Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]1[C:18](=[O:19])[N:17]2[C@H:12]([CH2:13][CH2:14][CH2:15][C@H:16]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1)(=O)OCC)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1)[CH:32]=O.O.[OH-].[Li+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C.O1CCCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:16]2[CH2:15][CH2:14][CH2:13][C@H:12]3[N:17]2[C:18](=[O:19])/[C:9](=[CH:32]/[C:31]2[CH:34]=[CH:35][C:36]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:29]([O:28][CH3:27])[CH:30]=2)/[CH2:10][CH2:11]3)=[CH:21][CH:22]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N2C1=O
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In nitrogen atmosphere, trimethylsilyl iodide (0.74 mL) was added to a methylene chloride solution (25 mL) of (6S,9aR)-6-(4-chlorophenyl)-octahydroquinolizin-4-one (877 mg) and N,N,N′,N′-tetramethylethylenediamine (1.76 mL) at 0° C. The resulting reaction solution was stirred at 0° C. for 30 min, and then iodine (1.26 g) was added thereto at 0° C. The resulting reaction solution was stirred at 0° C. for 1 hr, and a sodium thiosulfate aqueous solution and ethyl acetate were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to give (6S,9aR)-6-(4-chlorophenyl)-3-iodooctahydroquinolizin-4-one. A mixture of the (6S,9aR)-6-(4-chlorophenyl)-3-iodooctahydroquinolizin-4-one and triethyl phosphite (10 mL) was stirred at 120° C. for 2 hr. This reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure to give [(6S,9aR)-6-(4-chlorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonic acid diethyl ester. To a solution mixture of tetrahydrofuran (21 mL) and ethanol (7 mL) of the [(6S,9aR)-6-(4-chlorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonic acid diethyl ester and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (869 mg), lithium hydroxide monohydrate (422 mg) was added. The resulting reaction solution was stirred at room temperature for 2 hr, and then ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate system) and then by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system and then ethyl acetate-methanol system) to give 1.07 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]2[C:8](=[O:10])[CH2:9][C@H:4]2[S:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:30]I>>[I:30][CH:2]1[CH2:7][CH2:6][N:5]2[C:8](=[O:10])[CH2:9][C@H:4]2[S:3]1
Reactant: II
Reactant: O=C1C[C@H]2SC(O)CCN12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C[C@H]2SC(I)CCN12
Temperature: 80 °C

Procedure:
A preferred method for halogenation includes subjecting the 2-hydroxycepham to triphenylphosphine in an amount between about 1 and 2 molar equivalents, and iodine in an amount between about 1 and 2 molar equivalents in an inert organic solvent, heating the mixture at approximately 80° C. while stirring the mixture until no starting material is present, thus forming the 2-iodo cepham (IIIA).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([O:6][C:7]1=[O:8])[CH:4]=[CH:3][CH2:2]2.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:7]([CH:1]1[CH2:9][CH:5]([OH:6])[CH:4]=[CH:3][CH2:2]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OC2C=CCC1C2
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)C1CC=CC(O)C1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To 6-oxabicyclo[3.2.1]oct-3-en-7-one (2.6 g, 21 mmol) in xylenes (50 ml) under nitrogen was added benzylamine (3.42 g, 32 mmol). The mixture was heated under reflux for 16 h, then cooled to room temperature. The heavy white precipitate was collected by filtration, and recrystallized from dichloromethane/hexane to give the amide as a white solid (3.8 g, 78%, m.p. 127-128° C.).
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[O-:28][CH2:29][CH3:30].[Na+].O>O1CCCC1>[CH2:29]([O:28][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:30]
Reactant: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.64 g) in tetrahydrofuran (10 mL) was added sodium ethoxide (20% ethanol solution, 1.56 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (0.40 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:12])[CH2:8][N:9]2[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1CC(=O)Nc2ccc(Br)cc21
Yield: 97 %

