Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([OH:13])=[CH:6][CH:5]=1.N1C=CC=CC=1>ClCCl>[N+:10]([C:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[C:6]([Br:1])[C:7]=1[OH:13])([O-:12])=[O:11]
Reactant: BrBr
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Bromine, Br2 (63.9 g) in 50 ml of dichloromethane was added dropwise to a solution of 4-chloro-6-nitrophenol (34.7 g) in 300 ml of dichloromethane. After the addition was completed, the mixture was stirred at room temperature for 30 min. Pyridine (19.0 g, 240 mmol) in 50 ml of dichloromethane was added. This mixture was stirred at room temperature for 2 hours and a white precipitate was formed. The reaction mixture was quenched with 200 ml of water and the white precipitate was dissolved. The organic layer was then washed with water (2×150 ml), 150 ml of brine and dried over MgSO4. The solvent was evaporated under vacuum to give the crude product which was recrystallized from ethyl acetate to afford 41.5 g (82%) yellow crystalline 2-nitro-4-chloro-6-bromophenol. 1H NMR (300 MHz, CDCl3) δ8.11 (d, J=2.5 Hz, 1 H), 7.87 (d, J=2.5 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:27])[N:15]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([Br:9])[C:5]([F:8])([F:7])[F:6].O.[OH-].[Li+]>C1COCC1.O>[CH2:20]([N:15]1[C:16]2[C:12](=[C:11]([O:10][C:4]([Br:9])([C:5]([F:6])([F:7])[F:8])[C:3]([OH:28])=[O:2])[CH:19]=[CH:18][CH:17]=2)[CH:13]=[C:14]1[CH3:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C(Br)(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(OC(Br)(C(=O)O)C(F)(F)F)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1-benzyl-2-methyl-1H-indol-4-yloxy)-2-bromo-3,3,3-trifluoro-propionic acid methyl ester (4) (0.07 g, 0.177 mmole) in THF:H2O (4:1, 10 mL), lithium hydroxide mono hydrate (0.01 g, 0.238 mmole) was added. The mixture was stirred at room temperature for 30 minutes. THF was evaporated and the mixture was acidified with 2M HCl to pH 3. The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulphate and concentrated to afford intermediate (5) as a pink solid. Yield: (0.066 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[N:21]1([CH2:26][CH2:27][CH2:28]Cl)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[N:7]([CH2:28][CH2:27][CH2:26][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[N:18]=1
Reactant: ClCCCN1CCCC1
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)N(CCCN1CCCC1)c1ccccc1N(C)C2=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture consisting of 7.2 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 1.9 gm of 50% sodium hydride in mineral oil and 100 ml of dimethyl formamide was stirred at 60°-70° C. for 45 minutes. Thereafter, the mixture was cooled to room temperature, 7.4 gm of 3-pyrrolidino-propyl chloride were added dropwise and the mixture was refluxed for 3 hours. The solvent was then distilled off in vacuo, and the residue was recrystallized twice from acetonitrile, yielding 46% of theory of the compound named in the heading, which had a melting point of 134°-136° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])C.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7][C:6]=1[C:4]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: CCOC(=O)c1ncc2cc(Oc3cccnc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2cc(Oc3cccnc3)ccc2c1O
Yield: 84.4 %

Procedure:
A mixture of 4-hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (26 mg), 3-amino-propionic acid (30 mg) and NaOMe (0.50 mL, 0.5 M solution in MeOH) was microwaved at 130° C. for 1 h; then cooled, concentrated, residue was dissolved in water, acidified with 2 M HCl; solids were collected via filtration, washed with water and air dried to give the desired product (25 mg). LC MS ESI: 354 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2[N:3]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Reactant: C1COCCN1
Solvent: O
Product: CC(C)c1cc(N2CCOCC2)nc(-c2ccc(Cl)cc2)n1
Temperature: 130 °C

Procedure:
A mixture of 267 mg of 4-chloro-2-(4-chlorophenyl)-6-isopropylpyrimidine and 522 mg of morpholine was heated at 130° C. for 2 hours. After cooling, 20 ml of water were added, the mixture was stirred, and the solid was filtered off with suction and dried at 50° C. in vacuo. Yield: 0.28 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Yield: 102.9 %

