Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl>[OH:20][CH:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10](=[O:13])[O:9]1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(O)c2ccc([N+](=O)[O-])cc21

Procedure:
A mixture of 6-nitro-1(3H)-isobenzofuranone (8.99 g, 50.0 mmol) and N-bromosuccinimide (8.9 g, 50.0 mmol) in carbon tetrachloride (135 mL) was stirred and heated under reflux for one hour during which time the reaction mixture was exposed to the light from a 275 Watt, 125 Volt Hanovia sunlamp that was situated 8 inches from the flask. After cooling, the succinimide was removed by filtration, and the filtrate was evaporated in vacuo. The oily residue was mixed with water (200 mL), and the mixture was refluxed for one hour to give a clear, colorless solution. On cooling, the Compound 3a crystallized from solution. An analytical sample was prepared by recrystallization from water; m.p. 157°-160° C.; IR 3390 cm-1 (OH), 1770 cm-1 (C=O), 1H NMR (CDCl3 -Me2SO-d6 -D2O) δ6.78 (s, br, 1H, H3), 7.88 (d, 1H, H4, J4,5 =9 Hz), 8.56 (d, 1H, H5, J=9 Hz), 8.62 (s, 1H, H6).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([C@@H:32]([C@@H:34]1[C@@H:38]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:37]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35]1)[OH:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:40]([O:39][C@H:38]1[C@@H:37]([O:47][Si:48]([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35][CH:34]1[C@@H:32]([OH:33])[C@@H:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41]
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 33.1 %

Procedure:
By using an analogous procedure to that described in Example 1, a solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (99 mg, 0.32 mmol, obtained from Reference Example 18), tert-butyl (2S,3S)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (165 mg, 0.229 mmol, obtained from Reference example 5), acetic acid (4 drops) and sodium triacetoxyborohydride (97 mg, 0.457 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 4 hours. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(S)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (77 mg, 33%) as a white amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[ClH:20].[Cl:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Clc1cccc(COc2cnc(Cl)c(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 158 %