Procedure:
To a solution of 7-bromo-3-oxo-3,4-dihydroquinoxaline (6.8 g, 30 mmol) in pyridine (50 ml) was added a solution of isopropyl chloroformate in toluene (35 ml, 1M, 35 mmol) over 30 minutes. The mixture was triturated with water/chloroform, the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to obtain crude isopropyl 7-bromo-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate (9.3 g, 97%). A sample was recrystallized from ethanol: m p. 159-161° C. 1H-NMR (DMSO-d6) δ 1.25 (d, J=6.2 Hz, 6H), 4.25 (s, 2H), 4.90 (sep, J=6.2 Hz, 1H), 6.89 (d,J=8.6 Hz, 1H), 7.27 (dd,J=9.1, 2.1 Hz, 1H), 7.74(s, 1H), 12.51 (s, 1H), MS (ESI) m/z 330/332 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1)[NH2:21]
Reactant: Cn1cnc2c(Nc3ccncc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccncc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-pyridin-4-yl-amine and hydrazine monohydrate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[O:3][C:48](=[O:49])[C:47]([S:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH:37]([CH3:38])[CH3:39])=[C:51]([OH:52])[CH:1]=2)=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCc3ccccc3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4-benzyloxyacetophenone (0.3 g, 0.675 mmol), trimethylsilyl triflate (0.15 g, 0.675 mmol), triethylamine (0.14 g, 1.35 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (0.210 g, 0.675 mmol). m.p. 163-165° C.; 1H NMR (400 MHz, DMSO-d6) δ1.28 (d, 6H), 3.4 (m, 1H), 5.22 (s, 2H), 6.64(s,1H), 6.92 (d, 1H), 7.06 (t, 1H), 7.11(t, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.36 (q, 2H), 7.42 (d, 2H), 7.49 (d, 2H), 7.83 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1.[C:16]1(C)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[NH4+]>O.C(O)C>[CH3:12][C:9]1([CH3:13])[CH2:8][C:7](=[O:14])[C:6]2[CH:15]=[C:2]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:3]=[CH:4][C:5]=2[O:11][CH2:10]1
Reactant: Cc1ccccc1
Reactant: CC1(C)COc2ccc(Br)cc2C(=O)C1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)COc2ccc(-c3ccccc3)cc2C(=O)C1

