Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:9]([CH3:24])[CH:8]=1>C1COCC1.O>[C:20]([O:19][C:17]([CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:25])=[O:5])=[CH:8][C:9]=1[CH3:24])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: COC(=O)c1ccc(OCCCC(=O)OC(C)(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1OCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
Lithium hydroxide monohydrate (137 mg, 3.26 mmol) was added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid methyl ester from Example E42.2 (414 mg, 1.34 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 48 h at room temperature and concentrated in vacuo. The residue was dissolved in chloroform, acidified with 1M HCl then washed with brine, dried and concentrated in vacuo to yield the title compound (275 mg, 70%).
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:21][C:22]1[C:27]([CH2:28][NH:9][C:10]2[C:11]3[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc([N+](=O)[O-])c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Sodium iodide (15.0 g) and sodium carbonate (31.0 g) are added to a solution of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (14.7 g) and 6-methyl-2-nitrobenzylchloride (18.6 g) in acetone (100 ml) at RT and are heated to reflux for 6 h. After cooling to RT and evaporation of the solvent, the residue is dissolved in a mixture of ethyl acetate (200 ml) and water (200 ml), and the organic phase is separated off. After three further extractions with ethyl acetate (100 ml) the combined organic layers are dried over magnesium sulfate and concentrated to a volume of 80 ml. 12.1 g of the title compound crystallize as a faintly yellow solid. The mother liquor is evaporated and the residue is purified by chromatography on silica gel (toluene/dioxane=6:1 as eluent) to yield additional 14 g of crystalline material. After recrystallization of both fractions from ethyl acetate, 21.5 g (76%) of the title compound of m.p. 160°-162° C. are isolated.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1)C1C=CC=CC=1>CO.[Pd]>[OH:29][CH:19]([C:10]1[N:11]([CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])[C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=1
Reactant: NC(=O)c1ccc(C(O)c2c(OCc3ccccc3)c(=O)ccn2CCO)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(C(O)c2c(O)c(=O)ccn2CCO)cc1

Procedure:
0.7 g of 4-{[3-benzyloxy-1-(2-hydroxy-ethyl)-4-oxo-1,4-dihydro-pyridin-2-yl]-hydroxy-methyl}-benzamide is hydrogenated in 20 ml of methanol over 0.07 g of palladium on carbon (5%) under normal pressure and at room temperature. The catalyst is removed by filtration and the product is recrystallised from methanol, yielding 4-{hydroxy-[3-hydroxy-1-(2-hydroxy-ethyl)-4-oxo-1,4-dihydro-pyridin-2-yl]-methyl}-benzamide in the form of colourless crystals. M.p.: 215.4°-216.5° C.
Reaction SMILES: [CH2:1]([CH:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Ni]>[NH2:15][CH2:14][CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C#N)Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(CN)Cc1ccccc1

Procedure:
The resulting ethyl benzylcyanoacetate was dissolved in 200 ml of EtOH and hydrogenated over Raney nickel. After removal of the catalyst by filtration with suction and concentration, 8.2 . . . of oil were obtained, and chromatography over silica gel (EA to EA/MeOH 5/1) gave 5.5 g of ethyl 3-amino-2-benzylpropionate. This compound was reacted with Boc2O to give ethyl 2-benzyl-3-(tert.-butoxycarbonylamino)-propionate, which was hydrolyzed, and the product was coupled with H-Val-OMe by the PPA method. The resulting diastereomers were resolved by chromatography (toluene/diisopropyl ether 1/1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])[C:5]#[N:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(CO)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc(C=O)c(F)c1
Reaction time: 0.08 h

Procedure:
A solution of Example 53B (340 mg, 2.25 mmol) in dichloromethane (10 mL) at room temperature was treated with Dess-Martin periodinane (1.9 g, 4.5 mmol), stirred for 5 minutes, and concentrated. The concentrate was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10:1 hexanes/ethyl acetate to provide the desired product. 1H NMR (500 MHz, CDCl3) δ 10.42 (s, 1H), 8.01 (dd, 1H), 7.62-7.58 (m, 1H), 7.54 (dd, 1H);
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1>CO.[Pd].C(Cl)(Cl)Cl.CO>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)[C@@H](C)OC(C)(C)C

