Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.C(N(C(C)C)CC)(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:53]1([CH2:59][C:60]2[S:68][C:67]3[CH2:66][CH2:65][NH:64][CH2:63][C:62]=3[CH:61]=2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:22])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][CH2:16][O:17][CH2:18][C:19](=[O:21])[N:64]2[CH2:65][CH2:66][C:67]3[S:68][C:60]([CH2:59][N:53]4[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]4)=[CH:61][C:62]=3[CH2:63]2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Reactant: c1c(CN2CCCCC2)sc2c1CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCc3sc(CN4CCCCC4)cc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(4-Methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetic acid (AC6) (353 mg, 1.06 mmol), diisopropylethylamine (372 μl, 2.13 mmol), HOAt (15 mg, 107 μmol) and EDCI (306 mg, 1.60 mmol) were added to a solution of 2-(piperidin-1-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (TP10) (277 mg, max. 425 μm) in MC (25 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue obtained was purified by chromatography on silica gel (MC/(7 M NH3 in MeOH), 98:2 and 99:1). The product fractions were combined and evaporated to dryness. The residue was dissolved in dry acetonitrile (5 ml), the solution was dried by freeze drying and the solid was then dissolved in methylene chloride (10 ml). Solid NaHCO3 (approx. 500 mg) was added to this solution and the mixture was stirred for 1 hour. The mixture was then filtered and the filtrate was concentrated in vacuo. The yield was 105 mg (45% over 2 stages). MS, Rt=3.0 min, m/z=550.1 [MH]+
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3](=[CH:5][C:6](=[CH:8][CH:9]=1)[OH:7])[OH:4].[CH3:11]I>C[O-].[Na+]>[CH3:11][O:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2](=[CH:9][CH:8]=1)[CH:1]=[O:10]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C=O)c(O)c1

Procedure:
Beta-resorcyl aldehyde (13.8 grams) is dissolved in sodium methoxide (in amount equivalent to 2.3 grams of sodium), and 14.2 grams of methyl iodide are added. The mixture is refluxed for 4 hours. Alcohol (methanol) is distilled off and dilute HCl added. The resulting red liquid is separated from the aqueous layer, dried and steam distilled.
Reaction SMILES: [C:1]([C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7][C:6]([N:9]2[CH2:14][CH2:13][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH2:4]1)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:4][CH2:5][CH:6]([N:9]2[CH2:10][CH2:11][C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C2=CCC(C#N)(c3ccccn3)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCN(C2CCC(C#N)(c3ccccn3)CC2)CC1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred mixture of 4.5 parts of ethyl 1-[4-cyano-4-(2-pyridinyl)-1-cyclohexenyl]-4-phenyl-4-piperidinecarboxylate and 80 parts of ethanol are added portionwise 0.4 parts of sodium borohydride. Upon completion, stirring is continued first overnight at room temperature and further for 30 minutes at reflux. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 2 parts (35%) of ethyl 1-[4-cyano-4-(2-pyridinyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylate; mp. 157.1° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH3:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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]>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:25]3[S:24][C:23]([CH3:22])=[N:27][CH:26]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: Cc1nccs1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2cnc(C)s2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
To a degassed solution of compound 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, 1.2 mmol), 2-methylthiazole (244 mg, 2.5 mmol) and Na2CO3 (261 mg, 2.5 mmol) in DMF (6 mL) was added Pd(dppf)Cl2 (50 mg) under N2, and the mixture was stirred at 80° C. for 12 h. After the solvent was removed, the residue was purified by column chromatography (DCM:EtOAc=2:1) to give the product of 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-(2-methylthiazol-5-yl)benzofuran-3-carboxamide (240 mg, yield: 42%). 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 7.98˜8.01 (m, 1H), 7.68 (s, 1H), 6.06 (br s., 1H), 3.33 (s, 3H), 3.10 (s, 3H), 3.08 (d, J=5.2 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 458/460.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25]C4CCNCC4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][C:36]([OH:38])=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:5][CH2:9][N:8]([C:36](=[O:38])[CH2:35][CH2:34][O:33][CH3:32])[CH2:7][CH2:6]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: COCCC(=O)O
Product: COCCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 279.2 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 382 mg; 0.87 mmol) and 3-methoxypropanoic acid (180 mg; 1.73 mmol), 620 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EtOAc).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:37])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO.CN(C=O)C.C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:37])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)=Cc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Cc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)cc1
Reaction time: 2 h

