Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=O)[NH:14][C:13](=[S:17])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].[CH3:31]I>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:25](=[O:28])[N:14]([CH3:15])[C:13]([S:17][CH3:31])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=S)NC12CC(c1ccc(Cl)cc1)Oc1ccc(Br)cc12
Agent: [K+]
Solvent: CC#N
Product: CSC1=NC2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)C(=O)N1C
Yield: 67.2 %

Procedure:
To a mixture of 6-bromo-2-(4-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (450 mg, 1.07 mmol) and K2CO3 (588 mg, 4.27 mmol) in CH3CN (10 mL) was added MeI (610 mg, 4.27 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-2-(4-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (325 mg, 37%). 1H-NMR (CDCl3): 1.89 (m, 1H), 2.41 (m, 1H), 2.56 (t, 3H), 3.17 (m, 3H), 5.81 (m, 1H), 6.79 (m, 2H), 7.23 (m, 1H), 7.43 (m, 4H).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C[O-].[Na+].CO.[CH3:13][C:14]([CH3:23])([CH3:22])[CH2:15][C:16](=O)[C:17](OC)=[O:18]>O.C(O)(=O)C>[C:14]([C:15]1[CH:16]=[C:17]([OH:18])[N:7]=[CH:5][N:6]=1)([CH3:23])([CH3:22])[CH3:13]
Reactant: N=CN
Reactant: COC(=O)C(=O)CC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
First, 7.2 g of formamidine acetate, 7.5 g of sodium methoxide, and 70 mL of methanol were put in a 100-mL three-neck flask. Then, 10 g of methyl 4,4-dimethyloxovalerate was added to this mixed solution. The mixture was stirred at room temperature for 24 hours. After the predetermined time elapsed, a mixed solution of 17 mL of water and 7.2 mL of acetic acid was added to the mixture, and the mixture was stirred at room temperature. This mixture was condensed, and the given residue was dissolved in water. The solution was subjected to extraction with ethyl acetate. The obtained solution of the extract was washed with a saturated aqueous solution of sodium chloride, and anhydrous magnesium sulfate was added to the organic layer for drying. The obtained mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with ethyl acetate to give 4-tert-butyl-6-hydroxypyrimidine (white powder, yield of 49%). Synthesis Scheme (a-1) of Step 1 is shown below.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[Cl:16].C[O:18][B:19](OC)[O:20]C.Cl>C1COCC1>[Cl:16][C:8]1[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=[CH:12][C:7]=1[B:19]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to l-bromo-2-chloro-4-ethoxybenzene (19.5 mmol, 4.59 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming a white precipitate. The white precipitate (2.25 g, 58%) was filtered and dried to afford (2-Chloro-4-ethoxyphenyl)boronic acid. 1H NMR (CDCl3, 300 MHz): 7.87 (1H, d, J 8.4 Hz), 6.88 (1H, d, J 2.5 Hz), 6.84 (1H, dd, J 8.4 and 2.5 Hz), 5.53 (2H, br. s), 4.06 (2H, q, J 7.07 Hz), 1.42 (3H, t, J 7.0 Hz.)
Reaction SMILES: [CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2].[NH3:29]>>[CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:29])=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2]
Reactant: N
Reactant: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CNc1ccccc1CC
Product: CCCC1=NN(c2ccc(C(N)=O)cc2)C(=O)C1=CNc1ccccc1CC

Procedure:
From the reaction of 4-(4-(2-ethylaniIinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid and diluted ammonia solution, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzamide is obtained, Mp 170° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-].C1COCC1.Cl>CO.O>[C:11]1([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cnc(-c2ccccc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (3.15 g) and LiOH (0.71 g) in a mixture of MeOH, THF and water (1:1:1 in volume, 120 mL) is stirred at rt overnight. MeOH and THF are evaporated off to give an aqueous solution. The aqueous solution is acidified with 5% hydrochloric acid to adjust pH to between 2.5 and 3. The precipitate is filtered off and washed with water, dried in vacuo to yield 2.94 g (˜100%) of 2-phenyl-pyrimidine-5-carboxylic acid as a solid. MS: 201 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:12]=[CH:13][N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([O-])([OH:30])=[O:29]>CC(O)=O>[CH2:21]([O:20][C:19]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11](/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])=[C:17]([N+:28]([O-:30])=[O:29])[CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
3,4-Dibenzyloxy -β-nitrostyrene (12) (67.2 g; 0.186 mol) is dispersed in 1.5 L CH3CO2H. HNO3 (d 1.42) is added until the temperature reaches 40° C. The mixture is cooled to 20° C., and the remainder of the 375 mL HNO3 is added without further cooling. After stirring at 23° C. for three hours, the reaction mixture is poured onto 2 kg of ice, and filtered. The yellow powder is washed well with H2O. Recrystallization from CH3CO2H affords 70.3 g (93%) of (13) as yellow needles; mp 162°-164° C.
Reaction SMILES: [CH:1]1([O:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1(C)[CH:15]=[CH:14][CH:13]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:11]=1.N1C=CC=C[CH:22]=1>>[C:15]1([CH3:22])[CH:10]=[CH:11][C:12]([S:16]([O:9][CH2:8][CH2:7][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:18])=[CH:13][CH:14]=1
Reactant: OCCOC1CCCC1
Reactant: c1ccncc1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
2-Cyclopentyloxyethanol (4.3 g, 33.1 mmol) in pyridine (18 ml) was added dropwise to a solution of 3-toluenesulphonyl chloride (6.8 g, 35.7 mmol) in pyridine (27 ml) at 5° C. The mixture was allowed to warm to ambient temperature, and stirred overnight. The mixture was poured onto ice containing concentrated hydrochloric acid (46 ml) and the product was extracted with ether. The organic phase was washed with 2M hydrochloric acid, dried (MgSO4) and the solvent removed by evaporation to give 2-cyclopentyloxyethyl 4-toluenesulphonate (6.9 g, 73%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(Br)c(F)c1

