Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][N:68]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]=3)=[CH:21][N:20]=2)=[O:24])[CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
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: CN(C)C=O
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)nc3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 (0.12 mmol) in DMF (0.5 mL) is added HATU (0.13 mmol) and DIEA (0.36 mmol) at rt. The resulting mixture is stirred for 2 min and then a solution of piperazine-1-carboxylic acid tert-butyl ester (0.12 mmol) in DMF (1 mL) is added. The reaction mixture is stirred at rt for 4 h and directly purified by preparative LCMS to give 4-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester 6 as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.32 (s, 1H), 8.89 (s, 2H), 8.39-8.37 (m., 2H), 7.86 (dd, J=4.0 and 8.0 Hz, 1H), 7.71-7.69 (m, 2H), 7.08-7.06 (m, 2H), 3.81 (s, 3H), 3.55-3.51 (bm, 4H), 3.96-3.94 (bs, 4H), 1.42 (s, 9H). MS (m/z) (M+1)+: 491.1.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[Br-].[Na+].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CN(C)C=O>[C:12]([O:15][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: CC1(C)OCC(CCl)O1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1COC(C)(C)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a mixture of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (51.60 g, 0.343 mol) prepared by Example 1 and N,N-dimethylformamide (400 ml), sodium bromide (37.04 g, 0.36 mol) and sodium acetate (29.53 g, 0.36 mol) were added and the resulting mixture was stirred for 15 hours at 150° C. After cooling, the salt was filtered off and N,N-dimethylformamide was removed in vacuo. Water was added to the residue and it was extracted with toluene and the extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 38.24 g of 4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (yield 64%, b.p. 81° C. at 12 mmHg).
Reaction SMILES: C([O:4][CH:5]1[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[C:10]=2[C:9]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:8]=2[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6]1)(=O)C.[OH-].[Na+].C(O)(=O)C>CCOCC>[Cl:22][C:20]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15](=[O:16])[NH:14][C:13]([CH3:17])=[N:12][C:11]=3[CH:5]([OH:4])[N:6]=[C:7]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]=2[CH:21]=1
Reactant: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2-c2c1nc(C)[nH]c2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.1 g (5.3 mmol) of 5-(acetyloxy)-9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one and 50 mL of 3N sodium hydroxide was heated on a steam bath for 5 min. The reaction mixture was diluted with 200 mL of ice water and 50 mL of ether. The sodium hydroxide was neutralized with acetic acid and the resulting mixture stirred at room temperature for 30 min. The resulting precipitate was collected by filtration to give an off-white solid. Recrystallization from tetrahydrofuran gave the product as colorless crystals, mp 253°-255° (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C.O>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)cn2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a solution of N-(5-hydroxypyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (468 mg, 1.4 mmol) in DMF (30 mL) was added potassium tert-butoxide (486 mg, 4.33 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (293 mg, 1.87 mmol). The reaction was heated at 120° C. for 2 hours, then cooled to rt, diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL) and concentrated in vacuo. The residue was purified by a silica column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as an off-white solid (285 mg, 44%).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl.[C:16]([C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29])[CH3:25])=[CH:20][CH:19]=1)#[N:17].O>C(Cl)Cl>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:31])[CH3:32])[NH:29][C:9]([O:11][C:12]([CH3:14])=[CH2:13])=[O:10])[CH3:25])=[CH:34][CH:35]=1)#[N:17]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=C(C)OC(=O)N[C@H](C(=O)NC(C)COc1ccc(C#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.2 %

Procedure:
0.6 g of N-methylmorpholine, and subsequently 0.4 g of isopropyl chloroformate were added to a solution containing 0.9 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]L-valinamide hydrochloride dissolved in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.23 g of the desired product in the form of colorless grains (yield: 13% ).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1(=O)OC(=O)C=C1>CC(C)=O.CO>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)c1ccccc1
Yield: 163.4 %

