Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH2:23])[N:13]=1.N1C=CC=CC=1>ClCCl>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([O:11][CH3:10])[N:13]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH:23][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3])[N:15]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2N)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Methyl (chlorosulfonyl)acetate (13.0 g) in dichloromethane (20 ml) was added dropwise with stirring and cooling to 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-fluoroaniline (20 g) and pyridine (6.3 g) in dichloromethane (120 ml). After stirring for 2 hours, the mixture was allowed to stand at room temperature overnight. Washing with dilute hydrochloric acid and water, drying over magnesium sulfate, and running down, gave an oil which was triturated with ether. The resulting off-white solid was separated by filtration to give 20.4 g of the desired product, mp 111°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:33][C:22]3=[CH:23][C:24]4[C:25](=[O:32])[N:26]([CH3:31])[C:27](=O)[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:20][C:21]3=[CH:29][C:28]4[CH2:27][N:26]([CH3:31])[C:25](=[O:32])[C:24]=4[CH:23]=[C:22]3[N:33]=2)[CH3:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C)C3=O
Yield: 82.8 %

Procedure:
2-(4-(1-(5-Fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.35 g, 0.76 mmol) and zinc powder (1.20 g, 18.28 mmol) were suspended in acetic acid (30 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (100 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a pale-yellow solid product, 0.28 g, 82.8% yield. MS: 444.0 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.06 (s, 1H), 11.16 (s, 1H), 11.09-11.06 (m, 1H), 7.95 (s, 0.5H), 7.85 (s, 0.5H), 7.78 (s, 0.5H), 7.69 (s, 0.5H), 7.30-7.10 (m, 3H), 6.91-6.83 (m, 1H), 6.14-6.10 (m, 1H), 4.48 (s, 2H), 4.17-4.13 (m, 1H), 3.10 (s, 3H), 3.03-2.96 (m, 2H), 2.35 (d, 3H, J=4.9 Hz), 1.34-1.32 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1)=O.S(Cl)([Cl:16])=O.[Cl-:18].[Ca+2].[Cl-:20]>>[Cl:18][CH:1]([Cl:16])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([Cl:20])=[O:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Reactant: [Cl-]
Agent: [Ca+2]
Product: O=C(Cl)COc1ccc(C(Cl)Cl)cc1

