Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[C:16]([O:17][CH2:18][CH3:19])=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=[C:13]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[N:12]=1)=[O:10])[CH3:7]>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[C:16]([O:17][CH2:18][CH3:19])=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:14]=[C:13]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:30][CH:31]=2)[N:12]=1)=[O:10])[CH3:7]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)OCC)c(OCC)c(N3CCOCC3)n2)cc1
Yield: 25.2 %

Procedure:
Ethyl isocyanate (0.012 ml, 1.4 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in toluene (2 ml) and the mixture was reacted overnight at 80° C. The reaction mixture was extracted with EA, washed with brine. The crude was purified by chromatography to give a product (12 mg, 25.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1
Reactant: CO[C@@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: N
Product: CO[C@@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.3 g racemic 4-[4-Fluoro-2-((cis)-3-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (0.5 M in dioxan).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[C:26]([N:30]=[C:1]=[S:2])[N:27]=[CH:28][N:29]=2)=[CH:22][CH:23]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Product: S=C=Nc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 60 °C

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.666 g, 2.87 mmol) dichloromethane/N,N-dimethylformamide at room temperature was added 6-(4-chlorophenyl)pyrimidin-4-amine (0.59 g, 2.87 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-(4-chlorophenyl)-6-isothiocyanatopyrimidine (0.322 g, 1.300 mmol, 45% yield) as an orange oil. LCMS R.T.=2.82; [M]+=248.03.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:21][C:22]1[CH:27]=[C:26]([C:15]2[C:14]3[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 4-chloro-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester and 3-hydroxyphenylboronic acid according to the procedure of Example 1. MS (ES) m/z 359.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:12][CH2:13][O:14][CH3:15])[CH2:6][CH2:7][C:8]([CH3:11])([NH2:10])[CH3:9].[I:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24](S(C)=O)[N:23]([CH3:30])[C:22]2=[O:31]>CC(O)(C)C>[CH3:15][O:14][CH2:13][CH2:12][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7][C:8]([NH:10][C:24]1[N:23]([CH3:30])[C:22](=[O:31])[C:21]2[C:26](=[C:17]([I:16])[CH:18]=[CH:19][CH:20]=2)[N:25]=1)([CH3:11])[CH3:9]
Reactant: COCCN(CCOC)CCC(C)(C)N
Reactant: Cn1c(S(C)=O)nc2c(I)cccc2c1=O
Solvent: CC(C)(C)O
Product: COCCN(CCOC)CCC(C)(C)Nc1nc2c(I)cccc2c(=O)n1C
Temperature: 120 °C
Yield: 183.4 %

Procedure:
A glass microwave reaction vessel was charged with N1,N1-bis(2-methoxyethyl)-3-methylbutane-1,3-diamine (50 mg, 0.229 mmol) and 8-iodo-3-methyl-2-(methylsulfinyl)quinazolin-4(3H)-one (700b; 80 mg, 0.229 mmol) in tBuOH (0.5 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 120° C. for 45 min. Similarly another two batches (50 mg and 170 mg) were carried out. The three batches were combined and the solvent was removed. The residue was purified with silica gel chromatography (eluted with 0-5% MeOH in DCM) to give 2((4-(bis(2-methoxyethyl)amino)-2-methylbutan-2-yl)amino)-8-iodo-3-methylquinazolin-4(3H)-one (210 mg, 0.42 mmol). MS (ESI, pos. ion) m/z: 503 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][Si](C(C)(C)C)(C)C.[Li]CCCC.[CH3:22][N:23]([CH2:25][CH:26]1[C:33](=[O:34])[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27]1)[CH3:24]>C1COCC1.CCCCCC>[CH3:24][N:23]([CH2:25][CH:26]1[C:33]([C:2]2[CH:3]=[C:4]([OH:5])[CH:13]=[CH:14][C:15]=2[F:16])([OH:34])[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27]1)[CH3:22]
Reactant: CN(C)CC1CC2(CCC1=O)CC2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1CC2(CC2)CCC1(O)c1cc(O)ccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (472 mg, 1.547 mmol) in THF (40 mL) to −78° C. under N2. Then add dropwise a solution of n-BuLi (0.63 mL, 1.547 mmol) in hexane via syringe to the reaction solution. After being stirred at −78° C. for 2 hour, add dropwise a solution of 5-Dimethylaminomethyl-spiro[2.5]octan-6-one (70 mg, 0.387 mmol) in THF (1 mL) to the reaction mixture and stir the mixture at −78° C. for additional 2 hours. Quench the reaction with 20 mL of diluted HCl (2N), and stir at ambient temperature for 2 hours. Basify the resultant mixture with K2CO3 to pH=9, and extract with EtOAc (30 mL×2). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH=10:1) to afford 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol as white solid (41 mg, yield: 36.3%). MS (m/z): 294 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccccc1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7](C)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Cl:18]C1C(OC)=CC=CC=1N>>[Cl:18][C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[C:12]2[OH:14]
Reactant: COc1cccc(N)c1Cl
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(O)c2ccc(OC)c(Cl)c2n1

