Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a stirred mixture of (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.75 g, 9.37 mmol), Et3 N (7.84 ml, 56.2 mmol), DMSO (6.66 ml, 9.37 mmol) in CH2Cl2 (30 ml) at 0° C. was added SO3-pyridine (4.47 g, 28.1 mmol), then the resulting mixture was allowed to raise to room temperature. After 2.5 h stirring, the mixture was concentrated in vacuo. To the resulting mixture was added water and extracted with Et2O. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCl3/acetone (5/1)] to give (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidine carbaldehyde (2.54 g, 93%) as a yellow oil. 1H-NMR (CDCl3) δ 1.45 (s, 9H, one of isomers), 1.49 (s, 9H, one of isomers), 2.17 (br, 2H), 3.65–4.31 (m, 3H), 4.91 (br, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.77 (m, 1H), 7.28 (m, 2H), 9.66 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:21](B1OC(C)(C)C(C)(C)O1)=[CH2:22]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[CH:21]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1)=[CH2:22]
Reactant: Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=Cc1cc(C)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 64.1 %

Procedure:
To 1-bromo-3-methyl-5-(trifluoromethyl)benzene (500 mg, 2.51 mmol) was added THF (5 mL), aqueous tribasic potassium phosphate (2.0 M, 4.18 mL, 8.37 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (387 mg, 2.51 mmol), palladium(II) acetate (47 mg, 0.209 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene (99 mg, 0.209 mmol). The system was flushed with nitrogen gas and was heated at 80° C. for 1 hour. The reaction was filtered and then diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC to yield 1-ethenyl-3-methyl-5-(trifluoromethyl)benzene (300 mg, 1.61 mmol). 1H NMR (500 MHz, CDCl3) δ7.47 (s, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 6.76 (m, 1H), 5.85 (d, J=17.6 Hz, 1H), 2.43 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH2:12][C:13]#[CH:14])=[CH:5][CH:4]=1.[OH-].[Na+].[I:17]I>CO>[I:17][C:14]#[C:13][CH2:12][O:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: C#CCOCOc1ccc(OC)cc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCOCC#CI)cc1
Reaction time: 3 h
Yield: 72 %

Procedure:
1-Methoxy-4-[(2-propynyloxy)methoxy]benzene (Intermediate II-a) (9.8 g, 0.5 mol) prepared in the above example 2 and 48% w/v aqueous sodium hydroxide solution (11.0 g) were added to methanol (75 g). Iodine (14.0 g, 0.055 mol) was then added to the solution in several portions during which the inner temperature was maintained at below 10° C. The reaction mixture was stirred for further 3 hours and the solvent was then evaporated off. The residue was extracted with toluene (20 ml) and the toluene layer was washed with distilled water. Toluene was then evaporated off to obtain the desired 1-[[(3-iodo-2-propynyl) oxy]methoxy]-4-methoxybenzene (Derivative III-a)(12.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](O)=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](=[O:35])[NH:66][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccccc1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC

