Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:60]=[CH:59][C:14]([CH2:15][N:16]([CH2:49][CH2:50][O:51]CC3C=CC=CC=3)[C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Cl)(Cl)Cl.CO>ClCCl.C(=O)(O)[O-].[Na+]>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:60]=[CH:59][C:14]([CH2:15][N:16]([C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)[CH2:49][CH2:50][OH:51])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCOCc1ccccc1)Cc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCO)Cc1ccc(OCCN3CCCCCC3)cc1)C2
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of [4-(2-azepan-1-ylethoxy)benzyl] (2-benzyloxyethyl) {5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}amine (450 mg) in dichloromethane (23 ml) was added dropwise boron trichloride (1.0 M solution in dichloromethane) (4.2 ml) at −78° C., and the solution was stirred for 30 minutes. At −78° C., to the reaction solution was added methanol (2 ml), and the reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with chloroform, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (240 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[NH:17][C:16]([C@@H:18]([NH:28]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[N:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>CCOC(C)=O.CO.[Pd]>[NH2:28][C@H:18]([C:16]1[NH:17][C:13]([C:12]2[C:3]([O:2][CH3:1])=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:14][N:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A3 was dissolved in EtOAc/MeOH (1:1) (0.01 M) and treated with Pd/C. Mixture was purged with N2 and stirred under H2 atmosphere at room temperature for 24 h. Then, reaction mixture was filtered through a pad of silica and filtrate was concentrated under vacuum to give the title compound which was used as such in the next step. MS (ES+) C21H27N5O2: 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].Cl>CN(C=O)C.C(OCC)(=O)C>[C:17]([Si:21]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc(CO)ccc1F
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 9.17 g of (4-fluoro-3-methoxyphenyl)methanol [CAS No. 128495-45-4] in 100 ml of DMF, 5 g of imidazole and 17 g of t-butyl-chlorodiphenylsilane were added and the mixture was stirred overnight at room temperature. Next, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give t-butyl-(4-fluoro-3-methoxybenzyloxy)diphenylsilane as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([CH3:29])=[CH:27][C:26]([NH2:30])=[CH:25][N:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:41][CH2:42][N:43]=[C:44]=[O:45].NC(N)=O.[H-].[Na+]>C1COCC1>[CH3:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)=[N:24][CH:25]=[C:26]([N:30]2[CH2:41][CH2:42][NH:43][C:44]2=[O:45])[CH:27]=1
Reactant: O=C=NCCCl
Reactant: Cc1cc(N)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: NC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl-4-((1R,2 S)-2-{2-[(5-amino-3-methylpyridin-2yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (39 mg, 0.106 mmol) in THF (2.5 ml) at RT under nitrogen was added DIPEA (0.037 ml, 0.213 mmol), followed by 2-chloroethyl isocyanate (0.014 ml, 0.160 mmol). And the resulting solution stirred at room temperature overnight. LC/MS showed clean conversion to the uncyclized urea intermediate. The mixture was cooled to 0° C. and NaH (8.51 mg, 0.213 mmol) was added. The mixture was removed from the ice bath after ca. 15 minutes. LC/MS at 1 h showed complete conversion to the desired product. Formic acid (50 μl) was added and the reaction mixture stirred for 30 minutes. The material was concentrated under reduced pressure and the residue was purified by RP HPLC on a Gilson, SunFire-5C18 OBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes, hold at 100% for 1 minute, at 20 ml/min flow rate to afford the title compound. MS (ESI) m/z 479 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([N:16]1[C:17]2[C@@:18]3([CH3:28])[C:25]([CH3:27])([CH3:26])[C@H:21]([CH2:20][CH2:19]3)[C:22]=2[C:23](=[O:24])[N:15]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1Cc1ccccc1
Temperature: 100 °C
Yield: 84 %

Procedure:
A mixture of benzyl bromide (3.87 mL, 31.9 mmol), (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 2.14 g, 8.0 mmol) and tetra-n-butylammonium iodide (2.06 g, 5.6 mmol) in N,N-dimethylformamide (50 mL) was heated in an oil-bath at 100° C. for 16 h. The solvent was evaporated and dichloromethane (100 mL) and water were added. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL). The solvent was evaporated and the residue purified on an Isco 120 g column, eluting with 33-100% ethyl acetate/hexanes to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.41 g, 84%) as an off-white/tan solid. ES(+)-MS (M+H) 359.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[C:41]([F:49])[CH:40]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33]([N:16]2[CH2:15][CH2:14][C:13]3([CH2:12][C:11](=[O:23])[C:10]4[C:20](=[CH:21][CH:22]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[CH:9]=4)[O:19]3)[CH2:18][CH2:17]2)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[C:41]([F:49])[CH:40]=1)[CH3:25]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)c(F)c1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)c(F)c1

