Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31](=[O:38])[N:32]([CH2:34][C:35]([OH:37])=O)[CH:33]=2)=[CH:24][CH:23]=1.[NH2:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1O.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl>C(#N)C.N1C=CC=CC=1>[F:46][C:44]1[CH:43]=[CH:42][C:41]2[O:37][C:35]([CH2:34][N:32]3[CH:33]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)[CH:29]=[CH:30][C:31]3=[O:38])=[N:39][C:40]=2[CH:45]=1
Reactant: COc1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Reactant: Nc1cc(F)ccc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc(=O)n(Cc3nc4cc(F)ccc4o3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.1 %

Procedure:
According to Scheme 10 Method A: A solution of PPh3 (3 eq, 1.04 mmol, 0.27 g) in 1:1 acetonitrile/pyridine (3 mL) was added dropwise over a period of 1 hour to a mixture of 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetic acid (1 eq, 0.35 mmol, 0.09 g, Example 14 Step 2), 2-amino-4-fluorophenol (1 eq, 0.35 mmol, 0.04 g), Et3N (3 eq, 1.04 mmol, 0.15 mL) and CCl4 (4 eq, 1.39 mmol, 0.13 mL) in 1:1 mixture of acetonitrile/pyridine (3 mL). The reaction mixture was stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2 and NH4OH. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using CH2Cl2/AcOEt 90/10 as eluent to afford 1-((5-fluorobenzo[d]oxazol-2-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.06 mmol, 0.02 g, 16%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:39])([CH3:37])[CH3:36])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (2.24 g, 6.88 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.49 g, 13.77 mmol) and ethyl-2-bromoisobutyrate (4.04 mL, 27.53 mmol). The mixture was heated to 60° C. under N2 with stirring for 18 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 20% ethyl acetate/hexanes to yield 1.36 g (45%) of the desired 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.CN(C)CCCCl.C[N:13]1[C:18](=[O:19])[C:17]2[CH:20]=[N:21][C:22]3[NH:26][N:25]=[CH:24][C:23]=3[C:16]=2[N:15]2[N:27]=[CH:28][N:29]=[C:14]12.C(N1C2N=CC3C(=O)NC4N(N=CN=4)C=3C=2C=N1)C>>[CH3:1][S:2][CH2:3][N:13]1[C:18](=[O:19])[C:17]2[CH:20]=[N:21][C:22]3[NH:26][N:25]=[CH:24][C:23]=3[C:16]=2[N:15]2[N:27]=[CH:28][N:29]=[C:14]12
Reactant: CSCCl
Reactant: Cn1c(=O)c2cnc3[nH]ncc3c2n2ncnc12
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Agent: CN(C)CCCCl
Product: CSCn1c(=O)c2cnc3[nH]ncc3c2n2ncnc12

Procedure:
By substituting methylthiomethyl chloride for the 3-(dimethylamino)propyl chloride in the procedure of Example 2 and substituting the 4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one obtained in Example 11 for the 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one, 4-methylthiomethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH:39]1([CH2:43]Br)[CH2:42][CH2:41][CH2:40]1>O>[ClH:1].[CH:39]1([CH2:43][N:19]2[CH2:18][CH2:17][C@:15]34[C:16]5[C:3]6[O:2][C@H:14]3[C:13](=[O:20])[CH2:12][CH2:11][C@@:10]4([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:31][CH3:32])[CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Reactant: BrCC1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)N(CC2CCC2)CC[C@]314
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (500 mg, 1.19 mmol), potassium carbonate (1.00 g, 7.24 mmol) and cyclobutylmethylbromide (0.6 ml, 5.43 mmol) in water-free N,N-dimethylformamide (7 ml) was stirred for 24 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 20 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 100 ml dichloromethane, washed with water (3×100 ml) and saturated sodium chloride solution (4×100 ml), dried over sodium sulphate and evaporated down. The evaporation residue (520 mg of brown oil) was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 10 ml ether and precipitated by the addition of etherial HCl. Yield: 0.40 g (69%) of the compound 2.HCl as colourless crystals. Fp. 128-133° C.; MS (CI): 488 (M++1); IR (KBr): 1728 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.48 (s, wide, HN+), 7.30-7.15 (m, 5 arom. H), 6.87 (d, 1 arom. H, J=8.4 Hz), 6.77 (d, 1 arom. H, J=8.4 Hz), 4.93 (s, CH-5), 3.81 (s, CH3O).
Reaction SMILES: C(OC(=O)NCC([N:11]1[CH2:16][CH2:15][C:14]([CH2:25][NH2:26])([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)(C)(C)C.[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](=[NH:43])SC)=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1>O1CCCC1>[NH2:31][CH2:30][C:37]([N:26]([CH2:25][C:14]1([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[C:40]([NH:39][C:37]([C:30]1[C:29]([NH2:28])=[N:34][C:33]([NH2:35])=[C:32]([Cl:36])[N:31]=1)=[O:38])=[NH:43])=[O:38]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(CN)(CCc2ccccc2)CC1
Solvent: C1CCOC1
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)N(CC1(CCc2ccccc2)CCNCC1)C(=O)CN
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 130 mg (0.35 mmol) [2-(4-aminomethyl-4-phenethyl-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (A.50) and 80 mg (0.3 mmol) 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea in 5 ml tetrahydrofuran is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure and the residue is purified via preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure. Then the residue is co-evaporated with methanolic hydrochloric acid in order to remove the protecting group.
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13].N1P(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.[Br:32][C:33]1[C:34]([CH3:49])=[N:35][O:36][C:37]=1[NH:38][S:39]([CH:42]1[CH:46]=[CH:45][S:44][C:43]1=[C:47]=[O:48])(=[O:41])=[O:40]>C1COCC1.O>[Br:32][C:33]1[C:34]([CH3:49])=[N:35][O:36][C:37]=1[NH:38][S:39]([C:42]1[CH:46]=[CH:45][S:44][C:43]=1[C:47]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=1)=[O:48])(=[O:40])=[O:41]
Reactant: Cc1noc(NS(=O)(=O)C2C=CSC2=C=O)c1Br
Reactant: CCOC(=O)c1cccc(N)c1
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Nc2cccc(C(=O)O)c2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
Et3N (2.27 ml. 16. mmol), ethyl 3-aminobenzoate (0.836 ml, 5.44 mmol) and phosphonitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentially added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide (Example 17) (1 g, 2.27 mmol) in dry THF (20 ml). The reaction was stirred at room temperature for 1 hour and cooled. Water (5 ml) was added to quench the reaction. The resulting solution was concentrated on a rotavap. The residue was diluted with EtOAc and washed with 2N HCl (2×150 ml). The organic layer was dried (MgSO4). The solid was filtered off and the filtrate was concentrated. The residue was treated with 1 N NaOH (200 ml) and stirred at 0° C. for 15 minutes. The mixture was then acidified with conc. HCl to pH˜1. The resulting yellow precipitate was filtered off and recrystallized from CH3CN/H2O to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (153 mg., 11.6%) as a yellowish powder, m.p. 183-185° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=O.B.[Cl-].[Na+]>O1CCCC1>[CH3:31][Si:2]([CH3:1])([CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Temperature: 0 °C

