Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CO>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: NCc1ccccc1
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc(CNCCCOc2ccc(-c3csc4ccccc34)cc2)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, benzylamine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=98%, [M+H]+=374.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:31])[N:24]=[C:23]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:31])[N:24]=[C:23]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=1)(=[O:8])=[O:7]
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 100.8 %

Procedure:
1-((2'-((tert-butylamino)sulfonyl)(1,1'-biphenyl)-4yl)methyl)-2-butyl-4-chloro-imidazole-5-carboxylic acid, methyl ester (75.0 mg, 0.145 mmol) was stirred in trifluoroacetic acid (1.0 ml) containing anisole (20 μl) under nitrogen at room temperature for 24 hours. The trifluoroacetic acid was removed in vacuo and the residue chromatographed (silica gel, 35% ethyl acetate-hexane) to afford 1-((2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-imidazole-5-carboxylic acid, methyl ester (67.5 mg, 100%) as a white solid; 1H NMR (300 MHz, CD3OD/CDCl3) δ8.08 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.26 (d, J=7.7 Hz, 1H), 7.04 (d, J=8.1 Hz, 2H), 5.57 (s, 2H), 3.80 (s, 3H), 2.64 (t, J=7.4 Hz, 2H), 1.62 (quin, J=7.4 Hz, 2H), 1.31 (sext, J=7.4 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:3]1=[O:20].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:6]1[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:5]1=[O:7]
Reactant: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Reactant: BrCc1ccccc1Br
Product: CSc1ccc(N2C(=O)N(Cc3ccccc3Br)C(C)(C)C2=O)cc1C(F)(F)F

Procedure:
The reaction of 114.1 with 2-bromobenzyl bromide afforded 1-(2-bromobenzyl)-5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidine-2,4-dione (115.2). The further reaction with methyl 4-aminobenzoate under conditions as described for the preparation of compound I afforded methyl 4-{2-[5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)-2,4-dioxoimidazolidin-1-ylmethyl]phenylamino}benzoate; molecular weight 557.15 (C28H26F3N3O4S); retention time Rt=2.22 min. [B]; MS (ESI): 558.21 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[H][H]>CCOC(C)=O.[Pd]>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: CCOC(=O)CCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc2c(n1)NCCC2

Procedure:
A solution of 2-3 (2.3 g, 9.4 mmol) in 50 mL EtOAc was treated with 10% Pd/C (230 mg) and a hydrogen balloon. After 4 days the reaction filtered through celite, concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane), providing 2-4 as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:29])=[C:4]([C:21]([OH:28])=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[O:16][C:17]([F:20])([F:19])[F:18])=[O:6].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[C:3]([CH3:29])=[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]=2[OH:28])=[O:6])=[C:9]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)#[N:15]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
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: C1COCCO1
Product: Cc1c(-c2ccccc2)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-Bromo-5-tert-butyl-N-(2-trifluoromethoxy-4-cyano-phenyl)-6-hydroxy-2-methyl-benzamide (0.141 g, 0.3 mmole) in dioxane (5 ml) under nitrogen, phenylboronic acid (37.0 mg, 0.3 mmole), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmole) and sodiumcarbonate (1.05 ml, 2 M solution in water) were added. The reaction mixture was heated at 100° C. for 48 hours. The reaction mixture was evaporated, diluted with ethyl acetate and the organic phase was washed with citric acid solution (10%). The organic phase was dried over sodium sulphate and evaporated. The crude compound was purified by column chromatography.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.[CH3:32][O:33][C:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)=[O:35].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][O:33][C:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:20][C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=3[CH:30]=2)=[O:42])=[CH:39][CH:38]=1)=[O:35]
Reactant: COC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(C(=O)Oc2ccc3ccc(=O)oc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
13.4 g triphenylphosphine is added to a solution of 8.3 g 7-hydroxycoumarin, 10.0 g 4-methoxycarbonyloxybenzoic acid, 8.9 g diethyl azodicarboxylate and 50 ml tetrahydrofuran at 0° C. The reaction mixture was stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down, taken up in warm hexane, filtered to remove inorganic material and evaporated down again. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1/1 v/v) as eluent and recrystallisation from acetonitrile to yield 12.2 g of 2-oxo-2H-1-benzopyran-7-yl 4-methoxycarbonyloxybenzoate.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Cl)=[CH:7][CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:2][CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: N#CCC(=O)c1ccc(Cl)s1
Reactant: CC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCCC1
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)s1)CCCC2
Yield: 76 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 76%; IR (KBr) cm−1: 3349, 3237, 3131, 2911, 1577, 1547, 1430, 1281, 1006, 765; 1H NMR (CDCl3):δ1.59 (m, 2H), 1.65 (m, 2H), 2.35 (t, 2H, J=5.8 Hz), 2.55 (t, 2H, J=5.8 Hz), 6.07 (bs, 2H), 6.88 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); yellow solid, mp: 173-175° C. (petroleum ether).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][C:16]([NH2:19])=[C:15]4[O:20][C:21]([C:23]5[CH:32]=[CH:31][CH:30]=[C:29]6[C:24]=5[CH:25]=[CH:26][N:27]=[CH:28]6)=[CH:22][C:14]=34)[CH:10]=[N:9]2)[CH2:4][O:3]1.CO.Cl>>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][CH:5]([OH:6])[CH2:4][OH:3])[CH:12]=2)=[C:14]2[CH:22]=[C:21]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][N:27]=[CH:28]4)[O:20][C:15]=12
Reactant: CC1(C)OCC(Cn2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)O1
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2cnn(CC(O)CO)c2)c2cc(-c3cccc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.4 %