Procedure:
8-Chloro-2-ethoxy-7-methoxy-quinolin-4-ol was synthesized according to the method presented in the synthesis of 2-Ethoxy-7-methoxy-8-methyl-quinolin-4-ol in Example 132 with the exception of utilizing 2-Chloro-3-methoxy-aniline.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8](Br)[C:9]([OH:11])=[O:10].[CH2:13]([N:15]1[C:19]([C:20]([C:22]2[CH:27]=[C:26]([OH:28])[C:25]([OH:29])=[C:24]([Cl:30])[C:23]=2[Cl:31])=[O:21])=[CH:18][CH:17]=[N:16]1)[CH3:14].Cl>CN(C)C=O.O>[Cl:30][C:24]1[C:25]2[O:29][CH:8]([C:9]([OH:11])=[O:10])[O:28][C:26]=2[CH:27]=[C:22]([C:20]([C:19]2[N:15]([CH2:13][CH3:14])[N:16]=[CH:17][CH:18]=2)=[O:21])[C:23]=1[Cl:31]
Reactant: O=C(O)C(Br)Br
Reactant: CCn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Reaction time: 5 h
Yield: 38.1 %

Procedure:
6.9 g of potassium carbonate and 2.83 g of dibromoacetic acid are added to a solution of 3.01 g of (1-ethylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone in 30 ml of dimethylformamide and the mixture is at 80° C. for 5 hours. After cooling the reaction mixture, water is added thereto and the mixture is adjusted to pH 1 by addition of 6N hydrochloric acid. The resultant crystals are collected by filtration, washed with water and recrystallized from dimethylformamide-water to give 1.36 g of 4,5-dichloro-6-(1-ethyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:18])[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:30])([F:29])[CH2:27]I.O>CN(C=O)C>[F:25][C:26]([F:30])([F:29])[CH2:27][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18]
Reactant: O=c1cnc(-c2ccccc2)c2ccccc2n1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 5-phenyl-1,4-benzodiazepine-2-one (50 g, 0.211 mole) in DMF (100 mL) was treated with cesium carbonate (103.5 g, 0.317 mole) and trifluoroethyl iodide (109.7 g, 0.525 mole). The mixture was stirred at 50° C.-60° C. overnight. The reaction mixture was then poured into water (2 L) and extracted with ethyl acetate (3×1 L). The combined ethyl acetate fractions were dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The material was chromatographed on silica gel (1.5 Kg) eluting with 1:1 ethyl acetate/heaxane. The combined pure fractions were concentrated at reduced pressure. The residue was swished with warm ethyl ether, cooled and filtered to give the product. MP=130°-131° C.; 1H NMR CDCl3, δ7.65-7.60 (m, 2H), 7.60-7.45 (m, 5H), 7.40-7.20(m, 2H), 5.25 (dq, J=14, 8.6 Hz, 1H), 4.82(d, J=10.5 Hz, 1H), 4.15 (app sextet, J=8.6 Hz, 1H), 3.81 (d, J=10.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:25]=[CH:24][C:15]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]=2[N+:26]([O-:28])=[O:27])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-amino-3-nitrobenzophenone and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.61 (bs, 1H), 9.12 (d, J=8.7, 1H), 9.06 (d, J=2.4, 1H), 8.79 (d, J=1.8, 1H), 8.28-8.25 (m, 1H), 8.23-8.19 (m, 1H), 7.82-7.81 (m, 1H), 7.80-7.79 (m, 1H), 7.67-7.64 (m, 1H), 7.58-7.53 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=S)[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12](C)([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)[CH3:3].[C:24](C1C=C(C=C(C(C)(C)C)C=1O)C=O)(C)(C)C.S1CC(=O)NC1=S.CC(C1C=C(C=C2SCNC2=O)C=C(C(C)(C)C)C=1O)(C)C.CC(C1C=C(CC2SCNC2=O)C=C(C(C)(C)C)C=1O)(C)C.CC(C1C=C(CC2SC(=S)NC2=O)C=C(C(C)(C)C)C=1O)(C)C>C(O)(=O)C>[CH3:3][CH:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH3:24])[C:18]2=[O:23])[CH:8]=[C:9]([CH:12]([CH3:13])[CH3:14])[C:10]=1[OH:11])[CH3:1]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CC2SCNC2=O)cc(C(C)(C)C)c1O
Solvent: CC(=O)O
Product: CC(C)c1cc(C=C2SCN(C)C2=O)cc(C(C)C)c1O