Procedure:
A solution of 30.0 g (0.11 mole) of t-butoxycarbonylphenylalanine in 750 ml of tetrahydrofuran was hydrogenated at 60° for 24 hours using 50 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate concentrated to give the title compound (30.7 g) as a colorless oil. The oil was used without further purification. Structure assignment was supported by the nmr spectrum (loss of aromatic protons and appearance of cyclohexyl protons).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:15]=[CH:16][CH:17]=1.O>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:2][OH:3])=[O:27])[CH:15]=[CH:16][CH:17]=1
Reactant: NO
Reactant: COc1cccc(CCCCCCCCC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCCCCCCCC(=O)NO)c1
Yield: 33.7 %

Procedure:
To a cold stirred suspension of 0.7 gms hydroxylamine hydrochloride and 1 gm sodium carbonate in 10 ml CH2Cl2 was added a solution of 2.1 gms 9(3-methoxyphenyl)nonanoyl chloride in 10 ml CH2Cl2. After stirring this mixture for 1/2 hr, 1.1 ml H2O was added, and the reaction was stirred overnight at room temperature. 30 ml water was added, the layers were separated, and the aqueous layer 3×50 ml extracted with CH2Cl2. The organic phases were combined, washed 2×20 ml water, 2×20 ml NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo to give an oil which solidified on standing. The solid was crystallized from CH2Cl2 :hexanes but was still impure by thin layer chromatography. It was dissolved in 100 ml CHCl3, stirred with 20 gm silica gel, and filtered. The silica gel was suspended in 75 ml CHCl3, stirred, and filtered (process repeated three times). All filtrates were combined, evaporated in vacuo, and the residue recrystallized from CH2Cl2 :hexanes to give 0.7 gms product of m.p. 66°-8°. Elemental analysis: calculated C 68.79, H 9.02, N 5.01% found C 68.61, H 9.18, N 5.09%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Yield: 78.8 %

Procedure:
To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 g, 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in 40 mL of 50% ethyl acetate in hexanes and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50% ethyl acetate in hexanes and the filtrates were combined and concentrated in vacuo to give 2.01 g of product as a tan crystalline solid. 1H NMR (CDCl3) δ 7.89 (dd, 1H, J=9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J=2.8 Hz), 6.88 (d, 1H, J=9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:7]3[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=3)[C:1]#[N:2])[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(C#N)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 41.2 %

Procedure:
A solution of 3-Cyanophenylboronic acid (23 mg, 0.15 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA39 (14.9 mg, 41% yield). ESI-MS (M+H)+ m/z calcd 279.1, found 279.0.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)O1.C([O:36][C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=1[F:44])(=O)C>>[F:44][C:38]1[CH:39]=[C:40]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)[CH:41]=[CH:42][C:37]=1[OH:36]
Reactant: CC(=O)Oc1ccc(Br)cc1F
Reactant: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(C(F)(F)F)s4)c(=O)n3)CC2)OC1(C)C
Product: O=c1nc(N2CC=C(c3ccc(O)c(F)c3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 41 %

