Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:3]1.[CH2:15]=[O:16]>>[OH:16][CH2:15][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=O
Reactant: Cn1cnc(SCc2ccccc2)c1
Product: Cn1cnc(SCc2ccccc2)c1CO

Procedure:
As previously indicated, one method of preparing 5-carboxyaldehydehyde-1-methyl-4-(phenylmethyl)thioimidazole from 1-methyl-4-(phenylmethyl)thioimidazole comprises condensing 1-methyl-4-(phenylmethyl)thioimidazole with formaldehyde under weakly acidic conditions in a first step to form 5-hydroxymethyl-1-methyl-4-(phenylmethyl)thioimidazole and then oxidizing the formed primary alcohol in a second step to form the product. The first step is readily carried out by reacting using aqueous formaldehyde (e.g. 36.5% to 38% aqueous formaldehyde) in a buffered weakly acid medium, such as sodium formate/formic acid, preferably sodium acetate/acetic acid (pH ranging from about 5.5 to about 6.5) at 90° to 130° C., preferably at reflux over a time period ranging from about 2 to about 4 hours. The buffered weakly acid medium should be such as to protonate the formaldehyde but at most to partially protonate the imidazole moiety to enable an electrophilic attack on the imidazole ring. The second step of oxidizing the primary alcohol in the presence of a sensitive sulfide bond (i.e. without disturbing the sulfide bond) requires careful selection of oxidizing agent. Activated manganese dioxide is preferred for use as the oxidizing agent. Oxidizing agents which were functional but provided much lower yields than activated manganese dioxide included (a) 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO reagent) and CuCl, (b) RuCl2 (PPh3)3 and (c) pyridinium chlorochromate. This second step is readily carried out in a nonpolar or slightly polar solvent such as dichloromethane, acetonitrile or dioxane, preferably acetone, e.g. at a temperature ranging from room temperature to 45° C. for a time period ranging from 6 to 24 hours.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:17]([C@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[O:18])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:17]([C@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:21][NH:20]4)=[O:18])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nnc(-c2ccc3cnccc3c2)s1)[C@@H]1NCC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
To a stirred mixture of (±)-cis-tert-butyl 2-((5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamoyl)-3-phenylpyrrolidine-1-carboxylate (54 mg, 0.11 mmol) in DCM (3.0 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The crude residue was purified by flash column chromatography (eluting with a gradient of DCM to DCM containing 5% of 10% MeOH in ammonia) to provide (±)-cis-N-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-3-phenylpyrrolidine-2-carboxamide as a white solid (3.0 mg, 7%). LCMS (M+H) 402.2 calc. for C22H20N5OS 402.1. 1H NMR (400 MHz, CDCl3): δ ppm 9.23 (s, 1H) 8.55 (d, J=4.89 Hz, 1H) 8.08-8.29 (m, 2H) 7.97 (d, J=7.63 Hz, 1H) 7.65 (d, J=5.48 Hz, 1H) 7.15-7.24 (m, 5H) 4.42-4.87 (m, 1H) 3.89 (d, J=5.48 Hz, 1H) 3.56-3.72 (m, 1H) 3.35-3.51 (m, 1H) 2.18-2.54 (m, 2H). 2H obscured.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:30]1([CH2:36][CH2:37][OH:38])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[NH:50][C:49](=[O:51])[N:48]([CH:52]3[CH2:57][CH2:56][N:55]([C:58]([O:60][C@H:61]([CH2:80][C:81]4[CH:86]=[C:85]([C:87]([F:90])([F:89])[F:88])[C:84]([NH2:91])=[C:83]([Cl:92])[CH:82]=4)[C:62]([N:64]4[CH2:69][CH2:68][CH:67]([CH:70]5[CH2:75][CH2:74][N:73]([CH2:76][C:77](O)=[O:78])[CH2:72][CH2:71]5)[CH2:66][CH2:65]4)=[O:63])=[O:59])[CH2:54][CH2:53]3)[CH2:47][CH2:46][C:45]=2[CH:93]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[NH:50][C:49](=[O:51])[N:48]([CH:52]3[CH2:53][CH2:54][N:55]([C:58]([O:60][C@H:61]([CH2:80][C:81]4[CH:86]=[C:85]([C:87]([F:90])([F:88])[F:89])[C:84]([NH2:91])=[C:83]([Cl:92])[CH:82]=4)[C:62]([N:64]4[CH2:65][CH2:66][CH:67]([CH:70]5[CH2:75][CH2:74][N:73]([CH2:76][C:77]([O:38][CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][O:33][CH2:32][CH2:31]6)=[O:78])[CH2:72][CH2:71]5)[CH2:68][CH2:69]4)=[O:63])=[O:59])[CH2:56][CH2:57]3)[CH2:47][CH2:46][C:45]=2[CH:93]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)N3CCC(C4CCN(CC(=O)O)CC4)CC3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)N3CCC(C4CCN(CC(=O)OCCN5CCOCC5)CC4)CC3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
