Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=1[F:25]>>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[CH:18][C:17]=1[F:25]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Yield: 67.4 %

Procedure:
Using 1-(3,5-dimethylpyridin-2-yl)piperazine (2.87 g) described in Preparation Example 79 and 4-bromo-3-fluorobenzoic acid (3.29 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.97 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14].O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: COC(=O)Nc1ccc(C)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
100 ml of methylene chloride are introduced into a 2 l four-necked flask equipped with a stirrer, reflux condenser, thermometer and two dropping funnels, and 165.2 g (1 mol) of 4-tolylcarbamic acid methyl ester, dissolved in 400 ml of methylene chloride, and 109.3 g of 98% strength (1.7 mols) nitric acid dissolved in 150 ml of methylene chloride are added simultaneously in the course of 1 hour, at 20° C. and under normal pressure, the temperature being maintained by external cooling. After completion of the dropwise addition, the mixture is stirred for a further hour at 20° C., the resulting solution is extracted twice with 100 ml of water at a time, and the organic solvent is then distilled off. Yield: 209.3 g of crude product, of melting point 96° to 102° C. This crude product is introduced into dilute sodium hydroxide solution, consisting of 450 ml of water and 112 g (2.8 mols) of NaOH, and the mixture is heated to 95° C. and kept at this temperature for 3 hours, whilst distilling off the methanol formed during hydrolysis of the 2-nitro-4-tolylcarbamic acid methyl ester to the amino group. The mixture is cooled to 60° C. and stirred for a further 30 minutes at 60° C., and the product is filtered off and washed alkali-free with water. The moist product is dried to constant weight in vacuo at 60° C. Yield: 144.4 g of dry product (94.6% of theory); purity: 99.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CC(=O)NCCc2ccc(OC)c(OC)c2)cc1

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 4-methoxyphenyl acetyl chloride.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(O)=O>CN(C=O)C>[Cl:1][C@@H:2]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@@H](O)[C@H](Cl)C(=O)OCC
Reaction time: 3 h

Procedure:
Ethyl 2-chloro-3-oxohexanoate (194 mg), DMF (2.4 ml), RuCl[(S,S)—NpDPEN](p-cymene) complex (1 mol %) and triethylamine (5 equivalents) were mixed, and formic acid (5 equivalents) was gradually added thereto. The reaction was carried out at 40° C. for 3 hours. The reaction mixture was analyzed. As a result, the conversion ratio was 95%, and the isomer ratio of (2S,3R):(2S,3S):(2R,3R):(2R,3S) is 88.3:4.6:2.1:5.1.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:26]=1[CH2:27][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (622 mg) in DMF (7 mL) was added potassium carbonate powder (958 mg) and 2,4-bis(trifluoromethyl)-benzyl bromide (2.13 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-40% EtOAc/hexanes), followed by recrystallization with hexanes to yield the title compound as an orange solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C[Al](C)C.[CH3:12][C:13]1[N:14]=[C:15]([CH2:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[S:16][C:17]=1[C:18](O)=[O:19]>O1CCOCC1.C1(C)C=CC=CC=1>[O:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:18]([C:17]2[S:16][C:15]([CH2:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[N:14][C:13]=2[CH3:12])=[O:19])[CH2:3][CH2:4]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC1CCOCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a stirred suspension of 4-aminotetrahydropyran (123 mg, 1.2 mmol) in dioxane (5 mL) under argon at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 mmol). After 1 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.3 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (40 mg, 32%) as a colourless oil. MS: m/e=412.4 [M+H]+.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1cnccn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1cnccn1
Yield: 19 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(2-pyrazinyl)propionate (4.1 g) and benzylamine (4.0 g) were dissolved in acetonitrile (100 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(2-pyrazinyl)imidazole-4-carboxylate (1.0 g), melting point 196-197° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:25]4[CH2:26][CH2:27][N:22]([C:28]5[N:29]=[CH:30][CH:31]=[CH:32][N:33]=5)[CH2:23][CH2:24]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-piperazin-1-yl-pyrimidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=-100%, [M+H]+=450.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[PH2]([O-])=O.[Na+]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 75.3 %

Procedure:
To a mixture of 2-chloro-5,11-dihydro-11-ethyl-8-[trans-2-(4-pyridyl)ethen-1-yl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (2.3 g, 5.9 mmol) and palladium black (0.25 g) in 30 mL of 1,4-dioxane was added a solution of sodium hypophosphite (0.82 g 7.7 mmol) in 15 mL of water. The reaction mixture was heated at 80°-90° C. for 3 hours. The reaction mixture was then filtered through Celite and extracted with ethyl acetate. The product was purified by chromatography over silica gel, eluting with methanol/dichloromethane, and recrystallized from ethyl acetate/hexanes to give 1.75 g of the title compound as colorless crystals, m.p. 158°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:12]([S:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33](Cl)=[CH:32][C:31]=1[CH:37]1[CH2:39][CH2:38]1)[C:25](=[O:40])[CH:24]=[CH:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O1CCOCC1>[CH2:12]([S:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)=[CH:32][C:31]=1[CH:37]1[CH2:39][CH2:38]1)[C:25](=[O:40])[CH:24]=[CH:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(Cl)cc1C1CC1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(-c2cc(F)cc(F)c2)cc1C1CC1
Temperature: 150 °C