Procedure:
Solution "A" was prepared by dissolving 42.6 grams of para-aminobenzoic acid in 300 ml acetone plus 50 ml of methyl alcohol. Solution "B" was prepared by dissolving 36.6 g of maleic anhydride in 100 ml acetone. Solution "B" was added to solution "A" in one shot at room temperature with stirring. The mixture was allowed to stir for one to two hours until a yellow precipitate was formed. The precipitate was then washed with fresh acetone and dried to yield approximately 62 grams of maleamidated benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Product: COC(=O)c1ccc(Oc2cccc(F)c2)c(Br)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 3-bromo-4-fluorobenzoate and 3-fluorophenol: 1H-NMR (CDCl3) δ 8.33 (1H, d, J=2.0 Hz), 7.94 (1H, dd, J=8.6, 2.0 Hz), 7.38–7.29 (1H, m), 6.96–6.72 (4H, m), 3.92 (3H, s).
Reaction SMILES: [CH3:1][C:2]([Si:7]([CH3:10])([CH3:9])Cl)([CH3:6])[CH:3]([CH3:5])[CH3:4].Cl.[F:12][C:13]([F:19])([F:18])[S:14]([OH:17])(=[O:16])=[O:15]>>[F:12][C:13]([F:19])([F:18])[S:14]([O:17][Si:7]([C:2]([CH3:6])([CH3:1])[CH:3]([CH3:5])[CH3:4])([CH3:10])[CH3:9])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: Cl
Product: CC(C)C(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Temperature: 60 °C

Procedure:
50 ml of trifluoromethanesulfonic acid are slowly added dropwise at room temperature under argon to 101.57 g (0.57 mol) of (1,1,2,2-tetramethyleth-1-yl)-dimethylchlorosilane. Subsequently, the mixture is heated for 8 hours at 60° C. After this time, the evolution of HCl ceases. 111 g (67% of theory) of a colourless oil of boiling point=123°-124° C./28.6 mbar are obtained by distillation. The 1H-NMR spectrum is in agreement with the structure.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.C(O)(=O)/C=C/C(O)=O>C(O)C>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([O:8][CH3:9])[CH2:4][C@@H:3]1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[N:12]=1
Reactant: CO[C@H]1C[C@@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@H](O)[C@@H]1O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of 4-[(1R,2R,3S,4S)-(2,3-dihydroxy-4-methoxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline [cf. Example 39] (550 mg) in ethanol (5.5 ml) is added fumaric acid (94 mg), and the mixture is stirred at room temperature for 10 minutes. The precipitated crystals are separated by filtration, and the crystals are recrystallized from water-ethanol to give 4-[(1R,2R,3S,4S)-(2,3-dihydroxy-4-methoxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline 1/2 fumarate (387 mg) as crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:9]([C:11]1[CH:12]=[C:13](I)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][N:17]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16]2=[O:32])#[N:10]>>[C:9]([C:11]1[CH:12]=[C:13]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][N:17]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16]2=[O:32])#[N:10]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(I)cc3c2=O)c1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-ethyl piperazine was reacted with methyl 3-(8-cyano-6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate; Mass Spectrum: M+H+ 432.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C[CH2:11][O:12]CC.C([Li])CCC>CN(C)C=O>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([CH:11]=[O:12])[S:3][C:4]=1[CH3:9]
Reactant: Cc1sc(Br)c(C)c1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1sc(C=O)c(C)c1Br
Temperature: -35 °C

Procedure:
15.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 250 ml. of anhydrous ether and cooled to -70° C. with stirring under argon. 24 Ml. of a 2.4 M solution of n-butyl lithium was slowly added to the solution and the mixture was warmed to -35° C. for 10 minutes, and then cooled again to -70° C. 7.3 G. of dimethylformamide was added slowly to the mixture and the reaction mixture was warmed to room temperature for 14 hours. The resulting solution was poured into ice water, stirred for 20 minutes and extracted with ethyl ether. The ether extracts were combined, washed with an aqueous solution of 5% sodium carbonate, saturated sodium chloride solution, dried with sodium sulfate, filtered and evaporated to yield 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde, m.p. 44°-45° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]4)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: OCc1ccc2cc(I)ccc2c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: OCc1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2c1