113 mg (0.35 mmol) TBTU, 84 μL (0.60 mmol) triethylamine and 39 mg (0.30 mmol) 2-morpholin-4-yl-ethanol were added to a solution of 230 mg (0.29 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 5 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was poured onto a saturated NaHCO3 solution, the product precipitated was suction filtered and dried at 40° C. The crude product was dissolved in 25 mL dry isopropanol and precipitated with 0.5 M HCl in isopropanol as the salt. The precipitate was filtered off, washed with 5 mL isopropanol and 30 mL DIPE and dried overnight in the vacuum drying cupboard at 30° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13]C(=O)C1C=CC=CC=1)=[N:8][CH:7]=[CH:6]2.[ClH:22]>C(O)(=O)C>[ClH:22].[NH2:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][NH2:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: NCc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: NCc1ccc2c(N)nccc2c1

Procedure:
A solution of 5.8 g of N-[6-(aminomethyl)-1-isoquinolinyl]benzamide in 300 mL of 4N hydrochloric acid and 150 mL of acetic acid was refluxed for 6 hours. The reaction mixture was washed with diethylether to remove benzoic acid and the aqueous solution was concentrated under reduced pressure to give 3.0 g of the title compound. MS (m/e)=173.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([O:20][CH2:21][CH3:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[OH-].[Na+]>C(O)C.O>[CH2:21]([O:20][C:13](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:22]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4.0 g (13.2 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are suspended in 50 ml of ethanol and after the addition of 10 ml of 4N sodium hydroxide solution stirred for 90 minutes at ambient temperature. The solution is diluted with 150 ml of water, the crystalline product is suction filtered, washed and dried.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20]>C(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]=[C:19]=[S:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)c1ccccc1Oc1ccncc1N
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ccncc1N=C=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 137b (14.54 mg, 0.0600 mmol) in anhydrous DCM (1.0 mL) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 mL). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down to afford crude 137c which was taken directly onto the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)(=[O:11])[CH3:10].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)([OH:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: Brc1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (8.35 mL, 10.9 mmol) was added to a cooled solution of 1-bromo-4-iodobenzene (3.07 g, 10.9 mmol) in THF (8 mL) and the resultant solution was stirred for 1 hour at 0° C. Methyl trans-4-acetylcyclohexanecarboxylate (1.00 g, 5.43 mmol) in THF (2 mL) was added to the reaction mixture, stirred for 1 hour at 0° C. and saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate (2×), and then the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (ethyl acetate/hexanes) gave methyl trans-4-[1-(4-bromophenyl)-1-hydroxyethyl]cyclohexanecarboxylate as a colorless oil. MS ESI calcd. for C16H22BrO3[M+H]+341 and 343. found 341 and 343. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 3.63 (s, 3H), 2.16 (tt, J=12.3 Hz, 3.6 Hz, 1H), 2.03-1.91 (m, 2H), 1.84 (m, 1H), 1.60-1.53 (m, 2H), 1.52 (s, 3H), 1.36 (m, 2H), 1.11-0.98 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]/[N:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:12]=2)=[N:6][CH:7]=1.CCO>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:12]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: Ic1ccc(N/N=C/c2cccc(OCCN3CCOCC3)c2)nc1
Solvent: ClCCl
Solvent: CCO
Product: Ic1ccc2nnc(-c3cccc(OCCN4CCOCC4)c3)n2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a solution of Example 1 step a (10.93 g, 24.16 mmol) in DCM (100 mL)/EtOH (15 mL), was added Phl(OAc)2 (10.74 g, 33.35 mmol). The reaction was stirred at RT for 72 h, diluted with DCM (25 mL) then washed with aq. sodium hydroxide (1 M, 25 mL) and brine (25 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was triturated with Et2O (10 mL) and the resulting solid was collected by filtration to afford the title compound (9.98 g, 92%) as an off-white solid. LCMS (Method 1): Rt 2.11 min, m/z 451 [MH+]. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (1 H, s), 7.71 (1 H, d, J 9.5), 7.60 (1 H, d, J 9.5), 7.53 (1 H, t, J 7.9), 7.47-7.41 (2 H, m), 7.18 (1 H, d, J 8.1), 4.21 (2 H, t, J 5.7), 3.59 (4 H, t, J 4.5), 2.75 (2 H, t, J 5.7), 2.45 (4 H, m).
