Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:36])[CH2:34][F:35])=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.Cl.CC(O)C>C(Cl)Cl>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:36])[CH2:34][F:35])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(CF)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(CF)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO)c1ccc(Cl)c(Cl)c1)CC2
Reaction time: 1 h

Procedure:
To a solution of 240 (0.500 g, 0.898 mmol) and DCM (5 mL) at RT was added 6M HCl in IPA (1.50 mL, 8.98 mmol) and the reaction was stirred for 1 h and then concentrated to dryness. The residue was partitioned between aq. Na2CO3 and DCM. The organic fraction was dried, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:30 to 500:35) to afford 0.34 g (85.6%) of I-60 as a mixture of diastereomers: MS m/z (APCI-pos) M+1=442. The racemic mixture was resolved by chiral supercritical fluid chromatography.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: II
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC)c(I)c1
Reaction time: 4 h

Procedure:
Silver sulfate (3.47 g, 11.12 mmol) and iodine (0.576 mL, 11.12 mmol) were added successively to a solution of ethyl (1S,2S)-2-(4-methoxyphenyl)cyclopropanecarboxylate (2.45 g, 11.12 mmol) in EtOH (55.6 mL) at 25° C. and the reaction was stirred vigorously for 4 h. After this time the reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (100 mL), washed with water (2×25 mL), aq. NaHSO3 (2×25 mL), and brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 2088 mL) to afford ethyl (1S,2S)-2-(3-iodo-4-methoxyphenyl)cyclopropanecarboxylate, as a colorless oil. Rf=0.61 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.50 (d, J=2.3 Hz, 1H); 7.04 (dd, J=8.5, 2.3 Hz, 1H); 6.71 (d, J=8.5 Hz, 1H); 4.15 (q, J=7.2 Hz, 2H); 3.83 (s, 3H); 2.44-2.39 (m, 1H); 1.82-1.78 (m, 1H); 1.55-1.50 (m, 1H); 1.27 (t, J=7.2 Hz, 3H); 1.25-1.19 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.N.[Li]>C(O)C>[OH:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][C:3](=[O:2])[CH2:4]2
Reactant: COc1ccc2c(O)cccc2c1
Agent: N
Agent: [Li]
Solvent: CCO
Product: O=C1CCc2c(O)cccc2C1
Reaction time: 0.17 h

Procedure:
To a stirred slurry of 8.0 g. (0.048 mole) of 6-methoxy-1-naphthol and 200 ml. of liquid ammonia held below the reflux temperature by external cooling there is added 1.05 g. (0.15 g. - atom) of lithium ribbon over 25 minutes. After a further 10 minutes at this temperature, 20 ml. of ethanol is added over 30 minutes. As the blue color fades, the ammonia is evaporated and the residue stirred overnight under nitrogen wth 50 ml. of water, 50 ml. of tetrahydrofuran and 35 ml. of conc. hydrochloric acid. Extraction with three 100 ml. portions of chloroform followed by drying and solvent removal gives 7.24 g. of solid. Recrystallization (4:1) hexane-ethyl acetate gives 5.04 g. (68%) of ketone, m.p. 168°-171° (lit m.p. 155°-162° dec.), JACS 80, 2887 (1958).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH:26]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[CH3:35][CH2:36][OH:37]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15]3[C:16](=[CH:17][N:18]=[C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][C:24]4=3)[CH:26]=[CH:35][C:36]2=[O:37])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=Cc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1ccc2cnc3ccc(Cl)cc3c2n1-c1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4-(4-benzylphenylamino)-6-chloroquinoline-3-carbaldehyde (750 mg, 2.0 mmol) in EtOH (18 mL) was added triethyl phosphonoacetate (1.1 mL, 5.6 mmol) and K2CO3 (1.3 g, 9.3 mmol). The reaction mixture was stirred at 85° C. for 8 hours and then removed solvent. The reaction mixture was treated with 10 mL of water. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 97:3 v/v CH2Cl2: EtOH as solvent to afford title compound (510 mg, 64% yield) as a yellow solid.
Reaction SMILES: C(OC(=O)[CH:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)C.O.[Li+].[OH-]>CO>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1ccnc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of the product prepared in Step 1 (440 mg, 1.24 mmol) in methanol (13 mL) containing a drop of water, was added powdered LiOH (36 mg, 1.5 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated to remove the methanol, diluted in dichloromethane, and washed with water. The combined organic extracts were dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography eluting with 10-25% ethyl acetate in hexanes to give 4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine as a light yellow solid (100 mg, 29%). 1H NMR (CHCl3-d) δ 8.65 (d, J=4.7 Hz, 1H), 8.21 (m, 2H), 7.49 (s, 1H), 7.35 (m, 2H), 7.28 (m, 1H), 4.18 (s, 2H).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1cncs1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cncs1
Yield: 68 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-thiazolecarboxylic acid (4.5 g), N,N'-carbonyldiimidazole (6.8 g) and 2-amino-7-chloro-1,8-naphthyridine (5 g). The product obtained by precipitation in water is purified by recrystallization in a dimethylformamide/acetonitrile (5:5 by volume) mixture (120 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-thiazolecarboxamide (5.5 g), m.p. 292° C., is thereby obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=3[CH:18]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4-methyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[CH2:4][N:3]1[CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl.[NH2:24][CH2:25][C@H:26]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[C@@H:26]([NH:34][S:35]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH2:25][NH:24][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][N:3]([CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:2]2=[O:1])=[O:12])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2)NS(=O)(=O)c1ccccc1