Procedure:
A suspension of 4-(2-methylprop-1-enyl)phenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (30 mg, 0.057 mmol) and palladium on carbon (10 wt. %, wet) (20 mg, 0.188 mmol, Aldrich) in MeOH (4.0 mL) and DMF (0.5 mL) was placed under hydrogen (balloon) for 2 hrs and additional palladium on carbon (20 mg) was added. The resulting mixture was continuously stirred under hydrogen (balloon) for 1.5 hrs, diluted with CH2Cl2, filtrated through a pad of CELITE® 545 filter aid and concentrated in vacuo. The residue was purified by preparative HPLC (C18 column; 30-100% methanol in water containing 0.05% trifluoroacetic acid) to give Example 144 (21.4 mg, yellow solid, 71%) upon lyophilization. 1H NMR (500 MHz, CDCl3) 8.10 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.25 Hz, 2 H), 7.38 (d, J=7.70 Hz, 1 H), 7.14 (d, J=8.80 Hz, 2 H), 7.00 (d, J=8.25 Hz, 2 H), 6.56 (d, J=2.20 Hz, 1 H), 6.33 (dd, J=7.42, 2.47 Hz, 1 H), 4.62-4.74 (m, 1 H), 3.89-4.04 (m, 1 H), 3.85 (app brs, 1 H), 3.85 (app brs, 1 H), 3.57 (app brs, 1 H), 3.12 (s, 3 H), 2.46 (d, J=7.15 Hz, 2 H), 2.13 (app brs, 2 H), 1.89-1.98 (m, 2 H), 1.80-1.89 (m, 1 H), 0.90 (d, J=6.60 Hz, 6 H). MS (ESI) 525 (M+H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:41][CH2:40]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 71.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (508 mg, 1.32 mmol, 72%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[O:7][CH:8]([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>CO.[Pd]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:19][C:6]=1[O:7][CH:8]([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1N

Procedure:
To a solution of tert-butyl 2-(5-fluoro-2-nitrophenoxy)propylcarbamate (3.1 g) in MeOH (5 ml) was added 10% palladium on carbon (300 mg) and the reaction mixture was hydrogenated at room temperature at 50 psi. The catalyst was filtered off and the filtrate was concentrated in vacuo.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][C:19]2=[O:22])=[CH:14][CH:13]=1>CN(C=O)C>[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][C@@H:19]2[OH:22])=[CH:14][CH:13]=1
Reactant: O=C1CCCc2ccc(F)cc21
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@H]1CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 166 %

Procedure:
To an ice bath-cooled triethylamine (37.6 mL, 270.5 mmol, 7.4 equiv.) was added drop-wise formic acid (10.4 mL, 270.5 mmol, 7.4 equiv). The reaction solution was stirred at RT for 20 min. 7-Fluoro-3,4-dihydronaphthalen-1(2H)-one (6.0 g, 36.6 mmol, 1 equiv.) and Noyori(S,S) catalyst (560 mg, 2.5 mol %, prepared according to lit. 1, were added. Most was dissolved. DMF (10 mL) was added to make the reaction homogeneous. The reaction turned to dark red and was stirred at 40° C. overnight. TLC was checked and showed no more starting material. The solvents were removed by evaporation. The residue was mixed with water (100 mL) and stirred for 30 min to result a red solid, which was collected on funnel and washed with water and small amount of cold EtOH, then was dried in vacuo overnight. A red solid product (10.1 g, 100%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 7.16 (dd, 1H), 7.08 (t, 1H), 6.86-6.97 (m, 1H), 5.25 (d, 1H), 4.53 (q, 1H), 2.58-2.67 (m, 2H), 1.82-1.90 (m, 2H), 1.59-1.70 (m, 2H).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][C:5]1[N:13]2[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]3=[C:12]2[C:7](=[CH:8][CH:9]=[CH:10]3)[C:6]=1[CH3:22].[Na].N.ClC(OCC)=O>>[CH3:22][C@@H:6]1[C:7]2[C:12]3=[C:11]([CH:10]=[CH:9][CH:8]=2)[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[N:13]3[C@H:5]1[CH2:4][CH2:3][NH:2][CH3:1]
Reactant: Cc1c(CCN(C)C)n2c3c(cccc13)CCc1ccccc1-2
Agent: CCOC(=O)Cl
Agent: N
Agent: [Na]
Product: CNCC[C@H]1[C@H](C)c2cccc3c2N1c1ccccc1CC3