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:21]/[O:22][CH3:23])/[C:16]([O:18]CC)=[O:17])[N:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+].O>O1CCOCC1>[CH2:7]([O:6][P:4]([NH:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:21]/[O:22][CH3:23])/[C:16]([OH:18])=[O:17])[N:14]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)/C(=N\OC)c1csc(NP(=O)(OCC)OCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Yield: 59.3 %

Procedure:
A solution of 8.4 g (0.023 mol) (Z)-2-[(diethoxyphosphinyl)amino]-α-(methoxyimino)-4-thiazoleacetic acid, ethyl ester, 9.25 ml (0.046 mol) 5N sodium hydroxide, 30 ml water, and 50 ml dioxane was stirred at room temperature for 18 hours. The solvent was evaporated, 30 ml of 50% saturated sodium chloride was added, the pH was adjusted to 4.5, and 3×30 ml ethyl acetate was added. The aqueous layer was then adjusted to pH 2.5, and extraction with ethyl acetate followed by evaporation yielded 4.6 g of a yellow oil; MS ((+) FAB), 338 (M+H); NMR (300 MHz, DCCl3) δ 1.36 (2t, 6, OCH2CH3), 4.01 (s, 3, OCH3), 4.18 (m, 4, OCH2), 7.10 (s, 1, thiazole H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](Cl)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[CH3:23].CCN(CC)CC>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:12]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:13])[CH:19]=[CH:18][C:17]=1[CH3:23]
Reactant: Cc1ccc(N)nc1Cl
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(Cl)n3)CC2)cc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (21.1 mmol) in anhydrous dichloromethane (20 mL) was slowly added to a cooled solution (0° C.) of 6-chloro-5-methylpyridin-2-amine (21.2 mmol) in dichloromethane (50 mL) and Et3N (14.1 mL, 101 mmol). The reaction mixture was stirred at room temperature for 2Hours. The resulting mixture was diluted with dichloromethane and washed with water (1×30 mL), 1N NaOH (2×30 mL), 1N HCl (1×30 mL), saturated aqueous NaHCO3 (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield N-(6-chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (4.0 g, 63%) as a white solid. ESI-MS m/z calc. 316.1, found 317.3 (M+1)+. Retention time 1.98 minutes. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 3.88 (s, 3H), 2.31 (s, 3H), 1.72-1.69 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=4)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
Reactant: N#Cc1cccc(B(O)O)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(-c3cccc(C#N)c3)c2n1C
Temperature: 140 °C
Yield: 38.5 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (100 mg, 0.27 mmol), 3-cyanobenzeneboronic acid (51 mg, 0.35 mmol), Pd(PPh3)4 (31 mg, 0.03 mmol) and Cs2CO3 (175 mg, 0.54 mmol) in dioxane (3 mL) and H2O (1.5 mL) was heated for 30 min by microwave irradiation at 140° C. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 422 as a white solid (41 mg, 39%). LCMS (Method K): RT 3.08 min [M+H]+ 395. 1H NMR (DMSO-d6, 400 MHz): δ 8.03 (1H, s), 7.97 (1H, s), 7.94-7.91 (1H, m), 7.82-7.80 (1H, m), 7.72-7.66 (3H, m), 7.32 (2H, bs), 7.26 (1H, dd, J=8.0, 7.5 Hz), 7.07 (1H, dd, J=7.5, 1.0 Hz), 5.65 (1H, dq, J=7.0, 7.0 Hz), 3.29 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:16]=[C:15]([C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:26]([OH:28])=[O:27])=O)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:26]([OH:28])=[O:27])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)c2cc(C(=O)c3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1

Procedure:
A mixture of 21.1 grams of 4,6-bis(4-methylbenzoyl)isophthalic acid, 350 mL of acetic acid, and 2.10 grams of 5% palladium on carbon (as a catalyst) was heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The resulting mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 4,6-bis(4-methylbenzyl)isophthalic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1ccccc1CSc1ccc(Cl)cc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 57.9 %

Procedure:
