Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][N:13]([CH3:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[CH3:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: CN(C)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 85.5 %

Procedure:
The procedure is carried out as in Example 1, starting with 378 mg of 2,6-dichloropurine, 5 ml of butanol and 300 mg of N,N-dimethyl-p-phenylenediamine. 494 mg of the expected product are thus obtained.
Reaction SMILES: [C-]#N.[Na+].[CH:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.CN(C)[CH2:15][CH2:16][C:17]([C:19]1[S:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[O:18].[OH-].[NH4+]>CN(C)C=O.O>[C:5]1([C:4](=[O:11])[CH2:15][CH2:16][C:17]([C:19]2[S:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[O:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(=O)CCN(C)C)s1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [C-]#N
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)CCC(=O)c2ccccc2)s1
Reaction time: 1 h

Procedure:
To a stirred suspension of 1.2 grams (0.025 mole) of sodium cyanide in 70 ml of dimethylformamide was added dropwise a solution of 5.2 grams (10 moles) of freshly distilled benzaldehyde in 40 ml of dimethylformamide. The complete addition required 20 minutes. The reaction mixture was stirred for one hour. Separately, while the mixture stirred, 10.0 grams (0.043 mole) of 3-dimethylamino-1-(5-methyl-2-thienyl)propan-1-one hydrochloride was made alkaline in water with ammonium hydroxide, extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated. The so-prepared free Mannich base was dissolved in 40 ml of dimethylformamide and added dropwise to the benzaldehyde/sodium cyanide reaction mixture. The complete addition required one hour. The reaction mixture was stirred for an additional 16 hours, then concentrated under reduced pressure to a residual solid. The solid was taken up in water and extracted with three 100 ml portions of chloroform. The combined extracts were washed with water and dried with sodium sulfate. The organic layer was concentrated under reduced pressure to a solid residue. The solid was recrystallized from ethanol-water to give 8.3 grams of 1-phenyl-4(5-methyl-2-thienyl)-1,4-butanedione; m.p. 122.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)C(C)(C)C2
Yield: 80 %

Procedure:
To a mixture solution of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.0 g, 2.5 mmol), 4-tert-butylphenylboronic acid (582 mg, 3.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (289 mg, 0.25 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (924 mg, 80%) as a white solid: LC/MS m/e calcd for C29H32ClNO2 (M+H)+: 463.04, observed: 463.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:2].C(N(CC)CC)C.[C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:52])[CH3:51])[C:43](Cl)=O)#[N:39]>CN(C)C=O>[C:38]([C:40]1[CH:41]=[C:42]([C:43]2[O:21][N:20]=[C:18]([C:14]3[C:13]([CH3:22])=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]([CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][CH2:11]4)[N:19]=2)[CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:51])[CH3:52])#[N:39]
Reactant: CCOC(=O)CCCC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[4-(ethyloxy)-4-oxobutyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27; 240 mg, 0.572 mmol) in N,N-dimethylformamide (DMF) (4 ml) was added triethylamine (0.119 ml, 0.858 mmol) followed by 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (WO 2008128951; 141 mg, 0.629 mmol) in DMF (2 ml) dropwise over one minute at room temperature under nitrogen. The resulting mixture was stirred for 1 h at room temperature, then warmed up to 120° C. After 2 h at 120° C., most of the solvent was removed, and the residue diluted with ethyl acetate. The solution was washed with sodium bicarbonate then brine, dried over MgSO4 and concentrated in vacuo to give the crude product (ca. 300 mg). Purification by flash chromatography on silica gel, eluting with 8-38% ethyl acetate in cyclohexane, gave the title compound (120 mg) as a white foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:14]=3[S:13](=O)(=O)[C:12]=2[CH:23]=1.CCOCC.Cl>C(Cl)(Cl)Cl.O>[Br:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]3[CH:10]=[CH:9][C:8]([Br:7])=[CH:23][C:12]=3[S:13][C:14]=2[CH:19]=1
Reactant: O=S1(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: Brc1ccc2c(c1)sc1cc(Br)ccc12
Reaction time: 2 h
Yield: 48.1 %

