Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14](OC)=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].OB(O)[C:21]1[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][N:37](C=O)[CH3:38]>O>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[C:14]([N:37]([CH3:38])[CH3:36])[CH:15]=[CH:16][C:2]=1[C:21]1[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CN(C)c1ccc(-c2ccc(C(=O)O)s2)c(CNC(=O)OC(C)(C)C)c1
Temperature: 100 °C

Procedure:
A solution of tert tert-butyl (2-bromo-5-methoxybenzyl)carbamate (0.226 g, 0.69 mmol), 5-(dihydroxyboryl)thiophene-2-carboxylic acid (0.118 g, 0.69 mmol) and cesium carbonate (0.492 g, 1.51 mmol) in DMF (2 mL) and water (1 mL) was degassed. To this solution was added PdCl2dppf (1:1 complex with DCM, 0.020 g, 0.03 mmol). The reaction mixture was heated at 100° C. for 36 hr and then allowed to cool to rt and concentrated. The residue was suspended in acetonitrile (15 mL) and MeOH (2 mL) containing 0.1% TFA and adsorbed onto celite and purified by reverse phase chromatography to give a mixture of the desired product and remaining starting material. This mixture was suspended in half-saturated sodium bicarbonate solution (10 mL) and washed with EtOAc (20 mL). The organic solution was extracted with half-saturated sodium bicarbonate solution until no product was apparent in the organic solution. The pH of the aqueous solution was adjusted to 5 with 1N HCl and then was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 5-[2-{[(tert-butoxycarbonyl)amino]methyl}-4-(dimethylamino)phenyl]thiophene-2-carboxylic acid (0.036 g, 13%) as a yellow oil. LCMS: (AA) ES+ 377.2, ES-375.3.
Reaction SMILES: FC(F)[C:3]1[N:7](C2N=C(N3CCOCC3)N=C(OC3CCN(C(OC(C)(C)C)=O)CC3)N=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37](OC)[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:4]1[C:5]2[CH:37]=[CH:36][CH:35]=[CH:34][C:6]=2[N:7]=[CH:3]1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2[nH]cnc2c1

Procedure:
Treatment of tert-butyl 4-(4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate (112 mg, 0.2 mmol) with TFA (5 mL) in CH2Cl2 (10 mL), followed by quenching with aqueous NH3 gave 2-(difluoromethyl)-4-methoxy-1-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole: 1H NMR (DMSO-d6) δ 7.96 (dd, J=8.4, 0.5 Hz, 1H), 7.71 (t, JHF=52.8 Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 5.11 (m, 1H), 3.98 (s, 3H), 3.83 (m, 4H), 3.71 (m, 4H), 3.00 (m, 2H), 2.62 (m, 2H), 2.00 (m, 2H), 1.58 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOCC.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:6]2[CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(Br)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 106A (5.5 g) in N,N-dimethylformamide (60 mL) was added 1-(3-bromopropoxy)naphthalene (5.4 g) and Cs2CO3 (22 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether twice. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration of the mixture gave crude product, which was purified by flash chromatography (2% ethyl acetate in hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[NH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOCC.O1CCOCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:17]2[C:16](=[O:32])[NH:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1[nH]n(C2CCNCC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Reaction time: 2.25 h

Procedure:
To a solution of 4-[4-(4-Chloro-phenyl)-3-oxo-5-pyridin-4-yl-2,3-dihydro-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 200 mg in flask was added HCl in ether and dioxane. After 2.25 hours, the solvent was evaporated under reduced pressure to afford the title compound as yellow oil. MS (ES+): 355 (M+H)+; (ES−): 353 (M−H).
Reaction SMILES: CO[C:3]1[C:4]2[CH2:12][N:11]([C:13]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=3[C:15]#[N:16])[CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.CN(C)C1C=CC=CC=1.CN(C)C=O.P(Cl)(Cl)([Cl:38])=O.[OH-].[Na+]>C(#N)C>[Cl:38][C:3]1[C:4]2[CH2:12][N:11]([C:13]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=3[C:15]#[N:16])[CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncnc2c1CN(c1ccc(C)cc1C#N)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-(4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (4.15 g, 14.1 mmol), N,N-dimethylaniline (0.181 mL, 1.4 mmol), N,N-dimethylformamide (0.21 mL, 2.7 mmol) and acetonitrile (35 mL) was heated to dissolve at 105° C. Phosphoryl chloride (5.3 mL, 56 mmol) was added dropwise over 3 mins, and the reaction was heated to reflux at 110° C. After 40 mins, additional phosphoryl chloride (5.3 mL, 0.056 mol) was added dropwise over 3 mins. After another 20 hours, 1H NMR showed that the reaction was ca 70% complete and the reaction mixture was allowed to cool and poured over ice (200 g) and 45% aq. NaOH (75 mL) was added. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column (0-100% EtOAc/hexane) to yield a brown oil which became a solid in the freezer.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCOc1ccccc1CO
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccccc1CBr
Temperature: 0 °C

