Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C.[OH-].[Na+]>C(O)C>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:26])=[O:3])=[CH:17][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 33 g of α-[p-(1-cyclooctenyl)-phenoxy]-heptanoic acid ethyl ester in 120 ml of ethanol are added 120 ml of 2N sodium hydroxide solutuion and the mixture is stirred for 11/2 hours at room temperature. The reaction mixture is then evaporated to dryness in vacuo and the residue partitioned between N hydrochloric acid and ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is crystallised from pentane to yield the 2-[p-(1-cyclooctenyl)-phenoxy]-heptanoic acid of the formula ##STR8## (m.p. 57°-60° C; b.p. 0.04 185°-188° C.
Reaction SMILES: C1C2CCCCC=2C=CC=1N.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:24](=[CH:25][C:26]4[CH2:36][CH2:35][CH2:34][CH2:33][C:27]=4[CH:28]=3)[N:23]=2)[CH:21]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:28]4[CH2:36][CH2:35][CH2:34][CH2:33][C:27]=4[CH:26]=[CH:25][C:24]=3[N:23]=2)[CH:21]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Agent: Nc1ccc2c(c1)CCCC2
Product: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 131, steps A-B, using 5,6,7,8-tetrahydro-naphthalen-2-ylamine in step A. Step B yielded a 2:1 mixture of 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and the titled compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1)[CH3:7].Cl[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[CH2:6]([N:8]1[C:12]([CH2:13][CH2:17][C:16]([CH3:18])=[CH2:15])=[N:11][N:10]=[N:9]1)[CH3:7]
Reactant: C=C(C)CCl
Reactant: CCn1nnnc1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CCc1nnnn1CC
Temperature: -70 °C
Yield: 80.2 %

Procedure:
n-Butyl lithium (1.53 M) hexane solution (6.5 ml, 9.98 mmol) was added dropwise to a solution of 1-ethyl-5-methyl-1H-tetrazole (0.80 g, 7.13 mmol) in THF (15 ml) while stirring at −70° C., and the mixture was further stirred for 1.5 hours. A solution of 3-chloro-2-methyl-1-propene (0.77 ml, 7.84 mmol) in THF (5 ml) was added to the mixture, and the resulting mixture was stirred for 2 hours. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and then concentrated under reduced pressure to afford 1-ethyl-5-(3-methyl-3-butenyl)-1H-tetrazole (0.95 g, yield 80%) as a brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].CN(C=O)C.O=S(Cl)[Cl:25]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([Cl:25])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (70 mg, 0.26 mmol) in toluene (5 mL) were added catalytic amount of DMF and SOCl2 (0.2 mL, 2.61 mmol) and the reaction mixture was heated to reflux for 6 hours. The solvent was evaporated and the resulting 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (70 mg, crude) was used in the next step without further purification.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH2:9].[H][H]>[Pd]>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C:3]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH2:9]
Reactant: [H][H]
Reactant: NCC(O)COc1ccc([N+](=O)[O-])cc1N
Agent: [Pd]
Agent: Cl
Product: NCC(O)COc1ccc(N)cc1N

Procedure:
0.02 mol (5.3 g) of the 1-(2'-amino-4'-nitrophenoxy)-3-aminopropan-2-ol monohydrochloride prepared according to Example 4 is introduced into 50 ml of 96° strength alcohol and 0.2 g of 10% strength palladium-on-charcoal. The mixture is heated at 85° C. for one hour under 35 bars of hydrogen. After cooling, it is filtered to remove the catalyst, the filtrate being collected in 20 ml of iced ethanol saturated with hydrogen chloride. The expected product precipitates in the form of the trihydrochloride. After recrystallisation of this trihydrochloride from an ethanol/water mixture, it melts with decomposition at 236°-238° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=2)=[N:4][CH:3]=1
Reactant: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccc(F)cc2)ccc1=O
Solvent: Clc1ccccc1Cl
Product: CC(C)n1cc(-c2ncc(N)nc2-c2ccc(F)cc2)ccc1=O
Temperature: 167.5 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
3-Amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid (25 g) was suspended in 1,2-dichlorobenzene (125 ml). The suspension was heated at 165-170° C. with stirring for 4 hours. The reaction mixture was cooled to 20-25° C. To the cooled mixture was added IPE (250 ml). The suspension was stirred at 25-30° C. for 3 hours. The precipitate was collected by filtration and dried in vacuo. The above dried precipitate was purified by chromatography on silica gel (500 g) eluting with CHCl3:MeOH (9:1, 21). Evaporation of solvent in vacuo gave yellowish crystal residue, which was recrystallized from 70% EtOH (322 ml) to give 5-[5-amino-3-(4-fluorophenyl)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone as yellowish crystal (19.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]([NH:16][CH:17]=O)=[C:4]([Cl:19])[N:3]=1.C(OC(OCC)OCC)C.[ClH:30]>CO.[OH-].[Na+]>[ClH:19].[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:16]=[C:17]([Cl:30])[N:8]2[C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(OCC)OCC
Product: Nc1ncc2nc(Cl)n([C@H]3C=C[C@@H](CO)C3)c2n1
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (Example 7, 1.00 g, 3.50 mmol) and triethylorthoformate (Aldrich, Sure Seal, 18 mL) was stirred while concentrated hydrochloric acid (37%, 1.25 mL) was added in one portion. The resulting clear, colorless solution was stirred under nitrogen. A white precipitate began to form after 15 minutes. After 4 hours, TLC of a drop of the reaction mixture dissolved in methanol and neutralized with sodium hydroxide (silica gel plates developed in 10% methanol-chloroform, visualized in UV light) showed almost complete conversion of VIa to a higher-Rf material The precipitate was filtered, washed with t-butyl methyl ether (15 mL) and dried at 0.2 mm Hg/25° C. for 18 hours to give the title compound as a white powder (975 mg, 92%), m.p. >300° C. dec.; mass spectrum (CI/CH4): 266 (M+1); 1H-NMR (DMSO-d6)δ: 8.18 (s, 1, purine CH), 7.2-6.7 (br s, NH2, OH overlapped by water), 6.20 and 5.90 (both m, 1 each, CH═CH), 5.48 (m, 1, NCH), 3.47 (d, J=5.7 Hz, 2, CH2O), 2.90 (m, 1, CH), 2.75-2.55 and 1.75-1.60 (both m, 1 each, CH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.C[O-].[Na+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>CO>[CH3:16][CH:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:3]=2)[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 151.1 %

