Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[N:27]=[C:26]([CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[N:27]=2)[N:10]=1
Reactant: Cc1cccc(CN)n1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CNc2nc(F)nc3[nH]cnc23)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (6-methylpyridin-2-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.35 g (60%). δH (CDCl3, 500 MHz) 2.44 (3 H, s, CH3), 4.83-4.54 (3 H, m, NH and NHCH2), 7.1-7.05 (2 H, m, ArH), 7.61-7.55 (1 H, m, ArH), 8.13-8.09 (1 H, m, ArH), 8.61 (1 H, s, br, NH); δC (CDCl3, 500 MHz) 159.41 (C), 158.78 (C), 158.53 (C), 157.19 (C), 155.38 (C), 147.69 (CH), 137.03 (C), 136.93 (CH), 121.34 (CH), 117.76 (CH), 117.31 (C), 46.47 (CH2), 23.9 (CH3); m/z 259.2 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:23])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].BrC1C=CC(NC(=O)COC2C=CC=CC=2)=C(C=1)C(OC)=O.BrC1C=C2C(=CC=1)NC(=O)C(OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:23])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(Cl)cc1
Agent: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccc(Cl)cc1

Procedure:
The title compound was prepared using methyl 5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate (Intermediate 9, step a) in place of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (Intermediate 5, step a) according to the procedure described in Intermediate 5, step b.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=1
Reactant: Clc1ncccn1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1

Procedure:
9.4 g (50 mmol) of 4-nitrobenzylamine-hydrochloride, 11.7 g (110 mmol) of sodium carbonate and 7.5 g (50 mmol) of sodium iodide are added to a solution of 5.7 g (50 mmol) of 2-chloropyrimidine in 250 ml of ethanol. The mixture is refluxed for 20 hours. Then the salts are removed by suction filtering, the filtrate is evaporated down and taken up in 300 ml of ethyl acetate. It is washed with water, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol=97:3).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[CH3:19].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.C1(C)C=CC=CC=1>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>[CH3:19][C:3]1[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:7][C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1-c1ccccn1
Temperature: 116 °C

Procedure:
To a reaction vessel under argon containing 2-(6-bromo-5-methylpyridin-2-yl)isoindoline-1,3-dione (85 mg, 0.27 mmol), 2-(tributylstannyl)pyridine (123 mg, 0.32 mmol), Pd(PPh3)4(31 mg, 0.027 mmol) is added anhydrous toluene (0.7 ml). The mixture is heated to 116° C. with an oil bath for 18 hours, cooled to room temperature, diluted with ethyl acetate and filtered through a celite pad to remove any solids. The filtrate is concentrated to afford 2-(3-methyl-2,2′-bipyridin-6-yl)isoindoline-1,3-dione as a brown solid (LC-MS m/z: 316.1 (M+1)) which is used without further purification in the next step.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][C:9](=[O:22])[N:8]([CH2:23][C@@H:24]3[CH2:26][O:25]3)[C:7]=2[N:27]=1>CN(C=O)C>[OH:25][CH2:26][C@H:24]1[N:27]2[C:7]3[N:8]([C:9](=[O:22])[CH2:10][N:11]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[C:6]=3[CH:5]=[CH:4][C:3]2=[O:2])[CH2:23]1
Reactant: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CN2C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC(=O)N2C[C@@H](CO)n3c2c1ccc3=O
Temperature: 120 °C
Yield: 30.9 %

Procedure:
Phenylmethyl 6-(methyloxy)-4-[(2R)-2-oxiranylmethyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (crude, 15.93 g, estimated 32.8 mmol) was dissolved in DMF (250 ml) at room temperature and heated at 130° C. for 2 nights and at 120° C. for one night. The reaction was complete so DMF was evaporated and the residue treated with water/brine (350/50 ml) and DCM (500 ml). The layers were separated and the aqueous layer was extracted once more with DCM (500 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated to afford a brown oil which was dried under high vacuum over the weekend. The crude product was purified by silica chromatography using a 0-10% methanol/dichloromethane gradient to afford the desired product as a golden foam (3.6 g, 30.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]=[CH:7]2.[CH3:15]O>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2
Reactant: Nc1cccc2cnc(C(=O)O)cc12
Reactant: CO
Product: COC(=O)c1cc2c(N)cccc2cn1