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 21, 10 ml acetonitrile, 2.11 g of phosphorus tribromide and 0.339 g of pyridine. The reaction is cooled for 10 minutes at 0° C., followed by stirring at room temperature for i hour. The product, 2.58 g, is obtained as cream crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][CH2:7][CH3:8])=[O:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1/[C:14](=[N:18]/[OH:19])/[C:15]([OH:17])=[O:16]>CS(C)=O>[CH2:7]([O:6][NH:5][C:3]([CH2:2][O:19]/[N:18]=[C:14](/[C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)\[C:15]([OH:17])=[O:16])=[O:4])[CH3:8]
Reactant: CCONC(=O)CCl
Reactant: O=C(O)/C(=N\O)c1ccco1
Solvent: CS(C)=O
Product: CCONC(=O)CO/N=C(\C(=O)O)c1ccco1
Yield: 81 %

Procedure:
This compound was prepared from ethyl chloroacetohydroxamate and Z-2-(fur-2-yl)-2-hydroxyimino acetic acid by the method described in Preparation 4, τ(DMSO d6) 2.15, 3.2, 3.39 (furyl), 5.48 (--OCH2CO--), 6.18 (--OCH2 --), 8.88 (--CH3). Yield 81%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1.[CH2:13]=[O:14]>>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][OH:14])=[N:10][CH:11]=1
Reactant: COCOCc1ccc(C)nc1
Reactant: C=O
Product: COCOCc1ccc(CCO)nc1
Yield: 32.8 %

Procedure:
A mixture of 5-methoxymethoxymethyl-2-methylpyridine (30.5 g) and formalin (37% aq., HCHO, 22.2 g) was heated in a sealed tube at 150° to 160° C. for 8 hours. The reaction mixture was concentrated under reduced pressure and the oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (20:1, v/v) gave 2-(5-methoxymethoxymethyl-2-pyridyl)ethanol (11.8 g, yield: 33%) as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26](Cl)=[N:27]OS(C)(=O)=O)=[CH:24][CH:23]=1.CN(C)CCN(C)C.O>O1CCCC1>[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]2[NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:6][C:7]=3[N:27]=2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)ON=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc3[nH]c(-c4ccc(F)cc4)nc3c2)C1
Yield: 38.6 %

Procedure:
A solution of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (140 mg, 0.5 mol), 4-fluoro-N-(methylsulfonyloxy)benzimidoyl chloride (152 mg, 0.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (123 mg, 1.06 mmol) in tetrahydrofurane (0.8 ml) was shaken in a closed vial at 60° C. overnight. Water was added, and the mixture was extracted twice with ethyl acetate. The cobined organic layers were dried (MgSO4) and evaporated. Flash chromatography (10 g silica gel, 10 to 30% ethyl acetate in heptane) yielded a white solid (92 mg, 46%), MS (ISP): 398.2 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[CH2:8]([CH:10]1O[CH2:11]1)[Cl:9]>>[Cl:9][CH2:8][C@@H:10]1[O:4][CH2:3][C@@H:2]2[CH2:5][CH2:6][CH2:7][N:1]2[CH2:11]1
Reactant: OC[C@@H]1CCCN1
Reactant: ClCC1CO1
Product: ClC[C@H]1CN2CCC[C@H]2CO1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(S)-(+)-Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47 mL, 600 mmol) at 0° C. The solution was stirred at 40° C. for 0.5 h and then concentrated in vacuo. The residual oil was cooled in an ice bath and concentrated sulfuric acid (18 mL) was added dropwise with stirring. The mixture was heated at 170-180° C. for 1.5 h, poured into ice (300 mL) and then basified with sodium carbonate to pH-8. The mixture was partitioned with ethyl acetate/hexanes and filtered. The filtrate was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford oil that was purified by column chromatography (ethyl acetate for less polar product and then 30% methanol in ethyl acetate). (3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (less polar product) (1.87 g, 10.7 mmol, 18% yield): 1H NMR (400 MHz, CDCl3): 4.06 (dd, 1H), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15 (dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+). (3R,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (1.54 g, 8.77 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 3.94-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:21]1[C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:26]([C:25]1[C:21]([C:15]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[N:22][O:23][C:24]=1[CH3:29])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCNC(=O)OC(C)(C)C
Yield: 100.4 %

