Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C(C#C)C=1.[NH2:10][C:11]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=2)([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1>CO>[NH2:10][C:11]1[N:15]([CH3:16])[C:14](=[O:17])[C@:13]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=2)([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: C#Cc1cccc(Br)c1
Solvent: CO
Product: CN1C(=O)[C@@](c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N

Procedure:
Using essentially the same procedure described in Example 1, steps a-d, and employing 1-bromo-3-ethynylbenzene in step a, the racemic mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was obtained and separated by chiral chromatography technique (Chiralcel OJ, 2×25 cm, using 5% ethanol in 95% hexane and diethylamine as the mobile phase) to give the title enantiomer, MS m/e (M+H)+ 332; 1H NMR (400 MHz, DMSO-d6) 2.94 (s, 3H), 6.72 (brs, 2H), 7.1 (d, J=8.66 Hz, 2H), 7.13-7.35 (m, 2H), 7.38-7.43 (m, 4H), 7.56 (t, J=1.72 Hz, 1H); [a]25=−4 (C=1% in MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.CCN(CC)CC.[Si:17]([C:21]#[CH:22])([CH3:20])([CH3:19])[CH3:18].CCOCC>C1COCC1.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([C:22]#[C:21][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)cnc1N
Yield: 84.6 %

Procedure:
2-amino-5-bromo-3-iodopyridine (105.28 g, 0.3522 mol), CuI (0.6708 g, 3.522 mmol) and PdCl2(PPh3)2 (2.472 g, 3.522 mmol) were dissolved in dry THF (210 mL) and degassed (vacuum/nitrogen cycles×4). Et3N (107.0 g, 0.1474 L, 1.057 mol) and TMS-acetylene (44.97 g, 0.06471 L, 0.4579 mol) were added and the resultant mixture was stirred at ambient temperature for 1¼ hours. The reaction was cooled in an ice-bath and ether (210 mL) was added. The resultant mixture was stirred at 0° C. for ½ hour, filtered through celite and the celite was washed copiously with ether. The filtrate was concentrated under reduced pressure to give a brown/black solid which was redissolved in the minimum necessary DCM and purified by column chromatography (eluting with DCM). The product containing fractions were concentrated in vacuo and the residue recrystallised from cyclohexane. The precipitate was isolated by filtration to give the sub-title compound as a white powder (80.25 g, 84% Yield). Analytical data identical to that of commercially available compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=2)[C:11]1=[O:34].CO>C(O)C.C(Cl)(Cl)Cl>[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH3:3])[C:11]2=[O:34])=[CH:16]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(N3CCN(c4cnccc4C)C3=O)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2c[nH]c3ccccc23)C1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
LCMS purity: 92.68%, m/z=446.9 (M+1) 10% NaOH solution (10 mL) was added to a solution of 1-(4-methyl-pyridin-3-yl)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-imidazolidin-2-one (110 mg, 0.0002 mol) in ethanol (10 mL) and the resulting mixture was stirred at 90° C. for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and ice water. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 50 mg of the product (86.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[H-].[Na+].[NH4+:13].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:13])[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)c[nH]1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cn1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (3.5 g, 17.2 mmol, 1 eq) in DMF (120 mL) was added NaH (0.82 g, 20.6 mmol, 1.2 eq) at 0° C., and the mixture was stirred at 0° C. for 1 h, followed by the addition of o-(diphenylphosphinyl)-hydroxylamine (6 g, 25.8 mmol). The reaction mixture was stirred for another 1 h, then neutralized with 20% NH4Cl solution, and extracted with EA. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography on silica gel (PE/EA=4:1) to give 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.9 g, yield 77%) as a light yellow solid. MS (ES+) requires: 218, 220. found 219, 221 [M+H]+; purity: 97%.
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:18][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:30]
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1)c1cc2ccccc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of α-cyano-4-fluoro-3-phenoxybenzyl alcohol (437 mg, 1.8 mmol), 2-(2-benzothienyl)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mmol). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodiun bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated to give α-cyano-4-fluoro-3-phenoxybenzyl 2-(2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][C:30]1([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C@H:8]3[CH2:10][C@@H:9]3[C:11]([NH:13][C@@H:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=3)[CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH2:33][O:32][CH2:31]1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1cccc(O)c1)c1ccc(OCC(F)(F)F)cn1
Reactant: CC1(CCl)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1cccc(OCC2(C)COC2)c1)c1ccc(OCC(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 49.1 %

