Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]([OH:22])=[O:21])=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.C(=O)(O)[O-].[Na+].[CH2:32](O)[CH3:33]>>[CH2:32]([O:21][C:20]([C:19]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=12)=[O:22])[CH3:33]
Reactant: O=C(O)c1c(-c2ccccc2)nn2c1-c1ccccc1CC2
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2)nn2c1-c1ccccc1CC2
Reaction time: 0.25 h

Procedure:
2-Phenyl-5,6-dihydro-pyrazolo[5,1-a]isoquinoline-1-carboxylic acid (7.48 g.) is stirred at 90° C. for three hours with 3.77 ml. of SOCl2. The thionyl chloride excess is eliminated in vacuo and the residual acid chloride is dissolved in 80 ml. of ethanol at 40°-50° C. After 15 minutes, the reaction mixture is neutralized by addition of aqueous sodium bicarbonate and the solvent is eliminated by distillation. The residue is extracted with ethyl ether and, after evaporation of the organic solution, is crystallized from isopropyl ether. Yield of title compound 2.47 g.; m.p. 84°-5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH3:22])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: COc1ccc([C@@H](C)N)cc1
Product: COc1ccc([C@@H](C)NC(=O)c2ccc(OC)c(C)c2)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-(R)-(4-methoxy-phenyl)-ethylamine. MS (M+H, 300.1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:15])[C:11](OC)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C[AlH]CC(C)C)C>CCOCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:15])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: C=C(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 43.3 %

Procedure:
To a stirred solution of methyl 2-(4-nitrophenyl)acrylate (4.0 g, 19.323 mmol, 1.0 eq) in ether (40 mL) was added DIBALH (20% solution in toluene) (40 mL, 57.97 mmol, 3.0 eq) at −78° C., then the mixture was allowed to warm to 0° C. over a period of 2 h, then the mixture was quenched with water (1.0 mL), NaOH solution (15%) (3 mL), extracted with ether (20 mL×2), washed with water (20 mL), brine (20 mL), dried (MgSO4) and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (3:7) as eluent to get 2-(4-nitrophenyl)prop-2-en-1-ol (1.5 g, 43%, oil); TLC system: EtOAc/PE (1:1), Rf: 0.4).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23]([OH:25])=O)[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:72]1([CH2:77][C@H:78]2[NH:81][C:80](=[O:82])[C@H:79]2[NH2:83])[CH:76]=[N:75][CH:74]=[N:73]1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[N:72]1([CH2:77][C@@H:78]2[C@H:79]([NH:83][C:23](=[O:25])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:16])[CH2:18][CH2:19]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[S:29][CH:30]=3)[C:80](=[O:82])[NH:81]2)[CH:76]=[N:75][CH:74]=[N:73]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)cs1
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (prepared according to Yamawaki et al. Bioorg. Med. Chem. Lett. 2007, 15, 6716-6732) (150 mg, 0.279 mmol) in DCM:DMF (1:1, 2.8 mL) at 0° C. was added DIPEA (146 μL, 0.837 mmol) followed by HATU (127 mg, 0.335 mmol). To the resulting solution, after 20 min, was added a solution of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (51 mg, 0.31 mmol) in DCM. After 1 h of stirring it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (147 mg, 77%). LCMS: Rt=0.98 min, m/z=687.1 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[N:16]1.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:23][CH:22]=2)=[N:16]1
Reactant: C#CC(C)(C)C
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC(C)(C)C)cc3)[nH]c2=O)c1
Yield: 27.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (Intermediate-98, 0.060 g, 0.120 mmol), 3,3-dimethylbut-1-yne (0.014 g, 0.181 mmol), TBAF (0.094 g, 0.362 mmol), bis(triphenylphosphine)palladium (II) chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.015 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.03 (s, 6H), 1.30 (s, 9H), 2.50 (m, 1H), 4.27 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 3H), 7.61 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.38 (m, 1H); MS (m/z): 449.9 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[O:26])[CH2:3][N:4]([CH3:25])[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:23][CH3:24])=[CH:12][N:13]2[C:16]2[N:21]=[CH:20][C:19](Br)=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:56]=[C:55]([O:57][CH2:58]C)[CH:54]=[CH:53][N:52]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2](=[O:26])[CH2:3][N:4]([CH3:25])[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:23][CH3:24])=[CH:12][N:13]2[C:16]2[N:21]=[CH:20][C:19]([C:51]3[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][N:52]=3)=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOc1ccnc(Br)c1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N(C)CC(N)=O)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1ccnc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
PdCl2(dppf) (0.094 g, 0.115 mmol) was added under an argon atmosphere to a suspension of N-(2-amino-2-oxo ethyl)-1-(5-bromopyrimidin-2-yl)-N-methyl-3-(methylthio)-1H-indole-6-carboxamide (1.0 g, 2.3 mmol), bis(pinacolato)diboron (0.655 g, 2.58 mmol) and potassium acetate (0.68 g, 6.91 mmol) in dioxane (40 mL) and the mixture was stirred at 110° C. for 1 h. After cooling to room temperature, 2-bromo-4-ethoxy-pyridine (0.65 g, 3.45 mmol), a 2M potassium carbonate solution (8.0 mL) and tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.115 mmol) were added. The reaction mixture was stirred at 100° C. for 16 h, and then filtered through celite. The filter was washed with methanol/dichloromethane (1:9), the filtrate was concentrated and the residue purified by flash column chromatography [silica; methanol/dichloromethane=3.5:96.5]. White solid. Yield: 0.185 g
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=2)[CH2:23]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2CC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to afford a white solid. UPLC-MS (condition 1) tR=2.46 min, m/z=459.1-460.1 [M+H]+, m/z=457.2-458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76 (d, J=3.91 Hz, 1H) 1.82-1.93 (m, 1H) 2.65-2.72 (m, 1H) 2.68 (s, 3H) 3.00-3.11 (m, 2H) 3.18-3.27 (m, 1H) 4.17-4.25 (m, 1H) 4.86 (d, J=3.67 Hz, 1H) 6.96 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.81 (d, J=2.20 Hz, 1H) 7.83-7.88 (m, 2H) 7.92 (dd, J=8.80, 2.20 Hz, 1H) 8.73 (s, 2H) 10.08 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[C:8]1[C:14](=O)[C:13]2[N:16]3[C@@](OC)([C@H](COC(N)=O)[C:12]=2[C:10](=O)[C:9]=1[O:30][CH3:31])[C@H]1N[C@H]1C3>>[CH3:31][O:30][C:9]1[CH:10]=[CH:12][C:13]([NH2:16])=[CH:14][CH:8]=1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N)cc1

