Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH3:24])=[O:8].O1CCCC1.CO.[BH4-].[Na+]>[Cl-].[Na+].O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[OH:8])=[C:18]([CH3:24])[CH:19]=1
Reactant: Cc1cc(Cl)ccc1OCc1ccccc1C(=O)c1nccn1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)ccc1OCc1ccccc1C(O)c1nccn1C
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a mixture of 1.02 g (3 mmol) of 2-(4-chloro-2-methylphenoxymethyl)phenyl 1-methylimidazol-2-yl ketone, 6 ml of tetra hydrofuran and 3 ml of methanol was added 0.11 g (3 mmol) of sodium borohydride under ice-cooling and stirred at room temperature for an hour. After completion of the reaction, 100 ml of brine was added and extracted twice with 50 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure. The crystal thus obtained was recrystallized from ethyl acetate to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-hydroxybenzyl]-1-methylimidazole (0.57 g, 55.4%) as colorless crystals. mp. 159-160° C.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1.[OH-].[NH4+]>CN1CCCC1>[C:2]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)#[N:3]
Reactant: N#C[Cu]
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: CN1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc2c(cc1C#N)C(C)(C)CCC2(C)C
Temperature: 175 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
28.9 g (322 mmol) of copper(I) cyanide was added to 22.7 g (80.7 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 270 mL of N-methyl pyrrolidine. The reaction mixture was heated at 175° C. After 16 hours, the mixture was cooled to room temperature and treated with 400 mL of 10% aqueous ammonium hydroxide. The reaction mixture was filtered to remove salts and the solids were extracted with hot ethyl acetate. The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by gradient elution through a pad of silica gel (hexane-5% ethyl acetate/hexane) to give 18 g (95%) of 2-cyano-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (M+=227).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3=[N:12][O:13][N:14]=[C:10]3[C:9]=2F)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].C[O-].[Na+].[C:26](O)(=[O:28])C>CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3=[N:12][O:13][N:14]=[C:10]3[C:9]=2[O:28][CH3:26])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc3nonc3c2F)cc(N)c1Cl
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(-c2ccc3nonc3c2OC)cc(N)c1Cl
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
Methyl 4-amino-3-chloro-6-(4-fluorobenzo[c][1,2,5]oxadiazol-5-yl)picolinate (70 mg, 0.21 mmol) was dissolved in 2 mL dry methanol, treated with 0.20 mL 30% sodium methoxide solution in methanol and stirred for 90 min at 20° C. The excess sodium methoxide was neutralized by addition of acetic acid and the volatiles were removed by rotary evaporation. The residue was taken up in 10 mL ethyl acetate, washed with 2 mL saturated NaHCO3, 2 mL saturated NaCl, dried (Na2SO4) and evaporated to give the title compound as white solid (51 mg, 72%): mp 142-144° C.; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.3 Hz, 1H), 7.51 (d, J=9.3 Hz, 1H), 7.44 (s, 1H), 4.86 (s, 2H), 4.39 (s, 3H), 4.00 (s, 3H); ESIMS m/z 335 ([M+H]+), 333 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[C:19]([CH3:29])[CH:18]=1)=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[C:15]([C:17]1[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[C:19]([CH3:29])[CH:18]=1)[NH:6][C:4]2=[O:5]
Reactant: Cc1cc(C=O)cc(C)c1OCC(N)=O
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(-c3cc(C)c(OCC(N)=O)c(C)c3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A solution of 4-hydroxy-3,5-dimethoxybenzaldehyde (1.0 g, 6.66 mmol) in DMF (10 mL) was cooled to 0° C. under nitrogen. NaH (0.4 g, 10 mmol, 60% in oil) was added portion-wise. The reaction was stirred for 30 min, then 2-bromoacetamide (0.918 g, 6.66 mmol) was added and stirring was continued for 36 h at room temperature. The DMF was removed under reduced pressure and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with an aqueous solution of NaOH (50 mL, 10%), washed with water (50 mL) and brine solution (50 mL) and dried over MgSO4 and concentrated to give 0.6 g of crude intermediate, which was purified by flash column chromatography to provide the desired intermediate (366 mg, 26%), as a white solid. A mixture of 2-amino-4,5-dimethoxybenzamide (0.2 g, 1.019 mmol), 2-(4-formyl-2,6-dimethyl-phenoxy acetamide (0.211 g, 1.019 mmol), sodium hydrogensulfite (0.116 g, 1.121 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 16 h under nitrogen. The reaction mixture was cooled to room temperature and water (50 mL) was added. The white precipitate was filtered off and washed with cold water (30 mL×2) and dried under high vacuum to provide 2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide (300 mg, 76%) as a off white solid. Selected data: MS (ES) m/z: 384.1 (M+1); MP 354-356° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1.N1C=CN=C1.[CH3:22][CH:23]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH:23]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)([CH3:24])[CH3:22]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc2ccc(CO)cn12
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (59) (497.0 mg, 2.26 mmol), DMAP (12.2 mg, 0.1 mmol) and 1H-imidazole (154.0 mg, 2.26 mmol) in dichloromethane (10 mL), was added TIPSCl (523.0 mg, 2.71 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum to yield crude ethyl 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (60). MS m/z 377.2 (M+1)+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][SH:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:12][CH2:11][CH2:10][N:9]([CH3:13])[CH3:8])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)CCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 18.7 %