Procedure:
A DMF solution (10 mL) of acid 6-4 (382 mg, 1.28 mmol) 1-4 (517 mg, 1.54 mmol), HOBT (264 mg, 1.13 mmol) NMM (563 μl, 5.1 mmol) and EDC (331 mg, 1.73 mmol) was stirred under ambient conditions for 18 h. The DMF was removed at 50° C. and the residue partitioned between EtOAc and H2O. The organic layer was washed with sat. NaHCO3 solution, brine, and dried (MgSO4). Evaporation gave a yellow foam which was purified by flash chromatography (silica, 3:1 acetone/CH2Cl2) to provide 6-5 as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.Cl[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:14])[N:15]([O:17][CH3:18])[CH3:16])[N:10]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCl
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287c (10.4 g, 1.0 eq., 41.9 mmol), tert-butyl 2-chloroethylcarbamate (37.7 g, 5.0 eq., 210.0 mmol), Na2CO3 (22.3 g, 5.0 eq., 210.0 mmol), and DMF (100 mL). The reaction mixture was stirred at 110° C. overnight. After cooling to room temperature, the resulting mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 287d (10.8 g, 66%) as yellow oil. MS-ESI: [M+H]+ 392.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:12]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[N:12]=1
Reactant: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate (70 mg, 0.24 mmol) was mixed with 4-fluoro-1-nitrobenzene (27 μL, 0.25 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry DMF and heated at 120° C. for 4 h. The mixture was diluted with water and filtered to give a yellow solid which was chromatographed over silica gel (40% EtOAc in hexane) to afford a yellow solid (72 mg, 73%): 1H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 7.51 (m, 1H), 7.25 (m, 5H), 2.45 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:23][C:11]2=[N:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:15]([CH3:16])=[C:10]2[C:9]=1[NH:24][C:25]([NH:27]C(=O)C1C=CC=CC=1)=[S:26])=O)C.CN(C)C=O.I[CH2:42][CH3:43]>C(O)C>[CH2:42]([S:26][C:25]1[NH:27][C:6](=[O:5])[C:8]2[S:23][C:11]3[N:12]=[C:13]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[C:15]([CH3:16])[C:10]=3[C:9]=2[N:24]=1)[CH3:43]
Reactant: CCI
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)cc(C)c2c1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCSc1nc2c(sc3nc(-c4ccccc4)cc(C)c32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
10.5 ml (10.5 mmol) 1 M sodium hydroxide solution is added to 2.00 g (4.2 mmol) 3-(3-benzoylthioureido)-4-methyl-6-phenyl-thieno[2,3-b]-pyridine-2-carboxylic acid ethyl ester in 25 ml ethanol and refluxed for 30 min. Following the addition of 10 ml N,N-dimethylformamide, 5 ml (5 mmol) sodium hydroxide solution (1M) and 0.50 ml iodoethane (6.2 mmol) the next step is stirring at room temperature for 30 min. The precipitate precipitated following acidification with dilute hydrochloric acid is sucked off, washed with water, suck dried and dried in vacuo at 50° C. 1.23 g (83%) 2-ethylthio-9-methyl-7-phenyl-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidin-4-one is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:17])[NH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[C:18]([C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[Cl:22])=[O:32])[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:17])[NH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(=O)[nH]cnc3c2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(=O)[nH]cnc3c2)n1
Yield: 51 %