Procedure:
A mixture of (1S*,2S*)-2-(3-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 3-(Chloromethyl)-3-methyloxetane (24 mg, 0.197 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70° C. with stirring for 15 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 8.9 mg (49% yield) of the title compound.
Reaction SMILES: [H-].[Ba+2:2].[H-].[CH2:4]([O:6][CH2:7][CH2:8][OH:9])[CH3:5]>C1(C)C=CC=CC=1>[CH2:4]([O:6][CH2:7][CH2:8][O:9][Ba:2][O:9][CH2:8][CH2:7][O:6][CH2:4][CH3:5])[CH3:5]
Reactant: [Ba+2]
Reactant: CCOCCO
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOCCO[Ba]OCCOCC

Procedure:
Three grams of powdered barium hydride was stirred and reacted overnight with 2 ml. of 2-ethoxyethanol in 10 ml. of toluene, under argon atmosphere, yielding a slurry of di(2-ethoxyethoxy)-barium in toluene. To the slurry was added 10 ml. of a 1.7 molar solution of n-butyl-lithium in n-pentane. The mixture was stirred for 3 hours at room temperature, during which time a reaction ensued between the di(2-ethoxyethoxy)-barium, the n-butyl-lithium, and the toluene to give a partly hydrocarbon-soluble, lithium-containing, organometallic product having tolyl functionality.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)CCCC(C)C.C([O:33][CH:34]([CH2:52][CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[C:39]#[N:40])(=O)C>>[OH:33][CH:34]([CH2:52][CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:39]#[N:40]
Reactant: CCOC(=O)CCCCCCN(C#N)CCCC(CCCC(C)C)OC(C)=O
Agent: CC(=O)OC(CCCCl)CCCC(C)C
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CC(C)CCCC(O)CCCN(C#N)CCCCCCC(=O)O

Procedure:
The synthesis of this compound is carried out initially as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-8-methylnonane (Example B, Step 3). The product of Step A is thus ethyl 7-[N-(4 -acetoxy-8-methylnonyl)cyanamido]heptanoate. The hydrolysis (Step B) affords 7-[N-(4-hydroxy-8-methylnonyl)cyanamido]-heptanoic acid. This product is then treated as described in Example 3, Step A, to yield the subject compound 7-[N-(4-hydroxy-8-methylnonyl)thioureido]heptanoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[CH:16]=[C:17]([C:22]([CH3:24])=O)[C:18]([O:20][CH3:21])=[O:19]>C(O)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]2[C:3]3[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=3[NH:1][C:22]([CH3:24])=[C:17]2[C:18]([O:20][CH3:21])=[O:19])[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(=Cc1cccc(Cl)c1)C(C)=O
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2c(c(=O)n(C)c(=O)n2C)C1c1cccc(Cl)c1
Yield: 55 %

Procedure:
A mixture of 6-amino-N,N'-dimethyluracil (1.5 g, 10 mM) and methyl 2-(3-chlorobenzylidene)acetoacetate (2.38 g, 10 mM) in glacial acetic acid (20 ml) was stirred at reflux under N2 for 3 hrs., cooled to ambient, evaporated in vacuo and diluted with acetone to precipitate out the product. Recrystallization from MeOH/Acetone gave the title compound (2.0 g,53%), mp. 230° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[C:41]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-dichlorophenylboronic acid. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH2:11]([OH:13])[CH3:12].C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([O:13][CH2:11][CH3:12])[N:7]=1
Reactant: CCO
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1nc(Cl)nc(OC)n1
Reaction time: 1 h