Procedure:
4-Formylphenoxyacetic acid (5 parts) was heated for 90 minutes under reflux with thionyl chloride (25 parts) in a flask fitted with an anhydrous calcium chloride filled drying tube. The resultant red colored solution was evaporated under reduced pressure to give a red colored oil which was distilled at 120° C. and 0.4 mm Hg pressure to yield 4-(dichloromethyl)phenoxyacetyl chloride (1.2 parts).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27])[P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27])[P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOP(=O)(OCC)C(CCCCN)P(=O)(OCC)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCCCNC(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of benzoyl chloride (0.73 g, 5.0 mmol) in dichloromethane was added slowly to a solution of tetraethyl 5-aminopentane-1,1-bisphosphonate (1.50 g, 4.5 mmol) from Example 11, part A, and triethylamine (0.76 mL, 5.5 mmol) in dichloromethane at 0° C. After warming to room temperature for 30 minutes, the reaction was quenched by addition of 1N HCl (30 mL). The product was extracted into dichloromethane (2×20 mL) and the combined organic layers were washed with saturated NaHCO3 (2×15 mL), dried (Na2SO4), and concentrated in vacuo. Flash chromatography on silica gel eluting with 15% i-propanol in ethylacetate in EtOAc gave the title compound (0.64 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]#[N:15])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:26].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([NH2:15])=[O:26])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc(Cl)c(CC(N)=O)n2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 50 ml of ethanol was dissolved 3.5 g of 1-benzyl-4-chloro-2-(4-dimethylaminophenyl)-5-cyanomethylimidazole, and 10 ml of 1 N-sodium hydroxide was added to the solution, followed by stirring at 60° C. for 2 hours. The solution was allowed to cool, and the resulted crystals were recrystallized from 70 ml of 90% ethanol, thereby yielding 2.2 g of 1-benzyl-4-chloro-2-(4-dimethylaminophenyl)imidazole-5-acetamide as colorless needles, m.p. 215°-216° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1.CO>[Pd].C(O)C.Cl>[ClH:1].[NH2:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([O:24][C:25]([O:27][CH3:28])=[O:26])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Reaction time: 1.25 h
Yield: 97.5 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (5.3 g, 13 mmol) and 10% palladium-on-charcoal catalyst (1 g) in ethanol (100 ml), ethanolic hydrogen chloride (1.8 ml of a 7M solution) and methanol (20 ml) was stirred under hydrogen at 1.7 atmospheres pressure for 75 minutes. The catalyst was removed by filtration through diatomaceous earth and the filter pad thoroughly washed with methylene chloride, methanol and ether and the solvent was removed from the filtrate by evaporation to give 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (4.8 g, 97%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([CH2:14][CH2:15][C:16]#[CH:17])[C:3]([O:5]/[CH:6]=[C:7]1\[C:8](=[O:13])[NH:9][C:10](=[O:12])[S:11]\1)=[O:4].C(Cl)(Cl)=O.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[Cl:35][C:36]1[S:40][C:39](CO)=[CH:38][CH:37]=1>C1COCC1>[Cl:35][C:36]1[S:40][C:39]([CH2:29][O:28][C:27]([N:9]2[C:8](=[O:13])/[C:7](=[CH:6]\[O:5][C:3](=[O:4])[C:2]([F:1])([F:18])[CH2:14][CH2:15][C:16]#[CH:17])/[S:11][C:10]2=[O:12])=[O:33])=[CH:38][CH:37]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCCC(F)(F)C(=O)O/C=C1/SC(=O)NC1=O
Reactant: OCc1ccc(Cl)s1
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Product: C#CCCC(F)(F)C(=O)O/C=C1/SC(=O)N(C(=O)OCc2ccc(Cl)s2)C1=O

Procedure:
To a stirred solution of (E)-5-(2,2-difluoro-hex-5-ynoyloxymethylidenyl)-2,4-thiazolidindione, which may be prepared as described in Step (d) above, in THF is added 2 mol equivalents of a non-nucleophilic base such as one of those described above in Example 17, followed by 1 mol equivalent of phosgene or 0.33 mol equivalents of triphosgene, and the mixture is stirred. After stirring for from 1 minute to about 1 hour, 5-chlorothiophen-2-ylmethyl alcohol is added, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the reaction is partitioned between ethyl acetate and water. The organic layer is washed with 0.01 M sodium bicarbonate, water, brine, and dried over sodium sulfate. The mixture is rotary evaporated to give (E)-5-(2,2-difluoro-hex-5-ynoyloxymethylene)-2,4-dioxo-thiazolidine-3-carboxylic acid 5-chloro-thiophen-2-ylmethyl ester, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4=[C:18]([Cl:23])[N:19]=[N:20][C:21](Cl)=[C:16]4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:28].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][NH:20][C:21](=[O:28])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(Cl)nnc(Cl)c32)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(=O)[nH]nc(Cl)c32)cc1
Yield: 19 %

