Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH:18]=O)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:34]>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([CH2:18][C:11]2[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=2)=[C:25]1[CH3:34]
Reactant: CSc1ncc(S(=O)(=O)c2ccccc2)c(C=O)n1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2nc(SC)ncc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[N:26][C:27]#[N:28])[N:14]([C:15]4[CH:16]=[N:17][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:19][CH:20]=4)[C:5]=3[C:4]=2[CH:3]=1.[B:30]1(B2OC(C)(C)C(C)(C)O2)[O:34]C(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[C:27]([N:26]=[C:13]1[N:12]([CH3:29])[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([B:30]([OH:34])[OH:31])=[CH:3][C:4]=3[C:5]=2[N:14]1[C:15]1[CH:16]=[N:17][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:19][CH:20]=1)#[N:28]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(Br)ccc3ncc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(B(O)O)ccc3ncc21

Procedure:
N-(8-bromo-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (2.463 mmol) was dissolved in 15 mL of dioxane under argon atmosphere. Bis(pinacolato)diboron (1.347 mmol), potassium acetate (2.246 mmol) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (50 mg) while stirring. The reaction mixture was refluxed for 8 h. After completion of the reaction, the reaction mixture was cooled and diluted with 15 mL ethyl acetate and filtered through celite. The filtrate was concentrated and the crude product was purified (silica gel column, ethyl acetate/petroleum ether as eluent) to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26](=[O:29])([OH:28])[OH:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.CO.[NH2:34][C@H:35]([C:41]([OH:43])=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][NH2:40]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH:25][P:26]([O-:28])([O-:29])=[O:27])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[NH3+:40][CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]([C:41]([OH:43])=[O:42])[NH2:34].[NH3+:40][CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]([C:41]([OH:43])=[O:42])[NH2:34]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=P(O)(O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Solvent: O
Solvent: CO
Product: N[C@@H](CCCC[NH3+])C(=O)O
Product: O=P([O-])([O-])Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Yield: 61.3 %

Procedure:
To a mixture of (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)phosphoramidic acid (13 mg, 0.029 mmol) described in Example 2 and methanol (2 mL) was added a mixture of L-lysine (8.4 mg, 0.058 mmol) and water (0.8 mL) at room temperature, and the solvent was evaporated from the reaction mixture under a reduced pressure. The resulting residue was washed with methanol to obtain the title compound (13 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)[NH:5]C(OCC1C=CC=CC=1)=O.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Yield: 85.2 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.34 mmol, 159 mg), cyclohexene (1 mL) and 10% palladium on carbon (100 mg) in ethanol (3 mL) was heated to reflux for 20 min. Then, it was filtered through a pad of celite and the pad was washed with ethanol (10 mL). The combined filtrate was concentrated and the residue was dried under high vacuum to afford 96 mg (85% yield) of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a sticky yellow solid. ES-HRMS m/e calcd for C17H21N3O4 (M+Na) 354.1424, found 354.1424.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
To a solution of 4-chlorophenol (1.00 g, 7.78 mmol) in DMF (5 ml) at room temperature was added potassium carbonate (2.15 g, 15.56 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 15 min. Then, 4-chloro-3-nitropyridine (1.23 g, 7.78 mmol) was added and the resulting solution was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and evaporated. 4-(4-Chlorophenoxy)-3-nitropyridine (1.72 g, 88%) was obtained as a yellow solid, mp 93-94° C. (from EtOH), which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.N=[C:23]=[NH:24]>C1COCC1>[CH3:7][CH:8]([NH:9][C:10]1[CH:6]=[CH:5][CH:23]=[N:24][C:11]=1[N:16]1[CH2:21][CH2:20][N:19]([C:13]([C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[CH:7]=2)=[O:15])[CH2:18][CH2:17]1)[CH3:13]
Reactant: N=C=N
Reactant: C1CNCCN1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: C1CCOC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-nitroindole-2-carboxylic acid (0.86 g), 1-[3-(N-isopropyl)amino)-2-pyridinyl]piperazine (0.43 g), 1-(ethyl)-3-dimethylaminopropyl)carbodiimide (0.45 g) and THF (4 ml), the title compound is obtained, mp 153°-154°.
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].CO.[H][H]>O>[Cl:1][CH:2]([CH: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
Reactant: [H][H]
Solvent: CO
Solvent: O
Product: CCCC(O)C(Cl)C(=O)OCC
Temperature: 70 °C
Reaction time: 14 h
Yield: 72.3 %

Procedure:
Ethyl 2-chloro-3-oxohexanoate (2.5 g, 13 mmol), methanol (7.5 ml) and water (0.75 ml) were mixed, and nitrogen substitution was carried out after reducing the pressure. The above catalyst solution was added thereto, and hydrogen substitution (3 atmospheres) was carried out under reduced pressure. The mixture was stirred at 70° C. for 14 hours. After the mixture was cooled to room temperature, the solvent was evaporated away under reduced pressure. The concentrated matter was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.83 g, yield: 72%) ((2S,3R):(2S,3S):(2R,3S):(2R,3R)=6.2:58.5:33.2:2.2).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1.CCOCC.O>[OH:16][CH:15]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)[C:14]([CH3:18])([CH3:17])[CH3:13]
Reactant: Brc1cncnc1
Reactant: CC(C)(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1cncnc1
Temperature: -120 °C
Reaction time: 1 h