Procedure:
This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted. From 77 mg. of mitomycin A and 27 mg. of 4-methoxyaniline was obtained 70 mg. (74% yield) of the desired product having a melting point of 103°-108° C. (decomposition) and providing the following analysis:
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([Cl:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:16])[F:17])[C:8]([Cl:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Yield: 77.9 %

Procedure:
A mixture of 3-acetamido-6-chloro-4-nitrobenzotrifluoride (780 mg, 2.76 mmol) in concentrated HCl (3 mL) was refluxed overnight and it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 517 mg (78% ) of 3-amino-6-chloro-4-nitrobenzotrifluoride. 1H NMR (CDCl3): δ 6.205 (S, 2H); 7.206 (s, 1H); 8.263 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.[OH:16][CH:17]([C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)C>[OH:16][CH:17]([C:25]1[CH:26]=[C:27]([O:33][CH3:34])[C:28]([C:31]#[N:32])=[CH:29][N:30]=1)[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:14][CH:12]([OH:13])[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:15])[O:3][C@@H:2]([CH3:1])[CH2:11]3)[CH2:23][CH2:24]1
Reactant: COc1cc(C(O)CN2CCNCC2)ncc1C#N
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3)C[C@H](C)OC4=O)CC2)ncc1C#N
Temperature: 140 °C