Procedure:
In a 500-ml flask, lithium aluminum hydride (4.1 g) is slowly introduced in small amounts over 50 minutes into a mixture of 3,7-dibromodibenzothiophene dioxide (20 g) and anhydrous ether (200 ml) in an ice bath, and the resulting mixture is refluxed and stirred for 2 hours. Water (200 ml) is added thereto to deactivate lithium aluminum hydride. Chloroform (200 ml) and concentrated hydrochloric acid (40 ml) are added thereto, the mixture is thoroughly stirred, and the organic layer is separated. The aqueous layer is further extracted with chloroform (200 ml×2), the chloroform extract is combined with the organic layer, and the combined organic layer is washed with water (200 ml) and saturated brine (200 ml), and dried over calcium chloride. The solvent is distilled off, and colorless crystals thus obtained are recrystallized from ethyl acetate+ethanol (16:3). Thus, 8.8 g of 3,7-dibromodibenzothiophene is obtained.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]\[C:20]2[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]\[C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:27])=[CH:24][CH:25]=2)=[CH:16][CH:17]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(/C=C\c2ccc(Cl)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(/C=C\c2ccc(Cl)cc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.173 g (7.349 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 1.90 g (7.35 mmol) of (Z)-4-chloro-4'-stilbenecarboxylic acid and 4.10 ml (29.4 mmol) of triethylamine in 30 ml of N,N-dimethylformamide, 1.34 ml (8.82 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.Br[C:14]1C=C(OC)C2C([CH:22]=1)=NN(CC)C=2>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:14][CH3:22])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CCn1cc2c(OC)cc(Br)cc2n1
Reactant: COc1cc(Br)cc2[nH]ncc12
Product: CCn1ncc2c(OC)cc(Br)cc21

Procedure:
In accordance with Example 70 (Step 1), 6-bromo-4-methoxy-1H-indazole (329 mg) was used instead of 5-bromo-7-methyl-1H-indazole to obtain 6-bromo-1-ethyl-4-methoxy-1H-indazole (210 mg) and 6-bromo-2-ethyl-4-methoxy-2H-indazole.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cc2c(OCC(C)C)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COc1cccc2[nH]c(C(=O)O)cc12
Reaction time: 24 h

Procedure:
4-Isobutoxy-1H-indole-2-carboxylic acid ethyl ester 81 (5.2 g, 19.9 mmol) is mixed with a 1M-solution of KOH in EtOH (99.5 ml, 99.5 mmol) and stirred for 24 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with ether. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a beige powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][CH3:27])=[CH:4][CH2:3]1.[CH3:29][C:30]1(C)C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(=O)[CH2:32][CH2:31]1>>[CH3:28][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:27]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless flakes, recrystallized from hexane) using 0.268 g (1.42 mmol) of titanium tetrachloride, 172 mg (1.56 mmol) of thiophenol and 291 mg (2.88 mmol) of triethylamine.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[C:17]([NH:19][NH2:20])[CH2:16][N+:15]([O-:21])=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH:28]=1>C(Cl)Cl>[C:5]([NH:20][NH:19][C:17]1[CH2:16][N+:15]([O-:21])=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[CH:28]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=2[N:18]=1)(=[O:7])[CH3:6]
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.5 ml. of acetic anhydride was added to a solution of 2.5 g. of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 50 ml. of methylene chloride. After stirring for 15 minutes at room temperature, the mixture was concentrated and crystallized by addition of ether to yield 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine 4-oxide, which after recrystallization from dimethylformamide, had a melting point of 272°-275° dec.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: C1=CC2(CCNCC2)Oc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(C=Cc5ccccc5O4)CC3)nn2)n1

Procedure:
The object product (111 mg, 41%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), spiro[chromene-2,4′-piperidine] hydrochloride (190 mg) and potassium carbonate (274 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:23]([C:24]([O:26]C)=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.Cl>O1CCOCC1.O.O>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:23]([C:24]([OH:26])=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Yield: 96.2 %

Procedure:
To a solution of methyl 5-(benzyloxy)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (3 g, 6.2 mmol) in dioxane/H2O (1/1, 60 mL) was added LiOH.H2O (781 mg, 19 mmol), and the mixture was heated to reflux for 3 hours, and concentrated in vacuo. The residue obtained was dissolved in H2O, 1 N HCl was added until pH reached 3, and the resulting precipitate was collected by filtration, washed with water, dried to afford 5-(benzyloxy)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (2.8 g, yield: 96%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.4 (s, 1H), 8.97 (s, 1H), 7.74˜7.77 (m, 2H), 7.59 (s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.29˜7.43 (m, 3H), 7.26 (t, J=8.8 Hz, 2H), 5.32 (s, 2H), 3.54 (s, 3H), 3.20 (s, 3H), 3.00 (s, 3H). MS (M+H)+: 470.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40].C(N(CC)CC)C>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([OH:36])[CH2:35][O:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(CC(=O)N(C)C)CC3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C

Procedure:
A solution of Example 146C (0.047 g, 0.087 mmol), 2-chloro-N,N-dimethylacetamide (0.011 g, 0.091 mmol) and triethylamine (0.029 mL, 0.208 mmol) in 1-methyl-2-pyrrolidinone (0.8 mL) was heated to 75° C. for 1 hour. The reaction was cooled to ambient temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was taken directly to the next step without further purification. MS ESI(+) m/z 628.2 [M+H]+.
Reaction SMILES: CS([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)(=O)=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[OH-].[Na+]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A mixture of 2-(methylsulfonyl)-1H-benzo[d]imidazole (5.6 g), 4-bromophenol (24.69 g) and TEA (19.89 mL) was stirred at 120° C. for 15 h. The mixture was added with 8 M NaOH aqueous solution and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The precipitate was collected by filtration to give the first lot of the titled compound (5.77 g). The filtrate was evaporated, and the precipitate was collected by filtration to give the second lot of the titled compound (0.92 g).
Reaction SMILES: C[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10].CN(C(N(C)C)OC(C)(C)C)C>O1CCOCC1>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]([C:3]1[CH:4]=[CH:5][C:6](=[O:8])[NH:7][CH:2]=1)=[O:10]
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1cccs1
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1COCCO1
Product: O=C(c1ccc(=O)[nH]c1)c1cccs1