Procedure:
A solution of 3′-Chloro-6′-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (Compound I-3g) (40 mg, 0.091 mmol) in 1,4-dioxane (0.5 ml) at 23° C. was treated with HCl in 1,4-dioxane (4 M, 0.23 ml, 0.91 mmol). The resulting mixture was stirred at room temperature for 5 h (during which a precipitate appeared) and treated with ether. The solid was collected by filtration and washed with ether to afford the title compound 3-F (27 mg, 72%).
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50](O)=[O:51])[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=2)[CH:33]=[C:34]([F:36])[CH:35]=1.N1CCNCC1=O>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:51])[O:40][C:41]=2[C:42]2[CH:43]=[C:44]([C:48]#[N:49])[CH:45]=[CH:46][CH:47]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Agent: O=C1CNCCN1
Product: N#Cc1cccc(-c2oc(C(=O)N3CCNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 20A. Instead of 1.5 equivalents of piperazin-2-one, 1.1 equivalents are used. 55.0 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3]CCCCC.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2.CI>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([N:29]([CH3:3])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)N(C)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 0.23 g (5.7 mmol) of a 60 percent NaH/oil dispersion and 10 ml of hexane was stirred under N2 for 10 minutes. The hexane was decanted off, replaced with 20 ml of DMF and a solution of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide in 20 ml of DMF was added dropwise over a period of 30 minutes. The mixture was stirred at ambient temperature for 1.5 hours when a solution of 1.45 g (10 mmol) of methyl iodide in 10 ml of DMF was slowly added. The mixture was stirred at ambient temperature for 2 days and then quenched by cautious addition of a few drops of acetic acid and then water. The mixture was poured into water, extracted with three portions of ether and the combined organic layers dried over MgSO4 and evaporated to dryness. The residue was taken up in hot methylcyclohexane, treated with charcoal and filtered and then allowed to cool to give 1.03 g (50 percent) of the above-named product as colorless crystals, m.p. 137°-139° C. (Compound 41)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:44](O)=[O:45])[CH2:32][C:33]3[CH:42]=[C:41]([CH3:43])[C:36]4[NH:37][C:38](=[O:40])[O:39][C:35]=4[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:42]=[C:41]([CH3:43])[C:36]4[NH:37][C:38](=[O:40])[O:39][C:35]=4[CH:34]=3)[C:44]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:45])=[O:29])[CH2:26][CH2:27]2)[CH2:20][CH2:19][C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[NH:16]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(c3ccc(F)cc3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
234 mg (1.30 mmol) 1-(4-fluoro-phenyl)-piperazine were added to a solution of 600 mg (1.18 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 417 mg (1.30 mmol) TBTU, 183 μL (1.30 mmol) triethylamine in 10 mL DMF and the reaction mixture was shaken at RT. The reaction solution was purified by HPLC without any further working up, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])=[CH:21]2.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([C:10]3[N:9]=[N:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:12][CH:11]=3)=[O:15])[CH2:32][CH2:31]1)(=[O:29])=[O:28])=[CH:21]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: O=C(O)c1cnc(-c2ccncc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1cnc(-c2ccncc2)nn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (10 ml) were suspended 3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid and 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride (292 mg) at room temperature. To the reaction mixture were successively added 1-hydroxybenzotriazole (117 mg), N-methylmorpholine (191 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg), followed by stirring overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue to separate into layers. The organic layer was dried over magnesium sulfate and the filtrate was concentrated. Ethanol was added to the residue. Yellow crystals thus precipitated were collected by filtration and dried, whereby the free form (282 mg) of the title compound was obtained. The free form was suspended in ethanol and the resulting suspension was made acidic by the addition of 1N hydrochloric acid (in ethanol) and a small amount of water. After concentration of the resulting solution, ethanol and ethyl acetate were added and the resulting mixture was concentrated again. Crystals thus precipitated were collected by filtration and dried, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A round bottom flask equipped with magnetic stirrer and nitrogen inlet was charged with 2,6-dichlorobenzaldehyde (5.0 g, 28.57 mmol), acetone (42 ml, 0.571 mol) and water (20 ml). The mixture was cooled to 0° C. and a solution of sodium hydroxide (1.14 g, 28.57 mmol) in water (20 ml) was added drop wise during 1 hour to the vigorous stirred suspension. The reaction mixture was stirred for an additional 0.5 hour. The reaction mixture was concentrated in vacuo, poured onto 10% HCl (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (350 g) (eluent: n-hexane/ethyl acetate 10:1) to afford 6.0 g (97% of theory) of (E)-4-(2,6-dichloro-phenyl)-but-3-en-2-one in form of a pale yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].ClC(O[CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=O.N1C=CC=CC=1>O1CCCC1>[C:1]([O:6][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)C(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of 3.3 g (37.5 mmole) of pyruvic acid and 7.9 g (37.5 mmole) of trichloroethyl chloroformate in 20 ml of dry tetrahydrofuran at 0° is added dropwise 0.6 ml of pyridine. After stirring for 2 hours at room temperature, the mixture is concentrated in vacuum, diluted with water and extracted with ethyl acetate. The extract is washed with 5% HCl, dried over MgSO4, evaporated and distilled in vacuum to give 4.0 g (50%) trichloroethyl pyruvate, bp 75°-82° (17 mm).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[C:13]([Cu])#N.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)c1cccnn1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 168.4 %