Procedure:
To sodium hydride (600 mg, 15 mmol 60% in mineral oil) were added DMF (10 ml), 2-dimethylaminoethanethiol (1.3 g, 9.2 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred at 100° C. for 10 hours. After addition of saturated brine the reaction mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (10% methanol/chloroform) to give the subject compound (24 mg, yield 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:23](=[O:24])[CH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:29])[F:15])=[CH:27][CH:26]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCNC(=O)CCc3ccc(C(F)(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.3 g (1.57 mmol) 5-methoxytryptamine, 0.34 g (1.57 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available), 0.6 g (1.8 mmol) TBTU and 0.6 g (4.6 mmol) DIPEA in 6 mL DMF was shaken for 3 h at room temperature. 50 mL water was added and the mixture was extracted with DCM. The combined organic phases were washed with water, dried with MgSO4 and evaporated to dryness to yield the title compound which was used without further purification in the consecutive step.
Reaction SMILES: C([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH2:19][CH3:20])[C:12]([CH3:22])([CH3:21])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:19]([O:18][N:13]1[C:12]([CH3:22])([CH3:21])[CH2:11][CH:10]([OH:9])[CH2:15][C:14]1([CH3:16])[CH3:17])[CH3:20]
Reactant: CCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The ester obtained in Example 3A is hydrolyzed using sodium hydroxide and aqueous methanol to give the title compound as a white solid melting at 86-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[NH2:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([Cl:39])=[CH:34][N+:33]=1[O-].CCN(C(C)C)C(C)C>C(O)(=O)C.C1COCC1>[Cl:39][C:35]1[CH:36]=[C:37]([F:38])[C:32]([NH:31][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:25])=[N:33][CH:34]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Reactant: Nc1c(F)cc(Cl)c[n+]1[O-]
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CC1(C)Cc2c(c(C(=O)Nc3ncc(Cl)cc3F)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1

Procedure:
The title compound was prepared by following the same procedure described for Example-65 by using 2-[(2,6-Dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.200 g, 0.51 mmol), thionyl chloride (1.0 mL), 2-amino-5-chloro-3-fluoropyridine 1-oxide (Intermediate-43, 0.099 g, 0.612 mmol), DIPEA (2 mL), THF (5.0 mL). To a solution of obtained crude product (0.200 g) in acetic acid (10.0 mL) was added iron powder (0.200 g). The reaction mass was stirred at 80° C. for 2-3 h. Excess of Iron powder was separated. The reaction mass was diluted with water, it was extracted with ethyl acetate. The reaction mass was filtered through celite bed and organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 3.09 (s, 2H), 7.25 (m, 1H), 7.38 (m, 1H), 7.53 (d, J=7.8 Hz, 2H), 8.16 (d, J=9.6 Hz, 1H), 8.36 (s, 1H), 9.82 (s, 1H), 11.00 (br s, 2H); MS [M]+: 522.02.
Reaction SMILES: C([NH:3][C:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O.Cl.N>O>[NH2:3][C:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[S:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: O=CNc1c(-c2ccc(Cl)cc2)sc2ccccc12
Agent: Cl
Agent: N
Solvent: O
Product: Nc1c(-c2ccc(Cl)cc2)sc2ccccc12
Reaction time: 10 h
Yield: 74.4 %

