Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:28][C:29]([F:32])([F:31])[F:30])=[C:8]([NH:10][C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[C:21]([C:25]([NH2:27])=[O:26])=[N:22][N:23]([CH3:24])[C:14]=4[C:13]=3[N:12]=2)[CH:9]=1)([O-])=O.CO>O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:28][C:29]([F:30])([F:32])[F:31])=[C:8]([NH:10][C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[C:21]([C:25]([NH2:27])=[O:26])=[N:22][N:23]([CH3:24])[C:14]=4[C:13]=3[N:12]=2)[CH:9]=1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc([N+](=O)[O-])ccc3OC(F)(F)F)ncc1CC2
Agent: [Fe]
Solvent: O
Solvent: CO
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(N)ccc3OC(F)(F)F)ncc1CC2

Procedure:
To a suspension of 8-(5-nitro-2-trifluoromethoxy-phenylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (630 mg, 1.4 mmol) in methanol (6 mL) ammonium chloride (240 mg, 4.3 mmol) in water (25 mL) and iron (397 mg, 7.4 mmol) were added. The mixture was heated under reflux for 3 hours until HPLC revealed the disappearance of the starting material. The solvent was removed and the crude was diluted with trifluoroethanol. Iron was removed and the filtrate was concentrated to give the final compound as a light brown solid in quantitative yield.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:6][CH3:7])=[N:4][CH3:5].Cl.[C:9](Cl)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:7][NH:6][C:3]1[N:4]([CH3:5])[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:1][N:2]=1
Reactant: CN=C(NC)NN
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CNc1nnc(-c2cccnc2)n1C

Procedure:
A mixture of N-amino-N′,N″-dimethyl-guanidine (500 mg, 2.17 mmol) [J. Amer. Chem. Soc.; 1951; p. 1858] and nicotinoyl chloride hydrochloride (385 mg, 2.17 mmol) in pyridine (10 mL) was refluxed o.n. Aq. sat. K2CO3 was added and the mixture extracted with CHCl3. The organic phase was dried and concentrated. The crude product 240 mg (61%) was used in the next step without further purifications.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[C@@H:13]([CH2:14][F:15])[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[C@@H:13]([CH2:14][F:15])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CF)[C@](C)(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@]1(C)CNC[C@@H]1CF

Procedure:
To a solution of (3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoromethyl-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidine (1.35 g, 4.01 mmol) in ethanol (30 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 1.30 g), and the suspension was stirred in an oil bath at 40° C. for 12 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 932 mg (quantitative) of the crude target compound as a colorless transparent syrup substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:5]2=1.C1C(=O)N([Cl:40])C(=O)C1>>[Cl:40][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[CH:17]=1)=[CH:3][C:2]([CH3:1])=[N:11][CH:10]=3
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Cl)cc21
Yield: 45.6 %

Procedure:
(S)-tert-butyl (1-((2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.05 g, 0.114 mmol), prepared as described in Example 67, Part F, was subjected to chlorination using NCS (0.018 g, 0.137 mmol), using the procedure described in Example 20, Part A, to give (S)-tert-butyl (1-((9-chloro-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.052 mmol, 45% yield) as colorless oil. LC/MS (ESI) m/e 474.7 [(M+H)+, calcd for C25H32ClN3O4 474.2]; LC/MS retention time (method H): tR=0.94 min.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]2[O:25][C:26]([CH2:29]Cl)=[N:27][N:28]=2)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2[O:25][C:26]([CH2:29][N:5]3[C:6]4[C:11](=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])=[N:27][N:28]=2)[CH:21]=[N:20][CH:19]=1
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=1.7 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.48 (s, 1H), 8.16 (s, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 6.05 (s, 2H), 3.07 (t, J=7.6 Hz, 2H), 1.78-1.67 (m, 2H), 0.96 (t, J=7.6 Hz, 3H); MS (ES) m/z 448 (M+1).
Reaction SMILES: [OH:1][NH:2][CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:38](O)(=[O:40])[CH3:39].C(OC(=O)C)(=O)C>C1COCC1>[C:38]([N:2]([OH:1])[CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7])(=[O:40])[CH3:39]
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(O)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.100 g, 0.192 mmol) and acetic acid (2 mL) in THF (20 mL) was added acetic anhydride (0.018 mL, 0.192 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from EtOH-ethyl acetate-diethyl ether-hexane to give the title compound as a white powder (0.085 g, 79%).
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:15][C:16]1([CH3:24])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH:17]1[OH:23].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:23][CH:17]1[C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20][C:16]1([CH3:24])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1CN1C(=O)OCc1ccccc1
Reactant: CC1(C)CCC(C)(C)C1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(COC1C(C)(C)CCC1(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and 2,2,5,5-tetramethyl-1-cyclopentanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-1-(2-aminopropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C>CCOCC>[C:14]1([CH2:13][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[B:25]([OH:28])[OH:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COB(OC)OC
Reactant: Brc1c(OCc2ccccc2)ccc2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1c(OCc2ccccc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a suspension of 1-bromo-2-(phenylmethoxy)naphthalene (6.26 g, 20.0 mmol) in Et2O (75 mL) at −78° C. was added n-BuLi (8.0 mL, 2.5 M, 20 mmol) in hexanes and the mixture was stirred at 0° C. for 1 h. After re-cooling to −78° C., the mixture was treated with trimethyl borate (2.5 mL, 22 mmol) and allowed to warm to room temperature overnight. The resulting mixture was quenched with 1M HCl (50 mL) and stirred at room temperature for 45 min. The phases were separated and the extraction was completed with CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give the title compound, 2-(pbenylmethoxy)-1-napthaleneboronic acid as a white powder (4.62 g, 83%), which was used in the next step without further purification. For analytical purposes, a small amount of the product was re-crystallised from MeOH/H2O: mp 133.0-135.0° C. (MeOH/H2O); 1H NMR (250MHz, d4-MeOH) δ5.20 (s, 2H), 7.28-7.60 (m, 9H), and 7.56-7.88 (m, 2H); 13C NMR (63 MHz, d4-MeOH) δ71.95, 115.4, 124.8, 127.7 (2C), 128.4, 128.9, 129.5, 129.6, 130.7 (2C?), 131.8, 137.2, 139.0 and 159.7;i IR (CHCl3) νmax 3609, 3490, 1592, 1509, 1386, and 1332 cm−1; MS (EI+) m/z (rel intensity) 278 (10%, M+), 234 (10), and 91 (100); HRMS calcd for C17H15BO3 (M+) 277.1151. found 277.1163. Anal. Calcd for C17H15BO3: C, 73.42; H, 5.44. Found: C, 73.07; H, 5.33.
Reaction SMILES: C(N)(C)C.FC1C(F)=C(F)C(F)=CC=1C(=O)C[C:17]([O:19]CC)=[O:18].[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:35])[C:33]=1[F:34])[N:30]([CH:36]([CH3:38])[CH3:37])[CH:29]=[C:28](C(O)=O)[C:27]2=[O:42]>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:35])[C:33]=1[F:34])[N:30]([CH:36]([CH3:37])[CH3:38])[C:29]([C:17]([OH:19])=[O:18])=[CH:28][C:27]2=[O:42]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC(C)N
Product: CC(C)n1c(C(=O)O)cc(=O)c2cc(F)c(F)c(F)c21