Procedure:
A solution of 4-bromo-3-fluorobenzoic acid (117 mg, 0.50 mmol) in methanol (1 mL) and dichloromethane (2 mL) at room temperature was slowly treated with 2M trimethylsilyldiazomethane in hexanes until the solution became light yellow. The mixture was concentrated to provide the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCCCCC.CCOC(C)=O>[N:17]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C1CCNCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCCCC1

Procedure:
Prepared from 3-nitro-5-trifluormethyl-benzoic acid and piperidine (TPTU, CH2Cl2/CH3CN, Et3N): MS: [M+1]+=303; TLC Rf=0.27 (hexane/AcOEt 7:3).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH:40]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH3:41])[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH:40]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH3:41])[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)ncn1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)O)c2)ncn1)c1cccc(C(F)(F)F)c1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(4-(piperidin-1-yl)-2-(6-(1-(3-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)phenylcarbamoyl)benzylthio)-propanoate (90 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (4 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at 30° C. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 46.1 mg (55%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.78 (s, 1H), 7.71 (m, 4H), 7.53 (m, 6H), 7.27 (m, 2H), 6.93 (s, 1H), 5.40 (s, 1H), 3.92 (s, 2H), 3.48 (m, 4H), 2.61 (m, 4H), 1.59 (m, 10H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)=[N:5][C:6]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C1COCC1>[CH2:9]([C:6]1[N:5]=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:3]([CH2:2][NH:1][S:59]([CH3:58])(=[O:61])=[O:60])=[CH:8][N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ncc(CN)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1ncc(CNS(C)(=O)=O)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
5-Aminomethyl-2-butyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine, the intermediate from Example 32, is dissolved in THF containing triethylamine and treated with one equivalent of methanesulfonyl chloride. After the reaction is complete according to TLC analysis, the reaction mixture is washed with dilute aqueous sodium bicarbonate solution, dried and concentrated in vacuo to give 2-butyl-5-[methanesulfonamidomethyl]-4-{N-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine. The triphenylmethyl group is removed, as described in Example 1D, to give the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cn1nnnc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1nnnc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS (m/e): 379.3 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[N:6]=[CH:7][NH:8][C:9]=1[CH2:10][S:11][CH2:12][CH2:13][N:14]=[C:15]=[S:16]>C(O)C>[NH2:2][NH:3][C:15]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:9]1[NH:8][CH:7]=[N:6][C:5]=1[CH3:4])=[S:16]
Reactant: Cc1nc[nH]c1CSCCN=C=S
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc[nH]c1CSCCNC(=S)NN
Temperature: 25 °C

Procedure:
Hydrazine hydrate (0.01 mole) is added to a solution of 2-(4-methyl-5-imidazolylmethylthio)ethyl isothiocyanate (0.01 mole) in ethanol, and stirred for an hour at room temperature to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>O1CCOCC1.CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][O:34][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCN(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-dimethylaminoethanol in dioxane and DMF. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH3:38]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH3:38])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-methoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)-propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:15][CH:14]=4)[C:8]1([CH3:31])[CH3:30])[CH3:5])[CH3:2].[CH3:32][C:33]([CH3:36])([O-])[CH3:34].[K+].C1OCCOCCOCCOCCOCCOC1.ClCC(C)=C>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:16]([C@H:17]([CH3:20])[CH2:18][O:19][CH2:34][C:33]([CH3:36])=[CH2:32])[CH2:15][CH:14]=4)[C:8]1([CH3:31])[CH3:30])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO)[C@@]1(C)CC3
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C=C(C)CCl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)COC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(C)OCC)C(C)(C)[C@@H]1CC3
Temperature: 70 °C
Yield: 107.5 %