Following General Procedure B, the title compound (277 mg, 58%) was prepared from methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (300 mg, 0.98 mmol) and benzofuran-2-sulfonyl chloride (211 mg, 0.98 mmol) in pyridine (3 ml).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
The methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)acrylate (0.92 g, 3.1 mmol) was dissolved in methanol (30 ml) in a Parr shaker bottle. This was degassed with nitrogen and the 10% Pd/C catalyst was added. The reaction was charged with hyrodgen to 55 Psi, and shaken for 3 h. The reaction was complete, the catalyst filtered off and the methanol removed under reduced pressure to give methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (0.92 g, 100%) as a oil. Analytical LCMS (M+H-Boc)+: m/z=195.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:35]=[N:34][CH:33]=[N:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: OB(O)c1cncnc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4cncnc4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 55 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and pyrimidin-5-yl-5-boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (55%).
Reaction SMILES: OC(CN1C2C=CC=CC=2C(C2C=CC=CC=2F)=NC([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=2)=[O:25])C1=O)=O.Cl.Cl.CN1C2CCC1CNC2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[CH3:33][C:29]1[CH:28]=[C:27]([NH:26][C:24](=[O:25])[NH2:23])[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)O)C2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN1C2CCC1CNC2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 311.8 %

Procedure:
To a solution of N-[(3RS)-1-hydroxycarbonylmethyl-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.295 g) and 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (0.189 g) in N,N-dimethylformamide (10 ml) was added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (0.150 g), 1-hydroxy-1H-benzotriazole monohydrate (0.120 g) and a solution of triethylamine (0.255 g) in N,N-dimethylformamide (2 ml). The. mixture was stirred overnight at ambient temperature. Then the mixture was heated at 80° C. for 1 hour. The mixture was concentrated in vacuo. The residue was treated with water, alkalized with sodium carbonate and extracted with chloroform. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (50:1) to give N-[(3RS)-5-(2-fluorophenyl)-I-(8-methyl-3,8-diazabicyclo[3.2.1]-oct-3-yl)]carbonylmethyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.300 g) as a colorless crystal.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]([F:33])([F:32])[C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[N:20][C:19]([N:22]3[CH2:26][CH2:25][NH:24][C:23]3=[O:27])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]>>[CH2:2]([N:24]1[CH2:25][CH2:26][N:22]([C:19]2[N:20]=[N:21][C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C:7]4[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=4[C:5]([F:4])([F:32])[F:33])[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)[C:23]1=[O:27])[CH3:3]
Reactant: CCI
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Product: CCN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Yield: 72 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 1-iodoethane in place of 1-iodo-3-methylbutane to react with 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one, the title compound was obtained as a white solid in 72% yield (0.061 g). 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=9.9 Hz, 1H), 7.72-7.69 (m, 1H), 7.62-7.49 (m, 2H), 7.34-7.32 (m, 1H), 6.99 (d, J=9.9 Hz, 1H), 4.08 (t, J=7.8 Hz, 2H), 3.95-3.84 (m, 2H), 3.6 (t, J=5.1 Hz, 2H), 3.52-3.47 (m, 4H), 3.38-3.25 (m, 4H), 1.16 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ167.4, 156.9, 156.8, 150.03, 134.4, 132.2, 129.3, 127.4, 127.2, 127.02, 126.8, 126.6, 126.2, 125.4, 121.7, 119.9, 118.1, 116.2, 46.4, 45.9, 45.5, 41.2, 41.1, 41.03, 38.3, 12.5. MS (ES+) m/z 449 (M+1).