Procedure:
Using the procedure of Example VV with isopropyl amine, 3.0 g (11.33 mmol) of 2,3,4,5-tetrafluoro-β-oxo-benzeneproprionic acid, ethyl ester was converted to 1.21 g of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylethyl)-4oxo-3-quinolinecarboxylic acid, mp 256°-260° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:20]1([CH2:26][CH2:27]O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
2-methyl-3-(4-hydroxyphenyl)-4-(3H)quinazolinone synthesized according to Example 1-(1) and -(2) (100 mg, 0.40 mmol), 2-(1-piperidinyl)ethanol (89 mg, 0.50 mmol) and triphenylphosphine (125 mg, 0.50 mmol) were dissolved in dry tetrahydrofuran (2 mL) and cooled on an ice bath. Diethylazodicarboxylate (75 uL, 0.50 mmol) was dripped in at 0° C. and stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, ether was added, the solid precipitate was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) and the title compound (124 mg, 86%) was obtained as a light brown oily substance.
Reaction SMILES: Cl.[S:2]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[NH:5]1)(=[O:4])=[O:3].[CH3:14][OH:15]>>[CH3:14][O:15][C:6](=[O:7])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[S:2](=[O:4])(=[O:3])[NH2:5]
Reactant: CO
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: Cl
Product: COC(=O)c1ccccc1S(N)(=O)=O

Procedure:
An HCl stream is led under cooling into a suspension of 143.3 g (0.78 mol) in 600 ml absolute methanol until saturation. Subsequently the solution is refluxed yet two hours until the saccharine has gone completely into solution and the reaction has terminated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([S:20][CH2:21][CH3:22])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:28].CCCCCC>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([S:20]([CH2:21][CH3:22])=[O:28])[N:3]=1
Reactant: CCSc1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1

Procedure:
A stirred solution of (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (7.4 g, 23 mmol, Example 102) in dichloromethane (150 mL) at 0° C. was treated portionwise with 74% meta-chloroperoxybenzoic acid (6 g, 26 mmol) over about 30 minutes. The cold reaction mixture was quenched with 25 ml of 10% aqueous sodium thiosulfate solution and the layers separated. The organic layer was washed once with 10% aqueous sodium thiosulfate solution, twice with saturated aqueous sodium carbonate solution, once with brine, dried (Na2SO4) and evaporated. Trituration of the residue with hexane provided a quantitative yield of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone as a colorless solid, mp 165 dec. Mass Spectrum (LR-ES) (M+H)+: 342.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[S:12]([NH2:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+]>>[S:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:2][C:3]([NH:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4])=[CH:16][CH:15]=1)(=[O:13])(=[O:21])[NH2:22]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CCl)NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(NCC(=O)NC2CCCCC2)cc1