Procedure:
A Pyrex® vessel was charged with magnetic stirring bar and 3-(S)-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 23) (78 mg, 0.38 mmol), and isomer A of 6-(1-hydroxy-2-piperazin-1-yl-ethyl)-4-methoxy-pyridine-3-carbonitrile (INTERMEDIATE 38) (100 mg, 0.38 mmol), and 2 mL of ethanol. The resulting mixture was heated in the microwave at 140° C. for 1 hour. The mixture was cooled to room temperature and the solvent was evaporated and the resulting residue was purified by preparative TLC eluting with 10% methanol/dichloromethane. The resulting mixture of two diastereomers was separated to the individual isomers by SFC-HPLC using a Chiralcel® AD-3 column.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[O:21][CH:20]=[N:19][C:18]=2[C:22](O)=[O:23])[CH:14]=[CH:15][CH:16]=1)([CH3:6])([CH3:5])[CH3:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:50][C:51]1([C:56]2[O:60][C:59]([CH2:61][N:62]3[CH:66]=[CH:65][C:64]([NH2:67])=[N:63]3)=[CH:58][CH:57]=2)[O:55][CH2:54][CH2:53][O:52]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH3:50][C:51]1([C:56]2[O:60][C:59]([CH2:61][N:62]3[CH:66]=[CH:65][C:64]([NH:67][C:22]([C:18]4[N:19]=[CH:20][O:21][C:17]=4[C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:9][O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:26])[CH3:25])[CH:12]=4)=[O:23])=[N:63]3)=[CH:58][CH:57]=2)[O:55][CH2:54][CH2:53][O:52]1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(-c2ocnc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1(c2ccc(Cn3ccc(NC(=O)c4ncoc4-c4cccc(CCO[Si](C)(C)C(C)(C)C)c4)n3)o2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-{3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenyl}-oxazole-4-carboxylic acid (130 mg, 0.37 mmol) in CH2Cl2 (2.7 mL) was treated sequentially with DMAP (11 mg, 0.09 mmol), HOBt (60 mg, 0.45 mmol), EDC (179 mg, 0.94 mmol) and DIPEA (0.25 mL, 1.50 mmol) and the reaction mixture was stirred at rt for 1 h. A solution of 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine (93 mg, 0.37 mmol) in CH2Cl2 (1.0 mL) was then added and the reaction mixture was stirred at rt for 48 h. CH2Cl2 (10 mL) was added followed by water (10 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (1:2 hept-EA) gave the title compound as a colorless oil. TLC: rf (1:2 hept-EA)=0.26. LC-MS-conditions 02: tR=1.22 min, [M+H]+=579.74.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[F:12].Cl>C1COCC1.[OH-].[Na+]>[Br:10][C:8]1[C:7]([Cl:11])=[CH:6][C:5]([F:12])=[C:4]([CH:9]=1)[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Br)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(Cl)cc1F
Yield: 100.1 %

Procedure:
5-Bromo-4-chloro-2-fluoro-benzoic acid methyl ester (14.0 g, 52.4 mmol) was stirred vigorously in a mixture of THF (250 ml) and 1N NaOH (200 ml) for 16 hrs. The mixture was acidified to pH 3 with 6N HCl, concentrated partially to remove THF and then extracted with ethyl acetate. The organic phase was washed with water and brine and was dried over Na2SO4. The filtrate was concentrated to yield 5-bromo-4-chloro-2-fluoro-benzoic acid (13.3 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[CH2:15]([O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[NH:22])[CH2:16][CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:13]([C:4]1[N:3]=[C:2]2[N:22]=[C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH2:15][CH2:16][CH3:17])[NH:23][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc(CC)nc1Cl
Reactant: CCCOc1ccccc1C(=N)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(CC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 28 reaction of ethyl 4-chloro-2-ethyl-5-pyrimidine carboxylate (0.86 g) with 2-propoxybenzamidine (from sodium, 0.1 g, in ethanol, 10 ml, and 2-propoxybenzamidine methanesulphonate, 1.20 g) and triethylamine (0.4 g) in acetonitrile (25 ml) for 3 days at ambient temperature yielded a crude product, which was recrystallized twice from 2-propanol-ether to yield the title compound, 95 mg, m.p. 118-119° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:8]=1[C:9]#[N:10]>CCOC(C)=O.CCO.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH:3]2[CH2:4][CH:2]2[CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: CC1CC1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CC1COc1cccc(N)c1C#N
Yield: 79.1 %

Procedure:
A solution of 2-((2-methylcyclopropyl)methoxy)-6-nitrobenzonitrile (example 254c) (0.29 g, 1.25 mmol) in EtOAc/EtOH 1:1 (30 mL) was hydrogenated in an H-cube apparatus using 10% Pd/C as catalyst. The solution was evaporated to give 2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile (0.20 g, 79%) as a yellow oil. MS 203 (MH+).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1C=CC=CC=1>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(C)=O)c1ccccc1-c1ccccc1
Yield: 76.8 %

