Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:28][CH2:29][CH2:30]Cl)=[O:27])=[CH:21][C:20]=2[Cl:32])[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][C:26]3=[O:27])=[CH:21][C:20]=2[Cl:32])[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1CCCN(C(=O)c2ccc(NC(=O)OCCCl)cc2Cl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCCN(C(=O)c2ccc(N3CCOC3=O)cc2Cl)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 5-ethoxycarbonylmethyl-1-[4-(2-chloroethoxycarbonylamino)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.9 g), potassium carbonate (0.40 g) and sodium iodide (0.43 g) in dimethylformamide (15 ml) is stirred at 80° C. for 8 hours. To the reaction solution is added ethyl acetate, and the mixture is washed with water, and the organic layer is dried over magnesium sulfate, filtered, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=30:1) to give 5-ethoxycarbonylmethyl-1-[4-(2-oxotetrahydrooxazol-3-yl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.65 g) as colorless amorphous.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>CC(C)=O>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: CCNCC
Solvent: CC(C)=O
Product: CCOC(CN(CC)CC)OCC
Reaction time: 8 h
Yield: 20.7 %

Procedure:
2-bromo-1,1-diethoxyethane (10 g, 0.051 mol), diethylamine (11 g, 0.15 mol) and KI (8.5 g, 0.051 mol) were added in 100 mL acetone, and stirred for overnight at 40 degree. The resulting solution was filtered, concentrated and purified with silica gel column to give 2,2-diethoxy-N,N-diethylethanamine as brown oil 2.0 g (20.8% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:13]=[C:12]([Cl:14])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 255 mg of 4-chlorobenzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for 30 minutes. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. After chromatography on silica eluting with methylene chloride/CH3CN in a proportion of 70/30, 350 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:45][N:46]=[C:47]=[O:48].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:47](=[O:48])[NH:46][CH3:45])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: CN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Dissolve the compound of Example 3 (201 mg, 0.38 mmol) in dichloromethane (4 L) and add triethylamine (0.50 mL, 3.5 mmol) followed by methylisocyanate (500 mg, 8.7 mmol). After stirring for 30 minutes, pour the reaction mixture into saturated aqueous sodium bicarbonate and extract with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 4%) to give 130 mg of the title compound (60%): mass spectrum (ion spray): m/z=575.3 (M+H) and 518.3 (M-MeNCO).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2ccc(OCC(O)CCl)cc2o1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(C)=O)oc3c2)CC1

Procedure:
The procedures of Example 2b were repeated except that 1.3 g (0.005 mole) of 2-acetyl-6-(3-choro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed as starting materials. The obtained concentrated residue was crystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26](O)=[O:27])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:39][N:40]([CH2:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:52][C:51]4[CH:50]=[CH:49][C:48]([CH2:47][N:40]([CH3:39])[CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[CH:54][CH:53]=4)=[O:27])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxylic acid (80 mg) in THF (10 ml) were added a drop of DMF and then thionylchloride (0.02 ml) at 0° C. After stirring at room temperature for 30 minutes under a nitrogen atmosphere, the mixture was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (57 mg) and triethylamine (526 mg) in tetrahydrofuran (20 ml) at 0° C. The mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate). Recrystallization from hexane/ethyl acetate gave colorless crystals of 8-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxamide (Compound 1, 66 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:9]2([CH:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:33][C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])[CH2:13][C:12](=[O:14])[NH:11][CH:10]2[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[CH3:22])[C:23]1=[O:32])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 2 h
Yield: 78.3 %

Procedure:
At room temperature, to a mixture of racemic (2′S, 3S, 4′R)-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (540 mg, 0.8 mmol) and acetic anhydride (98 mg, 0.96 mmol) in DCM (20 mL) was added DMAP (10 mg, 0.08 mmol) slowly. After the mixture was stirred for 2 h, the solution was washed by 0.5N HCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give the title compound as a white solid (450 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:3]=12.CS(C)=O.[C:21]12([CH2:31][NH2:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.CS(O)(=O)=O.CO>O>[CH2:15]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:32][CH2:31][C:21]45[CH2:30][CH:25]6[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]6)[CH2:28]4)[CH2:22]5)=[C:3]2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:16]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: CCn1ncc2c(NCC34CC5CC(CC(C5)C3)C4)c3ccccc3nc21
Temperature: 110 °C
Yield: 18.6 %