Procedure:
8.5 g of 7-bromo-3,3-dimethyl-3,4-dihydro-2H-benzoxepin-5-one (0.0316 mol), 95 ml of toluene, 34.7 ml of a 2M sodium carbonate solution, 46 ml of ethanol, 4.19 g of phenyboric [sic] acid (0.0344 mol, 1.09 equivalents) and 0.677 g of tetrakis(triphenyl-phosphine)palladium are changed to a 250 ml reactor. The reaction mixture is brought to reflux for 8 h and is then allowed to return to room temperature. The reaction mass is poured into a mixture of 70 ml of water, 56.8 ml of a 30% aqueous ammonium hydroxide solution and 78 ml of a 2M aqueous sodium carbonate solution. The catalyst is filtered off through silica. Extraction is then carried out 3 times with 100 ml of ethyl acetate and the organic phases are washed with 3 times 100 ml of water and dried over anhydrous sodium sulphate before being concentrated under reduced pressure. 14 g of an oil are isolated, which oil is purified by column chromatography using a 4/1 hexane/ethyl acetate mixture. 8.5 g of the title compound are thus obtained in the form of a liquid.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[CH:11]=[C:10]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:9]=1.[O:28]1[CH2:33][CH2:32][CH:31]([CH:34]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH:18]=[CH:17][N:16]=2)[C:21]#[N:22])[CH:11]=[C:10]([CH:23]2[CH2:27][CH2:26][N:25]([CH2:34][CH:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)[CH2:24]2)[CH:9]=1
Reactant: O=CC1CCOCC1
Reactant: C[C@@H]1CCCN1c1cc(C2CCNC2)cc(Nc2cc(C#N)ccn2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CCCN1c1cc(C2CCN(CC3CCOCC3)C2)cc(Nc2cc(C#N)ccn2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
To a solution of 2-[[6-[(2R)-2-methylpyrrolidin-1-yl]-4-pyrrolidin-3-yl-2-pyridyl]amino]pyridine-4-carbonitrile hydrochloride (160 mg, 0.415 mmol) in methanol (3.0 mL) was added tetrahydropyran-4-carbaldehyde (0.086 mL, 0.831 mmol, 2.0 equiv.). It was heated @ 50° C. overnight. After cooling to room temperature, sodium triacetoxyborohydride (278.2 mg, 1.247 mmol, 3.0 equiv.) was added in portions. After 3 h, more sodium triacetoxyborohydride (278.2 mg, 1.247 mmol, 3.0 equiv.) was added, stirred @ rt for another o/n. It was quenched with 1N NaHCO3, extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC to afford 15.5 mg (8.3%) of product as yellow gum. LC-MS: m/z=447 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[C:9](Br)[S:8]1)=[O:5])[CH3:2].C([SnH](CCCC)CCCC)CCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[CH:9][S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=c1sc(Br)cn1-c1cccc(C(F)(F)F)c1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N=c1sccn1-c1cccc(C(F)(F)F)c1
Yield: 75.8 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-bromothiazoline (4.7 g), tributyltin hydride (6.9 g) and a catalytic amount of benzoyl peroxide in tetrahydrofuran (100 ml) was refluxed for 10 hours. The solvent was removed by distillation, and the residue was washed with hexane. Recrystallization from a mixture of hexane and ethanol gave 2.85 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazoline (Compound (xii)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH3:13])[NH:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].O.[C:22](Cl)(=[O:26])[CH:23]=[CH:24][CH3:25]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH3:13])[N:5]([C:22](=[O:26])[CH:23]=[CH:24][CH3:25])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12]
Reactant: CC=CC(=O)Cl
Reactant: COC(=O)[C@H](C)Nc1c(C)csc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC=CC(=O)N(c1c(C)csc1C)[C@@H](C)C(=O)OC

Procedure:
To 6.39 g (0.03 mol) of N-(2,4-dimethylthien-3-yl-alanine-methylester, 4.15 g (0.03 mol) of K2CO3, 10 ml of water and 100 ml of dichloromethane are added without cooling 3.14 g (0.03 mol) 2-butenoyl chloride.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:23]=[C:22]([Cl:21])[CH:28]=[C:27]([Cl:29])[CH:26]=2)=[O:13])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 22.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5-dichloroaniline (1.87 g, 11.7 mmol) in 15 mL of pyridine. The crude product was recrystallized from ethanol, then ethyl ether to yield 0.78 g of the title compound, mp 235-236° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40]1CCOCC1.N>C1COCC1.C(Cl)Cl>[NH2:40][C:36]([C@H:9]1[CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:38]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: CN1CCOCC1
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 102.6 %

Procedure:
A stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (7) (0.13 g, 0.232 mmol) in THF (5 ml) was cooled to −15° C. (acetone/ice). NMM (0.035 g, 0.348 mmol) was added to the solution followed by IBCF (0.041 g, 0.301 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with aqueous ammonia in THF (0.2 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (20 ml), washed with water (2×2 ml) and concentrated to give tert-butyl (2R,4R)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (8) (0.13 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 544.0.
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH3:33])[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.FC1C=CC([N+]([O-])=O)=CC=1C#[N:38]>>[NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:19][CH2:20]2)=[C:11]([C:33]#[N:38])[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Product: N#Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Yield: 12 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 2-fluoro-5-nitrobenzonitrile replacing 2-fluoro-5-nitrotoluene. A yellow solid is obtained (yield 12%).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:28][C@H:29]([C:36]([NH:38][C@H:39]([CH:44]=[N:45][NH:46][C:47]([NH2:49])=[O:48])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([CH:44]=[N:45][NH:46][C:47]([NH2:49])=[O:48])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 15 h