Procedure:
To a solution of compound 2 (100 mg, 0.22 mmol) in DMF (10 mL) was added CuCN (40 mg, 0.44 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) under N2 at room temperature. The resulting mixture was stirred 30 min at 180° C. in a microwave reactor. Water (15 mL) was added and the mixture was extracted with EtOAc (3×20 mL), and the combined organic layers were dried over Na2SO4 and concentrated to give the residue which was purified by preparative TLC on silica gel (petroleum ether:ethyl acetate=5:1) to give compound 3 (46 mg, 52%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution containing 32 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 2 ml of methanol was treated with 6 mg of sodium borohydride at rt under nitrogen. The mixture was then stirred at rt overnight. To the mixture was added 2 ml of water and then extracted with diethyl ether three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated to give 30 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-phenyl-methanol as a white solid which was used without further purification. Mass spectrum (ES) m/z 407[M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][C:25](=O)[CH:24]([F:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]([F:28])[CH:25]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:30]=2[Cl:29])[CH2:26]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(F)C1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(F)C(NCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Add sodium triacetoxyborohydride (156 mg, 0.73 mmol) to a mixture of 3-fluoro-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol) and 2,4-dichlorobenzylamine (65 μL, 0.5 mmol) in 1,2-dichloroethane (1.5 mL), followed by 2 drops of glacial acetic acid and stir overnight at room temperature. Pour the crude mixture into 2 N sodium hydroxide and extract with ethyl acetate, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel to give 3-(2,4-dichlorobenzylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.44 (2H, m), 7.20-7.28 (1H, m), 5.03 (1H, d, J=54.07 Hz), 3.21-3.95 (6H, m), 2.99-3.15 (1H, m), 1.45 (9H, s), MS (ES): m/z=363 [M+].
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[O-:28][CH2:29][CH3:30].[Na+].O>O1CCCC1>[CH2:29]([O:28][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:30]
Reactant: CC[O-]
Reactant: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.64 g) in tetrahydrofuran (10 mL) was added sodium ethoxide (20% ethanol solution, 1.56 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (0.40 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:54][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1>C(Cl)Cl>[CH:49]1([NH:54][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=3)[CH:28]=2)[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC3CCCC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) was bubbled with nitrogen for 5 min, then it was added HBTU (30 mg, 0.079 mmol) and cyclopentylamine (0.038 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (21 mg, 47%). LC-MS m/z 589 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6](Cl)=[O:7])[CH3:4].C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>C(#N)C>[CH3:2][N:3]([CH2:5][C:6]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:7])[CH3:4]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of N,N-dimethylaminoacetyl chloride hydrochloride (137, 10.1 g, 64.2 mmol) in acetonitrile (300 ml.) was added powdered sodium bicarbonate (11.9 g, 141 mmol) followed by 4-aminobenzoic acid (138, 9.68 g, 70.6 mmol). The mixture was vigorously stirred over 16 h at r.t. and acetonitrile was decanted. The remaining gum was triturated with methanol and filtration afforded the title compound 139 (10.9 g, 76% yield). 1H NMR: (400 MHz, DMSO-d6) δ(ppm): 10.21 (s, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 4.17 (bs, 2H), 2.27 (s, 6H). LRMS: (m/z): 223.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4](C(O)=O)[S:3]1.[C:15](=O)([OH:17])[O-:16].[Na+:19]>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][SH:3]1[C:15]([O-:17])=[O:16].[Na+:19]
Reactant: O=C(O)c1cc2ccccc2c(=O)s1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])[SH]1C=Cc2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a stirred suspension of 4.50 g. (21.8 mM) of the carboxylic acid of Example 2 in 200 ml. of distilled water is added 1.833 g. (21.82 mM) of sodium bicarbonate. The mixture is then stirred at 25°-35° for 2 hours, whereupon all the solids dissolve. The solution is frozen and freeze-dried to give sodium 1-oxo-1H-2-benzothiopyran-2-carboxylate as a pale yellow solid, m.p. >350°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[O:12][C:8]=2[C:7]=1[Cl:18].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].Cl>>[Cl:5][C:6]1[C:17]([C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=2)=[CH:16][C:9]2[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[O:12][C:8]=2[C:7]=1[Cl:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 90 °C

Procedure:
Anhydrous aluminum chloride (5.97 g., 0.0448 mole) was added in small portions to a stirred mixture of 2.6 g. (0.0112 mole) of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid and 6.24 g. (0.0336 mole) of 4-nitrobenzoyl chloride. The mixture was heated at 90° C. for 4 hours and then poured into 170 ml. of ice water and 10 ml. of concentrated hydrochloric acid. The product was extracted into ethyl acetate (200 ml.), washed with water, and then extracted with 5% aqueous sodium bicarbonate (100 ml.) from which the sodium salt of the product precipitated. The sodium salt of the product was filtered and transferred to a separatory funnel with 2 N hydrochloric acid (70 ml.) and ethyl acetate (150 ml.) and shaken until the solid dissolved. The ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The product was recrystallized from acetic acid; m.p. 243°-245°.