Procedure:
The aryl-substituted rhodanine derivatives of formula I are either known in the art or may be prepared by any of a number of well-known procedures. For example, Teuber et al., Leibigs Ann. Chem., 757 (1978) disclose 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-thiazolidinone (referred to in the following discussion as Compound A). The compound is prepared by reacting 3,5-di-tert-butyl-4-hydroxybenzaldehyde with rhodanine at reflux temperature in glacial acetic acid using fused sodium acetate as catalyst. 5-[[3,5-Bis(1,1-dimethylethyl) -4-hydroxyphenyl]methylene]-4-thiazolidinone (Compound B), 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone (Compound C) and 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-2-thioxo -4-thiazolidinone (Compound D) can be prepared from Compound A as follows.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:24]([NH2:26])=[O:25])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.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.[Cu]I>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:24]([NH2:26])=[O:25])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1
Reactant: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(I)ccc12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Temperature: 50 °C

Procedure:
A mixture of 1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-iodo-5H-pyrido[4,3-b]indole-4-carboxamide (0.19 g, 0.40 mmol), TMS acetylene (0.12 g, 1.2 mmol), Pd(PPh3)4 (0.047 g, 0.040 mmol), CuI (0.015 g, 0.081 mmol), and TEA (0.082 g, 0.81 mmol) in DMF (4 mL) was purged with nitrogen for 5 min, heated to 50° C. overnight, and cooled to room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-azetidin-1-yl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example C15) by hydrogenation with 5% Pt/C according to the general procedure J (method a).
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10](C(OC(C)(C)C)=O)[C:11]1[C:12]2[C:13]3[C:14](=[N:26][N:27]([CH2:29][C:30]4[C:35]([CH3:36])=[C:34]([O:37][CH3:38])[C:33]([CH3:39])=[CH:32][N:31]=4)[N:28]=2)[CH:15]=[C:16]([CH2:21][C:22](OC)=[O:23])[C:17]=3[CH2:18][S:19][N:20]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O1CCCC1.[OH-].[Na+]>CO>[OH:23][CH2:22][CH2:21][C:16]1[C:17]2[CH2:18][S:19][N:20]=[C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[C:12]3=[N:28][N:27]([CH2:29][C:30]4[C:35]([CH3:36])=[C:34]([O:37][CH3:38])[C:33]([CH3:39])=[CH:32][N:31]=4)[N:26]=[C:14]([C:13]=23)[CH:15]=1
Reactant: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2nc3cc(CCO)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Lithium borohydride (67 mg) was added to a mixture composed of methyl {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetate of Example 111 (957 mg) and dehydrated tetrahydrofuran (18 ml) under ice-cooling. The mixture was stirred at 0° C. for two hours, and then returned to room temperature and stirred overnight. The mixture was ice-cooled again and lithium borohydride (33 mg) was added, followed by stirring at 0° C. for two hours. Methanol (6 ml) and a 1 N sodium hydroxide solution (6 ml) were added to the reaction mixture. Then, the mixture was returned to room temperature and stirred for four hours. The organic solvent in the reaction mixture was evaporated under reduced pressure. Then, a 0.2 N hydrochloric acid solution was added, followed by extraction with chloroform. The organic layer was washed with brine, and then dried over magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (301 mg, 40%) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10](=[N:24][O:25][CH3:26])[CH:11]2[CH:16]3[CH:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH3:26][O:25][N:24]=[C:10]([CH:11]1[CH:16]2[CH:12]1[CH2:13][NH:14][CH2:15]2)[C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=1
Reactant: CON=C(c1ccc(Cl)c(Cl)c1)C1C2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CON=C(c1ccc(Cl)c(Cl)c1)C1C2CNCC21