Procedure:
In the same manner as in Reference Example 3-1, the intended compound was obtained as a colorless solid using 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride and 2,6-diethoxy-3′-fluoro-4′-(methoxycarbonyl)biphenyl-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:43]#[N:44])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:38]([F:41])([F:40])[F:39])[CH2:37][CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:42])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:43]#[N:44])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:38]([F:40])([F:41])[F:39])[CH2:37][CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:42])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
58 mg (0.09 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 35 mg (65% of theory)
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=[C:6]([O:18][CH:19]([CH3:21])[CH3:20])[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH:19]([O:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1)[C:3]([OH:22])=[O:2])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(OCCc2ccsc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 3-isopropoxy-5-(2-thiophene-3-yl-ethoxy)-benzoic acid methyl ester (9.5 mmol) in a mixture of THF/MeOH 1/1 (40 ml) is added at 0° C. NaOH 1N (28.6 ml). Then the reaction mixture is stirred at room temperature for 6 h and the solvents are concentrated in vacuo. The residue is diluted with water (100 ml), the aqueous phase is extracted with ethyl ether (2×50 ml), acidified to pH 3 with conc. HCl and extracted with ethyl acetate (2×100 ml). The combined organic layer is washed with brine (50 ml), dried over MgSO4 and the solvent removed in vacuo. The residue is triturated with ethyl ether and pentane then filtered. 3-Isopropoxy-5-(2-thiophene-3-yl-ethoxy)-benzoic acid is obtained as white powder in a yield of 90%; MS: 307.1 (M+H+);
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][CH2:21][CH:22]([OH:25])[CH2:23][CH3:24]>>[CH2:21]([CH:22]([O:25][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1)[CH2:23][CH3:24])[CH3:20]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Product: CCC(CC)Oc1nc(C)nc(Cc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared by the method analogous to that in Example 32 starting with 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)pyrimidine and 3-pentanol. White crystals, mp. 82-84° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27](O)=[O:28])[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1nsc(Cc2ccccc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nsc(Cc2ccccc2)n1

Procedure:
The 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-thiadiazole-3-carboxamide is prepared following method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride, 5-benzyl-1,2,4-thiadiazole-3-carboxylic acid (which can be prepared by procedures known to the skilled in the art), HATU and N,N-diisopropylethylamine in DMF.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[C:11]3=[CH:12][C:13]4[S:17][N:16]=[N:15][C:14]=4[C:18]([F:19])=[C:10]3[N:9]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[Cl:27])C2=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:19][C:18]1[C:14]2[N:15]=[N:16][S:17][C:13]=2[CH:12]=[C:11]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])[C:10]=1[NH:9][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[Cl:27]
Reactant: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3nnsc3cc2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.12 mmol) in THF (5 mL) was added potassium trimethylsilanolate (16 mg, 0.12 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product (30 mg, 52.7% yield). 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.02-7.98 (m, 1H), 7.85 (m, 1H), 7.60-7.56 (m, 1H), 7.14 (s, 1H), 6.83 (s, 1H), 2.81-2.72 (m, 1H), 1.33 (m, 2H), 1.15 (m, 2H). MS APCI (+) m/z: 478.8, [M+H].
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:33]=[CH:34][CH:35]=4)[O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:37].CCOCC>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:33]=[CH:34][CH:35]=4)[O:27][CH2:28][C:29]([O-:31])=[O:30])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:37]
Reactant: COC(=O)COc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C([O-])COc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (+)-methyl [3-[[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (1.92 g) in ethanol (30 ml) was added 1N-aqueous sodium hydroxide (4.1 ml). The reaction mixture was stirred for 1 hour at room temperature. Ether (50 ml) was added to the solution. The precipitated solid was collected by filtration to afford (+)-sodium [3-[[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (0.83 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>ClCCCl>[C:2]1([CH2:1][NH:8][C:9]2[N:14]=[C:13]([NH:15][C:35]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)=[O:36])[C:12]([C:16]3[NH:17][N:18]=[N:19][N:20]=3)=[CH:11][N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a solution of N2-Benzyl-5-(1H-tetrazol-5-yl)pyrimidine-2,4-diamine (27 mg, 0.1 mmol) in 1 mL of DCE, DIPEA (0.3 mmol, 3.0 eq.) was added followed by thiophene-2-carbonyl chloride (0.15 mmol, 1.5 eq.). The reaction was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated down in vacuo, and the residue redissolved in ethylacetate. This organic solution was extracted several times with water, dried with magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give 4.8 mg of the desired compound. 1H-NMR (400 MHz, d6-DMSO): δ 9.07 (t, 1H), 7.81 (dd, 1H), 7.77 (dd, 1H), 7.36-7.29 (m, 4H), 7.28-7.23 (m, 1H), 7.16 (t, 1H), 4.45 (d, 2H). MS (EI) for C17H14N8OS: 379 (M+H).
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].[Cl:6][C:7]([Cl:11])([Cl:10])[CH2:8][OH:9].Cl>>[P:2]([Cl:5])([Cl:3])(=[O:1])[O:9][CH2:8][C:7]([Cl:11])([Cl:10])[Cl:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCC(Cl)(Cl)Cl
Agent: Cl
Product: O=P(Cl)(Cl)OCC(Cl)(Cl)Cl
Yield: 56.3 %