Procedure:
2.36 g of Z-Tyr(tBu)-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH3 in 450 ml of methanol are hydrogenated with 500 mg of 10 % strength palladium on charcoal in the usual manner at room temperature. A colourless foam is obtained which is homogeneous according to a thin layer chromatogram and is further employed as such. The following Rf-values are obtained in a thin layer chromatogram on silica gel: in chloroform-methanol (95:5) Rf = 0.22; Rf89 = 0.42.
Reaction SMILES: [CH:1]1([O:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH2:35]1[C:40](=[O:41])[N:39]([O:42][C:43](ON2C(=O)CCC2=O)=[O:44])[C:37](=[O:38])[CH2:36]1>C(#N)C>[CH:1]1([O:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([O:25][C:43]([O:42][N:39]3[C:40](=[O:41])[CH2:35][CH2:36][C:37]3=[O:38])=[O:44])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CCOC(=O)C(O)c1ccc(NC(=O)OC2C=CCCCCC2)cc1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: CCOC(=O)C(O)c1ccc(NC(=O)OC2/C=C/CCCCC2)cc1
Agent: CCOC(=O)C(OC(=O)ON1C(=O)CCC1=O)c1ccc(NC(=O)OC2/C=C/CCCCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(OC(=O)ON1C(=O)CCC1=O)c1ccc(NC(=O)OC2C=CCCCCC2)cc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
The product 36 obtained above (80 mg, 0.23 mmol) was dissolved in 4.1 g acetonitrile. Diisopropylethylamine (215 mg, 1.67 mmol) was added, followed by N,N′-disuccinimidyl carbonate (217 mg, 0.85 mmol). The solution was stirred for 2 days at ca. 30° C. The solvent was removed by rotary evaporation and the residue was chromatographed on 16 g silica, using dichloromethane with gradually increasing amounts of TBME as the eluent. The product eluted with ca. 20% TBME. Rotary evaporation of the product fractions afforded the product minor-(E)-ethyl 2-(4-(((cyclooct-2-en-1-yloxy)carbonyl)amino)phenyl)-2-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)acetate (37) as a viscous oil (60 mg, 0.123 mmol, 53%).
Reaction SMILES: [CH:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O-:15][Mn](=O)(=O)=O.[K+].[Cr]([O-])(OC(C)(C)C)(=O)=O>>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12](=[O:14])[CH3:13])[CH2:2][CH2:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)NC1CCCc2ccccc21
Agent: CC(C)(C)O[Cr](=O)(=O)[O-]
Agent: [K+]
Product: CC(=O)NC1CCC(=O)c2ccccc21

Procedure:
Similarly, oxidation of N-(1,2,3,4-tetrahydro-1-naphthyl)acetamide with ceric ammonium nitrate, K2S2O8 /catalytic AgNO3, KMnO4 /catalytic ceric ammonium nitrate, t-butyl chromate, Na2Cr2O7, ceric sulfate, chromyl chloride and H2O2 /V2O5, respectively, under standard conditions and the general workup conditions described in Example 1, also affords the title compound.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([CH2:16][CH3:17])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]([OH:35])=[CH:23]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:16]([C:5]1[C:4]([CH2:3][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=3)[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]=2[OH:35])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:17]
Reactant: CCc1nc2ccc(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2CC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a stirred solution of 3-(chloromethyl)-2-ethyl-6-methoxyquinoline hydrochloride SMA 44014 (183 mg, 0.67 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (166 mg, 0.67 mmol) followed by a 2 N aq. LiOH solution (0.67 mL, 1.34 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided after evaporation 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.32 mL) and the mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 66 as a yellow solid (17 mg, 5% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (88 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A to produce 29.6 mg of 110 following reverse phase hplc purification. MS (Q1) 488.3 (M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:17](Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:9][S:17][N:8]=2
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(F)cc1N
Solvent: CCN(CC)CC
Product: Fc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
4-Fluoro-benzene-1,2-diamine (2.5 g, 19.8 mmol) was added into a 50-mL Schlenk flask. The system was flushed with argon before 200 mL of chloroform was added and followed by addition of triethylamine (11.05 mL, 79.3 mmol). A clear solution was observed after stirring at room temperature for 10 minutes. Thionyl chloride (5.18 g, 43.6 mmol) was added dropwise. The mixture was heated to reflux for 5 hours before being cooled down to room temperature. The organic layer was washed with brine (100 mL) and further dried over anhydrous MgSO4. After removal of the solvent, the product was purified by silica gel column with hexane/dichloromethane (v/v, 1/2) as the eluent. Removal of the solvent offered a colorless oil (1.35 g, 44.3% yield) after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 7.93 (d×d, 1H, J=9.0 Hz×5.0 Hz), δ 7.56 (d×d, 1H, J=9 Hz×2.5 Hz), δ 7.38 (m, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:7][O:8][C:9]([C:11]1[C:16]([NH:17][C:24](=[O:25])[C:23]2[CH:27]=[C:19]([Br:18])[CH:20]=[CH:21][C:22]=2[F:28])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(Cl)c1cc(Br)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Temperature: 40 °C
Yield: 74.9 %