Procedure:
A 125 g. sample of ethyl 4-[14-(trimethylsilyl)tetradecanamido]benzoate was dissolved into 1 l. dry tetrahydrofuran, and to this stirred solution under nitrogen was dropwise added 419 ml. 1M borane in tetrahydrofuran. The solution was refluxed for four hours, cooled, and poured with stirring into 11.2 l. ice-water which contained about 250 g. sodium chloride. The precipitate was filtered off and air dried. Crystallization from ethanol afforded the pure product, m.p. 91°-92° C.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][N:8]=1.CI.CC(O)=O>C1COCC1.CCOCC>[Cl:6][C:7]1[C:12]([CH3:1])=[C:11]([Cl:13])[CH:10]=[CH:9][N:8]=1
Reactant: [Li]CCCC
Reactant: Clc1ccnc(Cl)c1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CI
Product: Cc1c(Cl)ccnc1Cl
Yield: 72 %

Procedure:
1.6 M n-Butyl lithium in hexanes (3.75 mL, 6.0 mmol) and anhydrous THF (5 mL) were added to a flame-dried flask under nitrogen atmosphere. This solution was cooled to −78C, 2,4-Dichloro-pyridine was added dropwise while stirring and the mixture was stirred at −78C for 30 min after which time methyliodide (0.374 mL, 6.0 mmol) was added dropwise at −78C. This mixture was stirred at −78C for 1 h under nitrogen atmosphere after which time glacial AcOH (0.114 mL, 2.0 mmol) was added to give a reaction mixture pH (wet pH paper) of 5-6. The reaction mixture was dissolved in Et2O (100 mL), the organic layer was washed with water (10 mL), then brine (10 mL), dried with MgSO4, and the solvent was evaporated in vacuo to give an oil which was purified by flash chromatography using hexanes:CH2Cl2 (50:50 v/v) to hexanes:CH2Cl2:EtOAc (50:47:3 v/v/v) to give 2,4-dichloro-3-methyl-pyridine as a white solid (589 mg, 72%). It was noted that 2,4-dichloro-3-methyl-pyridine readily sublimates in vacuo. 1H NMR (CD3OD, 400 MHz) δ 8.15 (d, 1H), 7.46 (d, 1H), 2.50 (s, 3H). LRMS calculated for C6H5Cl2N: 160.98, found: (MH)+ 161.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(C2C=CC(C(=O)C)=CC=2)[CH:41]=[CH:40][N:39]=[CH:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(-n5ccnc5)cc4)ccc3c1)n2C1CCCCC1
Yield: 59 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-imidazol-1-yl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 59% yield). MS: 514.23 (M+H+); HPLC Procedure A, retention time=8.40 min.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]Cl)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:34]3[CH2:33][CH2:32][C:31]([C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=4)([OH:37])[CH2:36][CH2:35]3)[CH2:10][CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 80 °C
Yield: 60.1 %

