Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[C:5]#[N:6].FC(F)(F)C(O)=O.[I:20]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:20][C:8]1[C:9]([CH3:11])=[N:10][C:3]([O:2][CH3:1])=[C:4]([C:7]=1[CH3:12])[C:5]#[N:6]
Reactant: COc1nc(C)cc(C)c1C#N
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C)c(I)c(C)c1C#N
Temperature: 0 °C
Yield: 94 %

Procedure:
2-methoxy-4,6-dimethyl-nicotinonitrile (1.0 g, 6.166 mmol) was disolved in 30 mL of anhydrous methylene chloride and then added with 6 mL of trifluoro acetic acid and N-iodosuccinimide (2.2 g, 9.248 mmol) in this order while stirring at 0° C. under the nitrogen atmosphere and then stirred again at room temperature for about 4 hours. The mixture was added with 60 mL of a saturated solution of sodium carbonate and 60 mL of a saturated solution of Na2S2O3 and then extracted twice with 80 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, and filtered. A silica gel column chromatography (5% EtOAc/Hexanes) was performed on the resulting residue and 1.67 g (94%) of 5-iodo-2-methoxy-4,6-dimethyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH2:11])=[S:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14](=O)[S:15][CH3:16]>C(O)C>[CH3:16][S:15][C:14]1[N:11]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[S:10][CH:13]=1
Reactant: CSC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(N)=S
Solvent: CCO
Product: CSc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 50 %

Procedure:
N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine (1.00 g, 3.45 mmol) and SnCl2.2H2O (3.10 g, 13.8 mmol) in ethyl acetate (35 mL) was refluxed for 2 h and then cooled to room temperature. The pH was adjusted to 9-10 by treatment with 5% aqueous NaHCO3. The mixture was subjected to extraction with EtOAc. The combined organic layers were washed with saturated brine and H2O and dried. The solvent was removed under reduced pressure to give 0.79 g (89%) of N4-(3-ethynylphenyl)quinazoline-4,6-diamine as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][OH:22].C[O-].[Na+].O>O1CCCC1>[CH3:21][O:22][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
2-(2-Chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 was dissolved in anhydrous tetrahydrofuran (4 mL). A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 1.0 mL, 0.5 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. To the reaction mixture was added water, and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-(2-methoxypyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (1-34, 60 mg, 70%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:10]([F:21])[CH:9]=1)=[O:6].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:17][CH:16]=2)=[C:10]([F:21])[CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccccc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension consisting of 3,4-dichloro-3′-fluoro-4′-phenoxybenzanilide (5.05 g, 13.4 mmol) and succinic anhydride (1.48 g, 14.8 mmol) in 1,2-dichloroethane (25 mL) was added aluminum chloride (6.26 g, 47.0 mmol) under ice cooling, and the resulting mixture was stirred at the same temperature for 5 minutes, and then at room temperature for 1.5 hours. The resulting reaction solution was poured into ice water, and the resulting solid was collected by filtration. To the solid was added 50% aqueous acetone (200 mL), and the resulting solution was refluxed for 0.5 hours, then cooled. The obtained solid was collected by filtration, to thereby yield 6.30 g of the title compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([C:36](O)=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)(=[O:23])=[O:22]>>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:36]([C:26]4[CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=[CH:28][C:27]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:37])[CH2:17][CH2:18]3)=[C:9]([F:19])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CC1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(S(=O)(=O)C4CC4)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine (Example W) and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 543.3 MH+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@@H:27]1[C@@H:31]([OH:32])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@@H:27]3[CH2:28][NH:29][CH2:30][C@H:31]3[OH:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Br)c2c1
Reactant: N[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CNC[C@H]3O)c2c1