Procedure:
Using general method A, 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)quinazolin-4(3H)-one (120 mg, 0.424 mmol) and 2,3-dichlorophenylisocyanate (79 mg, 0.487 mmol) were combined to yield 1-(3-t-butyl-1-(4-oxo-3,4-dihydroquinazolin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (102 mg, 51% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): 9.41 (s, 1H), 8.79 (s, 1H), 8.25-8.23 (s, 1H), 8.16 (s, 1H), 8.08-8.02 (m, 1H), 7.82-7.75 (m, 2H), 7.32-7.30 (m, 2H), 6.46 (s, 1H), 1.30 (s, 9H). MS (ESI) m/e (M+H+) 471.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](C=O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([OH:31])=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1cccc(-c2ccccc2)c1OCc1ccccc1
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (14.4 g, 50 mmol) in dichloromethane (250 mL) was stirred on an ice bath and m-chloroperbenzoic acid (70%, 13 g) was added in portions over 20 min. Stirring was continued overnight at room temperature. The reaction mixture was diluted with dichloromethane (to 600 mL) and washed with saturated sodium bicarbonate (2×300 mL) and water (300 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator. The residue was taken in methanol (250 mL), potassium hydroxide (5 g) was added and this mixture was stirred at room temperature for 2 hr. The solvent was removed in a rotary evaporator. The residue was taken in water (200 mL) and made acidic with 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (450 mL). The organic extract was washed with water (100 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by chromatography on silica (360 g) with 10% ethyl acetate in heptane (4 L) to afford 30 (12 g, 87%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].C(N(CC)C(C)C)(C)C.[CH:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35]>C(#N)C>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:34]=[O:35])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C=O)CC1
Reaction time: 2 h

Procedure:
To as solution of (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride (0.12 mmole) from experiment K4 in acetonitrile (1.0 ml) was added at 22° C. N,N-diisopropylethyl amine (0.38 mmole) and p-nitrophenyl formate (0.14 mmole) and stirring was continued for 2 h. The mixture was evaporated, the residue partitioned between ethyl acetate and aqueous sodium carbonate, the organic layer was washed with water, dried and evaporated. The residue was purified by prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-formyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 482.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:14][OH:15])([CH2:12][OH:13])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][OH:13])([CH2:14][OH:15])[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(CO)CO
Solvent: CO
Solvent: C1CCOC1
Product: OCC1(CO)CNc2cc(Cl)ccc21
Temperature: 20 °C
Yield: 92.8 %

Procedure:
A mixture of 6-chloro-3,3-bis-hydroxymethyl-1,3-dihydro-indol-2-one (5.8 mmol), THF (10 mL) and a solution of borane-dimethylsulfide complex in THF (2 M, 30 mL) was heated at 70° C. for 3 h, then cooled to 20° C. MeOH (30 mL) was added dropwise (caution,) over 0.2 h, then mixture was heated at reflux for 2 h. Resulting mixture was cooled then evaporated in vacuo to give an oily residue. Chromatography (SiO2; gradient elution with 20-100% EtOAc in petrol) gave the title compound (1.15 g) as an oil which crystallised. MS: [M+H]+=214.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][NH:22][N:21]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2ccccc2)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-phenyl-chromen-4-one (0.4 g, 1.47 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). 4-Chloro-6-(4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol precipitated out on quenching as a pale yellow (0.37 g, 88%); Rf 0.3 Cf SM 0.7 ethyl acetate/hexane (75/25).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[NH:5][C:6]=1[CH2:7][CH2:8][CH3:9].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[N:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1[nH]c(C=O)cc1Cl
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(Cl)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 60 %

Procedure:
This compound was prepared using the same procedure as in Example 1. 5.2 g of 4-chloro-5-n-propyl-2-pyrrolaldehyde (0.030 moles) and 16.9 g of 4′-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl (0.030 moles) yield 12 g of product which are used in the subsequent step. Formula: C41H34ClN5O (m.w. 648.21). Yield 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=S)[CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[O:19][C:18]([C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[NH:10][C:11]=4[CH:17]=3)=[N:20][N:21]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C=Nc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 4 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-chloro phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.75 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 30 min. Allow to stir at room temp overnight. Dilute the reaction with EtOAc (50 mL) and extract with water (10 mL) and 1 N NaOH (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Combine the aqueous phases, chill to 4° C., and filter. Combine the solids and suspend them in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Dry to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (ddd, J=7.96, 2.02, 0.76 Hz, 1H) 7.40 (t, J=8.15 Hz, 1H) 7.50-7.55 (m, 1H) 7.62-7.67 (m, 1H) 7.70 (s, 1H) 7.72 (d, J=2.02 Hz, 1H) 7.75-7.91 (m, 3H) 8.11 (br. s., 1H) 10.99 (br. s., 1H) 13.28 (br. s., 1H); MS m/z=457.9 (M+1).