Procedure:
225 g of 5-bromopyrimidine are dissolved in 1.5 l of absolute tetrahydrofuran/1,000 ml of absolute ether and the solution is cooled to -120° C. 250 ml of 50% strength n-butyl-lithium (in n-hexane) are added dropwise at an internal temperature of -105° to -115° C. in the course of 2 hours. The mixture is subsequently stirred at this temperature for 1 hour. 309 ml of trimethylacetaldehyde are then added dropwise in the course of 2 hours. The reaction mixture is then subsequently stirred at this temperature for 4 hours. It is allowed to warm to room temperature overnight and 83 g of ammonium chloride, dissolved in a minimum amount of water, are then added. The aqueous phase is separated off and the organic phase is washed twice with saturated sodium chloride solution, dried over sodium sulphate and concentrated. After recrystallization of the residue from acetonitrile, 155 g (66% of theory) of 5-(1-hydroxy-2,2-dimethylpropyl)pyrimidine of melting point 94°-96° C. are obtained.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([OH:24])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[C:5]1=[O:25])(=[O:3])[CH3:2].[CH2:26](N(C(C)C)C(C)C)C.F[B-](F)(F)F.C[O+](C)C>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([O:24][CH3:26])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[C:5]1=[O:25])(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc3c(c2)OCO3)c2ccc(Cl)cc21
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
A solution of 20.9 g of 1-acetyl-6-chloro-3-[1-hydroxy-1-(3,4-methylenedioxyphenyl)-methylene]-2-indolinone and 40 ml of ethyldiisopropylamine in 200 ml dichloromethane is combined batchwise with 17.3 g of trimethyloxonium tetrafluoroborate, the mixture is stirred overnight and then extracted twice with water. The organic phase is dried with magnesium sulphate and evaporated to dryness. The residue is stirred with methanol, suction filtered, washed with methanol and dried at 80° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH2:26][CH:27]([C:31](OCC)=[O:32])[C:28]([CH3:30])=O)=[O:24].P(Cl)(Cl)(Cl)=O.CCCCCC>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]2[C:7]=1[C:28]([CH3:30])=[C:27]([CH2:26][CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[C:31](=[O:32])[O:8]2
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: CC(CCCc1ccccc1)c1cc(O)cc(O)c1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)CCc1c(C)c2c(O)cc(C(C)CCCc3ccccc3)cc2oc1=O
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 2-(3,5-dihydroxyphenyl)-5-phenylpentane (33 g., 0.13 M), (Preparation C) diethyl α-acetoglutarate (32.2 g., 0.14 M) and phosphorous oxychloride (20 g., 0.13 M), protected from atmospheric moisture, is stirred at room temperature. After 10 days, the mixture is dissolved in chloroform, washed three times with water, dried (Na2SO4), and evaporated. The residue is subjected to silica gel chromatography (eluents--9 benzene:1 ether) to yield 22 g. of the desired ester, m.p. 58°-70° C. from hexane. Further recrystallization from ethyl acetate/hexane affords an analytical sample: m.p. 78°-85° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[OH:28]O>C(O)(=O)C.O.N>[CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:28])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: COc1cc(SC)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reactant: OO
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reaction time: 50 h