Procedure:
Analogously to Example 47, 16.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 7.3 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 4.4 g of acetyl chloride to obtain, as reaction product, 14.0 g (76.2% of theory) of ethyl 4-[N-(biphenyl-2-yl)acetamido]butyrate as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude product obtained from isopropyl alcohol yields 10.1 g (79.0% of theory) of 4-[N-(biphenyl-2-yl)acetamido]butyric acid, MP 124° to 125°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]=[CH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[O:38]1[CH:17]2[CH:16]1[CH2:15][CH2:14][N:13]([C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])=[CH:25][CH:24]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)N2CCC=Cc3ccccc32)cc1)c1ccccc1Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCC3OC3c3ccccc32)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
1-[4-(2-Chlorobenzoylamino)benzoyl]-2,3-dihydro-1H-benzazepine (4.7 g) is dissolved in dichloromethane (50 ml) and thereto is added 80% m-chloroperbenzoic acid (3 g). The mixture is stirred at room temperature overnight. The dichloromethane layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 4,5-epoxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (4.26 g) as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][C@@H:35]1[C:53](=[O:54])[N:37]2[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]3[S:45][C:46]([CH3:49])=[N:47][N:48]=3)[CH2:40][S:41][C@H:36]12>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([NH:34][C@@H:35]2[C:53](=[O:54])[N:37]3[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]4[S:45][C:46]([CH3:49])=[N:47][N:48]=4)[CH2:40][S:41][C@H:36]23)=[O:18])=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cc4ccc(CNC(=O)OC(C)(C)C)s4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
The starting material is prepared as follows: A solution of 4.08 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid in 200 ml of methylene chloride containing 1.65 ml of 4-methyl-morpholine is cooled to -20° under exclusion of moisture and treated dropwise with 1.95 ml of chloroformic acid isobutyl ester. After 30 minutes a solution of 5.16 g of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 7.20 ml N,O-bis-(trimethylsilyl)-acetic acid amide in 150 ml of methylene chloride is added, whereupon the reaction mixture is stirred during one hour at -20° and during four hours while the temperature is allowed to slowly rise to room temperature and is then evaporated under reduced pressure. The residue is dissolved in water with the addition of sodium hydrogen carbonate until the pH reaches 8. The solution is washed with ethyl acetate, the separated aqueous layer is acidified to pH 2 with aqueous phosphoric acid of 20% strength and is extracted with ethyl acetate. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. One thus obtains the 7β-[2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid; thin layer chromatogram (silicagel): Rf=0.40 (system: n-butanol/acetic acid/water 45:45:10), ultraviolet absorption spectrum (ethanol): λmax 244 mμ (ε=16900); infrared absorption spectrum (in mineral oil): characteristic bonds at 2.93μ, 5.60μ, 5.90μ, and 6.55μ.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH2:4][NH:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:30]1([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:15]3[N:14]=[C:13]([CH2:12][CH2:11][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]5[C:10]=4[C:2](=[O:1])[NH:3][CH2:4]5)[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=3)=[CH:29][CH:28]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc5c4C(=O)NC5)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2cccc(CCc3nc(Nc4ccc(N5CCNCC5)cc4)ncc3C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
tert-Butyl 4-(4-((4-(2-(3-oxoisoindolin-4-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I63) (0.080 g, 0.137 mmol) was dissolved in DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.210 mL, 2.75 mmol) was added to the solution and the reaction was stirred at room temperature for 1 hour and then at 35° C. for another 30 minutes. More trifluoroacetic acid (0.100 mL) was added and the reaction was further stirred at 35° C. for another 30 minutes. Volatiles were removed in vacuo then EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give an oily solid which was taken up in DCM (˜10 mL) and concentrated in vacuo. The process was repeated twice after which the sample was further dried on high-vacuum to give the title compound (15) (0.050 g, 75% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.94 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.59-7.52 (m, 2H), 7.47-7.36 (m, 2H), 7.23-7.11 (m, 1H), 6.87 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 3.56 (t, J=7.6 Hz, 2H), 3.11 (t, J=7.4 Hz, 2H), 3.01-2.95 (m, 4H), 2.86-2.79 (m, 4H). LCMS Method A: rt 4.40 min; m/z 483.8 [M+H]+.