Procedure:
5-Aminoisoquinoline-3-carboxylic acid (25 g) is added to methanol (2 liters). The mixture is heated to the reflux temperature and a stream of dry hydrogen chloride is bubbled through for 3 hours. The mixture is heated under reflux for a further 3 hours and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue is dissolved in water (200 cc) and the solution is washed with ethyl acetate (2×100 cc). The aqueous solution is rendered alkaline to pH 9 by adding potassium carbonate. The precipitate formed is filtered off, washed with water and dried to yield 5-amino-3-methoxycarbonylisoquinoline (20.3 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[CH3:30][C:29]1[CH:28]=[CH:27][O:26][C:25]=1[C:23]([NH:22][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:12]2[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=2)[C:7]([N:6]=[S@@:5]([CH2:4][CH2:3][CH2:2][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)(=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: C1COCCN1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCOCC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and morpholine were converted to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C[Al](C)C.[NH:23](/[C:27](/[CH3:33])=[CH:28]\[C:29](OC)=[O:30])[C:24]([CH3:26])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:29](=[O:30])[CH:28]=[C:27]([CH3:33])[N:23]=[C:24]2[CH3:26])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(NCCCN2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of 2-fluoro-N1-(3-morpholinopropyl)benzene-1,4-diamine (1.60 g, 6.23 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (22 mL, 44 mmol, 2 M in toluene) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.98 g, 12.59 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a pale yellow solid (0.60 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[CH:6][C:7](=[O:18])[N:8]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:9]=1)=[O:3]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:1][C:2]([C:4]1[C:5]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[CH:6][C:7](=[O:18])[N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH:9]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cn(CC(=O)O)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
tert-Butyl (5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl)acetate (225 mg, 0.46 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and trifluoroacetic acid (10 mL) and stirred at R.T. for 2 h. All solvent was evaporated under a stream of nitrogen and the resulting oil was redissolved in MeOH (10 mL) to which was added sat. NaHCO3 (10 mL). This mixture was stirred at R.T for 1 h. then 1 M HCl (50 mL) added and the resulting white precipitate collected by filtration. Purification was carried out by recrystallisation from EtOAc/MeOH to afford (5-(aminocarbonyl)-4-(2-fluoro-4-iodoanilino)-2-oxo-1(2H)-pyridinyl)acetic acid as a white solid (76 mg, 38%), m.p. (EtOAc/MeOH) 296-300° C. 1H NMR [(CD3)2SO, 400 MHz] δ 13.10 (v br s, 1H), 10.42 (s, 1H), 8.32 (s, 1H), 7.86 (br s, 1H), 7.75 (dd, J=10.2, 1.9 Hz, 1H), 7.58 (dd, J=8.4, 0.8 Hz, 1H), 7.52 (br s, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.53 (d, J=1.0 Hz, 1H), 4.49 (s, 2H). Anal. Calcd for C14H11FIN3O4.0.5H2O: C, 38.2; H, 2.7; N, 9.5. Found: C, 38.0; H, 2.4; N, 9.1.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]([CH3:33])([CH3:32])[O:30][C:29](OCC)=[N:28][S:27]2(=[O:38])=[O:37])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]([CH3:32])([CH3:33])[O:30][C:29]([NH:19][C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:10][CH2:9][OH:8])=[N:28][S:27]2(=[O:37])=[O:38])=[CH:22][CH:21]=1
Reactant: CCOC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
In a round-bottom flask, 346 mg of 5-biphenyl-4-yl-2-ethoxy-6,6-dimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide were dissolved under inert gas in 2 ml of dichloromethane and admixed with 328 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine. After concentration by rotary evaporation, the residue was suspended in 0.5 ml of dichloromethane and stirred at room temperature for 18 hours. The conversion was checked by LCMS. Since reactant was still present, the reaction mixture, after the addition of 1 ml of toluene, was stirred at 50° C. for 1 hour. Even after stirring at 75° C. for a further 4 hours, the conversion remained incomplete. The solvent was removed under reduced pressure. To detach the protecting group, the residue was taken up in 1 ml of methanol and, after addition of 0.05 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. After concentration by rotary evaporation, the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and freed of the solvent under reduced pressure. The aqueous residue was extracted with ethyl acetate, and the combined organic phases were dried using a diatomaceous earth cartridge (Varian Chem Elut®) and concentrated by rotary evaporation. The residue was dissolved in a mixture of acetonitrile and water and lyophilized. This gave the product (221 mg) with a molecular weight of 482.6 g/mol (C26H27FN2O4S); MS (ESI): m/e=483 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]1[SH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:1][CH:2]1[N:7]=[C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]1[SH:12]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC1=C(C#N)C(Br)=NC(N)N1S
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)C(N2CCN(c3ccc(F)cc3)CC2)=NC(N)N1S