Procedure:
Prepared according to general working method I from (6-iodo-naphthalen-2-yl)-methanol (450 mg, 1.58 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (342 mg, 1.60 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2Cl)([O-:3])=[O:2].[CH3:22][NH:23][CH3:24].O>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[N:23]([CH3:24])[CH3:22])([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(Cl)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Temperature: 60 °C

Procedure:
6-Nitro-4-chloro-2-(3-fluoro-phenyl)-quinoline, 20 g (59.4 mmoles), was placed in a 500 mL three-neck round-bottom flask equipped with magnetic stirrer, nitrogen inlet, gas outlet, condenser and heating bath. The material was dissolved in 150 mL of N-methyl pyrrolidinone, stirred and 250 mL of a 40% aq. solution of dimethylamine was added. The mixture was then warmed to 60° C. for 48 hrs. At the end of this time the reaction was cooled, poured into 3 L of water in a 4 L Erlenmeyer flask and the mixture stirred until solids formed. The solids were collected by vacuum filtration and dried in a vacuum oven. The product was recrystallised from-ethanol in a −20° C. freezer to give 19.6 g (95%) yield of the desired product.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][NH2:16]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][NH:16][CH:5]1[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]1
Reactant: CN1CCC(=O)CC1
Reactant: NCCc1cccs1
Product: c1csc(CCNC2CCNCC2)c1

Procedure:
1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), thiophene-2-ethylamine (0.563 g, 1.0 eq.).
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1
Reactant: O=C1CNCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(c2c(F)cc([N+](=O)[O-])cc2F)CN1
Temperature: 25 °C

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 3,4,5-trifluoronitrobenzene (1 eq) and diisopropyl ethylamine (28.6 mL, 165 mmol) in dry DMF (80 mL) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was air dried to yield the nitro compound as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]([CH2:15][CH2:16]O)[CH2:12][CH2:13]O>>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:16][CH2:15][NH:11][CH2:12][CH2:13][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cccc(Br)c1
Product: Brc1cccc(B2OCCNCCO2)c1
Yield: 78 %

Procedure:
The title compound (78%, crystals) was prepared from 3-bromophenylboronic acid and diethanolamin.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([OH:32])[CH:34]=3)(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cccc(O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(O)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-hydroxybenzenesulfonamide [Tetrahedron Lett., 1993, 34, 2043]: 1H-NMR (CDCl3) δ 7.49-7.20 (11H, m), 7.05-7.00 (1H, m), 6.56 (1H, br.s), 6.17 (1H, br.s), 3.59-3.52 (2H, m), 2.92 (2H, t, J=6.1 Hz), 2.36 (3H, s), 2.30 (3H, s).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]([O:15][C@H:16]3[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C@:24]4([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][C@H:25]4[CH:27]=[CH2:28])=[O:22])[CH2:17]3)=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:34][C:35]1[N:36]=[CH:37][C:38]([C:41]([NH:43][C@@H:44]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[C:45](O)=[O:46])=[O:42])=[N:39][CH:40]=1.ON1C(=O)C2C(C3CC2C=C3)C1=O.Cl.CN(C)CCCN=C=NCC.CN(C)CCN>CN(C=O)C>[CH3:34][C:35]1[N:36]=[CH:37][C:38]([C:41]([NH:43][C@@H:44]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[C:45]([N:19]2[CH2:20][C@H:16]([O:15][C:7]3[N:6]=[C:5]4[C:14](=[C:13]5[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]5)[CH:1]=[CH:2][CH:3]=[CH:4]4)[CH2:17][C@H:18]2[C:21]([NH:23][C@:24]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][C@H:25]2[CH:27]=[CH2:28])=[O:22])=[O:46])=[O:42])=[N:39][CH:40]=1
Reactant: C=CCCCCC[C@H](NC(=O)c1cnc(C)cn1)C(=O)O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c3ccccc23)CN1)C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)CCN
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCCCCC[C@H](NC(=O)c1cnc(C)cn1)C(=O)N1C[C@H](Oc2nc3ccccc3c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C