Procedure:
The 2,4-dichloro-6-methoxy-s-triazine obtained as described in Example A-3 is suspended in acetone, 46 parts of ethanol and 90 parts of sodium bicarbonate are slowly added, and the reaction is carried out at a temperature of between 40° and 50° C. for about one hour. The mixture is then evaporated to give the compound 2-chloro-4-methoxy-6-ethoxy-s-triazine as a powder which contains electrolyte salts and serves as the monochloro-triazine starting compound in the synthesis of dyestuffs according to the invention.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[N:21]([C:22]3[S:23][C:24]4[C:25]([N:34]=3)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:9]=1>CO>[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:17][NH:18][CH2:19][CH2:20][N:21]2[C:22]2[S:23][C:24]3[C:25]([N:34]=2)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ncc(C(F)(F)F)cc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)(F)c1cnc2nc(N3CCNCC3COc3cccnc3)sc2c1
Reaction time: 8 h
Yield: 52 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 3-((pyridin-3-yloxy)methyl)-4-(6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (134 mg, 0.271 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were combined and brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.036 mL) was added. The mixture was concentrated under reduced pressure to give 60.5 mg (52%) of the desired product as the hydrochloride salt. LC-MS: RT=4.53 min, [M+H]+=396.6.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:25]=O)=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:25][NH:6][CH3:5])=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2ccc(F)cc21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cc(F)ccc12
Yield: 35 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 6-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.11 g, 35%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([OH:23])([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:8][O:9][C:10](=[O:14])[CH2:11][CH2:12]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:10]([O:9][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:23])[C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:16])(=[O:14])[CH:11]=[CH2:12]
Reactant: O=C(CCCl)OCC(O)(C(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)OCC(O)(C(=O)c1ccccc1)c1ccccc1

Procedure:
7.8 g (23.4 mmol) (2,3-diphenyl-2-hydroxy-3-oxopropyl)-3-chloro-propionate was dissolved in 75 ml acetone. 4.9 g (35.1 mmol) K2CO3 and 50 mg BHT were added and the mixture was refluxed for 5 hours. The inorganic salts were removed by filtration and the solvent was evaporated under reduced pressure. The residue was treated with 50 ml n.-hexane, 2,3-diphenyl-2-hydroxy-3-oxopropyl acrylate was isolated by filtration and dried. 6.3 g of 2,3-diphenyl-2-hydroxy-3-oxopropyl acrylate (91%) was isolated. Based on 1H-NMR-analysis the conversion proved to be 98%.
Reaction SMILES: O[C:2]1([C:17]([OH:19])=[O:18])[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:6][CH2:5][C:4](=[O:16])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:7]1[C:2]([C:17]([OH:19])=[O:18])=[CH:3][C:4](=[O:16])[CH2:5][CH2:6]1
Reactant: COc1ccccc1C1CCC(=O)CC1(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccccc1C1CCC(=O)C=C1C(=O)O
Yield: 78 %

Procedure:
396.7 g (1.5 mol) of 1-hydroxy-6-(2-methoxyphenyl)-3-oxocyclohexane-1-carboxylic acid were heated at reflux for two hours in 13.3 dm3 of toluene in the presence of 39.7 g of para-toluenesulphonic acid. The reaction mixture was subsequently concentrated under reduced pressure and the precipitate formed was filtered off, washed with isopropyl ether and then dried at 50° C. 288 g (78%) of (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene-1-carboxylic acid were thus obtained in the form of a brown solid, the characteristics of which were as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]>>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1ccccc1CCl
Agent: [Na]
Product: Cc1ccccc1CSc1cccc[n+]1[O-]
Yield: 85 %