Procedure:
To 90 g (0.59 mol) of POCl3 at 25° C. was slowly added 72 g (0.48 mol) of 2,2,2-trichloroethanol over a two hour period. The mixture was heated and maintained at 100°-125° C. for 14 hours during which time 22 g (0.60 mol) of HCl was recovered in the water scrubber. The mixture was distilled to give 72 g (0.27 mol) of 2,2,2-trichloroethyl phosphorodichloridate, bp 84° C. at 3 mm (57% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8]O)=[CH:6][N:5]=[CH:4]1)[CH3:2].BrP(Br)Br.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([N:3]1[C:7]([CH2:8][S:21][C:19]2[N:18]=[C:17]([OH:22])[CH:16]=[C:15]([CH3:14])[N:20]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1CO
Reactant: Cc1cc(O)nc(S)n1
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cncc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 12 %

Procedure:
To a solution of (1-ethyl-1H-imidazol-5-yl)methanol (631 mg, 5.0 mmol) in dichloromethane (20 mL) was added dropwise tribromophosphane (0.94 mL, 10.0 mmol). The resulting mixture was stirred at room temperature for 6 hours. After evaporation, the crude 5-(bromomethyl)-1-ethyl-1H-imidazole was dissolved in cold ethanol (30 mL), and 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 5 mmol) and triethylamine (2.8 mL, 20 mmol) were added. After 2 hours, the solvent was evaporated, and the residue was purified by chromatography (4% methanol in dichloromethane) to provide a white solid (150 mg, 12% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 2.22 (s, 3H), 4.02 (q, 2H), 4.46 (s, 2H), 6.03 (br, 1H), 6.88 (s, 1H), 7.64 (s, 1H); M+251.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:20]=2[CH3:27])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CC#N.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=2[CH3:27])[CH:25]=[O:26])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C=O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one (1.5 g, 3.33 mmol) was dissolved in 75% CH3CN/CH2Cl2 (20 ml) and cooled to 0° C. Dess-Martin Periodinane(2.8 g, 6.66 mmol) was added and the reaction stirred for four hours. At this time, the reaction was quenched with 5% sodium bisulfite (aq.). The product was extracted with ethyl acetate. The combined organic extracts were then washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The resulting residue was taken up in diethyl ether and the precipitate was collected on a filter pad and washed with more diethyl ether to yield a white solid (1.35 g, 91%). 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.91 (dd, J=7.65, 1.61 Hz, 1H), 7.65 (m, 2H), 7.57 (d, J=7.85 Hz, 1H), 7.03 (m, 1H), 6.95 (ddd, J=12.69, 8.86, 2.62 Hz, 1H), 6.19 (s, 1H), 5.31 (s, 2H), 2.20 (s, 3H), 1.96 (s, 3H); ES-MS m/z 448 (M+H). ES-HRMS m/z 448.0347 (M+H calcd for C21H17BrF2NO3 requires 448.0354).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]([CH2:21][CH3:22])[C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=1[CH:10]=[N:11]O>CO.[Ni]>[NH2:11][CH2:10][C:9]1[CH:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:8]=1[N:7]([CH2:6][C:5]1[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=1)[CH2:21][CH3:22]
Reactant: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=NO
Agent: [Ni]
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde oxime (241 mg) is dissolved in methanol (10 ml) and thereto is added Raney nickel (0.5 g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→0:1) to give (2-aminomethyl-4-trifluoromethyl-phenyl)-(3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (210 mg). MS (m/z): 445 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O.[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CC1=C(C)C(=O)C(CCCCCC(=O)O)=C(C)C1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Reaction time: 12 h

Procedure:
To a well stirred solution of 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the free form) (0.21 part) in ethanol (10 volume parts) was added 3 drops of concentrated sulfuric acid under cooling in ice bath and kept standing for 12 hours. After addition of water, the reaction mixture was extracted with diethyl ether and the diethylether layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted wth chloroform to give 2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of ethyl ester) (0.20 part) as an orange oil.