([CH3:37])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]>C(#N)C>[CH2:19]([N:23]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)[C:24]1[C:25]([CH3:37])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)COc1ccc(CCl)cc1C
Reactant: CCCCNc1cccc(-c2ccc(C)cc2)c1C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Ethyl [4-(chloromethyl)-2-methylphenoxy]acetate (35.9 g, 0.148 mols) was dissolved in dry acetonitrile (285 mL). Sodium iodide (20.1 g, 0.135 mols 1 eq) was added in one portion and mixture stirred for 5 mins. A solution of the N-butyl-N-(2,4′-dimethyl-1,1′-biphenyl-3-yl)amine (34 g. 0.135 mol) and disopropylethylamine (23.5 mL, 0.135 mol) in dry acetonitrile (285 mL) was added over 10 min and cooling applied to maintain reaction temperature at ca. 16° C. during the addition. The reaction was concentrated in vacuo and the resultant orange oil partitioned between DCM (700 mL) and water (700 mL). The aqueous was extracted with DCM (500 mL) and the combined organic extracts were cautiously washed with brine (300 mL). After drying (Na2SO4) the mixture was concentrated in vacuo to give a dark orange oil. Purification using flash chromatography on (2 kg silica column), eluting with 1:1–0:1 cyclohexane:DCM afforded the title compound as a yellow oil (48.8 g).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]([O:7]C)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
A mixture of 13.0 grams (0.058 mole) of methyl 2-cyclopropyl-2-(4-chlorophenyl)acetate and 5.0 grams of an aqueous, 50% sodium hydroxide solution in 50 mL of methanol was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with 150 mL of water, and the solution was decanted from a solid residue. The liquid portion was washed with three portions of diethyl ether. The combined ether washes were, in turn, washed with an aqueous, dilute sodium hydroxide solution. The combined aqueous layers were made acidic by the slow addition of aqueous, 10% hydrochloric acid. The acidified mixture was extracted with five portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 7.4 grams of 2-cyclopropyl-2-(4-chlorophenyl)acetic acid as a solid, m.p. 95°-96° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]#[N:16])[C:11]([I:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:34])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:34])[NH:18][C:9]4[CH:10]=[C:11]([I:17])[C:12]([CH2:14][C:15]#[N:16])=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CC(C)(C)OC(=O)Nc1cc(CC#N)c(I)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCc1cc2c(cc1I)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-cyanomethyl-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-iodo-phenyl}-carbamic acid tert.-butyl ester (Example M21) (520 mg, 0.89 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light pink solid (297 mg).