Procedure:
(1R,2S)-ethyl 1-((2S,4R)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate, the title compound of Example 49a, N-hydroxy-5-norbornene-2,3-dicarboximide, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride can be mixed and stirred in DMF, followed by addition of N,N-dimethylethylene diamine. The reaction produces (1R,2S)-ethyl 1-((2S,4R)-1-((S)-2-(5-methylpyrazine-2-carboxamido)non-8-enoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate, which can be dissolved in isopropyl acetate and extracted with aqueous H3PO4, and then extracted with aqueous K2HPO4. The product can be reacted with di-tert-butyldicarbonate in the presence of dimethylaminopyridine, followed by extraction with a mixture of a citric acid solution and a sodium chloride solution, to produce the title compound of Example 49b.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([NH:30][C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:27][C:28]=3[F:29])=[CH:11]2)(=O)=O)C=CC=CC=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:19]1([C:18]2[C:13]3[C:12]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([NH:30][C:31]5[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:27][C:28]=4[F:29])=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(Nc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ccc(Cc3c[nH]c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To [5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (76, 0.170 g, 0.320 mmol) in 10.0 mL of tetrahydrofuran, tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-4023, 100.4 mg). MS (ESI) [M+H+]+=390.8.
Reaction SMILES: BrC1C=C2C(=CC=1)C=C(C(=S)N(C)CC(O)=O)C=C2.C[O:21][C:22](=[O:39])[CH2:23][N:24]([C:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[Br:38])[CH:29]=1)=[S:27])[CH3:25]>>[Br:38][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[CH:36]=[CH:37][C:28]([C:26](=[S:27])[N:24]([CH3:25])[CH2:23][C:22]([OH:39])=[O:21])=[CH:29]2
Reactant: COC(=O)CN(C)C(=S)c1ccc2c(Br)cccc2c1
Agent: CN(CC(=O)O)C(=S)c1ccc2cc(Br)ccc2c1
Product: CN(CC(=O)O)C(=S)c1ccc2c(Br)cccc2c1

Procedure:
In the same manner but replacing N-[(6-bromo-2-naphthalenyl)thioxomethyl]-N-methylglycine with an equivalent amount of another ester of formula V, other compounds of formula I are obtained. For example, replacement with N-[(5-bromo-2-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester, described in the preceding example, gave N-[(5-bromo-2-naphthalenyl)thioxomethyl]-N-methylglycine; mp 180° C. (dec); NMR (DMSO-d6) δ 3.2 and 3.55 (2s, 3H), 4.25 and 4.85 (2s, 2H), 7.75 (m, 6H); IR (Nujol*) 2900, 1690, cm-1 ; UVλmax (EtOH) 276 nm (ε15,900), 247 (32,470), 319 (42,720); Anal Calcd: C, 49.72% H, 3.58% N, 4.14%; Found: C, 50.04% H, 3.75% N, 4.25%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl.[CH3:35][O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]1)=[O:38]>C(N(CC)CC)C>[CH3:35][O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH:46][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([CH2:17][S:14]([CH:13]=[C:11]3[CH2:12][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:10]3)(=[O:16])=[O:15])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: COC(=O)C1CCC(CN)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(CNC(=O)c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Yield: 38.2 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM), 0.026 cm3 of triethylamine and 39 mg of 4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride. 47 mg of 4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylic acid methyl ester are thus obtained in the form of a pale yellow paste [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 0.90 to 1.05 (mt, 2H), from 1.20 to 1.40 (mt, 2H), 1.52 (mt, 1H), from 1.70 to 2.00 (mt, 4H), 2.27 (mt, 1H), 2.98 (s, 3H), 3.12 (t, J=6.5 Hz, 2H), 3.60 (s, 3H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.50 (t, J=6 Hz, 1H)].