Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:63]([C:52]1[C:51]([NH:50][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:56][CH:55]=[CH:54][C:53]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(=[O:64])[NH2:65]
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
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: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.4 g, 10 mmol) in DCM (40 mL) was added HATU (5.3 g, 14 mmol) and DIPEA (3.6 mL, 28 mmol) and the reaction mixture was stirred at room temperature for 1 h. 3-Aminobiphenyl-2-carboxamide (from Example 218) (1.5 g, 7.07 mmol) was added and the resulting mixture stirred for an additional 16 h. The reaction mixture was washed with water, the organic portion dried, filtered and concentrated under reduced pressure. The resulting residue was purified by ISCO chromatography (50% ethyl acetate in hexanes) to yield tert-butyl 4-(2-carbamoylbiphenyl-3-ylcarbamoyl)piperidine-1-carboxylate (1.0 g, 22% yield) as a white solid. LCMS Method T: retention time 1.71 min; [M+1]=423.0.
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][C@@H:11]([C:13]([NH:15][C@H:16]([C:21]([N:23]1[CH2:41][CH2:40][CH2:39][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][C:18](=[O:20])[OH:19])=[O:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](C1C=CC(O[C:52](=[O:76])[C@H:53]([CH:65](CC2C=CC=CC=2)[C:66]([OH:68])=[O:67])[NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=CC=1)([O-])=O>>[C:55]([NH:54][C@H:53]([C:52]([NH:12][C@H:11]([C:13]([NH:15][C@H:16]([C:21]([N:23]1[CH2:41][CH2:40][CH2:39][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][C:18](=[O:19])[OH:20])=[O:14])[CH2:10][O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:76])[CH2:65][C:66](=[O:67])[O:68][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O:57][CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:56]
Reactant: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)COCc1ccccc1)C(=O)O
Agent: Cl
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A method which comprises reacting O-benzyl-L-seryl-L-aspartyl-L-prolyl-L-arginine hydrochloride with N-carbobenzoxy-β-benzyl-L-aspartic acid p-nitrophenyl ester to give N-carbobenzoxy-O-benzyl-L-aspartyl-O-benzyl-L-seryl-L-aspartyl-L-prolyl-L-arginine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.C(O[Na])(C)=O.[CH:19]([C:21]1[N:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]([C:31]#[N:32])=[C:24]2[O:33][CH:34]([CH3:36])[CH3:35])=O>CC(O)=O>[CH:34]([O:33][C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([CH:19]=[C:10]3[S:9][C:8]([NH:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:12][C:11]3=[O:13])[N:22]=2)[N:27]=[CH:26][C:25]=1[C:31]#[N:32])([CH3:36])[CH3:35]
Reactant: O=C1CSC(NCc2cccs2)=N1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc12
Temperature: 80 °C
Yield: 50.8 %

Procedure:
To a mixture of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmol, (prepared as described below), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (57.9 mg, 0.24 mmol) (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 80° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in AcOEt (20 mL) and filtered. The solid was washed with AcOEt and dried to give 4-isopropoxy-6-{4-oxo-2-[(thiophen-2-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a light brown solid (35.4 mg, 50.8%). HR-ES (+) m/e calcd for C21H17N5O2S2 (M+H)+ 436.0897. found 436.0895.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:31][CH2:30][C:21]2([CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:31][CH2:30][C:21]2([CH2:22][CH:23]([O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:24]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Oc1ccccc1F)C2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
After dissolving 148 mg of 2-fluorophenol in 10 mg of dimethylformamide, 53 mg of sodium hydride (70% suspension in oil) was added, the mixture was stirred at 80° C. for 30 minutes, a solution of 148 mg of 7-(tert-butoxycarbonyl)-2-methanesulfonyloxy-7-azaspiro[3.5]nonane in N,N-dimethylformamide (7 ml) was added and the mixture was stirred at 80° C. for two nights. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with a 1N sodium hydroxide solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (163 mg, 100% yield).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:15]([NH:18][CH:19]=O)([CH3:17])[CH3:16].P(Cl)(Cl)(Cl)=O>>[CH:15]([N:18]=[CH:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)([CH3:17])[CH3:16]
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: CC(C)NC=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N=CN1c2ccccc2Cc2ccccc21