Procedure:
2-Chloro-N-cyclohexylacetamide (8.7 g) and sulfanilamide (17.2g) were heated for 30 min. at 160°C. The mixture was then added to 2N NaOH and extracted with ethyl acetate to yield 8.2 g, product, m.p. 223° - 225°C
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C([N:13]([CH:25]1[CH2:31][C:30]2[CH:32]=[C:33]([O:36][CH2:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][C:29]=2[CH2:28][CH2:27][CH2:26]1)[CH2:14][C@H:15]([OH:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:24][C@H:15]([CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][NH:13][CH:25]1[CH2:31][C:30]2[CH:32]=[C:33]([O:36][CH2:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][C:29]=2[CH2:28][CH2:27][CH2:26]1
Reactant: [H][H]
Reactant: NC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: NC(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Yield: 92.5 %

Procedure:
A mixture of 2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamide methanesulfonate (240 mg) and 10% palladium on activated carbon (50% wet, 50 mg) in ethanol (5 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours. After filtration, the filtrate was evaporated in vacuo and followed by trituration with diisopropyl ether to give 2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamide methanesulfonate (187 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14](Cl)[N:13]=1.Cl>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)nc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
With cooling with ice, benzyl alcohol (3.4 mL) was dropwise added to a DMF (100 mL) suspension of sodium hydride (3.2 g). This was stirred at that temperature for 1 hour, then a DMF (30 mL) solution of 2,6-dichloropyridine-4-carboxylic acid (6.38 g) was dropwise added to the reaction solution with cooling with ice, and stirred at that temperature for 1 hour and 30 minutes and then overnight at 90° C. With cooling with ice, diluted hydrochloric acid was added to it, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A mixed solution of hexane/ethyl acetate=2/1 was added to the residue, and the formed precipitate was removed. The filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil. Not purified, this was used in the next step.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C[O:10][CH2:9][CH2:8]1>>[CH3:3][C:2]([C:1]([O:6][CH2:8][CH2:9][OH:10])=[O:5])=[CH2:4]
Reactant: C1CCOC1
Reactant: C=C(C)C(=O)[O-]
Product: C=C(C)C(=O)OCCO

Procedure:
The 1H NMR spectrum of the PIB before, as seen in FIG. 7a, and after, as seen in FIG. 7b, methacrylation are provided. The resonance at δ3.6 ppm, corresponding to the —CH2— protons next to the hydroxyl group, as seen in FIG. 7a, disappeared and new resonances attributed to the vinylidene [δ5.6 (e2), δ6.1 (e1)], methyl [δ2.0 (f)] and methylene protons adjacent to the methacrylate end group [δ4.2 (g)] appeared at the expected positions. The integration ratios of (e2):(e1):(g):(f) were 1:1:2:3 which demonstrated quantitative functionalization. The use of THF solvent gave incomplete conversion after 24 hours, although PEG-MA was obtained in quantitative yield under similar conditions. At this point we do not understand the reason for this discrepancy. We hope to get a better understanding of the mechanism of enzymatic polymerizations, which we are actively investigating.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 508.0 [M+H]+; single peak at tR=2.84 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](=[CH:28][OH:29])[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 42 %

Procedure:
6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-1,3-dihydro-indol-2-one (0.100 g, 0.278 mmol) and ethyl formate (0.066 mL, 0.834 mmol) were dissolved in anhydrous ethanol (0.600 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.519 mL, 1.39 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered yielding 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-3-hydroxymethylene-1,3-dihydro-indol-2-one as an orange solid in 42% yield (0.045 g, 0.117 mmol).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1([S:21]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O>ClCCCl>[C:1]1([CH2:7][C:8]([C:26]2[CH:27]=[CH:28][N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:25]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(Cc1ccccc1)c1ccn(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
Under N2, a mixture of phenyl-acetyl chloride (1.5 g, 9.7 mmol) in 1,2-dichloro-ethane (20 mL) was added AlCl3 (2.24 g, 16.8 mmol) and then stirred at room temperature for 15 minutes. 1-(phenylsulfonyl)-1H-pyrrole (1.74 g, 8.4 mmol) was added. The mixture was stirred at room temperature overnight, followed by a standard aqueous/EtOAc workup. Purified by column chromatography to afford the Intermediate 52 (1.4 g, yield 51.8%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16](OC)=[O:17].O.[NH2:27][NH2:28]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:27][NH2:28])=[O:17]
Reactant: NN
Reactant: COC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Product: NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1

Procedure:
A solution of methyl 3-[(2-naphthyl)methoxy]-5-nitrobenzoate (0.97 g, 2.87 mmol) and hydrazine hydrate (0.56 mL, 11.5 mmol) in MeOH (50 mL) was stirred under reflux overnight. Formation of solid hydrazide from a boiling mixture was observed in the morning. Mixture was cooled, solid filtered and air-dried. Greenish-white plates, yield 0.60 g (62%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.15 (br.s, 1H); 8.27 (s, 1H); 8.05-7.91 (m, 6H); 7.63 (d, J=7.5 Hz, 1H); 7.59-7.52 (m, 2H); 5.48 (s, 2H); 4.66 (br.s, 2H).