Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH3:17])[CH:3]=1.[Cl-].[CH:19]1([Zn+])[CH2:21][CH2:20]1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([Si:7]([O:6][C:5]1[C:14]([CH3:16])=[CH:15][C:2]([CH:19]2[CH2:21][CH2:20]2)=[CH:3][C:4]=1[CH3:17])([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: [Zn+]C1CC1
Reactant: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy)tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12](Cl)([Cl:14])=[O:13]>ClCCl>[Cl:14][C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl anthranilate (6.0 g) in dichloromethane (50 ml) was added dropwise over 15 min to a 0° solution of phosgene (20% in toluene, 100 ml) in dichloromethane (50 ml) under a nitrogen atmosphere. After addition the resulting opaque solution was stirred at room temperature for 5 h before concentrating to dryness to give the title compound as a white solid (8.0 g), m.p. 80°-82°.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([NH:9][NH2:10])=[O:8].[C:15](=S)=[S:16]>O.C(O)C>[SH:16][C:15]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][C:13]([OH:14])=[C:4]([OH:3])[CH:5]=2)=[N:9][N:10]=1
Reactant: NNC(=O)c1ccc(O)c(O)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1ccc(-c2nnc(S)o2)cc1O
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
19.8 g (0.353 mol) of potassium hydroxide was dissolved in 5.1 ml of water and 830 ml of ethanol, and 39.6 g (0.236 mol) of 3,4-dihydroxybenzohydrazide and 99 ml (1.65 mol) of carbon disulfide was added thereto. The mixture was heated for 24 hours under reflux. The reaction solution was stirred for 1.5 hours under cooling with ice. The precipitated crystals were collected by filtration and washed with 200 ml of ethanol. The crystals were dissolved in 3 liter of water and adjusted to pH1.5 with 6N hydrochloric acid under cooling with ice. The solution was extracted with 1 liter of ethyl acetate and 400 ml of ethyl acetate. The organic layers were put together, washed twice with 300 ml of a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 42.8 g (yield: 86.5%) of 2-mercapto-5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole.
Reaction SMILES: BrC1C=CC([C@](CC=O)(C(O)CCCCCCCCCC(C)C)C([O-])=O)=CC=1.[OH:29][C@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:31][C:32]([O:34][CH3:35])=[O:33].O[Li].O.C1CCC(NC2CCCCC2)CC1.BrC[C:68]([C:70]1[CH:75]=[CH:74][C:73]([Br:76])=[CH:72][CH:71]=1)=[O:69]>>[OH:29][C@H:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:31][C:32]([O:34][CH2:35][C:68]([C:70]1[CH:75]=[CH:74][C:73]([Br:76])=[CH:72][CH:71]=1)=[O:69])=[O:33]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COC(=O)C[C@H](O)CCCCCCCCCCCC(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)CCCCCCCCCC(O)[C@](CC=O)(C(=O)[O-])c1ccc(Br)cc1
Agent: [Li]O
Solvent: O
Product: CC(C)CCCCCCCCCCC[C@@H](O)CC(=O)OCC(=O)c1ccc(Br)cc1
Yield: 89.8 %

Procedure:
In a manner similar to the synthesis of 116, compound 115 (960 mg, 3.2 mmol) was hydrolyzed with LiOH.H2O (202 mg, 4.8 mmol), recrystallized by refluxing with DCHA (0.76 mL, 3.84 mmol) and protected by reacting with 2,4′-dibromoacetophenone (979 mg, 3.52 mmol) to afford 118 as an amorphous solid (1.39 g, 90%). Rf=0.35 (DCM); [α]25D=−1.2° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.74 (d, 2H, J=8.4 Hz, aromatic), 7.60 (d, 2H, J=8.4 Hz, aromatic), 5.39 (d, 1H, J=16.5 Hz, CH′2a), 5.29 (d, 1H, J=16.5 Hz, CH′2b), 4.08 (m, 1H, H-3), 2.65 (dd, 1H, J2a,2b=15.0 Hz, J2a,3=3.0 Hz, H-2a), 2.54 (dd, 1H, J2a,2b=15.0 Hz, J2b,3=9.0 Hz, H-2b), 1.58-1.46 (m, 3H, H-4, H-15), 1.24-1.13 [m, 20H, H-(5-14)], 0.83 (d, 6H, J15,16=6.6 Hz, H-14). 13C NMR (75 MHz, CDCl3): δ 191.60 (C═O), 171.86 (C═O), 132.49-129.24 (m, aromatic), 68.38 (C-3), 65.74 (C-2′), 41.96 (C-2), 39.00 (C-14), 36.54 (C-4), 22.61 (C-16). HR MS (m/z) calculated for C25H39BrO4 [M+Na]+, 505.1924. found, 505.1160.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[CH3:26][N:27]([CH3:37])[C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:26][N:27]([CH3:37])[C:28](=[O:36])[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[NH:17][S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:34][CH2:35]1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: O=S(=O)(Nc1cccc2cc(-c3ncc(CCl)s3)[nH]c12)c1cccs1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.2 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.250 g) in N,N-dimethylformamide (6 ml) were added N,N-dimethyl-2-piperazin-1-ylacetamide (0.208 g) and triethylamine (0.17 ml), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and recrystallized from ethyl acetate-hexane to give the title compound (0.230 g, yield 69%) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Br:33])=[O:21])[CH2:2][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][CH2:17][CH3:18].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>C1(C)C=CC=CC=1>[Br-:33].[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[O:21])[CH2:2][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][CH2:17][CH3:18]
Reactant: c1ccnnc1
Reactant: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: C=C(COC(=O)CCCCC[n+]1ccccn1)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: [Br-]
Temperature: 64 °C
Reaction time: 20 h