Procedure:
A microwave vial charged with 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.254 g, 0.359 mmol), (3,5-difluorophenyl)boronic acid (1.133 g, 7.18 mmol), 6-(benzylthio)-1-(4-chloro-2-cyclopropylphenyl)quinolin-2(1H)-one (1.500 g, 3.59 mmol), potassium phosphate (2.285 g, 10.77 mmol) and 10 ml and dioxane 3 ml water was heated to 150° C. in a Biotage Initiator microwave reactor for 30 minutes. The organic layer was removed and concentrated. The crude residue was used in the following step without purification. m/z (ESI) 496.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: COc1cc(C=CC(C)=O)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
To a methylene chloride (100 mL) solution of 1-(4'-hydroxy-3'-methoxyphenyl)-1-butene-3-one (10.0 g, 52 mmol) is added triethyl amine (5.8 g, 57.2 mmol) and t-butylchlorodimethyl silane (15.7 g, 104 mmol). The reaction is stirred at room temperature for 12 hours under an argon atmosphere. The mixture is washed with water (3×100 mL) and brine (100 mL). The organic layer is dried over MgSO4 and evaporated. Flash chromatography (ethyl ether/hexane 1:1) affords 12.8 g (80%) of the desired 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-butene-3-one, mp=65°-68° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:20][C:19](=[O:21])O[C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:35])=O.O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C>[Cl:35][C:4]1[C:3]2[S:20][C:19](=[O:21])[NH:1][C:2]=2[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2oc(=O)sc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred suspension of 7-amino-5-[[(2,3-difluorophenyl)methyl]thio][1,3]oxathiolo[5,4-d]pyrimidin-2-one (5.03 g) and benzyltrimethylammonium chloride (2.58 g) in acetonitrile (25 ml) at 50° C., was first added N,N-diethylaniline (2.46 g) followed by acetonitrile (5 ml), and then phosphorus oxychloride (7.41 g) followed by acetonitrile (5 ml). The reaction mixture was heated to reflux and maintained at this temperature for 36 hours, before cooling to ambient temperature and adding to water (25 ml) at 50° C. with stirring over 30 minutes. An additional acetonitrile (5 ml) rinse of the reaction vessel was added to the drown-out mixture, before heating to 75° C. and slowly cooling to 25° C. at <0.5° C./min. The resulting mixture was held at 25° C. for 30 minutes and then collected by filtration, washing four times with water (25 ml), to afford the title compound as an off-white solid (3.5 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2/[CH:13]=C/C.[O:16]=[O+][O-].CSC>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[O:16]
Reactant: O=[O+][O-]
Reactant: C/C=C/c1cccc2c(=O)cc(C)oc12
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(=O)c2cccc(C=O)c2o1
Temperature: -60 °C

Procedure:
18.5 g (62.8 mmol) of 2-methyl-8-[(1E)-prop-1-en-1-yl]-4H-chromen-4-one are dissolved in 400 ml of dichloromethane and cooled to −60° C. Ozone is passed into the reaction solution for 30 min. Dimethyl sulfide is then added to the reaction mixture. After warming to room temperature, the solvent is removed in vacuo and the residue is slurried in a little methanol. The solid remaining after filtration is recrystallized from diethyl ether. 9.1 g (77.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH2:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([NH:40][C@@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42](O)=[O:43])(=[O:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH:35][C:42](=[O:43])[C@@H:41]([NH:40][C:37](=[O:39])[CH3:38])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](N)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Reaction time: 1 h

