Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:14][C:15]1[C:19]([N:20]=[C:21]=[O:22])=[C:18]([CH3:23])[O:17][N:16]=1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:21]([NH:20][C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:23])=[O:22])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Cc1noc(C)c1N=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 48.2 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.23 mmol) and 3,5-dimethylisoxazol4-yl isocyanate (31 mg, 0.23 mmol) in 1.0 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (40 mg, 49%). LC-MS (m/z) 361.0 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[I-].[K+].II>C(O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: Sc1ccccc1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Brc1cccc2[nH]cc(Sc3ccccc3)c12
Temperature: 45 °C
Yield: 99.6 %

Procedure:
A stirred solution of 4-bromo-1H-indole (4.69 g, 23.9 mmol) in ethanol (110 mL) was added thiophenol (2.46 mL, 23.9 mmol). A solution of potassium iodide (3.97 g, 24 mmol) and iodine (6.07 g, 24 mmol) dissolved in water (5 mL) and ethanol (5 mL) is added over 5 minutes and the reaction was heated at 45° C. for 12 hours. The brown reaction is concentrated in vacuo to a dark brown oil and diluted with ethyl acetate (250 mL). The organic layer is washed with water (80 mL×2), saturated Na2S2O3 (80 mL), and brine (80 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (20-30% ethyl acetate/petroleum ether) gave the title compound as a white solid (7.24 g, 99.5%). Mp: 137-139° C. MS (ES−): 302 (M−H).
Reaction SMILES: [Br-].[CH3:2][C:3]1[N:8]=[C:7]([Zn+])[CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15](=[O:31])[N:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([O:14][C:15](=[O:31])[N:16]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[N:8]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: Cc1cccc([Zn+])n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cncc(N(C(=O)OC(C)(C)C)c3ccc(Cl)cc3)n2)n1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (54 mg, 0.076 mmol) was dissolved in degassed tetrahydrofuran (5 mL) Diisobutylaluminum hydride (1M in hexanes, 0.15 mL, 0.15 mmol) was added and the mixture was stirred for 15 minutes. 6-Methyl-2-pyridylzinc bromide (0.5 M in tetrahydrofuran, 2.29 mL, 1.15 mmol) and a solution of (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester (260 mg, 0.76 mmol) in tetrahydrofuran (3 mL) was added and the mixture was stirred at room temperature over night. The reaction was quenched with aqueous sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate (4×15 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-[6-(6-methyl-pyridin-2-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (113 mg, 23%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.S(Cl)([Cl:25])=O>>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([Cl:25])=[O:18])=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1

Procedure:
To a solution of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate (0.95 g, 3 mmol) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C., lithium hydroxide monohydrate (250 mg, 6 mmol) was added. The mixture was stirred at that temperature for 2 h. The resulting mixture was neutralized to pH=5 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4) and concentrated to obtain a white solid of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (0.76 g, yield 83%). LC-MS (ESI) m/z: 303 (M+1)+. 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoic acid (610 mg, 2 mmol) was added to thionyl chloride (10 mL), and the mixture was added at room temperature for 48 h. Then the solvent was removed under reduced pressure, dried in vacuum to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoyl chloride.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:4]1[C:5]([O:13][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CC(=O)c1cc2ccoc2cc1O
Product: CC(=O)c1cc2ccoc2cc1OCCCc1ccccc1
Yield: 81 %

Procedure:
5-Acetyl-6-hydroxybenzofuran (60 mg, 0.34 mmol) and 1-bromo-3-phenylpropane were reacted according to General Procedure A. The crude residue was purified by flash chromatography, eluting with diethyl ether:petroleum ether (1:9) to afford the title compound as a white solid (81 mg, 81%). 1H NMR (300 MHz, CDCl3): δ 2.26-2.16 (m, 2H), 2.69 (s, 3H), 2.85 (t, J=7.3 Hz, 2H), 4.07 (t, J=6.3 Hz, 2H), 6.72 (d, J=1.7 Hz, 1H), 6.99 (s, 1H), 7.32-7.19 (m, 5H), 7.54 (d, J=2.2 Hz, 1H), 7.99 (s, 1H). MS (ES+) m/z 294.9 (M+H+).
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[OH:1][CH:2]([CH2:24][O:25][C:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A solution of 9 (28 mmol) in 80 ml of dichloromethane/pyridine (1:1) is added dropwise with triphenylmethyl chloride (36 mmol) and stirred at room temperature for 48 hours. The solvent is removed, and the residue is added twice with 50 ml of toluene and concentrated. The residue is diluted with 100 ml of H2O and extracted three times with 50 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by chromatography on silica gel using heptane/ethyl acetate (2:1). Yield: 81% of a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:15][N:2]([CH2:3][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:12]=[CH:13][CH:14]=1)[CH3:1]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cccc(CO)c1
Yield: 55.7 %