Procedure:
Pyridine (7.75 g, 98.0 mmol) was added at 0° C. under N2 to a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester 101 (1.5 g, 9.80 mmol) and 5-bromo-2-fluorobenzoylchloride (9.45 g, 49.0 mmol) in CH2Cl2. The reaction mixture was warmed at 40° C. for 4 h, then cooled down at room temperature. The reaction mixture was quenched with 20 mL of ethanol, evaporated, partitioned between CH2Cl2 and 1N NaHCO3, dried (Na2SO4) and evaporated. The crude material was triturated in EtOH, filtered, washed with EtOH and ether to give 2.6 g of 3-(5-bromo-2-fluorobenzoyl-amino)pyrazine-2-carboxylic acid methyl ester 102 as a white powder (LCMS analysis).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:21])=[C:13]([F:12])[CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: Fc1ccc(CBr)cc1F
Product: CCOC(=O)c1ccn(Cc2ccc(F)c(F)c2)c1C

Procedure:
Prepared in analogy to that of Example 5(a) from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3,4-difluorobenzyl bromide. The title compound, ESI MS (m/z): 280 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1.O>CN(C)C=O>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][S:6][C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
A solution of tert-butyl {3-[(3-aminobenzyl)thio]phenyl}carbamate (0.55 g, 1.7 mmol) in N,N-dimethylformamide (5.0 mL) was treated with potassium carbonate (0.30 g, 2.2 mmol) and stirred at 25° C. for 5 min. The reaction mixture was treated with 2,4,5-trichloropyrimidine (0.25 mL, 2.2 mmol) and stirred at 25° C. for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude gum. This material was purified by flash column chromatography to give the desired product (0.67 g, 84%) as a solid. LCMS for C22H22Cl2N4O2SNa (M+Na)+: m/z=499.0, 501.0.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[N:22]([CH3:23])[CH:21]=[C:8]2[C:9]3[CH:19]=[C:18]([F:20])[CH:17]=[C:11]4[CH:12]=[CH:13][C:14](=[N:15][NH:16][C:7]2=[C:6]1[C:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=1)[C:10]=34)[CH3:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH2:3]([CH:5]1[N:22]([CH3:23])[CH:21]=[C:8]2[C:9]3[CH:19]=[C:18]([F:20])[CH:17]=[C:11]4[CH:12]=[CH:13][C:14](=[N:15][NH:16][C:7]2=[C:6]1[C:24]1[CH2:25][CH2:26][N:27]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:28][CH:29]=1)[C:10]=34)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1C(C2=CCNCC2)=C2NN=C3C=Cc4cc(F)cc(c43)C2=CN1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1C(C2=CCN(S(C)(=O)=O)CC2)=C2NN=C3C=Cc4cc(F)cc(c43)C2=CN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Example 9 (35 mg, 0.08 mmol) in dichloromethane (5 mL) was added triethylamine (0.07 mL, 0.482 mmol) and methanesulfonyl chloride (14 mg, 0.121 mmol). The mixture was stirred at room temperature for 2 hours, and purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, CD3OD): δ 0.81-0.86 (m, 3H), 1.22-1.30 (m, 1H), 1.37-1.45 (m, 1H), 2.62-2.69 (m, 1H), 2.73-2.81 (m, 1H), 2.88 (s, 3H), 2.98 (s, 3H), 3.36-3.41 (m, 1H), 3.42-3.48 (m, 1H), 3.96 (dd, J=5.80, 3.05 Hz, 2H), 4.28 (dd, J=9.00, 5.65 Hz, 1H), 6.11 (s, 1H), 7.21-7.29 (m, 2H), 7.35 (d, J=5.49 Hz, 1H), 7.77 (dd, J=10.68, 2.75 Hz, 1H), 8.22 (d, J=5.19 Hz, 1H), 11.51 (s, 1H). MS (ESI+) m/z 441 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([S:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Mg+2].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([S:16]([Cl:23])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S([O-])c1cccc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Magnesium 3-benzyloxyphenylsulfinate bromide, as described above in Step B, (4.5 g, 14 mmol) was dissolved in dry CH2Cl2 (175 mL) and cooled to 0° C. under argon. Sulfuryl chloride (19 mL of a 1.0 M solution in CH2Cl2, 19 mmol) was added dropwise, and the mixture was stirred for 18 hours at ambient temperature, during which time a precipitate formed. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure to give the product as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:34])[N:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=1)#[N:2].[C:35]([O:38][C:39]1[CH:40]=[CH:41][C:42](Cl)=[N:43][CH:44]=1)(=[O:37])[CH3:36].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C.CCCCCC>[C:35]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:13]2[CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:10](=[O:34])[N:11]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:12]=2)=[N:43][CH:44]=1)(=[O:37])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccccc2C#N)c(=O)n(-c2ccccc2)c1
Reactant: CC(=O)Oc1ccc(Cl)nc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1ccc(-c2cc(-c3ccccc3C#N)c(=O)n(-c3ccccc3)c2)nc1
Temperature: 120 °C
Reaction time: 8.5 h
Yield: 38.4 %