Procedure:
To a stirring solution of (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (70 mg, 0.138 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42 mg, 0.166 mmol) and triethylamine (77 μL, 0.552 mmol) in CH2Cl2 (3 mL), benzylamine (18 μL, 0.166 mmol) is added. The resulting solution is refluxed for 2 h and then quenched by the addition of aqueous NaHCO3 solution. The organic layer is separated, and the aqueous phase is extracted 3 times with CH2Cl2. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude material is purified by preparative HPLC (C18-ODB-AQ, 5 μm, 20×50 mm, YMC, eluent: CH3CNIH2O+0.1 % HCOOH flow: 20 mL/min). The HPLC fractions are collected and lyophilized to afford the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 598.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.60 min.
Reaction SMILES: COCCOC[O:7][CH:8]([C:10]1[CH:11]=[C:12]([S:19]([NH2:22])(=[O:21])=[O:20])[S:13][C:14]=1[S:15]([CH3:18])(=O)=[O:16])[CH3:9].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>CO>[OH:7][CH:8]([C:10]1[CH:11]=[C:12]([S:19]([NH2:22])(=[O:21])=[O:20])[S:13][C:14]=1[S:15]([CH3:18])=[O:16])[CH3:9]
Reactant: COCCOCOC(C)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(S(N)(=O)=O)sc1S(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a stirred solution of 4-[1-(methoxyethoxymethoxy)ethyl]-5-methylsulfonylthiophene-sulfonamide (6.58 g, 0.0186 mol) in methanol (25 ml) was added dropwise over a 10 minute period a cold solution of 50% (by volume) sulfuric acid. The solution was stirred for an additional 20 minutes at room temperature. The reaction solution was basified with NaHCO3 with cooling and was concentrated to dryness in vacuo at 40° C. bath temperature. The solid residue was extracted with hot ethyl acetate and with 20% methanol/ethyl acetate. Concentration of the extracts in vacuo gave 4.0 g of solid which was purified by chromatography on silica gel using 5% methanol in methylene chloride. There was obtained 3.0 g (60%) of product, m.p. 172-185° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccccc1F
Product: Fc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-fluorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[F:16][C:17]([F:47])([F:46])[C:18]1[CH:19]=[C:20]([CH2:28][CH2:29][N:30]([CH3:45])[C:31](=[O:44])[C@H:32](OS(C)(=O)=O)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(N(CC)CC)C>CC(C)=O>[F:16][C:17]([F:46])([F:47])[C:18]1[CH:19]=[C:20]([CH2:28][CH2:29][N:30]([CH3:45])[C:31](=[O:44])[C@@H:32]([N:9]2[CH2:10][CH2:11][CH:6]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:8]2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=1
Reactant: OCCCN(CC1CC1)C1CCNCC1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](OS(C)(=O)=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](c1ccccc1)N1CCC(N(CCCO)CC2CC2)CC1
Yield: 46.2 %

Procedure:
4.7 g of 4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidine are stirred together with 9.6 g of (R)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared from D-(−)-mandelic acid) and 3.4 ml of triethylamine in 200 ml of acetone for four hours at 65° C. The mixture is evaporated down in vacuo, combined with 100 ml of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic fractions are dried over sodium sulphate and freed from solvent in vacuo. The residue is chromatographed with methylene chloride/methanol 1:1 over silica gel. The uniform fractions according to TLC are collected and the solvents are eliminated in vacuo. 5.5 g of (S)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide are obtained as a yellowish-brown oil, [α]D20=+29.6°
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)=[O:17]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 43.42 g of ethyl 4-aminobenzoate and 40.8 g of 2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in an ice bath and 26.56 g of triethylamine is added dropwise. After the addition, the solution is stirred at room temperature overnight. The mixture is poured into water and the organic layer separted. The organic layer is washed with water, 1N HCl, 1M NaHCO3 and dried over Na2SO4. The solvent is removed and the solid slurried with ethyl acetate and filtered to give 57 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate as crystals, m.p. 110°-115° C. A mixture of 50.7 g of the preceding compound in 280 ml of ethyl alcohol and 55 ml of 10N NaOH is refluxed for 5 minutes. The mixture is cooled to room temperature, diluted with 200 ml of water and acidified with concentrated hydrochloric acid (pH 1-2). The mixture is filtered and the solid washed with water and dried to give 51 g of the desired product as white crystals, m.p. 270°-275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([OH:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2ccc(Cl)cc2CCc2cccnc21
Yield: 80.6 %