Procedure:
The intermediate 2-(2-methylphenylmethylthio)-pyridine N-oxide is prepared by the procedure described in U.S. Pat. No. 3,960,542, Example 2 from α-chloro o-xylene and 2-mercaptopyridine N-oxide sodium salt. Melting point 134°–136° C. Yield 85% theory. Structure confirmed by IR and NMR.
Reaction SMILES: FC1C=CC(COC2C=CC(CO)=CC=2)=CC=1.C[O:19][C:20](=[O:47])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:33][CH:32]=2)=[CH:25][C:24]=1[CH3:46]>>[F:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][O:37][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][S:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:20]([OH:47])=[O:19])=[C:24]([CH3:46])[CH:25]=3)=[CH:36][CH:35]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3)cc2)cc1C
Agent: OCc1ccc(OCc2ccc(F)cc2)cc1
Product: Cc1cc(SCc2ccc(OCc3ccc(F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 57A. MS m/z 215 (M-Cl). Step 3. Preparation of {4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (Compound 57C)
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.O.[SH-:13].[Na+].CN1CCCC1=O.O>C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=[S:13])[C:5]=2[S:4][CH:3]=1
Reactant: [SH-]
Reactant: Clc1ncnc2c(Br)csc12
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: S=c1[nH]cnc2c(Br)csc12
Reaction time: 1 h

Procedure:
A solution of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (see below for preparation) (2.0 g), sodium hydrosulfide hydrate (0.66 g) and N-methylpyrrolidinone (10 ml) was heated at 102° C. for 1 hour. Water (500 ml) and ethyl acetate (500 ml) were added and stirred for 1 hour. The layers were separated and the aqueous phase extracted with ethyl acetate (300 ml). The combined organic extracts were washed with brine (300 ml), dried (MgSO4), treated with activated charcoal, then filtered through a silica pad and the solvent removed to give the title product, m.p. 328° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].C(=O)=O>CO>[CH3:8][S@:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)=O)cc3)nc2)CC1
Agent: O=C=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc([S@@](C)=O)cc3)nc2)CC1
Yield: 34.4 %

Procedure:
The racemic sulfoxide 1-methylethyl 4-[({6-[4-(methylsulfinyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (Example 173, 370 mg) was subjected to Chiral HPLC [column: Chiralpak AS-H, column mobile phase: 65% CO2: 35% MeOH (1 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (100 mg) was isolated as a white solid with Tr of 3.73 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]([CH3:16])([CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]([O:7]C)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20]2[N:26]([CH:27]=1)[CH2:25][C:24]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:23]=1[N:22]=[C:21]2Cl.C(=O)(O)[O-].[Na+].[OH-].[Li+]>O.C(O)(=O)C.C(#N)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[N:26]([CH:27]=1)[CH2:25][C:24]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:23]=1[N:22]=[C:21]2[N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:4]([CH3:16])([CH3:3])[C:5]([OH:7])=[O:6])[CH2:11][CH2:12]1
Reactant: Cc1ccc2c(c1)Cn1cc(Cl)cc1C(Cl)=N2
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)Cn1cc(Cl)cc1C(N1CCN(CC(C)(C)C(=O)O)CC1)=N2
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
Dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)-propanoate dihydrochloride (1.49 g, 5.47 mmoles) in water and absorb onto an SCX2 column. Wash the column with methanol and elute methyl 2,2-dimethyl-3-piperazin-1-yl-propanoate with 2M ammonia in methanol. Remove the methanol in vacuo and add the methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate to acetonitrile (12 mL). Add 2,11-dichloro-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.85 g, 3.22 mmoles) and sodium bicarbonate (0.405 g, 4.83 mmoles) to the acetonitrile solution. Heat and stir in the microwave for 30 minutes at 140° C. Cool to room temperature, absorb the reaction mixture onto silica and purify by chromatography (gradient elution with EtOAc/isohexane 0:100% to 100:0%). Collect the fractions containing product and evaporate the solvent in vacuo and dissolve the residue in methanol (10 mL) and add lithium hydroxide (0.235 g, 9.65 mmoles). Heat and stir the methanolic solution in the microwave for 12.5 minutes at 140° C. Cool to room temperature and acidify with acetic acid and then evaporate the solvent under reduced pressure. Dissolve the residue in excess 2M HCl (aq) and then evaporated to dryness. Dissolve the residue in water and immobilise onto a macroporous polystyrene hydrogen carbonate (PL-HCO3) resin. Wash the resin with water and elute from the resin with 2M HCl (aq). Evaporate the solution to dryness to give 3-[4-(2-chloro-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoic acid dihydrochloride (0.177 g; 11.28% yield). MS (m/z): 415.18 (M+1).