Procedure:
The 1-(2-dimethylaminoethyl)-6,7-dihydro-2-methylindolo[1,7-ab][1]benzazepine obtained according to part A of this Example could be reduced using sodium/ammonia and demethylated using ethyl chloroformate/alkali in either sequence to yield the trans-1,2,6,7-tetrahydro-2-methyl-1-(2-methylaminoethyl)-indolo[1,7-ab][1]benzazepine [boiling point 144°-152° C/10-4 to 10-5 mm Hg] in the same manner as described in part B of Example 2. The hydrochloride melted at 198°-200° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20]CC)[CH2:16][CH2:15]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:23].[C:24]([Cu])#[N:25]>CN1C(=O)CCC1>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:23])#[N:25]
Reactant: CCC[C@H]1CC[C@H](C2COC(c3ccc(Br)c(F)c3)OC2)CC1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: C[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(C#N)c(F)c3)OC2)CC1

Procedure:
In 40 cm3 of NMP, 6.2 g (0.016 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane and 2.2 g (0.024 mol) of CuCN were refluxed with a mantle heater for 2 hours.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].O1CCCC1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].C(OCC)(=O)C>O>[CH3:1][N:2]1[C:12](=[O:13])[C:11](=[O:15])[NH:5][C:3]1=[O:4]
Reactant: CNC(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)NC(=O)C1=O
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
6.6 g of methylurea was added to 200 ml of anhydrous tetrahydrofuran and the suspension was stirred in an ice-water bath. 12.5 g of oxalyl chloride was added dropwise to the suspension, and the stirring was continued for 30 minutes in an ice-water bath. 200 ml of ethyl acetate and 70 ml of water were added to the reaction mixture and the organic layer was obtained by extraction. The water layer was further extracted with 130 ml of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated to dryness, and the crude residue was recrystallized from ethyl acetate-hexane to give 10.0 g of 1-methylimidazolidinetrione in the form of colorless needle crystals. The resulting compound was stirred in 1N ammonia water for a hour at room temperature. The solution was evaporated to dryness and the residue was recrystallized from water-ethanol to give 7.7 g of 5-methyloxaluric acid ammonium salt (compound 1) in the form of colorless prism crystals.
Reaction SMILES: [CH:1]1[N:9]=[C:8](Br)[C:7]2[C:3](=[N:4][S:5][N:6]=2)[C:2]=1[Br:11].[CH2:12]([C:28]1([CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[C:51]2[CH:50]=[C:49]([Sn](CCCC)(CCCC)CCCC)[S:48][C:47]=2[C:30]2[S:31][C:32]([Sn:34]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:33][C:29]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>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.C1(C)C=CC=CC=1>[Br:11][C:2]1[C:3]2[C:7](=[N:6][S:5][N:4]=2)[C:8]([C:49]2[S:48][C:47]3[C:30]4[S:31][C:32]([Sn:34]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][C:29]=4[C:28]([CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:51]=3[CH:50]=2)=[N:9][CH:1]=1
Reactant: Brc1cnc(Br)c2nsnc12
Reactant: CCCCCCCCCCCCCCCCC1(CCCCCCCCCCCCCCCC)c2cc([Sn](CCCC)(CCCC)CCCC)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC1(CCCCCCCCCCCCCCCC)c2cc(-c3ncc(Br)c4nsnc34)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Temperature: 75 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a solution of 4,7-dibromo-pyridal[2,1,3]thiadiazole (0.28 g, 0.95 mmol) and 1b (1.14 g, 0.95 mmol) in freshly distilled toluene (10 ml) was added Pd(PPh3)4 (109.8 mg, 0.095 mmol) under nitrogen, and then capped with a rubber septum. The reaction mixture was stirred at 75° C. for 10 hours. The solvent was removed and purified by column chromatography (silica was pretreated by 10 v/v % triethylamine/hexane solution) with hexane as eluent. The column separation was run for 3 times to give 268 mg of viscous purple oil, with yield of 25%. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.92 (s, 1H), 8.49 (s, 1H), 7.39 (s, 1H), 2.21 (m, 4H), 1.77 (m, 6H), 1.54-1.25 (m, 68H), 1.12-1.01 (m, 15H). 13C NMR (125 MHz, CD2Cl2) δ (ppm): 163.10, 160.00, 156.32, 148.09, 147.92, 145.93, 144.00, 142.24, 141.83, 140.28, 129.79, 127.62, 106.17, 53.53, 37.86, 31.92, 29.97, 29.66, 29.63, 29.59, 29.54, 29.42, 29.39, 29.35, 29.32, 29.29, 29.02, 28.99, 27.21, 24.58, 22.69, 22.65, 13.88, 13.45, 10.96.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:32](=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCOc1ccccc1CBr
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccccc1CN(Cc1ccccn1)C(C)=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.45 g of product from Example 22, 0.960 g of product from Example 12, 0.322 g of washed 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at 0° C. for 1 hour, room temperature for 18 hours; followed by heating at reflux temperature for 6 hours. The residue is purified by column chromatography (silica gel: 80% ethyl acetate/hexane) to give 0.976 g of the desired product as a yellow oil. The spectral data shows the presence of 2 rotomers.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([O:19]C)=[O:18].[OH-].[Na+]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1cccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(F)c2F)CC(=O)N1
Temperature: 60 °C
Yield: 54.8 %