Procedure:
The title A compound, (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (79 mg, 0.155 mmol) and (S)-2-acetylamino-3-phenyl-propionic acid (33.7 mg, 0.162 mmol) are dissolved in CH2Cl2 (3.1 mL). HOBt (24.8 mg, 0.162 mmol) is added as a solid, followed by EDCl (31.0 mg, 0.162 mmol) and TEA (0.023 mL, 0.162 mmol) in a slurry of CH2Cl2 (1 mL). After 1 h, EtOAc (100 mL) is added and the mixture is washed three times with 2N aqueous HCl (50 mL) followed by saturated aqueous NaHCO3 (50 mL). The EtOAc layer is dried over anhydrous Na2SO4 and concentrated to yield (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a white powder.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])[CH3:3].C1CCC(NC2CCCCC2)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][C:66]=1[O:73][CH3:74])[CH:61]=[CH2:62]>CN(C)C=O>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13](=[O:15])[N:63]([CH2:60][CH:61]=[CH2:62])[CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][C:66]=1[O:73][CH3:74])[CH2:10][CH:11]=[CH2:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCNCc1ccc(OC)cc1OC
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC=C)Cc1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(R)-N-Boc-allylglycine (2.3 g, 9.9 mmol) was dissolved in dimethylformamide (20 ml) and activated with the coupling reagent TATU (3.5 g, 10.9 mmol) and Hünig's base (3.8 ml, 21.9 mmol) for 2 min. Allyl-(2,4-dimethoxy-benzyl)-amine (2.1 g, 9.9 mmol) dissolved in dimethylformamide (20 ml) was added to the chilled (ice-water bath) reaction mixture and the stirring was continued overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, 1 M KHSO4 solution, brine, dried (MgSO4.2H2O), filtered and concentrated under reduce pressure and purified over silica gel (ethyl acetate/n-heptane 1:4): colorless gum 2.6 g (62%);
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[O:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:16][C:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 89.2 %

Procedure:
13 g of methyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate, 50 ml of dimethylformamide and 9.6 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 11 g of methyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[C:12]2=[O:17])[CH2:9][CH2:8][C@@H:7]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=[O:3])[CH3:2].Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=2)[N:30]=[CH:29][N:28]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[CH:35]=4)[N:30]=[CH:29][N:28]=3)[C:12]2=[O:17])[CH2:9][CH2:8][C@@H:7]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.8 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-amino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (˜3.4 mmol) in isopropanol (10 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (0.97 g, 1.2 eq) and diisopropylethylamine (0.88 g, 2 eq). The mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure. The residue was purified with silica gel column chromatography eluting with 1% and 5% MeOH in dichloromethane to provide tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexylcarbamate (2.0 g, ˜100%). LC/MS found [M+H]+=551.
Reaction SMILES: ClN1[C:7](=[O:8])[N:6]([Cl:9])[C:5](=O)N(Cl)C1=O.[Br:13][CH2:14][CH:15]1[O:19]C(=O)NC1>C(Cl)Cl>[Cl:9][N:6]1[CH2:5][CH:15]([CH2:14][Br:13])[O:19][C:7]1=[O:8]
Reactant: O=C1NCC(CBr)O1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: O=C1OC(CBr)CN1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.86 grams (0.0166 moles) trichlorocyanuric acid and 1.79 grams (0.0166 moles) 5-bromomethyl-2-oxazolidinone are added to MeCl2 and stirred overnight at room temperature. The reaction mix was dried over magnesium sulfate and rotovaped. Proton NMR Data: δ3.9(m, 4 protons]5.1(m, 1 proton).
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH:25]1([C:28]2[C:37]3[C:32](=[C:33]([O:41][CH2:42][CH2:43][OH:44])[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=3)[CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26]1.C1(C2C3C(=C(OC)C=C(C(O)=O)C=3)C=CN=2)CC1>>[NH2:3][C:2](=[O:4])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:38]([C:35]3[CH:36]=[C:37]4[C:32]([CH:31]=[CH:30][N:29]=[C:28]4[CH:25]4[CH2:26][CH2:27]4)=[C:33]([O:41][CH2:42][CH2:43][OH:44])[CH:34]=3)=[O:39])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8]
Reactant: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2c1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Agent: Cl
Product: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(OCCO)c4ccnc(C5CC5)c4c3)CC1)O2

Procedure:
The intended compound was produced according to the procedure described in reference Example 37 but using 4-oxospiro(chroman-2,4′-piperidin)-6-yl-carboxylicacidcarbamoylmethyl amide hydrochloride and 1-cyclopropyl-5-(2-hydroxy-ethoxy)-isoquinoline-7-carboxylic acid in place of methyl 5″-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate di-hydrochloride and 1-cyclopropyl-5-methoxy-isoquinoline-7-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.75 (1.0H, t, J=5.7 Hz), 8.36 (1.0H, d, J=5.7 Hz), 8.31 (1.0H, d, J=2.4 Hz), 8.09 (1.0H, dd, J=8.8, 2.4 Hz), 8.05 (1.0H, s), 7.85 (1.0H, d, J=5.9 Hz), 7.34 (1.0H, s), 7.22-7.14 (2.0H, m), 6.99 (1.0H, s), 5.00 (1.0H, t, J=5.7 Hz), 4.39-4.25 (1.0H, m), 4.21 (2.0H, t, J=4.8 Hz), 3.84 (2.0H, q, J=4.8 Hz), 3.78 (2.0H, d, J=5.9 Hz), 3.62-3.17 (3.0H, m), 2.95 (2.0H, s), 2.93-2.85 (1.0H, m), 2.15-1.77 (4.0H, m), 1.15-0.99 (4.0H, m). MS [M]+=572.