Procedure:
1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (from Preparation 9) (0.28 g) was dissolved in toluene (5 ml). Pyridazine (0.18 ml) was added, and the mixture was stirred at 64° C. for 20 hours. The mixture was evaporated to dryness in vacuo to give the desired product.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[C:12](Cl)(=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.CCOCC.CCOC(C)=O>[CH2:14]([O:13][C:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1)=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 5 °C
Yield: 111.4 %

Procedure:
A 500-mL 4-necked round-bottom flask was charged with a solution of NaOH (8 g, 198.00 mmol, 1.00 equiv, 99%) in H2O (200 mL). To this was added piperidine-3-carboxylic acid (25.8 g, 197.75 mmol, 1.00 equiv, 99%), in small portions at 0° C. Then, a solution of benzyl carbonochloridate (39.2 g, 227.48 mmol, 1.15 equiv, 99%) in Et2O (50 mL) was added at 0° C. over 40 minutes. Then a solution of NaOH (12 g, 1.50 equiv) in H2O (300 mL) was added drop wise with stirring at 0-10° C. The resulting solution was allowed to stir overnight at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1/1). The pH adjusted to 3 with 10% aqueous HCl. The resulting solution was extracted with ethyl acetate (3×500 mL). Combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to afford 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (58 g) as white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)#[N:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:8])[CH:21]=1)#[N:29]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 100 mg, 0.224 mmol) was dissolved in DMF (1.5 mL). 4-Cyanopyridine-3-boronic acid pinacol ester (77 mg, 0.336 mmol), K2CO3 (0.224 mL, 0.448 mmol) and Pd(PPh3)4 (12.95 mg, 0.011 mmol) were added at RT. The vial was evacuated/purged with argon and sealed. The light yellow solution was stirred at 130° C. for 4 h. The yellow reaction solution was diluted with EtOAc (50 mL) and washed with water (3×30 mL). the combined extracts were dried over Na2SO4, filtered, the solvent was evaporated off under reduced pressure to give a crude that was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 95:5). The fractions containing product were evaporated to dryness under reduced pressure and the residue was dissolved in hot MeOH (2 mL). The yellow solution was allowed to cool down to RT under stirring and the resulting suspension was stirred at RT for 1 h then filtered. The solid was washed with MeOH (1 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=5.91 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=470 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.97 (m, 2H) 2.84 (d, J=10.95 Hz, 1H) 3.07-3.18 (m, 1H) 3.19-3.30 (m, 1H) 3.32-3.45 (m, 1H) 4.21 (br. s, 1H) 4.82-5.00 (m, 1H) 7.36 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 7.94-8.05 (m, 1H) 8.12 (d, J=6.26 Hz, 1H) 8.80-8.90 (m, 2H) 9.03 (s, 1H) 10.21 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH2:13])=[CH:10][CH:11]=2)[N:6]=1.[C:14](OCC)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: NCc1ccc(-c2csc(N)n2)s1
Reactant: CCOC(=O)c1cccnc1
Solvent: CCO
Product: Nc1nc(-c2ccc(CNC(=O)c3cccnc3)s2)cs1

Procedure:
To a solution of 4.0 g of 2-amino-4-(5-aminomethyl-2-thienyl)thiazole in 100 ml of ethanol is added 2.85 g of ethyl nicotinate, and refluxed for 8 hours. After the reaction mixture is cooled with ice, the precipitated crystals are collected by filtration and recrystallized from dimethylformamide to give 2-amino-4-(5-nicotinoylaminomethyl-2-thienyl)thiazole, melting at 240°-241° C. with decomposition.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1C=CC=CC=1.O>[Cl:8][C:7]1[C:2]([O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][O:20]3)=[O:18])=[CH:25][CH:26]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)N1CCCO1
Temperature: 120 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 2,3,5-trichloropyridine (18.3 g), N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 120° C. for 4 hours. To the reaction mixture, after cooling, were added water and benzene whereby to form two layers. The organic layer so separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionyl]isoxazolidine (31.4 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 105.5°-107.5° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)(=[O:9])[CH3:8]>>[CH3:15][C:13]1[N:14]=[C:10]([C:7]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)([OH:9])[CH3:8])[O:11][CH:12]=1
Reactant: CC(=O)c1nc(C)co1
Reactant: Brc1nccs1
Product: Cc1coc(C(C)(O)c2nccs2)n1