Procedure:
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.13-8.10 (d, J=7.6 Hz, 1 H), 8.06 (s, 1 H), 7.95-7.90 (d, J=7.2 Hz, 1 H), 7.78-7.70 (m, 2 H), 7.65-7.58 (m, 2 H), 6.16 (s, 1 H), 5.3 (q, J=1.2 Hz, 2 H), 4.65-4.40 (m, 2 H), 4.50-4.40 (m, 2 H), 4.12-3.95 (m, 1 H), 3.80-3.68 (m, 3 H), 3.60-3.50 (m, 1 H), 3.48-3.40 (d, J=7.2 Hz, 1 H), 2.47 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CNC
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: CN(C)c1c([N+](=O)[O-])cnn1C
Yield: 100 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and dimethylamine gave N,N,1-trimethyl-4-nitro-1H-pyrazol-5-amine as a yellow solid (210 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 3.75 (s, 3H), 2.90 (s, 6H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(Br)c1NC1CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-bromo-2-fluoro-3-nitrobenzene (4.1 g, 18.6 mmol) and cyclopropanamine (1.29 mL, 18.6 mmol) in THF (10 mL) was stirred under N2 at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water, filtered on a pad of Celite™, washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo. Purification of the residue by flash chromatography on a silica gel column using 30 to 50% gradient of DCM in hexane as eluent gave 2-bromo-N-cyclopropyl-6-nitroaniline: LC-MS (ESI) m/z 259.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1ccccc1F
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3ccccc3F)c2C(N)=O)cc1
Yield: 89 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.91 g (7.01 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.47 g of 1-(4-t-butylbenzyl)-4-(2-fluorobenzoylamino)-5-imidazolecarboxamide (yield 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].CCOC(C)=O.O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(N2CCOCC2)cncc1[N+](=O)[O-]

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XLVI) (1 eq.), in neat morpholine in a sealed tube was heated at 120-140° C. overnight. The solution was poured into a mixture of EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4 and concentrated to get a residue. The crude product was purified on a silica gel column eluting with chloroform:MeOH gradient. The fractions containing product were mixed and concentrated under vacuum. The residue was triturated with hexane to give 3-morpholino-5-nitropyridin-4-amine (LIII).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:57]([O:61][C:62]([N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][NH2:72])[CH2:66][CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([O:61][C:62]([N:64]1[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][NH:72][C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:68][CH2:69]1)=[O:63])([CH3:60])([CH3:59])[CH3:58]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (519 mg, 1 mmol) in DMF (5 mL) was added HOBt (202 mg, 1.3 eq.), EDAC.HCl (288 mg, 1.5 eq.) and TEA (302 mg, 3 eq.). After stirring at rt for 30 mins, to the mixture was added 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (298 mg, 1.3 eq.). After stirring at 40° C. for 24 hours, the reaction was concentrated and the residue was purified on a silica gel column to give 4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH3:13][N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=1
Reactant: CN1CCCC1c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCCC1c1ccc(C=O)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 2-(4-bromophenyl)-1-methylpyrrolidine (0.45 g, 2 mmol) in dry THF (10 mL) was added dropwise n-BuLi (0.88 mL, 2.2 mmol, 2.5 mol/L in hexane) at −78° C., after the addition was completed the mixture was stirred for 1 h, then dry DMF (0.18 mL, 2.4 mmol) was added to the reaction system and stirring was continued for another 1 hr. Then the reaction mixture was partitioned between EtOAc and 1 N HCl, the aqueous solution was extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude product (0.28 g, yield 74%) as a yellow oil. The product was used directly in the next step without further purification. LC-MS (ESI) m/z: 189 (M+1)+.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][PH:8]([CH2:10][OH:11])=[O:9])[C:3]([OH:5])=[O:4].[C:12]([NH2:15])(=[O:14])[CH3:13]>O>[C:12]([NH:15][C:2](=[CH:6][CH2:7][PH:8]([CH2:10][OH:11])=[O:9])[C:3]([OH:5])=[O:4])(=[O:14])[CH3:13]
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Reactant: CC(N)=O
Solvent: O
Product: CC(=O)NC(=CC[PH](=O)CO)C(=O)O