Procedure:
A mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoline (1 g), DMSO (3 ml) and adamantylmethylamine (1 g) is heated at 110° C. overnight. The reaction mixture is poured into water, and a precipitate forms which is collected by filtration and dried to afford the product as a free base. The free base is treated with methanesulfonic acid/methanol, the methanol is evaporated and the salt is recrystallized from 2-propanol to afford 290 mg of 1-ethyl-N-(adamantylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.CH3SO3H, m.p. 310° C.
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].OC(C(O)(C)C)(C)C.[Li]CCCC.[B:24]([O:33][CH:34]([CH3:36])[CH3:35])([O:29][CH:30]([CH3:32])[CH3:31])OC(C)C>C1COCC1.CCCCCC>[CH3:36][C:34]1([CH3:35])[C:30]([CH3:31])([CH3:32])[O:29][B:24]([C:8]2[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=2)[O:33]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCc1cccs1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a cooled (−78° C.) mixture of 2-n-pentylthiophene (5.0 g, 32.1 mmol) and pinacol (11.5 g, 97.23 mmol) in anhydrous THF (60 mL) was added dropwise to a solution of n-BuLi (22.3 mL, 35.6 mmol) in hexane. The mixture was stirred at −78° C. for 10 minute. The reaction mixture was then brought to 0° C. and stirred for 1 h before cooling to −78° C. before the addition of triisopropyl borate (7.3 g, 38.9 mmol) in THF (24 mL) using a dropping funnel. The mixture was slowly brought to room temperature while stirring overnight. The crude product was purified by flash chromatography (silica gel. eluent: hexane/EA) 10:1) to afford a reddish brown liquid 7.35 g (81.0%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:22])([F:21])[CH2:19]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:19][C:18]([F:22])([F:21])[F:17])[CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)CI
Reactant: O=c1[nH]cnc2scc(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(-c3ccccc3)csc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 47.6 %

Procedure:
A mixture of 5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (20 g, 88 mmol), 1,1,1-trifluoro-2-iodoethane (36.8 g, 175 mmol) and potassium carbonate (26.6 g, 193 mmol) in DMF (100 ml) was heated at 70° C. for 0.5 h and at 100° C. for 2 h. A further portion of 1,1,1-trifluoro-2-iodoethane (36.8 g, 175 mmol) was added and the resulting mixture was heated at 100° C. for a further 16 h. The reaction mixture was cooled down and diluted with water (750 ml) and the precipitate was filtered to give the title compound as a light yellow solid (13 g, 48%). LCMS RT=1.30 min, M+H+=311.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39](=[NH:56])[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[CH:43][N:44]2[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:56]=[C:39]([C:40]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:41]=3[CH:42]=[CH:43][N:44]4[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
The 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (113 mg, 0.55 mmol), EDAC (115 mg, 0.60 mmol) and HOBt (82 mg, 0.60 mmol) were dissolved in DMF (5 ml) and left standing for 15 minutes. Added ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg, 0.55 mmol) and stood overnight at RT. Heated solution at 80° C. for 2 hours. LC/MS showed mostly product. After heating for a few more hours there was no change. Added EtOAc (20 ml) and washed with water (30 ml). Washed with saturated sodium hydrogen carbonate (30 ml) and water (2×30 ml). Dried over MgSO4 and evaporated off the solvent to obtain 81 mg of the title compound as a pale brown solid. MS (ES) C25H44N4O4 requires 444; found 445 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[Cl:34][C:32]1[CH:33]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2cc(Cl)cc(Cl)c2)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)c1)C(=O)O
Yield: 4 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3,5-dichloro-phenyl)-5-methyl-oxazole, the title compound was obtained in 4% yield as a pale yellow solid. MS: (M+H)+ 473.1 and 475.2.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[C:13]3[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH:25]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:4]1O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[C:13]3[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH:25]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC1Cc2c(-c3cc4ccccc4c4ccccc34)cccc2C1O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1=Cc2c(cccc2-c2cc3ccccc3c3ccccc23)C1
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 12.3 g (36.3 mmol) of 2-ethyl-1-hydroxy-4-(9-phenanthryl)indane, 19.7 ml (142 mmol) of triethylamine and 61.5 ml of methylene chloride. To the mixture was gradually dropwise added a solution containing 3.3 ml (42.6 mmol) of methanesulfonyl chloride dissolved in 5 ml of methylene chloride under a nitrogen atmosphere at 0° C. After the addition was completed, the temperature was elevated to room temperature, and the reaction mixture was stirred for additional 4 hours. To the reaction mixture was added 80 ml of a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with water, and then a saturated aqueous solution of sodium chloride, followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluting with hexane, and hexane/ethyl acetate (100/3 parts by volume)) to give 9.61 g of the desired product (mixture of two isomers) as a pasty pale yellow-green liquid (yield: 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:7](C)[CH2:6][CH2:5][C@H:4]([CH3:9])[C@H:3]1[CH:10]=[O:11].CC1(C)[C@@H](C)CC[C@H](C)[C@@]21OC2>>[CH3:12][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:9])[C@@H:3]1[CH:10]=[O:11]
Reactant: C[C@H]1CC[C@H](C)C(C)(C)[C@@H]1C=O
Agent: C[C@H]1CC[C@H](C)[C@@]2(CO2)C1(C)C
Product: C[C@H]1CCCC(C)(C)[C@H]1C=O