Procedure:
3-(N,N-Dimethylamino carbonyl)benzoic acid, methyl ester (36 g) in dry tetrahydrofuran was added to lithium aluminium hydride (16.6 g) in dry tetrahydrofuran. The reaction mixture was heated at 60° for 3 hours, cooled and treated with water. The solvent was removed and the residue treated with dilute hydrochloric acid. The mixture was basified with sodium hydroxide and extracted with chloroform. The organic extracts were dried and distilled to give an oil (16 g) b.p. 95°-100° (0.1 mm). TLC silica/methanol Rf 0.57.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[N:27]=[N:26]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:34])[N:27]=[N:26]1
Reactant: N#Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Cyano-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride (50 mg, 0.137 mmol) and 4-(1H-1,2,3-triazol-4-yl)butanoic acid (25.6 mg, 0.165 mmol) were suspended in EtOAc (5 mL) and triethylamine (0.067 mL, 0.481 mmol) was added. After 5 mins at RT, T3P, 50% in EtOAC (0.164 mL, 0.275 mmol) was added and the mixture allowed to stir at RT for 20 hours. EtOAc (30 ml) was added and the mixture washed with a 10% solution of citric acid and a saturated solution of brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. Purification via silica chromatography eluting with 0-10% MeOH/DCM gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:12]3[CH:11]=[CH:15][N:14]=[CH:13]3)=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12

Procedure:
9.54 g (30 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid and 6.32 g (39 mmol) of N,N'-carbonyldiimidazole in 50 ml of dry dimethylformamide are stirred at room temperature for 1 hour and at 50° for 1 hour. Subsequently, the mixture is poured into about 300 ml of water, the precipitated material is filtered off under suction, washed with water and dried to constant weight. There is obtained (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole of melting point 240°-241.5°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[CH:14]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([N:30]3[CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28][CH2:29]3)=[O:12])=[C:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: Cc1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Reactant: FC1(F)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCC(F)(F)CC2)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Yield: 99.1 %

Procedure:
In a flask were mixed together the above prepared 5-chloro-6-(1-isopropyl-piperidin-4-yloxy)-3-methyl-benzofuran-2-carboxylic acid (0.200 g, 0.406 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.077 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.216 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.166 mL) in 4 mL of abs. THF and stirred over night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) yielded 0.183 g of the title compound as white solid.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Li+].[F:10][C:11]([F:16])([F:15])[CH:12]1[CH2:14][O:13]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([NH:24][CH2:14][CH:12]([OH:13])[C:11]([F:16])([F:15])[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)C1CO1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: OC(CNCc1ccccc1)C(F)(F)F
Temperature: -10 °C

Procedure:
Lithium triflate was suspended in CH3CN (15 mL) and the mixture is cooled to −10° C. 2-(Trifluoromethyl)oxirane is added and the suspension is allowed to warm to RT with stirring. Benzylamine (6.33 mL, 58 mmol, Aldrich) is added all-at-once and the resultant solution is stirred for 25 minutes. The reaction is quenched by pouring into CH2Cl2 (200 mL) and washing 3× with H2O (200 mL). The organic layer is dried over Na2SO4 and filtered. The product is purified on a Biotage Flash 75L using 20:70:10 CH2Cl2: pentane: triethylamine as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 100° C. yielding a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[NH:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:42].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:38]1[CH2:39][CH2:40][CH2:41][NH:35][C:36](=[O:42])[CH2:37]1)=[O:5])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C1CNCCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCCNC(=O)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
Prepared analogously to Example 1d from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, PFTU, diisopropylethylamine, and [1,4]diazepan-2-one in dimethylformamide. Yield: 63%; C22H21Cl2N5O3 (474.346); mass spectrum: (M+H)+=474/476 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]1([C:32]2[S:36][C:35]([C:37](OCC)=[O:38])=[N:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([C:35]4[S:36][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:33][N:34]=4)=[O:38])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: CCOC(=O)c1ncc(-c2ccccc2)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Temperature: 80 °C
Yield: 29 %