Procedure:
To a solution of 221 mg of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 400 mg of bis-(p-toluenesulfonic acid) salt of L-histidyl-L-leucinal semicarbazone in 5 ml of dry N,N-dimethylformamide were successively added dropwise 202 mg of diphenylphosphoryl azide and 0.28 ml of triethylamine under ice-cooling, and then the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1 by volume) to obtain 71 mg of N-[2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl-L-leucinal semicarbazone (isomer A) and 166 mg of isomer B.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[S:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:37])=[O:36])C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]([S:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:44])[CH3:42])(=[O:36])=[O:37])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: COc1ccc(-n2c(C(=O)N(C)C)c(OCc3ccccc3)c(OCc3ccccc3)c2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C(=O)N(C)C)c(O)c(O)c2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Yield: 54.9 %

Procedure:
tert-Butyl (3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrol-2-yl)sulfonyl carbamate (10) (166 mg, 0.26 mmol) in methanol (2.5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford tert-butyl (5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrol-2-yl)sulfonylcarbamate (UL1-030) (65 mg, 52%) as a yellow solid: m/z 456 (M+H)+ (ES+); 454 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 11.04 (s, 1H), 8.75 (s, 1H), 8.35 (s, 1H), 7.07-7.00 (m, 2H), 6.92-6.86 (m, 2H), 3.77 (s, 3H), 2.80 (br s, 6H), 1.35 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH3:16])([CH3:13])[CH3:12]
Reactant: CCC(=O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(=Nc1c(C(C)C)cccc1C(C)C)c1ccccc1
Temperature: 205 °C
Yield: 73.3 %

Procedure:
2,6-Diisopropylaniline (3.8 mL, 20 mmol, Aldrich) was mixed with propiophenone (2.7 mL, 20 mmol, Aldrich) and p-TsOH (0.4 g, 2.1 mmol, Aldrich). The resulting mixture was heated at 205° C. for 1.5 h under a slow stream of Ar to remove H2O that formed. After cooling to RT the reaction mixture was poured into hexanes (50 mL), filtered, the precipitate was washed with additional hexanes (2×20 mL) followed by the evaporation of the filtrate and distillation of the residue. After the initial fraction of starting materials (80–110° C./0.5 mm) the product was collected as a yellow oil, bp 110–125° C./0.5 mm. Crystallization from methanol at −30° C. it afforded product as yellow crystals (4.3 g, 73.3%). 1H NMR (CDCl3) 7.99–7.91 (m, 2H); 7.54–7.44 (m, 3H); 7.20–7.13 (m, 2H); 7.12–7.04 (m, 1H); 2.78 (septet, 2H; J=6.9 Hz); 2.53 (q, 2H; J=7.7 Hz); 1.21 (d, 6H; J=6.9 Hz); 1.16 (d, 6H; J=6.9 Hz); 0.99 (t, 3H; J=7.7 Hz).
Reaction SMILES: NC(N)=[S:3].O1[CH2:19][CH:6]1[CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18]>CO>[S:3]1[CH2:19][CH:6]1[CH2:7][N:8]1[C:12](=[O:13])[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: NC(N)=S
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CC1CS1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiourea (1.873 g, 24.61 mmol) was added to a solution of N-(2,3-epoxypropyl)phthalimide (2 g, 9.84 mmol) in methanol (25 mL). The mixture was stirred at room temperature for 16 hours, then concentrated under vacuum. The residue was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with brine (50 ml) passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Si:1]([O-:7])([O-:6])([O-:5])[O:2][CH2:3][CH3:4].Cl>C(O)C>[CH2:3]([OH:2])[CH3:4].[Si:1]([OH:7])([OH:6])([OH:5])[O:2][CH2:3][CH3:4]
Reactant: CCO[Si]([O-])([O-])[O-]
Agent: Cl
Solvent: CCO
Product: CCO[Si](O)(O)O

Procedure:
10 parts by weight of ethyl orthosilicate, 87.5 parts by weight of ethanol and 15 parts by weight of a 0.05N hydrochloric acid were mixed, whereby an ethyl orthosilicate ethanol solution was prepared.