Procedure:
4-{1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1H-pyrazol-4-yl}-2-(isoquinolin-5-yl)furo[2,3-c]pyridin-7-amine (25.0 mg, 0.0566 mmol) was dissolved in MeOH (0.5 mL, 10 mmol) and HCl (4 M in 1,4-dioxane, 0.30 mL, 1.2 mmol) was added. The reaction stirred at RT for 16 h. The product mixture was then concentrated in vacuo to a solid. Purification by flash chromatography (0 to 10% 7 N NH3/MeOH:EtOAc) afforded 1 mg (4%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 9.35 (s, 1 H), 8.59 (d, J=6.06 Hz, 1 H), 8.51 (d, J=6.06 Hz, 1H), 8.37 (dd, J=7.33, 1.26 Hz, 1H), 8.26 (d, J=8.34 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J=3.79 Hz, 2H), 7.81-7.89 (m, 1H), 7.54 (s, 1H), 4.40 (dd, J=14.02, 4.17 Hz, 1H), 4.19-4.27 (m, 1H), 4.01-4.12 (m, 1H), 3.52-3.61 (m, 2H); MS (ESI): 402.15 [M+H]+; HPLC tR=0.79 min (TOF: polar—3 min).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[K+].C1(C)C=CC(S(O[C:15]2[CH2:16][C@@H:17]3[CH2:31][C:30](=[O:32])[N:18]3[C:19]=2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>C(#N)C.ClCCl>[CH2:23]([O:22][C:20]([C:19]1[N:18]2[C:30](=[O:32])[CH2:31][C@H:17]2[CH2:16][C:15]=1[N:1]=[N+:2]=[N-:3])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)C[C@H]3C2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
Potassium azide (11.6 mg, 143. micromol) was added to a stirred ambient temperature solution of benzyl 2-(p-toluenesulfonyloxy)-carbapen-2-em-3-carboxylate (20.0 mg, 48.4 micro mol) prepared according to the analogous procedure described in U.S. Pat. No. 4,424,230, hereby incorporated by reference for this particular purpose, and 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (12.8 mg, 48.4 micro mol) in anhydrous acetonitrile (1.0 ml) and dichloromethane (0.2 ml). After 1 hour the mixture was applied to two 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plates and developed with 3:2 (v/v) toluene-ethyl acetate. The band centered at Rf 0.6 was eluted with ethyl acetate and the elulate was evaporated under vacuum to provide 9.2 mg (67%) benzyl-2-azido-carbapen-2-em-3-carboxylate as a pale yellow glass. The glass was crystallized from 5:1 (v/v) diethyl etherdichloromethane to provide pale yellow rosettes of needles, m.p. 84°-85° C. (dec); I.R. (neat film): 2110, 1785, 1710, 1605, 1285, 1210, 1190 cm-1 ; NMR (CDCl3):δ (del) 2.99 dd (J1 =3 Hz, J2 =16 Hz, 1H), 3.07 d (J=9 Hz, 2H), 3.52 dd (J1 =5 Hz, J2 =16 Hz, 1H), 4.25 m (1H), 5.30 d (J=8 Hz, 1H), 5.33 d (J=8 Hz, 1H), 7.37 m (5H); UV (CH2Cl2) λmax (ε): 310 (10,000) nm; MS (m/e): 256 (M+ -N2), 243, 228, 214, 178, 162, 160, 127, 120, 107.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:25]([C:24]1[C:23]([CH3:27])=[C:22]2[C:18]([C:19](=[O:28])[O:20][CH2:21]2)=[C:17]([OH:29])[C:16]=1[CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH3:26]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Yield: 72.6 %