Procedure:
N-t-butyloxycarbonyl-1,3-diaminopropane (574 mg, 3.29 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (903 mg, 3.29 mmol) were converted to 1.36 g of the title compound by the procedure of Preparation 1. (100%). EA calculated for: C19H23N3O4ClF: C, 55.41; H, 5.63; N, 10.20. Found: C, 55.17; H, 5.71; N, 9.99. MS(IS) m/z 412 (M+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](Cl)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>CC(O)C.CO>[NH2:2][C:3]1[N:4]=[C:5]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([Br:17])[CH:19]=2)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1
Reactant: Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 2-amino-4-chloroindolo[2,3-d]pyrimidine hydrochloride (123 mg, 0.6 mmol) and 3-bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is heated at reflux for 4 hr, filtered through a celite pad, and concentrated in vacuo. The residue is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous phase is extracted with further ethyl acetate (2×20 mL), followed by washing the combined extracts with 1% aqueous sodium hydroxide (25 mL), water (2×40 mL), saturated brine (40 mL), and drying (Na2SO4). The solution is evaporated to dryness under reduced pressure to afford 105 mg crude product as a tan powder. The solid is dissolved in a minimum amount of methanol, filtered, and further purified by preparative plate chromatography (SiO2 ; 1:1, EtOAc: CH2Cl2 ; Rf =0.40 ). After extraction of the product from the silica gel with ethyl acetate, the volume of the warm solution is reduced to minimum, and it is filtered through celite, and the solvent is removed under reduced pressure. The oily solid thus obtained is dissolved in a minimum amount of 2-propanol and allowed to crystallize at 3 C. over an 18 h period. The crystals are collected by suction filtration, washed with a small amount of cold 2-propanol, and dried in vacuo to give 2-amino-4-(3-bromoanilino) indolo[2,3-d]pyrimidine (34 mg, 17%). 1 HNMR, (DMSO): δbrs), 8.57 (1H, s), 8.11 (1H, d, J =8.0 Hz), 8.01 (1H, s), 7.94 (1H, d, J=8.2 Hz), 7.34-7.12 (5H, m), 6.41 (2H, brs).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18].O>CN(C=O)C>[F:12][C:2]([F:11])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:16][C:17]([OH:19])=[O:18])[CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1cc(C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COCc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [4-(trifluoromethyl)pyridin-2-yl]methanol (340 mg, 1.9 mmol) in DMF (10 mL) was added sodium hydride (150 mg, 3.8 mmol). After being stirred at room temperature for 5 min. 1,1-dimethylethyl bromoacetate (0.28 mL, 1.9 mmol) was added. Stirring was continued at room temperature for 1 h. Water (20 mL) was added and the resulting solution was extracted with EtOAc. The water layer was neutralized to pH=5 with HCl and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum to give the title compound which was used for the next reaction without purification. MS (M+H) 292.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[C:25]([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][CH2:33][CH:34]=[CH2:35]>CN(C=O)C.CC(OC)(C)C>[CH3:25][O:16][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:32][CH2:33][CH:34]=[CH2:35])[CH:13]=1
Reactant: C=CCCBr
Reactant: O=C([O-])[O-]
Reactant: COc1cc(NC(=O)OCc2ccccc2)cc(C(=O)O)c1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C=CCCN(C(=O)OCc1ccccc1)c1cc(OC)cc(C(=O)OC)c1
Temperature: 40 °C