Procedure:
To a mixture of 25.03 g (103 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 200 mL of MeOH at room temperature and under a nitrogen atmosphere was added portionwise over a period of about 1 hour 4.82 g (124 mmol) of sodium borohydride. Occasional cooling with an ice bath was necessary at times during the addition in order to avoid excessive reflux. After 1.6 hours the mixture was poured into ice cold water and then extracted with EtOAc (3×). The combined organic portions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized from hot isopropyl ether. The remaining filtrate was purified via flash chromatography (20% EtOAc in hexanes) to yield more product which solidified on standing. Both batches were combined to yield 20.41 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([O:19]CC)=[O:18])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[K+]>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(COCc2ccccc2)nc1O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of step C product (2-d) (10.0 g, crude) in a 3% KOH solution (200 mL) was stirred at 70° C. for 1 h, then cooled to room temperature. The material then washed with DCM (200 mL×2). The aqueous phase was acidified with 5% HCl to pH 1˜2, filtrated and then dried to afford product as a white solid (2-e) (6.2 g, 95% for 2 steps). 1H NMR (300 MHz, CD3OD): δ4.56 (s, 2H), 4.72 (s, 2H), 7.33-7.40 (m, 5H), 8.61 (s, 1H), LC-MS: (M+H)+ 261.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+]([C:13]1[CH:14]=[C:15](S(O)(=O)=O)[CH:16]=[CH:17][CH:18]=1)([O-])=O.P(=O)(O)(O)O.C(=O)/C=C/CCC.O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[C:18]([CH2:17][CH2:16][CH3:15])[CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: Nc1cc(F)ccc1Br
Agent: CCC/C=C/C=O
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: CCCc1ccc2c(F)ccc(Br)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.0 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (65.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, trans-2-hexenal (6.51 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane, and then dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel, followed by drying under reduced pressure to give 625 mg of 8-bromo-5-fluoro-2-propylquinoline as a yellowish white solid (yield: 9.33%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[N:3][CH:4]=1
Reactant: COC(CN)OC
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(CNc1ccc(Br)cn1)OC

Procedure:
After 50 g of 2,5-dibromopyridine and 50 mL aminoacetaldehyde dimethyl acetal were heated at 130° C. for 8 hours, an aqueous saturated sodium bicarbonate solution was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane), to give 23.53 g of the title compound (pale yellow oil).
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:27][CH:28]([CH3:34])[CH2:29][C:30]([NH:32]O)=[NH:31]>CN(C=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([C:12]2[O:14][N:32]=[C:30]([CH2:29][CH:28]([OH:27])[CH3:34])[N:31]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(O)CC(=N)NO
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (500 mg, 2.49 mmol) in 2 mL of DMF at 0° C. was added carbonyldiimidazole (403 mg, 2.49 mmol). The reaction mixture was stirred at room temperature for 30 min, and 3,N-dihydroxy-butyramidine (480 mg, 4.06 mmol) was added as a solution in 2 mL of DMF. The pale yellow, faintly cloudy reaction mixture was stirred at room temperature for 30 min and then heated at 100° C. for 15 h. After cooling to room temperature, the reaction mixture was diluted with 15 mL of water and extracted with 50 mL of ethyl acetate. The organics were washed with 2×15 mL of water and 15 mL of brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford 242 mg (34%) of {1-[3-(2-hydroxy-propyl)-1,2,4-oxadiazol-5-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:40]=[CH:39][C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=CC(CCCCCCCCCC)=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:17]=2[OH:38])=O)=[CH:11][CH:10]=1)[CH2:2]CCCCCC.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44](S(O)(=O)=O)=[CH:43][CH:42]=1>ClC1C=CC=CC=1Cl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:38][C:17]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:2][C:1]([CH2:9][CH2:10][CH2:11][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH3:51])=[CH:24][CH:23]=4)=[CH:21][C:16]=3[N:15]=2)=[CH:39][CH:40]=1)[CH2:2][CH2:19][CH2:18][CH2:17][CH2:16][CH2:21][CH3:20]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)c(NC(=O)c3ccc(CCCCCCCC)cc3)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCc1ccc(-c2ccc3oc(-c4ccc(CCCCCCCC)cc4)nc3c2)cc1
Reaction time: 0.67 h
Yield: 156.8 %