Procedure:
(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was added and the reaction was stirred at room temperature. After 20 hrs the reaction was quenched with MeOH (0.3 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 14.2 mg (57%) of the free phosphonic acid [MS: 484 M++1].
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Si]([N:21]=[N+:22]=[N-:23])(C)C>C1(C)C=CC=CC=1>[N:21]([C:11]1([CH3:10])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:22]=[N-:23]
Reactant: CC1(O)CCCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(N=[N+]=[N-])CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
BF3.Et2O (934 mg, 6.23 mmol) was added drop-wise at 20° C. to a stirred solution of 1-methylcyclopentanol (520 mg, 5.19 mmol) and trimethylsilyl azide (716 mg, 6.23 mmol) in 6 mL of toluene. Then the solution was stirred at room temperature for 16 hours. The organic phase was washed with a 10% solution of NaHCO3 (10 mL), water (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was evaporated at 35° C. under reduced pressure to give 1-azido-1-methylcyclopentane (720 mg) as a crude product. It was used directly in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:10]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1cccc(CC2OCCO2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3cccc(CC4OCCO4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1,3-dioxolan-2-ylmethyl)benzoic acid (1.0 g, 4.80 mmol) in a mixture of pyridine (5 mL) and N,N-dimethylformamide (5 mL) was treated with 1,1′-carbonyldiimidazole (0.856 g, 5.28 mmol) at 45° C. for 2 hours. 2,3-diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.08 g, 4.80 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue purified by flash chromatography on silica gel with 10% methanol in 2:1 ethyl acetate/hexane. The product was dissolved in acetic acid (20 mL) and the solution heated at 60° C. for 2 hours and at 80° C. for 1.5 hours, cooled and concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was concentrated and the residue purified on silica gel with 10% methanol in 2:1 ethyl acetate/hexane to give 1.13 g of the title compound. MS (APCI) m/z 324 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[O:11])[CH2:3][CH2:2]1>CCOC(C)=O.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:11])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=1
Reactant: O=C(NCCN1CCOCC1)Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)NCCN2CCOCC2)c(C(F)(F)F)c1

Procedure:
A mixture of 1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea (651 mg, 1.80 mmol, 1.0 equiv) and 10% Pd/C (20 mg) in EtOAc (25 mL) and MeOH (2 mL) was exposed to an atmosphere of H2 (balloon). Upon completion of the reduction, the reaction mixture was filtered through celite and concentrated in vacuo to afford 1-(4-amino-2-(trifluoromethyl)phenyl)-3-(2-morpholinoethyl)urea, which was advanced without further purification. MS m/z: 333 (M+H+); Calculated for C14H19F3N4O2: 332.2
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.36 ml (5 mmol) of propionaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1:1→1:2→1:4) to yield 1.37 g (75.8%, light orange oily substance) of the desired product.
Reaction SMILES: [CH2:1]([C:4]1([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[S:8][C:7]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:6]=2[CH:5]1Cl)[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([C:4]1([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[S:8][C:7]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(Cn2ccnc2)Sc2cc(Cl)ccc2C1Cl
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCC1(Cn2ccnc2)Cc2ccc(Cl)cc2S1

Procedure:
Heat a reaction mixture of 1.4 g (4.3 mmoles) of the title compound of Example 7 and 2.5 g (8.5 mmoles) of tri(n-butyl)tin hydride in 20 mL of toluene at reflux overnight. Evaporate to give a residue. Chromatograph the residue on silica gel, eluting with 1:1 (v/v) ethyl acetate:hexane to give the title compound as an oil, m/e 290.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:4].[CH:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:28]1[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(O)cc2c(CC2CCCC2)n1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: COC(=O)c1cc2ccc(Oc3ccc(C(C)C)cc3)cc2c(CC2CCCC2)n1

Procedure:
1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid methyl ester (prepared in example E-1) was treated with 4-isopropylphenylboronic acid by the general procedure G to yield 7-(4-isopropyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester. This ester was hydrolyzed by the general procedure C to afford 7-(4-isopropyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid. This acid was coupled with Compound E-6 by the general procedure A to yield 2(S)-{[1-cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbonyl-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester. This ester was hydrolyzed by the general procedure C to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (98.0 mg, 0.172 mmol) in DCM (5 ml) was added TFA (2.0 ml) and the reaction mixture was stirred at rt for 3 hours. The reaction was quenched with saturated sodium bicarbonate, diluted with EtOAc, and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (50.0 mg, 0.114 mmol, 66% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.30 (m, 1H), 7.73 (s, 1H), 7.45 (d, 1H), 7.22-7.36 (m, 2H), 7.08 (s, 1H), 6.88 (s, 1H), 4.49 (d, 2H), 4.37 (s, 1H). LC-MS (ES+) m/z 438.01, [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:20]OS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.ClC1C=CC=CC=1.O>[CH3:20][NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Clc1ccccc1
Product: CNc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Yield: 99.5 %

Procedure:
A mixture of 1-aminoanthraquinone (purity 99.6%, 22.4 g), monochlorobenzene (224 g), tetra-n-butyl ammonium bromide (3.4 g), 96% potassium hydroxide (11.7 g) and dimethylsulfuric acid (25 g) was stirred while being maintained at 30° C. for 24 hours. After water (150 g) was added, the solution was stirred for 1 hour, being maintained at 50° C. pH of the aqueous phase was 10 or higher. Then, acetic acid (0.5 g) was added for neutralization (pH of the aqueous phase being 7) and then monochlorobenzene was recovered by heating. After being cooled down to 50° C., the solution was filtered, and a solid was washed and then dried to obtain 1-methylaminoanthraquinone (23.7 g, purity 97.6%, yield 97.6%).