Procedure:
Reaction of acridan, isopropylformamide and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-[(ISOPROPYLIMINO)METHYL]ACRIDAN, m.p. 149.5°-150.5° C. (corr.), from n-hexane.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[C:12]([OH:32])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: COCOc1cc(COCc2ccccc2)c(C=O)c(OCOC)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 112.8 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzaldehyde (0.80 g, 2.3 mmol) was dissolved in tert-butyl alcohol (20 mL) and the obtained solution was added with 2-methyl-2-butene (10 mL, 94 mmol), sodium chlorite (2.0 g, 22 mmol), sodium dihydrogen phosphate (2.0 g, 17 mmol) and water (5 mL), followed by stirring at a room temperature for 10 hours. The reaction mixture was extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (0.94 g, 100%).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[C:62]([C:66]#[N:67])=[CH:63][S:64][CH:65]=1.CC1(C)C(C)(C)OB([C:76]2[CH:81]=[CH:80][C:79]([OH:82])=[CH:78][CH:77]=2)O1>>[OH:82][C:79]1[CH:80]=[CH:81][C:76]([C:61]2[C:62]([C:66]#[N:67])=[CH:63][S:64][CH:65]=2)=[CH:77][CH:78]=1
Reactant: N#Cc1cscc1Br
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1cscc1-c1ccc(O)cc1

Procedure:
Compound 51A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 4-bromothiophene-3-carbonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.68 (s, 1H), 8.62 (d, J=3.38 Hz, 1H), 7.73 (d, J=3.07 Hz, 1H), 7.44 (d, J=8.59 Hz, 2H), 6.86 (d, J=8.59 Hz, 2H). MS (ESI(+)): m/z 200 (M−H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:16][OH:17])[CH:7]=[CH:8][C:9]=1[N:10]1[C:14]([CH3:15])=[CH:13][N:12]=[CH:11]1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[CH2:27][CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]([CH3:15])=[CH:13][N:12]=[CH:11]1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[CH2:27][CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: Cc1cncn1-c1ccc(CO)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cncn1-c1ccc(COc2cc3n(c(=O)n2)CCN3C)cc1F

Procedure:
Prepared in a manner similar to that described for E1 using NaH (17.46 mg, 0.727 mmol), (3-fluoro-4-(5-methyl-1H-imidazol-1-yl)phenyl)methanol (100 mg, 0.485 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]-pyrimidin-5(1H)-one (90 mg, 0.485 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20](C3C=NC=CC=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N:6]4[CH:7]=[CH:2][CH:3]=[N:4][CH2:5]4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3cccnc3)cccc21
Product: CC1c2cccc(N3C=CC=NC3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:27]=[CH:26][C:25]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].I[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C=O)C.O>[CH2:50]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:27]=[CH:26][C:25]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:22])[C:11]1=[O:19])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: COc1cccc(-c2c(NC(=O)Nc3cc(CN4CCOCC4)ccc3C(C)(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCn1c(=O)c(NC(=O)Nc2cc(CN3CCOCC3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(morpholinomethyl)phenyl]urea (300 mg, 0.55 mmol) in DMF (10 ml) are added successively potassium carbonate (91.8 mg, 0.66 mmol), potassium iodide (18.4 mg, 0.11 mmol) and 1-iodohexane (117 mg, 0.55 mmol), and the mixture is stirred at room temperature for one hour, and stirred at 40-50° C. for 4 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (chloroform→3% methanol/chloroform) to give the title compound (290 mg, 0.47 mmol) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[C:9]1=[C:16]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])CBr.CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([C:26]([O:25][CH3:24])=[O:29])[CH:10]([CH3:15])[CH:9]1[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CN(C(=O)OC(C)(C)C)C(=C=O)C(C)N1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1C(C)CN(C(=O)OC(C)(C)C)C(C)C1C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3,5-dimethyl carbonyl piperazine-1-carboxylic acid t-butyl ester (18.7 g), potassium carbonate (14.5 g), bromo acetic acid methyl ester (14.7 g), DMF (90 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound. This compound was provided to the next reaction without further purification.
Reaction SMILES: [C:1]([O:9]CC)([O:6][CH2:7][CH3:8])(OCC)[CH3:2].[Cl:12][C:13]([Cl:24])([C:20]([F:23])([F:22])[F:21])[CH:14](O)[CH:15]=[C:16]([CH3:18])[CH3:17].C(O)(=O)C(C)C>>[Cl:12][C:13]([Cl:24])([C:20]([F:21])([F:22])[F:23])[CH:14]=[CH:15][C:16]([CH3:18])([CH3:17])[CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:9]
Reactant: CC(C)=CC(O)C(Cl)(Cl)C(F)(F)F
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(C)C(=O)O
Product: CCOC(=O)CC(C)(C)C=CC(Cl)(Cl)C(F)(F)F