Procedure:
In analogy to the procedure described in example 20b, 2-amino-4-bromo-6-methyl-sulfanyl-pyrimidine-5-carbonitrile (see example 69) was treated with 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature during 36 hours to yield 2-amino-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-methyl-sulfanyl-pyrimidine-5-carbonitrile as a yellow powder; MS: [M+H]+=345.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (73 mg, 20%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.C(OCC)(=O)C.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1ccc(CC(=O)O)cc1Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(C)C(=O)O)cc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2-(3-chloro-4-(methylthio)phenyl)acetic acid (2 g, 0.009 mol) was taken in THF (20 mL, 10 times) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (27.77 mL, 3 eq) was added drop wise at −78° C. and allowed to stir for 2 h at the same temperature. Then methyl iodide (1.31 g, 1 eq) was added drop wise at −78° C. and the overall reaction mass was allowed to stir for 3 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.2). As the reaction was not completed, reaction mass was warmed to room temperature and allowed to stir for 10 h. Again TLC was monitored and still the reaction was not completed. Then the reaction contents were quenched with saturated ammonium chloride solution and acidified with diluted HCl. THF layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extract was dried over sodium sulfate, concentrated under reduced pressure and the crude product obtained was purified by column chromatography (10% ethyl acetate/n-hexane) to yield 2-(3-chloro-4-(methylthio)phenyl)propanoic acid as a pale yellow colored solid (1.2 g, 53%).
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[CH:6]=[CH:5][S:4][C:3]=2[O:2]1>C(O)CCC.[Fe]>[CH2:9]1[O:8][C:7]2[C:6](=[CH:5][S:4][CH:3]=2)[O:2][CH2:1]1
Reactant: c1cc2c(s1)OCCO2
Agent: [Fe]
Solvent: CCCCO
Product: c1scc2c1OCCO2
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
PEGdTh (400) (0.64 mmol) was dissolved in n-butanol (0.5 ml), mixed with 32.4 g of Baytron® C from Bayer (50% wt. Fe(pTS)3 in butanol, =23 mmol of iron), and heated under stirring to 80° C. Freshly distilled ethylenedioxythiophene (EDOT from Bayer; 1.6 g=11.3 mmol) was dissolved in 120 ml of n-butanol (final concentration of 10−2 M) and slowly added to the hot mixture of PEGdTh and Baytron® C over a 1.5 hr period under stirring. After the addition was completed, the reaction was kept at 80° C. for 1.5 hr, then cooled to room temperature and stored overnight. The following day the solution was dark blue and no precipitate was present.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]I)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:11]([O:10][C:2]([CH:3]([CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCCCCCCCc1ccc(CCI)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(C(=O)OCC)C(=O)OCC)cc1
Temperature: 40 °C
Reaction time: 0.05 h
Yield: 65.9 %

Procedure:
Sodium (2.67 g) was dissolved in absolute ethanol (100 ml) and diethyl malonate (18.6 g) was dropwise added thereto at 27°-30° C. for 3 minutes. The mixture was stirred at 40° C. for 40 minutes and 2-(4-octylphenyl)ethyl iodide (40 g) was dropwise added to the reaction mixture at 44°-45° C. over 10 minutes. The mixture was refluxed at 50° C. for 1 hour and stirred under heating for 1.5 hours. The reaction mixture was cooled and the solvent was distilled away under reduced pressure. Water was added thereto and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was subjected to silica gel column chromatography to give the subject compound (28.8 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2cccc(Cl)c2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH:30]1([NH:29][C:27](=[O:28])[C:26]2[CH:36]=[CH:37][C:23]([NH:22][C:2]3[N:12]=[C:11]4[C:5](=[CH:4][N:3]=3)[N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]4[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:24]([O:38][CH3:39])[CH:25]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CN1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)CC1
Reactant: COc1cc(C(=O)NC2CCCCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NC2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCN(C)CC1)CCC(=O)N2C
Temperature: 100 °C

Procedure:
10-chloro-6-methyl-2-(1-methyl-4-piperidyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 118; 39 mg, 0.13 mmol), 4-amino-N-cyclohexyl-3-methoxy-benzamide (Intermediate 119; 31 mg, 0.13 mmol) and p-toluenesulphonic acid monohydrate (60 mg, 0.31 mmol) were combined in 4-Methyl-2-pentanol (2 mL) and heated at 100° C. for 16 hrs. The reaction mixture was cooled to room temperature and dissolved in Methanol and added to a 5 g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant material was dissolved in DCM and purified on silica eluting with a shallow (25 column volumes) gradient of 0-10% MeOH/DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a white solid. (15 mg, 23%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH2:24][NH:25][OH:26]>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH2:24][N:25]1[C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[C:6](=[O:7])[O:26]1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1cc(Cl)ccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)C(=O)ON(Cc2cc(Cl)ccc2Cl)C1=O
Reaction time: 16 h
Yield: 39 %

Procedure:
To a stirred solution of 4.1 grams (0.024 mole) of dimethylmalonyl chloride and 3.8 grams (0.048 mole) of pyridine in 100 ml of dry toluene at 0° C., 4.7 grams (0.024 mole) of N-(2,5-dichlorophenylmethyl)hydroxylamine (Intermediate D) was added dropwise over 30 minutes, while the temperature was maintained at 0°±5° C. The reaction mixture was allowed to rise to ambient temperature and was stirred about 16 hours. A white solid was separated and washed with toluene. Filtrate and washings were combined, washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Sodium sulfate was separated, and the liquid was concentrated under reduced pressure to a viscous liquid, and ultimately to a solid. Recrystallization from hexane-ethyl acetate yielded 2.7 grams of solid product; mp 78°-80° C. The nmr and ir spectra were consistent with the assigned structure.