Procedure:
To a solution of the compound of example 6 (405 mg, 1.2 mmol) and ethyl 5-phenylthiazole-2-carboxylate (233 mg, 1 mmol) in toluene (15 mL) in a sealed tube, was added 2M solution of AlMe3 (135 mg, 1.875 mmol) and the reaction mixture was heated at 80° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride. The resulting solution was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to obtain a crude material, which was purified using column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[OH:22])(=[O:3])[NH2:2].[C:23]1([CH:29]2[O:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:30][CH:29]([OH:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]=1[OH:22])(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(OCCCNCc2ccccc2)cc1O
Reactant: c1ccc(C2CO2)cc1
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCCN(Cc2ccccc2)CC(O)c2ccccc2)cc1O

Procedure:
A solution of 12.7 g of N-[3-(4-carbamoyl-3-hydroxy-phenoxy)propyl]-benzylamine and 7.6 g of phenylethylene oxide in 80 ml of isopropanol is refluxed for 16 hours. The reaction mixture is evaporated, the residue is partitioned between 100 ml of 6N hydrochloric acid and 100 ml of ether and the aqueous phase is separated off and rendered alkaline with 2N ammonia solution. The N-[3-(4-carbamoyl-3-hydroxy-phenoxy)-propyl]-N-(2-hydroxy-2-phenyl-ethyl]-benzylamine thus obtained is isolated by extraction with ethyl acetate an debenzylated in the form of the crude product.
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O>CCOC(C)=O>[ClH:1].[ClH:1].[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCc1ccc2c(n1)NCCC2
Reaction time: 0.5 h

Procedure:
HCl gas was rapidly bubbled through a solution of 1-7 (2.5 g, 8.6 mmol) in EtOAc (100 ml) at 0° C. for 10 minutes. After 30 minutes, the solution was purged with argon for 30 minutes. The solution was concentrated and then azeotroped with CH3CN to give the amine 1-8 as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:33])[CH:15]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])P(OC)(OC)=O.CN(C)C(N(C)C)=N>O1CCCC1>[CH2:26]([O:25][C:23]([NH:22]/[C:15](=[CH:8]\[C:7]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)/[C:14]([O:13][CH3:12])=[O:33])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CC(C)c1ccc(C=O)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc(C(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 72 h

Procedure:
4-Isopropylbenzaldehyde (2.00 g, 13.50 mmol) and methyl{[(benzyloxy)carbonyl]amino}-(dimethoxyphosphoryl)acetate (3.58 g, 10.80 mmol, 0.8 equivalent) are dissolved in tetrahydrofuran (20 ml) and cooled to −78° C. At −78° C., N,N,N′,N′-tetramethylguanidine (27.92 g, 0.24 mol, 11.5 equivalents) is added dropwise and then stirred at −78° C. for 3 h and subsequently at room temperature 3 days. The mixture is then extracted by shaking with ethyl acetate (twice 100 ml) and water, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration, the crude product is chromatographed (Biotage 40M, cyclohexane/ethyl acetate 5/1). 3.47 g (73% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.5 g) and ethyl bromoacetate (0.91 mL) in DMF (10 mL) was added potassium carbonate (1.41 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.77 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[N:15]([O-:17])=[O:16].[Na+]>O>[N+:15]([N:2]([CH3:1])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O-:17])=[O:16]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN([C@@H](Cc1ccccc1)C(=O)O)[N+](=O)[O-]
Temperature: 5 °C

Procedure:
N-Methyl-L-phenylalanine (2.50 g) was suspended in water (25 ml) and conc. HCl (1 ml) was added, with stirring. The solution was cooled to 5° C. and solid sodium nitrite (1.35 g) was added to the stirred solution. After stirring at 5° C. for 1 h, the reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine and dried (MgSO4). After filtration the solvent was evaporated to yield N-nitro-N-methyl-L-phenylalanine as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[Cl:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Cl
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl

Procedure:
Using 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (55 mg, 0.20 mmol) and methyl 2-chloro-4-hydrazinocarbonylbenzoate (50 mg, 0.22 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (86 mg, yield 89%).