Procedure:
A finely divided mixture of 2-oxo-4-(hydroxymethylphosphinyl)butanoic acid (1.80 g, 10 mmol) and acetamide (1.18 g, 20 mmol) were heated at 100° for 5 hours at 20 mm Hg. The mixture melted with evolution of water vapour. The final product was a yellow glass-like solid which was evacuated at 0.1 mm Hg at 100° for one hour to remove excess acetamide.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>CN(C)P(N(C)C)(N(C)C)=O>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:22])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(NCCC2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1ccc(NCCC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 4-(2-cyclohexylethylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 4-(2-cyclohexylethylamino)phenylacetate.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH2:9][CH:8]=[C:7]([O:10][CH3:11])[CH2:6][CH:5]=1)[CH3:3].[CH2:12]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH2:12]([O:19][C:20]([NH:1][C@H:2]([C:4]1[CH2:9][CH:8]=[C:7]([O:10][CH3:11])[CH2:6][CH:5]=1)[CH3:3])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC1=CCC([C@H](C)N)=CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1=CCC([C@H](C)NC(=O)OCc2ccccc2)=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the above diene (31) in THF (250 mL) was added in one portion N-(benzyloxycarbonyloxy) -succinimide (40 g) (slightly exothermic) followed by after 15 min triethylamine (23 mL). The reaction was stirred for 16 h at room temperature, evaporated, taken up in ethyl acetate, washed with 1N Na2CO3, saturated NaCl, dried over MgSO4 and evaporated to give crude product (32). TLC Rf 0.26 (10% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.24 (3H, d, J=7 Hz), 2.73(4H, br s), 3.55(3H, s), 4.27(1H, q), 4.64(1H, br s), 4.78(1H, br d), 5.12(2H, s), 5.64(1H, br s), 7.38 (5H, s).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=O)C.[C:12]([O:15][C:16](C)=[CH2:17])(=[O:14])[CH3:13]>>[C:12]([O:15][C@@H:16]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1ccc(Cl)cc1
Reactant: C=C(C)OC(C)=O
Product: CC(=O)O[C@H](C)c1ccccc1
Yield: 95 %

Procedure:
The procedure of Example 1 was repeated except that 3 molar equivalents of p-chlorophenyl acetate (a conventional acylating agent) was used in place of isopropenyl acetate in the presence of three times the amount of the enzyme catalyst used in Example 1 over a reaction period of 42 hours, to obtain (R)-1-phenylethyl acetate having an optical purity of higher than 99%, at a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][Cl:8])=[CH:5][S:4][C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH2:28])=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:9]([C:3]2[S:4][CH:5]=[C:6]([CH2:7][Cl:8])[C:2]=2[Cl:1])=[O:10])=[CH:17][CH:18]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1scc(CCl)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a solution of 3-chloro-4-chloromethyl-2-(chlorocarbonyl)thiophene (3.1 g, 13.5 mmol) in methylene chloride (40 mL) at 0° C. was added N-(4-chlorophenyl)-2-amino-5-chlorobenzamide (3.8 g, 13.5 mmol), followed after 5 minutes by pyridine (1.6 mL, 16 mmol). The mixture was warmed to ambient temperature. After 17 hours, the mixture was concentrated of all volatiles in vacuo. The resulting solid was triturated with water and a small amount of acetonitrile and dried in vacuo to afford 5.1 g (80% yield) of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a tan powder: NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 4.8 (s, 2) ppm.
Reaction SMILES: [OH:1][P:2]([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:3].[NH2:35][C@H:36]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:3][P:2]([CH2:4][CH:5]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([NH:35][C@H:36]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:37])=[O:7])([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:1]
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[C@H](NC(=O)C(Cc1ccccc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 71.9 %

Procedure:
The process is performed according to the operating conditions described in 1.8, starting with 300 mg (0.62 mmol) of 3-[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]-2-(phenylmethyl)propanoic acid synthesized in 1.7., and 219 mg (0.62 mmol) of phenylmethyl alaninate in the form of the p-toluenesulphonic acid salt. 288 mg of product are recovered (yield=71.9%).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[Cl:37]>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:26][C:25]=3[Cl:37])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][N:16](C=O)[CH3:17].C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([N:16]([CH3:17])[CH3:15])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Suspended the 6-bromoquinoline-2-carboxylic acid (1.0 g, 3.93 mmol) in CH2Cl2 (20 mL), added DMF (0.91 mL, 11.78 mmol) and cooled in an ice bath. Added oxalyl chloride (0.688 mL, 7.86 mmol) dropwise over a few min. Warmed to rt and stirred for 1 hr then bubbled in dimethylamine gas for several min. The dark amber mixture was stirred at rt overnight. In am, the solution was diluted with water and extracted with CH2Cl2 (3×). Washed extracts with brine (1×), dried over MgSO4, decolorized with charcoal, filtered, evaporated and dried under high vac, rt to afford the title compound (990 mg). LC/MS: m/e 279, 281 (M+H)+.