Procedure:
In dioxane (15 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-4,7-dichloropyrrolo [2,3-d]pyridazine (1.08 g). Then, sodium hydroxide (4.42 g) and water (5 ml) were added and the mixture was refluxed for 69 hours. This reaction mixture was diluted with water (120 ml) and the resulting crystals were collected by filtration. The crystals were purified by silica gel column chromatography (stationary phase 50 g; dichloromethane: ether=1:0-9:1; ethyl acetate: methanol=1:9) to provide 416 mg (yield 40%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-4-chloropyrrolo [2,3-d]pyridazin-7(6H)-one(A) and 196 mg (yield 19%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-7-chloropyrrolo [2,3-d]pyridazin-4(5H)-one(B).
Reaction SMILES: [CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C@@H:9]([OH:42])[CH:10]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:11][C:12]([CH3:29])([CH3:28])[CH2:13][CH2:14][O:15][C:16]([O:18]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:51]>O1CCCC1.C(OCC)C>[CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[C@@H:9]([OH:42])[CH:10]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:33])=[O:32])[CH2:11][C:12]([CH3:28])([CH3:29])[CH2:13][CH2:14][O:15][C:16](=[O:18])[NH2:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCOC(N)=O)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
To a solution of the product from step 1 (520 mg, 0.73 mmol) in tetrahydrofuran (10 mL) at 5° C. was added ammonium hydroxyde (30%, 2 mL) and the reaction was stirred at 5° C. for 40 minutes. The mixture was diluted with ethyl ether, washed with saturated sodium bicarbonate, dried (magnesium sulfate), and evaporated to provide the title compound (490 mg) containing p-nitrophenol (˜10%). 1H NMR (DMSO-d6): δ 0.93 (3H, s), 0.96 (3H, s), 1.2 (9H, s), 1.6 (2H, t), 2.45 (1H, dd), 2.78 (1H, d), 2.85-2.95 (2H, m), 3.3-3.6 (3H, m), 3.7 (1H, quartet), 3.8 (3H, s), 3.96 (2H, t), 5.0 (1H, d), 6.4 (2H, br s), 6.6 (1H, d), 7.05 (2H, d), 7.10-7.25 (5H, m), 7.7 (2H, d).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].Br[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](Br)[N:17]=1.[CH3:25][N:26]([CH:28]=[O:29])C>CCCCCC>[C:25]1([NH:26][C:28]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:17]=2)=[O:29])[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: COc1cc(Br)nc(Br)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
2.00 g (0.00937×1.2 mol) of 3-(trifluoromethoxy) phenol was dissolved in about 20 ml of DMF. The solution was further mixed with 0.39 g (ca. 60% in mineral oil; 0.00937×1.04 mol) of NaH and then with 2.50 g (0.00937 mol) of 2,6-dibromo-4-methoxy pyridine. After stirring at about 110° C. for about 4 hours, the obtained mixture was allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the obtained solution was washed with saturated brine and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), and the obtained eluate was subjected to recrystallization using hexane, thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=2)=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-isocyanatobenzonitrile as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.33 (m, 2H), 9.01 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.75 (s, 1H), 7.65 (s, 4H), 7.20 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 4.20 (d, 2H), 2.90 (m, 6H), 2.69 (m, 1H), 1.89 (m, 2H), 1.61 (m, 2H). LCMS for C32H30ClN8O2 (M+H)+: m/z=593.2.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8].C(OCC)(=O)C>CN(C)C=O>[C:1]([S:3][CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8])(=[O:4])[CH3:2]
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)Br)nc21
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)SC(C)=O)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Potassium thioacetate (0.54 g, 48 mmol) was added to 7-(1-bromoethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.57 g, 40 mmol) dissolved in dimethylformamide (16 ml), followed by stirring at room temperature for 2 hours. The reaction solution was mixed with ethyl acetate, washed with water and with brine, and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7-(1-acetylthioethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.13 g, 73%).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2C([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+].CC(O)=O>O.Cl>[N+:16]([C:5]1[CH:6]=[C:7]([C:14]([OH:15])=[O:13])[C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][CH:9]=2)([O-:18])=[O:17]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Yield: 61.6 %

Procedure:
To a solution of 3-nitro-1,8-naphthalic anhydride (21.8 g, 89.7 mmol) in H2O (550 mL) containing 14.4 g of NaOH was added a solution of yellow HgO (25.1 g) in a mixture of H2O (75 mL) and glacial AcOH (25 mL). After reflux for 4 days, the reaction mixture was cooled and filtered to afford the mercurated product, which was then refluxed in 700 mL of 5N HCl for 3 h. The cream-colored precipitate was filtered, washed with cold H2O, dried, and recrystallized from hot glacial AcOH to yield 3-nitronaphthalene-1-carboxylic acid (12 g). 1H NMR (300 MHz, DMSO-d6): δ 13.7 (brs, 1H), 9.18 (s, 1H), 8.93 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.76 (t, J=6.9 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]1[CH3:29].O1CCCC1.[OH-].[Li+].Cl>O>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:30])=[O:2])[C:6]([CH3:29])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2sccc2S(=O)(=O)c2cccs2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[3-(thiophene-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}acetic acid methyl ester (0.17 g), tetrahydrofuran (0.35 mL) and water (0.35 mL) was treated with lithium hydroxide (0.088 g), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C., pH adjusted to 5 by the addition of 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3:7 to 9:1 by volume) to afford the title compound as a white solid (0.089 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]=1.C1C=CC=CC=1.[C:14]([Cl:17])(=O)[CH3:15].[OH2:18]>[Cl-].[Zn+2].[Cl-]>[C:4]([O:5][CH2:6][CH2:7][C:2]([CH3:1])=[CH:15][CH2:14][Cl:17])(=[O:18])[CH3:3]
Reactant: CC(=O)Cl
Reactant: O
Reactant: CC1=CCOCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CC(=O)OCCC(C)=CCCl
Temperature: 0 °C