Procedure:
To a solution of 6-hydroxy-α-methyl-2-naphthaleneacetic acid (10.8 g, 50 mmol) in methanol (100 ml) is added sodium methoxide (100 mmol). After 10 minutes the solvent is removed and replaced with dimethylformamide (250 ml). 2-(Chloromethyl)quinoline (17.8 g, 100 mmol) is then added and the reaction mixture is stirred for 8 days at room temperature. The reaction mixture is partitioned between water and methylene chloride, the organic layer is washed with water and evaporated to yield 27 g of an oil. Recrystallization of this oil twice from acetonitrile gives 10.6 g of white crystals of intermediate ether ester (42% yield, m.p. 106°-108° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CC(O)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CC=Cc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: N#CC=Cc1cccc(N)c1
Reaction time: 3 h

Procedure:
A solution of 3-(3-nitro-phenyl)-acrylonitrile (500 mg, 2.87 mmol) in 5% aqueous AcOH (10 ml) was heated to 80° C. Iron powder (1.44 g, 25.8 mmol) was then added and the resulting mixture was stirred for 3 h. The reaction mixture was filtered through celite and the filter cake washed with MeCN (4×50 ml). The combined MeCN layers were evaporated in vacuo and the residue was re-dissolved in EtOAc (30 ml) and HCl (30 ml). The aqueous layer was separated, basified to pH 10 with 6M NaOH, and extracted with EtOAc (3×80 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12](=O)[CH3:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:8][CH:9]=3)[CH3:13])[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(=O)c1csc(-c2ccccc2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C(C)c3csc(-c4ccccc4)n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-(2-phenyl-1,3-thiazol-4-yl)ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 434.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]=1[NH2:15])#[N:2].C(N(CC)CC)C.Cl[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:5][C:4]=1[N:15]1[CH2:24][CH2:25][CH2:26][C:27]1=[O:28])#[N:2]
Reactant: Cc1c(-c2ccccc2)[nH]c(N)c1C#N
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)[nH]c(N2CCCC2=O)c1C#N
Temperature: -50 °C
Yield: 22.8 %

Procedure:
To a solution of 3-cyano-4-methyl-2-amino-5-phenylpyrrole (4.9 g) in THF (80 ml) was added triethylamine (2.5 g) and while the mixture was stirred at -50° C., 4-chlorobutyryl chloride (3.5 g) was added. This reaction mixture was then stirred at room temperature for 1.5 hours, after which the insoluble matter was filtered off. The filtrate was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous solution of sodium hydrogen carbonate, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from benzene/n-hexane. The crystals were suspended in ethanol (40 ml), and potassium tert-butoxide (1.32 g) was added thereto. The mixture was stirred at room temperature overnight and the resulting crystals were collected by filtration, washed with water, and air-dried. The crude crystals thus obtained were recrystallized from ethanol to provide the title compound as light-yellow needles (1.5 g). m.p. 140-141° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[N:4](COCC[Si](C)(C)C)[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(=O)[nH]ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.0 g) and triethylsilane (1.27 g) was added trifluoroacetic acid (17.31 mL) at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue were added acetonitrile (11 mL) and aqueous ammonia solution (25%, 11 mL), and the mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration, and washed with acetonitrile and ethyl acetate to give the title compound (1.06 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15]Br)[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCCOC(C)=O)NC=O
Product: CCOC(=O)C(C=C(CCCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
6.1 g (17.4 mmol) of 7-acetoxy-4-bromomethyl-2-formylaminohept-3-enoic acid ethyl ester and 19.1 ml (69.6 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified on silica gel with ethyl acetate. 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(OC(C1CCN(C2C=CC=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Agent: CCOC(=O)C1CCN(c2ccccn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4cccc(C(F)(F)F)c4)c3)cn2)CC1