Procedure:
The product from Step 1 (600 mg, 2.13 mmol) was dissolved in methanol (15 mL), NaOH solution (5 mL, 2.5 M) was added, and this reaction mixture was heated to 60° C. for 18 h. The reaction mixture was concentrated, and then poured into EtOAc (20 mL) and water (5 mL). The aqueous layer was acidified to pH<3 with 6N HCl, and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with 5% ether/hexanes to afford the title compound (312 mg, 55%). MS (ES+) m/e 268 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:26])[C:13]=1[S:14][C:15]1[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].[CH3:27][S:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>ClCCl.O1CCCC1.C(OC(=O)C)C>[Cl:26][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([Cl:7])[C:13]=1[S:14][C:15]1[S:19][C:18]([C:20]([NH:31][CH2:30][CH2:29][S:28][CH3:27])=[O:22])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]
Reactant: CSCCN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
Oxalyl chloride (0.934 g, 3.92 mmol) followed by N,N-dimethylformide (0.1 mL) was added dropwise to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (0.60 g, 1.71 mmol) in dichloromethane (30 mL) and the mixture was stirred at ambient temperature for 8 hour. After this time, TLC analysis showed no acid remaining so the mixture was allowed to be concentrated in vacuo to give a yellow solid. The resulting acid chloride solid was dissolved in dry tetrahydrofuran (10 mL). 2-(methylthio)ethanamine (0.047 g, 0.52 mmol) followed by triethylamine (0.066 g, 0.65 mmol) was added to a 2.5 mL aliquot of acid chloride solution in tetrahydrofuran at 0° C. The resulting mixture was stirred at ambient temperature for 3 hours. TLC analysis showed no acid chloride remaining so the mixture was diluted with ethylacetate and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford a brown oil. The crude material was purified by silica gel chromatography using an 85:15 mixture of hexane and ethyl acetate as eluent to afford the title product as a brown solid (55 mg, 13% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (1H, m), 8.98 (2H, m), 8.41 (1H, s), 3.39 (2H, m), 2.59 (2H, m), 2.08 (3H, s). MS m/z: 422.20, 424.21 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])[CH3:12]
Reactant: OCc1cccc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(CO)c1
Yield: 95.1 %

Procedure:
To a mixture of 3-hydroxybenzyl alcohol (3.56 g) and acetone (100 ml) were added iodoethane (6.7 g) and potassium carbonate (7.9 g), and the resulting mixture was heated at reflux for 61 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue and the resulting mixture was washed successively with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3-ethoxybenzyl alcohol (4.15 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1cc(Cl)ccc1C(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2OC)nc1C
Yield: 77.6 %

Procedure:
In ethanol (50 ml), 4-chloro-2-methoxythiobenzamide (4.00 g, 20.0 mmol) prepared in the Step 7-1-2 was suspended, and ethyl 2-chloroacetoacetate (3.62 g, 22.0 mmol) was added to the suspension. The mixture was heated under reflux overnight. After the mixture was allowed to cool, the solvent was distilled off under a reduced pressure, and ethyl acetate and a saturated sodium bicarbonate solution were added to the mixture. The resulting mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was suspended in ethyl acetate-n-hexane (ethyl acetate:n-hexane=1:1) and separated by filtration. The separated product was washed with the same solvent and dried under a reduced pressure to give the title compound (4.84 g, 78%) as a light-yellow powder.