Procedure:
C-2. 6-[2-(Dimethylamino)ethenyl]-5-(2-thienylcarbonyl)-2(1H)-pyridinone--To a mixture containing 57.8 g of 6-methyl-5-(2-thienylcarbonyl)-2(1H)-pyridinone in 400 ml of p-dioxane was added with stirring 62 g of bis(dimethylamino)-t-butoxymethane and the resulting reaction mixture was heated on a steam bath for 2 and 1/2 hours and then cooled. The separated product was collected, washed with isopropyl alcohol, dried in a vacuum oven at 90° C. to yield 70.1 g of 6-[2-dimethylamino)ethenyl]-5-(2-thienylcarbonyl)-2(1H)-pyridinone, m.p. 248°-250° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22]3=[N:27][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: Cc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 370 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.583 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-methylphenoxy)phenyl)pyridin-2-amine (511 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (514 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]=[C:9]=[S:10])=[O:5].[CH3:11][C:12]([CH3:32])=[CH:13][CH2:14][CH2:15]/[C:16](/[CH3:31])=[CH:17]/[CH2:18][CH2:19]/[C:20](/[CH3:30])=[CH:21]/[CH2:22][S:23][CH2:24][C@H:25]([NH2:29])[C:26]([OH:28])=[O:27].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][CH2:7][NH:8][C:9](=[S:10])[NH:29][C@@H:25]([CH2:24][S:23][CH2:22]/[CH:21]=[C:20](\[CH3:30])/[CH2:19][CH2:18]/[CH:17]=[C:16](\[CH3:31])/[CH2:15][CH2:14][CH:13]=[C:12]([CH3:32])[CH3:11])[C:26]([OH:28])=[O:27])[CH3:1]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CCOC(=O)CCN=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=S)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, to a suspension of ethyl-3-isothiocynato propionate (159 mg, 1 mmol) and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol) dropwise. The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (60 mL) and washed by 0.5 N HCl (10 mL×1), H2O (10 mL×1) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (220 mg, 45%) to yield Compound N-73. 1H-NMR (500 MHz, CD3OD): δ 1.17 (t, J=5.0 Hz, 3H), 1.50 (s, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-2.06 (m, 8H), 2.54 (t, J=5.0 Hz, 2H), 2.77 (dd, J=5.0, 15.0 Hz, 1H), 2.95-2.96 (m, 1H), 3.05-3.06 (m, 1H), 3.16-3.20 (m, 1H), 3.68 (broad, 2H), 4.06 (q, J=5.0 Hz, 2H), 5.00-5.01 (m, 2H), 5.09-5.14 (m, 2H). 13C-NMR (125 MHz, CD3OD): δ 14.65, 16.19, 16.31, 17.83, 25.97, 27.39, 27.80, 30.70, 33.22, 33.91, 34.80, 40.80, 40.90, 57.89, 61.03, 61.71, 61.93, 121.35, 121.70, 125.16, 132.11, 136.24, 140.52, 173.76, 174.47, 210.16; ES-MS: mass calcd for Chemical Formula: C24H40N2O4S2 484.72. Found (M+) m/z 485.3, (M+Na) m/z 507.3.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl:22][C:23]1[C:24]([F:35])=[C:25](I)[C:26]([O:32][CH3:33])=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:29]([C:27]1[C:26]([O:32][CH3:33])=[C:25]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:24]([F:35])=[C:23]([Cl:22])[CH:28]=1)(=[O:31])[CH3:30]
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1I
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: COc1c(C(C)=O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
Zinc (0.682 g, 10.4 mmol) was suspended with 1,2-dibromoethane (0.0598 mL, 0.694 mmol) in N,N-dimethylformamide (12 mL). The mixture was heated at 70° C. for 10 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.088 mL, 0.69 mmol) was added dropwise and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.5 g, 8.7 mmol) in N,N-dimethylformamide (10 mL) was then added and the mixture was heated at 40° C. for 1 hour before a mixture of 1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone (3.0 g, 9.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.16 g, 0.17 mmol) and tri-(2-furyl)phosphine (0.081 g, 0.35 mmol) in N,N-dimethylformamide (20 mL) was added. The reaction mixture was warmed to 70° C. and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH4Cl solution. The organic layers were washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 25% EtOAc in hexanes) to give the desired product (0.8 g). LCMS calculated for C17H21ClFNO4Na (M+Na)+: m/z=380.1; Found: 380.1.