Procedure:
3.42 g of 3-(2-cyanophenyl)-1-phenyl-5-(tri-n-butyl stannyl)-1,2-dihydropyridin-2-one, 1.57 g of 5-acetoxy-2-chloropyridine and 352 mg of tetrakistriphenylphosphine palladium were added to 40 ml of xylene, and the mixture was stirred at 120° C. in a nitrogen atmosphere for 8.5 hours. The reaction mixture was refined by silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 953 mg of the subject compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1.CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: Cc1ccnc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc(Nc2cccc(Br)c2C)c1
Temperature: 190 °C
Yield: 33.6 %

Procedure:
A mixture of 3-bromo-2-methylaniline (200 mg, 1.075 mmol), 2-fluoro-4-methylpyridine (155 mg, 1.397 mmol) and potassium tert-butoxide (193 mg, 1.72 mmol) in DMSO (4 mL) was heated in a sealed tube via microwave irradiation at 190° C. for 40 min. The mixture was partitioned between EtOAc and water, and the organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-4-methylpyridin-2-amine as a yellow solid (100 mg, 34%). 1H NMR (400 MHz, chloroform-d) δ 8.05 (1H, d, J=5.3 Hz), 7.38 (2H, d, J=8.1 Hz), 7.06 (1H, t, J=8.0 Hz), 6.58 (1H, d, J=5.3 Hz), 6.40 (1H, s), 6.23 (1H, br. s.), 2.37 (3H, s), 2.23 (3H, s). Mass spectrum m/z 277, 279 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[C:25]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[O:16])[S:12][CH:13]=1)C>[Li+].[OH-]>[CH:27]1([C:25]([C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[NH:17][C:15](=[O:16])[NH:14][C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][NH:6][CH2:5][C:4]([OH:32])=[O:3])[N:10]=2)=[O:26])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CNCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCNCC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Yield: 83.6 %

Procedure:
(2-{-2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl amino)-acetic acid (18 mg, 95%) was prepared from (2-{-2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl amino)-acetic acid ethyl ester (0.02 g, 0.05 mmol) and 2.5M LiOH (20 uL) following the general procedure J.