Yield: 198.2 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 6-((3,4-dichlorophenyl)(methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (90 mg, 0.23 mmol) obtained in step-1 of example 3 in dry DCM (5 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 3-azabicyclo[3.1.0]hexan-6-yl(3,4-dichlorophenyl)methanone O-methyl oxime (65 mg, 86%) as a white solid as a mixture of isomers.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:14][CH2:13]2)(=O)=O)=CC=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:25])=[C:21]([CH:24]=1)[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:11][C@@H:12]2[O:14][CH2:13]2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A mixture of (R)-glycidyl 4-toluenesulphonate (10.0 g), 5-chloro-2-hydroxybenzaldehyde (8.92 g) and potassium carbonate (7.87 g) in dimethylformamide (200 ml) was stirred and heated at 60° C. for 5 hours then allowed to stand for 18 hours. Water (200 ml) was added and the resultant mixture extracted with ether (3×150 ml). The combined ether extracts were washed with brine (3×150 ml), dried over magnesium sulphate and the solvent evaporated. The oily residue was purified by flash chromatography on silica eluting with a 25:1 followed by a 10:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate to give (R)-5-chloro-2-(2,3-epoxypropoxy)benzaldehyde (8.1 g) contaminated with ~10% of an unknown impurity, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:35]=[C:36]=NC2CCCCC2)CCC[CH2:31][CH2:30]1.CNCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:6]([C:7]([N:35]([CH3:36])[CH2:29][CH2:30][CH3:31])=[O:9])[CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)c1cc(OC(F)F)cc(C(=O)O)c1
Agent: CCCNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(OC(F)F)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Treat a solution containing crude 5-difluoromethoxy-isophthalic acid monomethyl ester (2.5 g, 10 mmol) in THF (20 mL) at room temperature with 1-hydroxybenzotriazole hydrate (1.62 g, 12 mmol), 1,3-dicyclohexylcarbodiimide (12 mL, 1 N, 12 mmol), and n-methylpropylamine (1.23 mL, 12 mmol). Stir at room temperature overnight, filter through a filtering agent, wash with 1: 1 ethyl acetate:hexanes (50 mL). Concentrate the combined filtrates and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound as a solid (1.6 g, 53%).
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC(COC3C=CC=CC=3)=O)C(=[O:9])N2[C@H]1C(O)=O.CN(C1C=CC=CN=1)C.[CH2:34]1[CH2:39][CH2:38][CH:37]([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:36][CH2:35]1>C(Cl)Cl>[CH:43]1([NH:42][C:41]([NH:40][CH:37]2[CH2:36][CH2:35][CH2:34][CH2:39][CH2:38]2)=[O:9])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 4 °C
Reaction time: 144 h

Procedure:
In a 10 mL round-bottomed flask, 0.400 g (0.178 mmol) of the poly(PEG-Lys) having ethanolamide pendant functional groups of Example 6 was dissolved in 4 mL of methylene chloride. To this solution was added 0.094 g (0.267 mmol) of Penicillin V (Sigma) and 0.008 g (0.065 mmol) of dimethylaminopyridine (Aldrich). The reaction mixture was cooled in an ice water bath and then 0.048 g (0.232 mmol) of DCC was added. After a few hours at 0° C., the reaction vessel was moved to a cold room maintained at 4° C. and allowed to stir for almost six days. A precipitate of dicyclohexyl urea formed and was removed by filtration. The drug conjugate was precipitated with cold ether. About 0.250 g of crude product was obtained which was purified by reprecipitation twice from isopropanol. TLC in methanol showed absence of free drug.
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8]Cl)=[O:6]>C(#N)C>[CH3:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][I:1])=[O:6]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)C(=O)OCI
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
Sodium iodide (dried) (15.0 g, 100 mmol) was added in one portion to a solution of 2,2-dimethylpropanoic acid, chloromethyl ester (10.0 g, 66.7 mmol) in dry acetonitrile (80 mL) at RT under argon. The heterogeneous reaction was stirred at RT for 6 h, then concentrated in vacuo. The residue was partitioned between toluene (150 mL) and 5% sodium bisulfite (40 mL). The organic layer was washed with 5% sodium bisulfite (40 mL) and water (20 mL), then dried over MgSO4. Evaporation gave title iodide (12.1 g, 75%) as a pale yellow oil.