Procedure:
Step iv) In a 50 ml-round-bottomed flask, 1.30 g (2.40 mM) of 2-(4-octylbenzoylamino)-4-(4-decylphenyl)phenol, 0.13 g (0.68 mM) of p-toluenesulfonic acid and 20 ml of o-dichlorobenzene were placed, followed by stirring for 40 min. at 189°-192° C. After the reaction, o-dichlorobenzene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 0.62 g of 2-(4-octylphenyl)-5-(4-decylphenyl)benzoxazole (yield: 49.3%). ##STR19##
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][C@@H:4]1[C:10]([O:12][CH3:13])=[O:11].[BH4-].[Na+]>CO.[NH4+].[Cl-].C(OCC)(=O)C>[OH:9][C@@H:7]1[CH2:6][CH2:5][C@H:4]([C:10]([O:12][CH3:13])=[O:11])[C@H:3]([O:2][CH3:1])[CH2:8]1
Reactant: COC(=O)[C@H]1CCC(=O)C[C@H]1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@H](O)C[C@H]1OC
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of methyl (1S,2R)-2-methoxy-4-oxocyclohexanecarboxylate (racemic, cis-isomer from last step) (1.35 g, 7.25 mmol) in methanol (30 mL) was added sodium tetrahydroborate (270 mg, 7.2 mmol) at −78° C. After stirring for 1 h, the reaction was diluted with sat. NH4Cl solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified with flash chromatography (eluting with 70% ethyl acetate in hexanes) to give the desired product (1.26 g, 92%). 1H NMR (500 MHz, CDCl3) δ 3.96 (2H, m), 3.72 (3H, s), 3.38 (3H, s), 2.45 (1H, m), 2.31 (1H, m), 2.11 (1H, m), 1.97 (1H, m), 1.77 (1H, m), 1.50 (2H, m) ppm.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:31])=O>>[Cl:31][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 60 %

Procedure:
Dimethylformamide (2.0 ml) was added dropwise to a solution of 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydro-quinazolin-4-one (83.0 g, 261 mmol) in thionyl chloride (700 ml) and the reaction was heated at reflux for 3.5 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo, the residue was taken up in water (500 ml) and this aqueous solution was taken to pH 9 by addition of saturated aqueous sodium bicarbonate solution (300 ml). The aqueous phase was extracted with dichloromethane (2×400 ml), the organic solution was washed with brine (400 ml) and the solvents were removed in vacuo. Trituration of the solid residue with ethyl acetate (150 ml), followed by drying in vacuo, yielded 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (53 g, 60% yield) as a pale brown solid:
Reaction SMILES: CC1CC(C)CN(C2N=CC=CC=2C(O)=[O:12])C1.ON1C2C=CC=CC=2N=N1.Cl.C(OC(=O)C1C=CC(CCN)=CC=1OC)C.[CH:45]1([N:51]=[C:52]=[N:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C)C=O.C(N(CC)CC)C>[C:52]([NH:51][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1)([NH:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)=[O:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1CC(C)CN(c2ncccc2C(=O)O)C1
Agent: CCOC(=O)c1ccc(CCN)cc1OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
5.85 g of 2-(3,5-dimethylpiperidino)-nicotinic acid (prepared from 2-chloronicotinic acid and 3,5-dimethylpiperidine) were dissolved in 25 ml of dimethylformamide. After the addition of 10.41 g of 1-hydroxybenzotriazole (32.4%), 6.5 g of 4-(2-aminoethyl)-2-methoxybenzoic acid ethyl ester . hydrochloride, 6.92 ml of triethylamine and 6.18 g of dicyclohexylcarbodiimide the mixture was stirred for 30 minutes at 50° C. and left to stand overnight at room temperature. Dicyclohexylurea obtained was suction-filtered and washed with 25 ml of dimethylformamide. The combined filtrates were poured into 250 ml of ice-water. Extraction three times with 100 ml of ethyl acetate each time, washing of the acetic ester phase with sodium dicarbonate solution and water and concentration in vacuo gave the ethyl 4-(2-<2-(3,5-dimethylpiperidino)-pyridine-3-carboxamido>ethyl)-2-methoxybenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:31]=[C:32]=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:32]([NH:31][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:33])=[CH:20][CH:21]=1
Reactant: CCCCCCCCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, octyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 2 hours. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 32 mg of the title compound (yield: 41%).