Procedure:
245 grams of 4-methyl-5,6-dihydro-(2H)-pyran was dissolved into 500 milliliters of benzene in a reactor, in which 12.5 grams of zinc chloride was suspended, and into the suspension was added dropwise 196 grams of acetyl chloride in 6 hours 55 minutes. During the foregoing operation the reactor was cooled in an ice-water bath to maintain the reaction temperature below 5.5° C. After the completion of the dropwise addition of acetyl chloride the system was still cooled in the ice-water bath for 35 minutes while stirring. Then, 100 milliliters of water was added to the reaction system, still continuing cooling the system with ice-water, whereby the reaction was stopped. The temperature rise of the reaction system at the time of adding water was only up to 25.5° C. The aqueous layer was then separated from the benzene layer of the reaction system, and the benzene layer was washed with 100 milliliters of water three times and subsequently with 100 milliliters of saturated aqueous solution of sodium bicarbonate twice. Then, under slightly reduced pressure benzene was distilled off from the benzene layer, and by subsequent distillation a fraction of the boiling point range of lower than 87.0° C./3.1mmHg was collected to obtain 264.7 grams of 5-chloro-3-methyl-3-pentenyl acetate. The product obtained as above was identified to be a mixture of both cis-and trans-isomers on their y - g double bond by nuclear magnetic resonance spectroscopy. The product is a colorless transparent liquid having a sweet apple-like odor, boiling in the range of 82.8° C./3.0mmHg - 85.2° C./2.8mmHg, showing elementary analytic values; C, 54.7%; H, 7.5%; Cl, 19.8%; O, 18.0%; refractive index, nD30 ; 1.4606; and density, p430 ; 1.0623.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].C1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(F)cc1Cl
Reaction time: 13 h
Yield: 15.7 %

Procedure:
m-Chlorofluorobenzene (240 g. 1.85 moles) is added to a mixture of sulfuric acid (185 g. 1.85 moles) and nitric acid (166 g., 1.85 moles) at -5° C. in 3.5 hours, stirred 13 hours, then benzene (200 ml.) and hexane (200 ml.) are added. The extract is washed with water (1×300 ml.), sodium carbonate solution (1×300 ml.), and water (1×300 ml.), dried and the solvents removed. The residue is distilled to give 138 g. of mixed isomers. The 4-nitro isomer crystallizes and is filtered off to give 3-chloro-4-nitrofluorobenzene (51 g. 16.7%) m.p. 36°-38° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-fluoro-3-nitroaniline (0.5 g, 0.023 mol) in DCM (10 ml) and pyridine (0.98 g, 0.012 mol) was added methanesulfonyl chloride (0.54 g, 0.0048 mol) portion wise at 0° C. with constant stirring. The reaction mixture was allowed to stir at 0° C. for 4 h. The reaction mixture was concentrated and diluted with water (20 ml) and extracted with DCM (3×15 ml). The combined organic layers were washed with 1 N HCl and NaHCO3 solution dried over Na2SO4 and concentrated in vacuo to afford the desired product N-(4-fluoro-3-nitrophenyl)methane sulfonamide as off a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.23 (s, 1H), 7.93-7.91 (d, J=8.4 Hz, 1H), 7.62-7.54 (m, 2H), 3.59 (s, 3H). LCMS (ES) m/e MS (M−1=233). Purity: 80%.