Procedure:
In DMF, 9.0 g of 1-[4-(diphenylmethyl)piperazinyl]-3-chloropropane (2.0 eq) and 4-(4-chlorophenyl)-4-hydroxypiperidine (2.0 eq.) were dissolved (20 v/w), and the obtained solution was heated to reflux at 80° C. for 6 hours. The solution was allowed to cool and then concentrated, and purified by silica gel column chromatography (Wakogel C-200, 100 g) to obtain 8.3 g of 1-[4-(diphenylmethyl)piperazinyl]-3-[4-(4-chlorophenyl)-4-hydroxy-piperidinyl]propane (yield 60.1%), which is a target compound, as a white solid in an amorphous state.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:32])C.[Li+].[OH-]>>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[S:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])=[C:8]([CH3:32])[CH:9]=3)[N:17]=2)=[CH:27][CH:26]=1)([CH3:30])([CH3:31])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d1, [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C:34](O)(=[O:37])[CH2:35][OH:36]>>[OH:37][CH2:34][C:35]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:36]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: O=C(O)CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)CO)C3)ccc1-2
Yield: 27 %

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 31 and glycolic acid were reacted. Purification by reverse phase preparative HPLC (Gemini C18 column, gradient 5-98% MeOH in H2O+0.1% HCO2H) gave 397 as a white solid (46 mg, 27%). LCMS: RT=10.33 min, [M+H]+=426. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.20 Hz), 8.05 (1 H, s), 7.20-7.15 (1 H, m), 7.01 (1 H, d, J=1.82 Hz), 5.82-5.72 (1 H, m), 4.88-4.81 (1 H, m), 4.55-4.46 (1 H, m), 4.34-4.29 (2 H, m), 4.30-4.17 (1 H, m), 4.16 (1 H, dd, J=9.24, 5.41 Hz), 3.90 (2 H, d, J=5.77 Hz), 3.89-3.77 (2 H, m), 3.41-3.35 (2 H, m), 1.49 (6 H, d, J=6.59 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 61.8 %

Procedure:
A mixture of 3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), malonic Acid (12.5 g, 120.2 mmol), and piperidine (5 mL) was heated at 100° C. for 2 h and at 150° C. for 1 h. The reaction was poured onto 3N HC1 (200 mL) and the precipitate was removed via filtration. The product was purified by recrystallization (100 mL hot EtOH) to afford 3-(3,5-dichlorophenyl)-acrylic Acid (11.5 g). 1H NMR (250 MHz, DMSO-d6) δ 12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6,72 (d, 1H).
Reaction SMILES: CO.[OH-].[Na+].C([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[N:15][C:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH:34]5[CH2:36][CH2:35]5)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:18]=2)[C:9]1=[O:37])(=O)C>O>[CH:34]1([C:30]2[CH:31]=[C:32]([CH3:33])[C:27]([N:24]3[CH2:25][CH2:26][N:21]([C:19]([C:16]4[N:15]=[N:14][C:13]([N:10]5[CH2:11][CH2:12][NH:8][C:9]5=[O:37])=[CH:18][CH:17]=4)=[O:20])[CH2:22][CH2:23]3)=[N:28][CH:29]=2)[CH2:35][CH2:36]1
Reactant: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)nn2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)nn2)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and 1-acetylimidazolidin-2-one (64 mg) and by the reaction and treatment in the same manner as in Example 511, 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one was obtained as a crude product (170 mg). Methanol (1.2 mL) and 1N aqueous sodium hydroxide solution (0.57 mL) were added to the obtained crude product (170 mg) of 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one, and the mixture was stirred at 40° C. for 1 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (48 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:40][CH2:39][C:38]5[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)cc1
Yield: 68.7 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-methoxybenzylamine (available from Aldrich Chemical Company, Inc.; 85 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-methoxy-benzylcarbamoyl)-biphenyl-2-carboxylic acid (85 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 9.08 (t, J=5.9 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 4.44 (d, J=6.0 Hz, 2H), 3.73 (s, 11H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[Li]CCCC.[CH3:12][C:13]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[C:17]([B:28]2[O:32]C(C)(C)[C:30](C)(C)[O:29]2)[C:14]=1C=O>C1COCC1>[OH:32][B:28]1[C:17]2[CH:18]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:20]=[C:13]([CH3:12])[C:14]=2[CH:30]([CH2:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3])[O:29]1
Reactant: COS(C)(=O)=O
Reactant: Cc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COS(=O)(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(C)c21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−78° C.) solution of methyl methanesulfonate (1.56 mL, 20 mmol) in 15 ml anhydrous THF was added 1.6 M n-BuLi in hexanes (11.25 ml, 18 mmol) dropwise. The mixture was stirred at −78° C. for 20 minutes, then a solution of 2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.07 g, 6 mmol) in 15 mL THF was added slowly via syringe. After stirring at −78° C. for 10 minutes, the reaction was quenched with saturated ammonium chloride at −78° C. It was then extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by flash column. (1.64 g) MS (ESI) m/z=713 [2M+H]+.