Procedure:
5.1 gm of 7,7-dimethyl-2-(2-methoxy-4-methylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were reacted in 100 ml of 70% acetic acid with 1.7 gm of 30% hydrogen peroxide, and the mixture was allowed to stand for 50 hours at room temperature (the first 3 hours while stirring). After 18 and again after 26 hours 1.3 gm of 30% hydrogen peroxide were added. The reaction mixture was then diluted with water, and ammonia was added until alkaline reaction. The precipitate was suction-filtered off and the filtrate was extracted twice with chloroform. The combined chloroform phases were evaporated, and the evaporation residue was combined with the precipitate. The thus obtained product was purified on a silicagel column (eluant: chloroform/acetone 19:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]([C:10]([NH:12][CH2:13][C:14](=O)[CH3:15])=[O:11])=[O:9])=[O:5])[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:14]([CH3:15])=[CH:13][N:12]=[C:10]([OH:11])[C:8]1=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)C(=O)NCC(C)=O
Solvent: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(C)cnc(O)c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a stirred solution of N-(ethoxycarbonylmethyl)-N′-(2-oxo-1-propyl) oxamide (6.9 g, 30 mmol), as prepared in the preceding step, trifluoroacetic acid (2.32 mL, 30 mmol) and trifluoroacetic anhydride (4.3 mL, 30 mmol) in acetic acid (100 mL) was heated to 80° C. under nitrogen for 10 hours. Additional trifluoroacetic acid (1.5 mL, 20 mmol) and trifluoroacetic anhydride (3.0 mL, 20 mmol) were added, the mixture was stirred at 80° C. for additional 24 hours under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was stirred with acetic acid (13 mL) for 15 minutes at 60° C., then ethyl acetate and hexane (4:1, 60 mL) were added dropwise to the warm mixture. The precipitates were allowed to cool to room temperature, filtered, and dried under high vacuum to give the title compound as an off-white solid (4.9 g, 77%). 1H NMR (400 MHz, CDCl3) δ 11.20 (s(br), 1H), 6.17 (s, 1H), 4.66 (s, 2H), 4.24 (q, 2H, J=7.1 Hz), 2.27 (s, 3H), 1.30 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ncc(Cn3cc(N)cn3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ncc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=393.91.
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].[CH:11]([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=1[OH:26])([CH3:13])[CH3:12]>C(Cl)Cl>[CH:23]([C:16]1[CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[O:26][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3])([CH3:25])[CH3:24]
Reactant: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Oc1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1H NMR (CDCl3): δ1.35 (t, 3H), 4.1 (s, 2H), 4.25 (q, 2H). A mixture of ethyl sulfoacetate (16.82 g, 100 mM) and POCl3 (30.67 g, 200 mM) was heated at 125° C. for 5 hours. The mixture was cooled and filtered, and excess POCl3 was removed to give ethyl chlorosulfonylacetate. The ethyl chlorosulfonylacetate (18.66 g, 100 mM) was added dropwise with stirring to a solution of 2,4,6-triisopropylphenol (22.1 g, 100 mM) in 50 mL CH2Cl2 maintained at 0° C. The mixture was stirred at room temperature for an additional 18 hours. The solvent was removed and the residue was redissolved in 100 mL ethyl acetate and washed with 1 N HCl and brine. The ethyl acetate was evaporated to provide ethyl (2,4,6-triisopropylphenoxysulfonyl)acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:67]=[N+:68]=[N-:69])(C)C.[SiH3]N=[N+]=[N-]>C(#N)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[N:12]([CH2:13][CH2:14][C:15]#[N:16])[N:69]=[N:68][N:67]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [N-]=[N+]=N[SiH3]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide (20 g, 51.2 mmol) in acetonitrile (220 mL) under nitrogen is added triphenyl phosphine (33.6 g, 128 mmol). The suspension is cooled to 0°. Diisopropyl azodicarboxylate (24.8 mL, 125.6 mmol) is placed in an addition funnel. In a separate addition funnel is placed trimethylsilyl azide (16.8 mL, 127.2 mmol). The two reagents are introduced dropwise, allowing the azoester to be added about 1 minute faster than the silyl azide and keeping the reaction temperature below 10°. The slightly yellow suspension is gradually (10°/hour) warmed up to 35°. The reaction is then monitored by TLC (ethyl acetate/hexane:3/1) until practically complete conversion is observed. A clear solution is then usually obtained. The excess of azide is destroyed by cooling the solution to 10° and adding sodium nitrite (3.2 g) in water (16 mL), followed by acetic acid (16 mL). The mixture is stirred at 20°-25° for at least 2 hours, until a nitrite-free aliquot of the acetonitrile layer shows a negative zide test (ferric chloride paper). The lower salt phase is separated and the organic layer is concentrated in vacuo at 45°. The semi-solid residue is dissolved in isopropanol at 80°. Some insoluble material is filtered from the hot solution. The title compound crystallizes at about 60° after seeding. The suspension is cooled to 25° within 2 hours then left at 0°-5° for 1 hour. The product is filtered, washed with cold ispropanol (3×20 mL) and dried under reduced pressure at 50° to constant weight to obtain (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1)#[N:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:31]#[N:32])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 30.8 mg (0.21 mmol) of 3-cyanophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 32 mg (62.1% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([OH:15])=O)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(C1NC=CN=1)([C:18]1[NH:19]C=CN=1)=O.CN.Cl>O1CCCC1>[CH3:18][NH:19][C:13]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)=[O:15]
Reactant: O=C(O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
250 mg 6-nitro-1H-indole-3-carboxylic acid are dissolved in 10 ml of tetrahydrofuran, combined with 240 mg carbonyl-diimidazole and stirred for 30 minutes at 60° C. Then 750 μl of a 2 M solution of methylamine in tetrahydrofuran is added and the mixture is stirred overnight at 60° C. Then 1 N hydrochloric acid is added and the precipitated solid is suction filtered. Then the solid is extracted from ethyl acetate, suction filtered and dried.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:15])=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[O:5][C:4]1=[O:16])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:10]1[CH:9]=[C:8]([F:15])[C:7]2[N:3]([CH2:1][CH3:2])[C:4](=[O:16])[O:5][C:6]=2[CH:11]=1
Reactant: CCn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCn1c(=O)oc2cc(N)cc(F)c21

Procedure:
Prepared from 3-ethyl-4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (Step 1, 1.05 g, 4.90 mmol), ammonium chloride (2.62 g, 49 mmol) and iron powder (1.09 g, 19.6 mmol) in ethanol (30 ml) and water (15 ml) according to the method of EXAMPLE 86, Step 7 (0.95 g, 99%).