Procedure:
vii)—A mixture of (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-dien-21-ol (1.0 g), dry toluene (67 ml), potassium t-butoxide (3.34 g), 18-crown-6 (0.581 g) and 3-chloro-2-methyl-1-propene (1.14 ml) was heated at 70° C. for 1.5 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-oxacholesta-8,14,25-triene (1.21 g), which was used in the following step without further purification.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[N+:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C-:22]>C1COCC1>[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:15][CH:22]=[N:21][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:12][CH:11]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Triethylamine (10.0 mL, 71.9 mmol) was added to a solution of 4-(trifluoromethyl)benzoyl chloride (5.0 g, 24.0 mmol) in THF (50 mL) at 0° C. Ethyl 2-isocyanoacetate (2.9 mL, 26.4 mmol) was added dropwise and the mixture was warmed to ambient temperature. After 3.5 days the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 20% to 50% EtOAc/hexanes eluant, 30 min) yielded 4.30 g (63%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.18 (d, J=8.2, 2H), 7.92 (d, J=8.3, 2H), 4.31 (q, J=7.1, 2H), 1.28 (t, J=7.0, 3H). MS (DCI+) m/z 286 (M+H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:14][C:15]([OH:17])=[O:16].C[OH:19]>[Rh]>[CH2:1]([CH:7]([CH2:12][CH2:11][C:10]([OH:13])=[O:19])[CH2:14][C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O
Reactant: CO
Reactant: CCCCCCc1ccc(O)cc1
Agent: [Rh]
Product: CCCCCCC(CCC(=O)O)CC(=O)O

Procedure:
A stirred suspension of 4-n-hexylphenol (972 g; 5.46 mol), 61.7 g of 5% rhodium on carbon catalyst (46.0 g of Alfa Chemical Co. lot 063081 and 17.7 g of MCB Chemicals lot A12M04), HOAc (21 ml), and MeOH (5.0 L) was hydrogenated in a 5 gallon autoclave (100 psi) at 35°-55° until 73% of theoretical H2 was consumed. A sample was withdrawn and NMR and GC tests showed that a small amount of the hexylphenol remained. Hydrogenation was continued until a total of 78% of theoretical H2 was consumed. The catalyst was filtered off, and the clear filtrate was concentrated in vacuo to a clear oil, 1065 g (106%); IR (neat) cm-1 3400, (OH) 1715 (carbonyl); NMR (CDCl3) no aromatic absorbance was observed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=1)[C:41]([O:43][CH3:44])=[O:42]>CCN(CC)CC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16][NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][C:38]2[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=2)[C:41]([O:43][CH3:44])=[O:42])=[CH:11][C:10]=1[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Reactant: COC(=O)c1cccc(CC(C)(C)N)c1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Yield: 36.5 %

Procedure:
Intermediate 6 (1.6 g, 2.89 mmol) and Intermediate 19 (900 mg, 4.3 mmol) were heated neat at 95° C. for 3 days. The reaction mixture was cooled then chromatography (3:1 Hexanes/EtOAc, 0.1% Et3N) afforded the title compound (730 mg, 37%). ES/MS calcd. for C40H62NO5Si2+ 692.4. found m/z=692.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13][C:14]#[N:15])=[CH:11][CH:10]=[C:9]2[C:16]([OH:18])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[C:28]([Br:29])=[CH:27][C:26]([Br:30])=[CH:25][C:21]=1[C:22](O)=[O:23].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:30][C:26]1[CH:27]=[C:28]([Br:29])[C:20]2[N:19]=[C:16]([C:9]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[C:12]([S:13][C:14]#[N:15])=[CH:11][CH:10]=3)[O:18][C:22](=[O:23])[C:21]=2[CH:25]=1
Reactant: N#CSc1ccc(C(=O)O)n1-c1ncccc1Cl
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: N#CSc1ccc(-c2nc3c(Br)cc(Br)cc3c(=O)o2)n1-c1ncccc1Cl

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].[SH:26][C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(O)C.ClCCl>[O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[C:12]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCCOc2ccccc2)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(OCCOc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture comprising 1.0 g of [4-(2-phenoxyethoxy)-3-methylpyridine-2-yl]methanol, 0.60 ml of thionyl chloride and 12 ml of dichloromethane was kept at 40° C. for 60 minutes to carry out the reaction. The reaction mixture was distilled to remove the solvent. Thus, a brown syrupy residue was obtained. 50 ml of ethanol, 0.70 g of sodium hydroxide and 1.2 g of 2-mercaptobenzimidazole were added to the residue. The obtained mixture was heated at 70° C. for two hours and distilled to remove the ethanol. The obtained residue was chromatographed over a silica gel column and eluted with 30% ethyl acetate in hexane and then with ethyl acetate to obtain 1.2 g of the title compound as a white solid.