Procedure:
29.5 g (0.103 mol) of 3-formamido-2-(4'-chloro-phenyl) benzo(b)thiophene with 300 ml of hydrochloric acid at 25% are refluxed with stirring for 10 hours. After cooling, the mixture is poured into water, made alkaline by ammonia and extracted with CH2Cl2. By evaporating the organic phase dried over K2CO3 and recrystallising the residue in acetone, 19.9 g (73% of theory) of 3-amino-2-(4-chlorophenyl)-benzo(b)-thiophene are obtained, yellow crystals, mp. 152°-154° (benzene).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1N methanolic HC1, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180° C for six hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[C:11]([CH:13]=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[K+]>O1CCCC1>[C:29]1([CH2:28][O:35][CH2:36][CH2:37]/[CH:38]=[CH:13]\[C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C\c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)\CCOCc1ccccc1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of the aldehyde (16) (19.65 g, 58.1 mmol) in dry tetrahydrofuran (1 L), was added (3-benzyloxypropyl)triphenyl phosphonium bromide (30.02 g, 61.1 mmol). The resulting suspension was cooled to 15° C., and then a 1.0M solution (61.4 mL; 61.4 mmol) of potassium t-butoxide in tetrahydrofuran was added over five minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The reaction mixture was filtered through Celite; the filter cake was washed with tetrahydrofuran (2×150 mL); the filtrate and washings were combined, diluted with ether (800 mL) and refiltered through fresh Celite. The filtrate was concentrated under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of hexanes-ethyl acetate (3:1 to 2:1), to obtain the title compound (17) as a pale yellow powder, mp 101-104° C. MS(FAB) 471 (MH+).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:18]([CH3:20])[CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[C:18]([CH3:20])[CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of KOH (154 mg, 2.75 mmol) in ethanol (2 mL) was added to a solution 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.2 g, 2.50 mmol) in ethanol (10 mL) and methylene chloride (4 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in water. Ethyl acetate was added and the organic layer was washed with 0.5 M HCl, water, brine and dried. After filtration and concentration under reduced pressure gave crude 2-(6-[N,N-bis(tert-butoxy-carbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:48])[CH2:43][O:44]C(=O)C)[CH2:38][CH2:37]2)=[O:32])[C:25]=1[CH3:49])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:48])[CH2:43][OH:44])[CH2:38][CH2:37]2)=[O:32])[C:25]=1[CH3:49])(=[O:12])=[O:11]
Reactant: CC(=O)OCC(=O)N1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCN(C(=O)CO)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of acetic acid 2-{4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl ester (100 mg), 10% potassium carbonate in water and methanol (5 mL) was stirred at 40° C. for overnight. The reaction was concentrated, extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give the titled compound as an orange-red solid. MS m/z 686 [M−1].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[C:12]([O:18][CH3:19])[C:11]=2[F:20])=[O:9])=[CH:6][C:5]([Cl:21])=[CH:4][N:3]=1.[CH:22]([B-](F)(F)F)=[CH2:23].[K+]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:5]1[CH:6]=[C:7]([C:8]([C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[C:12]([O:18][CH3:19])[C:11]=2[F:20])=[O:9])[C:2]([CH:22]=[CH2:23])=[N:3][CH:4]=1
Reactant: C=C[B-](F)(F)F
Reactant: C=Cc1ccc(OC)c(F)c1C(=O)c1cc(Cl)cnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCCO
Product: C=Cc1ccc(OC)c(F)c1C(=O)c1cc(Cl)cnc1C=C
Temperature: 25 °C

Procedure:
To a stirred solution of (2,5-dichloropyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanone (11.6 g, 35.6 mmol) in nPrOH (200 mL) were added potassium vinyltrifluoroborate (5.00 g, 37.3 mmol), PdCl2(dppf) (580 mg, 0.71 mmol), and TEA (4.96 mL, 35.6 mmol). The reaction mixture was purged with N2 for 10 min, heated to reflux for 3 h, cooled to room temperature, treated with water, and concentrated. The residue was extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.63 (d, 1H); 7.62 (d, 1H); 7.41 (d, 1H); 7.36 (dd, 1H); 7.09 (t, 1H); 6.57 (dd, 1H); 6.54 (d, 1H); 5.63 (m, 2H); 5.23 (d, 1H); 3.92 (s, 3H). LRMS (ESI) calc'd for (C17H13ClFNO2) [M+H]+, 318.1; found 318.1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:13]([CH3:15])[N:14]=1.FC(F)(F)C(O)=O>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=1
Reactant: COc1nccc(I)c1-c1nc(C)c(C(=O)OC(C)(C)C)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc(I)c1-c1nc(C)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A stirred solution of tert-butyl 2-(4-iodo-2-methoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylate (0.047 g, 0.1131 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.6 mL) and the reaction was stirred at room temperature overnight. The solvent was evaporated after adding toluene (1 mL) and the residue was purified on Prep HPLC (trifluoroacetic acid/acetonitrile/water) to give the title material (0.039 g, 96%). 1H NMR (400 MHz, MeOH-d4) δ (ppm): 2.70 (s, 3H) 3.97 (s, 3H) 7.70 (d, J=5.56 Hz, 1H) 8.11 (d, J=5.56 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[N:7]=1.CCO.[OH-].[Na+]>C1COCC1>[C:20]1([C:17]2[O:16][C:15]([C:13]([NH:12][C:8]3[N:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=3)=[O:14])=[CH:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)n1
Reaction time: 2 h

Procedure:
The ester (39) (35 mg, 0.10 mmol) was hydrolysed using Method C, except that EtOH (2 mL), THF (1 mL) and 1 M NaOH (2 mL) were used, and the reaction was stirred for 2 hours. After work-up, the crude product was purified by preparative HPLC to give the title compound. Yield: 9.8 mg, 29%; LC-MS tr 2.00 min; HPLC Purity: 97%; MS (ES+) m/z 335 (M+H); 1H NMR (400 MHz; MeOH): δ 6.95 (d, 1H), 7.05 (d, 1H), 7.35-7.55 (m, 5H), 7.65 (d, 1H), 7.85-8.00 (m, 3H), 8.30 (d, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
tert-Butyl 4-(4-nitrophenylsulfonyl)piperidine-1-carboxylate (2.214 mmol, 820 mg) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to give the intermediate 4-(4-nitrophenylsulfonyl)piperidine (640 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(=O)Cl
Reaction time: 3 h

Procedure:
4-Chloro-2-methylbenzoic acid (1.365 g, 8 mmol, commercially available from e.g. Maybridge, Fluorochem or Sigma-Aldrich) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.770 mL, 8.80 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.464 g.