Procedure:
An optically active enantiomer of 2,2,c-3,t-6-tetramethyl-r-1-cyclohexanecarbaldehyde, i.e., (+)-(1R,3S,6S)-2,2,3,6-tetramethyl-1-cyclohexanecarbaldehyde [containing 10% of its (1S,3S,6S) diastereomer], was prepared in a similar way starting from (+)-(3S,5S, 8S)-4,4,5,8-tetramethyl-1-oxaspiro[2.5]octane described in example 1d.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (290 mg) is dissolved in ethanol (5 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (604 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (277 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (200 μl), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (278 mg). MS (m/z): 691 [M−Na]−
Reaction SMILES: C(N1C2C(=CC=CC=2)C(C2C(O)=C[C:19]3[O:20]COC=3C=2)C1=O)CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:38]1[C:46]([OH:47])=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=1)[C:31](=[O:37])[NH:32]2.BrCC(OCC)=O.C=O>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:38]1[C:46]([OH:47])=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=1)([CH2:19][OH:20])[C:31](=[O:37])[NH:32]2
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCO2
Agent: C=O
Agent: CCOC(=O)CBr
Product: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 31D, and making non-critical variations to replace 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, and ethyl bromoacetate with para-formaldehyde, the title compound was obtained (70%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.00 (br, 1H), 7.13-6.95 (m, 3H), 6.84 (d, 1H), 6.16 (d, 1H), 5.90-5.84 (m, 2H), 5.16-4.83 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.8, 150.4, 147.1, 146.8, 139.8, 130.2, 129.3, 125.8, 117.7, 115.8, 109.3, 107.9, 101.2, 97.6, 63.5, 57.4.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].O>C(Cl)Cl>[CH:1]([C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([O:8][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:4]([O:5][CH3:6])[CH:3]=1)=[O:13]
Reactant: COC(=O)CBr
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)COc1c(OC)cc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a solution of syringaldehyde (3.0 g, 16.5 mmol) in methylene chloride (33 mL, 0.5 M) was added Hunig's base (5.7 mL, 32.7 mmol) and methyl bromoacetate (1.87 mL, 19.8 mmol), and the mixture was stirred for 15 hours at room temperature, followed by addition of H2O. The reaction mixture was then extracted with chloroform, washed with saturated saline, next dried over magnesium sulfate, and evaporated under diminished pressure. The residue was subjected to silica gel chromatography, and a white solid product (3.895 g, 92.9%) was obtained from an ethyl acetate/hexane eluent (1:1.5 v/v). Recrystallization of a portion of the white solid product from ethyl acetate gave a colorless needle-like crystal (m.p. 100 to 102° C.).