Procedure:
A mixture of 0.75 g (2.38 mmol) 3-benzyloxycarbonylamino-5-methoxy-benzoic acid, 1.07 g (2.85 mmol) NaI, 2.3 g (7.14 mmol) Cs2CO3 and ca. 1 ml (10 mmol) 4-bromo-but-1-ene in 2 ml DMF is heated at 40° C. for 18 h. After cooling down the reaction mixture is diluted with TBME and washed with water. The organic phase is dried with sodium sulfate and evaporated. Purification of the crude product by chromatography on silica gel (hexane EtOAc 5:1) gives the 3-(benzyloxycarbonyl-but-3-enyl-amino)-5-methoxy-benzoic acid methyl ester.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:12]=1.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH:12]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Agent: Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride and benzyl isocyanate were reacted as described in Example 2, Step 3, to provide {5-[2-(3-benzyl-1-ethyl-ureidomethyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester. The ester was hydrolyzed to the acid as described in Example 12, Step 4.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([NH:14][C:15](=[O:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[C:18](Cl)(=[O:20])[CH3:19]>ClC(Cl)C>[C:18]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([NH:14][C:15](=[O:17])[CH3:16])([CH3:5])[CH3:7])=[CH:13][CH:12]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)NC(C)(C)c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Aluminum chloride (41.5 g) was portionwise added to a solution (75 ml) of N-(1-methyl-1-phenylethyl)acetamide (25 g) and acetyl chloride (16.6 g) in dichloroethane under ice-cooling. The mixture was stirred at said temperature for 1 hour and then at 50°-60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure to give crystals which were then recrystallized from ethyl acetate-isopropyl ether to give 20.4 g of N-(1-(4-acetylphenyl)-1-methylethyl)acetamide.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][NH:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:21]([O:30]N1C(=O)CCC1=O)([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=O>CC(C)=O.O>[C:10]([O:9][C:8]([NH:7][C@H:3]([CH2:4][N:5]([CH3:6])[C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[CH2:2][OH:1])=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CNC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of crude tert-butyl (R)-3-hydroxy-1-(methylamino)propan-2-ylcarbamate in acetone (30 mL) and water (10 mL), there was added K2CO3 (12.8 g, 92.4 mmol), followed by Teoc-OSu (8.0 g, 30.8 mmol). The resulting mixture was stirred at rt until no starting material remained (˜1 h). Acetone was removed under vacuum and the aqueous residue was extracted with CH2Cl2 (4×15 mL). The combined organic layers were concentrated and the crude residue was purified by flash column chromatography to give (2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol (2.12 g, 20% steps). 1H NMR (400 MHz, CDCl3): 5.08 (br, 1H), 4.14 (m, 2H), 3.66-3.42 (m, 4H), 3.02 (m, 1H), 2.90 (s, 3H), 1.40 (S, 9H), 0.98 (m, 2H), 0.02 (s, 9H); MS m/z 349 (M+H+).
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].[CH:7]([N:10]=[N:11][C:12]1(Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])[CH3:8].O>CO>[CH:7]([N:10]=[N:11][C:12]1([S:3][CH2:4][CH2:5][OH:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])[CH3:8]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N=NC1(SCCO)CCCCC1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4.8 grams (.06 moles) of 50% sodium hydroxide in 60 ml of methanol in a 125 ml erlenmeyer flask was added 5.46 grams (.07 moles) of 2-mercaptoethanol while holding the reaction temperature below 25° C. After the addition was complete, the mixture was stirred for 20 minutes at 10° C. and 9.5 grams (0.05 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise over 25 minutes while holding the temperature below 15° C. After the addition was complete, the reaction was stirred an additional 60 minutes at 5° to 15° C. A .02 mole portion of 50% sodium hydroxide was added, the reaction stirred an additional 10 minutes, poured into 200 ml of water and the product extracted into 100 ml of pentane. The pentane solution was separated and washed successively with 50 ml portions of 5% HCl, water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid weighing 8.5 grams (74% crude yield). The infrared spectrum was in agreement with the structure of 1-isopropylazo-1-(β-hydroxyethylthio)cyclohexane (absence of carbon-chlorine band at 800-825 cm-1 and presence of a strong OH band at 3325 cm-1.)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH2:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:25][N:26]([CH:28]=O)[CH3:27]>C(Cl)Cl>[CH3:25][N:26]([CH:28]=[N:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH2:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:27]
Reactant: CN(C)C=O
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OCC
Temperature: 55 °C

Procedure:
To a stirred solution of methyl 2-amino-4,5-diethoxybenzoate (4.79 g, 20 mmol) in 20 ml of DMF at 0° C. was added phosphorous oxychloride (2.24 ml, 24 mmol) during 15 m. The mixture was warmed to 55° C. and stirred for 45 m. The resulting solution was diluted with methylene chloride, cooled to 0° C., and treated with 80 ml of precooled N/1 sodium hydroxide during 5 m. The organic layer was separated and washed at 0° C. with with water. The solution was dried and concentrated to give an amber oil; NMR (CDCl3) δ 3.00(s, Me2N).