Procedure:
From 2-bromothiazole and 2-acetyl-4-methyloxazole (J. Chem. Soc., Chem. Commun., 1984, 258).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=1
Reactant: Cc1ccc(F)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cc(F)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 11.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (3.1 g, 8.5 mmol) and DMAP (0.54 g) in dry CH2Cl2 (45 mL), Et3N (2.58 g, 3.6 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (4.0 g, 43 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water (50 mL). The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with 10% citric acid (2×50 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (400 mg, HPLC≧98%). 1H NMR (CDCl3) δ 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 4.4 (m, 1H), 4.1 (m, 1H), 3.7 (m, 1H), 3.6 (s, 3H), 3.2 (m, 2H), 2.9 (m, 2H), 2.3 (s, 3H), 1.75 (m, 1H), 1.6 (m, 1H), 1.4 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OCC)([O:9]CC)[CH3:8])=[N:4][CH:3]=1.FC(F)(F)C(O)=O.O>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1
Reactant: CCOC(C)(OCC)c1ncc(Br)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a solution of the product of Step 2 (981 mg, 3.50 mmol) in dichloromethane (4 mL) at room temperature, under nitrogen, were added trifluoroacetic acid (6.204 mL, 81 mmol) and water (208 μL, 11.55 mmol). The mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and was washed with 5% aqueous sodium bicarbonate (3×) and brine, dried (sodium sulfate) and concentrated to give 1-(5-bromo-1,3-thiazol-2-yl)ethanone (654 mg, 3.17 mmol, 91% yield) as a yellow solid that was used without further purification.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:23]([C:22]2[CH:17]=[CH:18][C:19]3[O:27][CH2:26][O:25][C:20]=3[CH:21]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCO3)c2cc3c(cc21)OCO3
Yield: 41 %

Procedure:
The title compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)phenyl]urea and piperonal by the procedure described in example 10 in 41% yield, mp: 87-89° C. 1H NMR (CDCl3,): 6.77 (s, 3H), 6.68 (s, 1H), 6.28 (s, 1H), 5.96 (s, 2H), 5.92-5.90 (m, 2H), 5.22 (d, J=1.8, 1H), 4.98 (br s, 1H), 4.44 (m, 2H), 1.58-1.54 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=O)=[CH:16][C:3]1=2.[CH3:21][N:22](C=O)[CH3:23].S(Cl)(Cl)=O.N(C)C>C(#N)C>[CH3:21][N:22]([CH3:23])[C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: CNC
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 2.5 °C
Yield: 60 %

Procedure:
8 g (0.029 moles) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid were dissolved in 30 ml of acetonitrile and 0.15 ml of DMF were added to this solution. 2.3 ml (0.032 moles) of thionyl chloride were added to the resulting solution at 20-25° C. Once the reaction had ended, the reaction mixture is slowly poured over an aqueous solution of 40% Me2NH (14.4 g, 0.32 ml) cooled at 0-5° C. and stirring was maintained at this temperature for 30 minutes. Subsequently, the organic part was distilled under reduced pressure and 80 ml of methylene chloride were added. The phases were decanted, separating the organic phase. The solvent was distilled, obtaining an oil with the product of the title with a yield of 60%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:16]C1C=CC(C(O)=O)=C(OC)C=1.N[C:29]1[C:34]([NH2:35])=[CH:33][CH:32]=[CH:31][N:30]=1>P(Cl)(Cl)(Cl)=O>[ClH:15].[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:16][C:33]2=[CH:32][CH:31]=[N:30][CH:29]=[C:34]2[N:35]=1
Reactant: COc1cc(N)ccc1C(=O)O
Reactant: Nc1cccnc1N
Reactant: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2cnccc2[nH]1
Product: Cl
Temperature: 80 °C

Procedure:
Five grams of 2-methoxy-4-chlorosulfonyl-benzoic acid (prepared from 4-amino-2-methoxy-benzoic acid via the corresponding diazonium compound) were dissolved in 400 ml of phosphorus oxychloride and heated to 80° C. for 30 minutes. Then, 3.6 gm of 2,3-diaminopyridine were added, and the mixture was refluxed for four hours. The reaction mixture was concentrated by evaporation in vacuo and re-evaporated with toluene, and the solid residue was processed further without any other purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[O:29])[CH:20]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)c1cccc(-c2cccnc2)c1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3cccnc3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-3-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g crude 3-(pyridin-3-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 mg, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added 3-(pyridin-3-yl)benzoyl chloride (1.5 g, 7 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.