Procedure:
5′-(6-Methyl-3′-trifluoromethyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 3-trifluoromethylphenyl boronic acid following a method similar to the one described in the synthesis of 5′42-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient, HRMS m/z calcd for C28H28N3O3F3 [M+H]+: 512.2156. Found: 512.2155.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1.C(O)(=O)C>O>[O:1]=[CH:2][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1
Solvent: CC(=O)O
Solvent: O
Product: O=CCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.4 %

Procedure:
A solution of 6.30 g of 5-{4-[2-(1,3-dioxolan-2-yl) ethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Preparation 106) in 50 ml of a 4:1 mixture of acetic acid and water was stirred at 60° C. for 6 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.20 g of the title compound, melting at 48°-51° C.
Reaction SMILES: C1O[CH:5]([CH:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([I:19])=[C:14]([F:20])[CH:13]=3)[CH2:8][CH2:7]2)[O:4]C1C.C(O)=O>C1(C)C=CC=CC=1>[F:18][C:16]1[CH:17]=[C:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH:5]=[O:4])[CH2:11][CH2:10]2)[CH:13]=[C:14]([F:20])[C:15]=1[I:19]
Reactant: CC1COC(C2CCC(c3cc(F)c(I)c(F)c3)CC2)O1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=CC1CCC(c2cc(F)c(I)c(F)c2)CC1
Yield: 96.4 %

Procedure:
To 50 ml of toluene were added 23 g (56 mmol) of 4-(3,5-difluoro-4-iodophenyl)cyclohexanecarboaldehyde propylene ketal obtained above and 39 g (848 mmol) of formic acid, and the mixture was refluxed for 2 hours. The reaction solution was washed with water, further with a saturated aqueous sodium bicarbonate and then with water and dried over magnesium sulfate. The solvent was distilled off to afford 19 g (54 mmol) of 4-(3,5-difluoro-4-iodophenyl)cyclohexanecarboaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:8]1[C:7]([CH3:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(F)c1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc(F)c1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a 0° C. solution of 2-fluoro-6-methyl-benzoic acid (1.48 g, 9.60 mmol) in conc. H2SO4 (40 mL) was added NBS (1.79 g, 10.1 mmol). The mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into ice water (200 mL), and extracted with ether (2×200 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to give the title compound (Compound QQ, 2.15 g, 96% yield) as a solid. 1H NMR (400 MHz, chloroform-d) δ 7.64 (dd, J=8.84, 5.31 Hz, 1H), 6.92 (t, J=8.84 Hz, 1H), 2.54 (s, 3H); MS 231.0 [M+H].
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:21][C:20]([O:19][C:17]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:18])([CH3:23])[CH3:22]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A 10.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 10.41 g of tert-butyl dicarbonate were added to a mixture of 50 ml of toluene, 6.95 g of potassium carbonate and 30 ml of water and stirred at 20° C. overnight, and then the organic layer was washed with 30 ml of water. The thus obtained organic layer was concentrated under a reduced pressure and then dried to obtain 14.59 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-methylpropan-2-yl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard, 80° C.): δ 1.39 (9H, s), 2.72-2.91 (2H, m), 3.28-3.32 (1H, m), 3.80-3.89 (1H, m), 6.18 (1H, s), 7.07-7.33 (9H, m), mass spectrum: m/z=310 [M +H]+ (FAB)).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:32])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O>[CH:1]([C:4]1[N:5]=[C:6]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:32])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N(C)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
The obtained N-[4-[3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]propionyl]phenyl]-N-methyl-2-nitrobenzenesulfonamide (230 mg, 0.372 mmol) was dissolved in anhydrous dimethylformamide (5 mL). Potassium carbonate (154 mg, 1.116 mmol) and thiophenol (46 μL, 0.446 mmol) were added to the solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (8:2, v/v) to give the desired compound (154 mg) as yellow crystalline product (yield 95%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:5]=[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 40.2 %

Procedure:
To a solution of methyl 2-(4-methyl-2-phenyl-6-p-tolylpyrimidin-5-yl)pentanoate (80 mg; 0.214 mmol) in tetrahydrofuran (2.136 mL) was added a 10 N sodium hydroxide solution (214 μL; 2.136 mmol) and the mixture was heated at 100° C. for 18 h. The volatiles were removed under reduced pressure and the mixture was acidified by adding 6N hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure to give 31 mg (40%) of the title compound as a white solid. ESI/APCI(+): 361 (M+H).