Procedure:
A mixture of triethyl orthoacetate (25 ml), 5,5-dichloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (3.5 g), and isobutyric acid (0.11 g) was heated at the reflux temperature. The refluxing volatiles were condensed and collected in a Dean & Stark apparatus containing molecular sieves (4 A) to collect the by-product ethanol and separate it from the orthoacetate which was returned to the mixture. After 30 minutes the more volatile components were removed by evaporation under reduced pressure and the residual oil (consisting principally of 5,5-dichloro-4-(1,1-diethoxyethoxy)-2-methyl-6,6,6-trifluorohex-2-ene, 3.8 g) collected. This was then heated with isobutyric acid (10 μl) at the reflux temperature for 16 hours under a condenser containing molecular sieves (4 A) to remove ethanol from the condensate. The residual oil was subjected to purification by column chromatography using a 15:1 (by volume) mixture of hexane:ethyl acetate as eluant and a silica gel column (230-400 mesh, 60Å) to obtain ethyl 6,6-dichloro-3,3-dimethyl-7,7,7-trifluorohept-4-enoate, identified by nuclear magnetic resonance, and gas chromatographic mass-spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
The mixture of 2-amino-4-nitrophenol (5 g, 32.44 mmol) and CDI (6.3 g, 38.93 mmol) in THF (60 mL) was heated at refluxing for 16 h. Cooled to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in DCM (100 mL) and poured into 2N HCl solution (200 mL) with stirring, after 30 min, collected the solid and washed with water (50 mL×2), dried in vacuo to get compound 39-1 as a yellow solid (5.1 g, yield 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13]C[C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(=O)NCCCC1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[O:17])=[O:9])=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28]([S:31]([NH2:34])(=[O:33])=[O:32])([CH3:30])[CH3:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:34][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: CC(C)S(N)(=O)=O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and isopropylsulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (13%); 1H NMR (d6-DMSO) δ 11.60 (br s, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.86 (d, J=8.1 Hz, 2H), 6.48 (d, J=15.7 Hz, 1H), 3.64 (m, 1H), 2.37 (q, J=7.3 Hz, 2H), 1.23 (d, J=7.0 Hz, 6H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 460 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:6]2.[CH3:17]N(C=O)C.[H-].[Na+].CI>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[N:6]2[CH3:17]
Reactant: Clc1ncnc2nc(-c3ccccc3)[nH]c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1c(-c2ccccc2)nc2c(Cl)ncnc21
Reaction time: 0.33 h

Procedure:
To a solution of 6-chloro-8-phenyl-7H-purine (0.200 g, 0.000867 mol) (Example 109, step a) in DMF (8.0 mL, 0.10 mol) was added sodium hydride (0.025 g, 0.0010 mol). The mixture was stirred for 20 minutes and to this was added methyl iodide (0.065 mL, 0.0010 mol) and the mixture was stirred for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (3 to 10% acetone/toluene) to obtain 145 mg (68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:25](C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:25])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCNC3)c1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of 205a (2.75 g, 7.5 mmol), formaldehyde (37 percent in water, 30 ml, 375 mmol), NaBH(OAc)3 (4.75 g, 22.5 mmol) and acetic acid (25 ml, 150 mmol) in methanol (125 ml) was stirred for 4 hours at room temperature. The mixture was then brought to basic condition with saturated NaOH solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 4:1 ethyle acetate/methanol to give 205b (2.0 g, 77%). LC/MS: m/z 349 (M+H)+
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]([C:9]1([S:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[S:22])[C:17]([F:29])=[CH:16][C:15]=2[Cl:30])[CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:30][C:15]1[C:14]([S:13][C:9]2([C:7]([O:6][CH3:5])=[O:8])[CH2:12][CH2:11][CH2:10]2)=[CH:19][C:18]([N:20]=[C:21]2[N:23]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:1](=[O:2])[S:22]2)=[C:17]([F:29])[CH:16]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(Sc2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)CCC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
While stirring at a temperature of +10° C., 12.5 ml of a 20% solution of phosgene in toluene are added dropwise to a solution of 10.4 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclobutanecarboxylic acid methyl ester and 10 ml of triethylamine in 100 ml of toluene. The reaction mixture is then stirred for 6 hours and then introduced into ice-water. The organic phase is then separated off and dried over sodium sulfate. Concentration by evaporation and subsequent chromatographic purification by means of silica gel chromatography yield 4.6 g of 9-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclobutylthio)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7one, ηD22 1.6010.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][CH2:52][C@H:51]([NH:55][C:56](=[O:65])[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][CH2:52][C@H:51]([NH:55][C:56](=[O:65])[O:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH2:50]3)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.408 g) in DCM (21 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.394 g), HOBT (0.278 g) and triethylamine (0.286 ml) and stirred at room temperature for 1 h. A solution of benzyl (3S)-piperidin-3-ylcarbamate (0.3619) in DCM (1 ml) was then added and stirring continued for 72 h. The mixture was partitioned between DCM and water. The separated organic extracts were washed with water and brine, dried (over magnesium sulphate), and concentrated under reduced pressure. The residue was purified using Biotage™ chromatography (eluting with hexane:ethyl acetate 1:7→1:10) to give the title compound (0.268 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=439.2, tR (minutes, Method D)=0.84