Procedure:
The synthesis was performed using a crude product obtained by synthesis using 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(t rifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 346 and 4-bromo-2-fluorophenyl acetate in a similar manner to Reference Synthesis Example 139, in a similar manner to Reference Synthesis Example 2 (two step yield 41%).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2c(ccc3c2ccn3S(=O)(=O)c2ccc(Cl)cc2Cl)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,4-dichlorobenzenesulfonyl chloride (28 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,4-dichlorophenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (2 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (0.7 mg). MS m/z 412 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([F:15])([F:14])[F:13].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CCN(CC)CC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:17]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([F:15])([F:13])[F:14])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1ccccc1SCC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccccc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-aminomethyl-(2,2,2-trifluoroethylthio)benzene hydrochloride (500 mg, 1.94 mmol) in CH2C2 (20 mL) were added successively (BOC)2O (465 mg, 2.13 mmol), DMAP (23.7 mg, 0.194 mmol) and Et3N (0.27 mL, 1.94 mmol). The reaction mixture was stirred overnight at room temperature and was then diluted with EtOAc and washed successively with 10% aqueous citric acid, brine, and water. The organic layer was dried over MgSO4 and concentrated at reduced pressure. Silica gel chromatography (isocratic elution with 20% EtOAc-hexanes) afforded the title compound as a colorless oil:
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[CH2:4]([O:11][CH:12]1[CH2:16][CH2:15][C:14]([CH3:1])([OH:17])[CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC(OCc2ccccc2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methylmagnesium bromide (4.8 mL, 1.4 M solution in toluene/tetrahydrofurane 3:1) is added dropwise under argon to a solution of 3-(benzyloxy)cyclopentanone (420 mg) in tetrahydrofurane (10 mL) at −78° C. The mixture is stirred for 12 hours while warming to room temperature and partitioned between 1 M aqueous HCl solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated in vacuo to give the title compound. Yield: 400 mg; LC (method 7): tR=0.93 min; Mass spectrum (ESI+): m/z=229 [M+Na]+.
Reaction SMILES: C[Li].[Li+].[Br-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:14]=[C:15]([C:17](N(OC)C)=[O:18])[N:16]=2)=[CH:8][CH:7]=1.C[Li].[C:35](O)(=O)C>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[CH:14]=[C:15]([C:17](=[O:18])[CH3:35])[N:16]=2)=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Methyl lithium-LiBr complex (1.5 M in ethyl ether) (0.47 ml, 0.7 mmol) was added by syringe to a cold (−70° C.) solution of 2-(4-chlorophenyl)-N-methoxy-N-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxamide from step 2 (250 mg, 0.6 mmol) in 50 ml tetrahydrofuran. The reaction was warmed to 0° C. and re-cooled to −60° C. before additional methyl lithium (0.47 ml) was added. The reaction was warmed to room temperature. After stirring for two days, 50 ml of 10% acetic acid was added and the mixture was concentrated to a gum. The gum was dissolved in 50 ml ethyl acetate, washed with water (2×50 ml), dried over Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography: Anal. Calc'd. C18H15N2O3SCl.¼H2O: C, 56.99; H, 4.12; N, 7.38. Found: C, 56.88; H, 4.05; N, 7.6838
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][C:5]([SH:10])=[C:6]([O:8][CH3:9])[CH:7]=1.O.NN>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([SH:10])=[CH:4][C:3]=1[NH2:11]
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(N)cc1S
Yield: 77.8 %

Procedure:
To a solution of 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-mercaptoanisole (0.65 g) in tetrahydrofuran (20 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was heated at reflux for 1.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=2)[C:11]=1[CH:12]=O)=[O:5])[CH3:2].Cl.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][NH2:38])=[CH:33][CH:32]=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][N:38]=[CH:12][C:11]2[C:14]([O:18][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCCOc1cccc(Oc2nc(OC)cc(OC)n2)c1C=O
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(Oc2nc(OC)cc(OC)n2)c1C=NNc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 67.3 %

Procedure:
A mixture of 2.93 g (7.5 mmol) of 2-(3-ethoxycarbonyl-propoxy)-6-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-benzaldehyde (cf. Example 1), 1.5 g (8.3 mmol) of 4-chloro-phenylhydrazine-hydrochloride, 0.76 g(9.3 mmol) of sodium acetate and 150 ml of methylene chloride is stirred at 20° C. for 15 hours, then washed with saturated disodium hydrogen phosphate solution, dried with sodium sulphate and filtered. The filtrate is concentrated, the residue is stirred with methanol and the crystalline product is isolated by filtering off with suction. 2.6 g (67% of theory) of 2-(3-ethoxycarbonyl-propoxy)-6-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-benzaldehyde-4-chloro-phenylhydrazone of melting point 139° C. are obtained.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26].Cl>CS(C)=O>[CH3:14][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:16])[C:5]2[CH:4]=[C:3]([C:2]#[C:31][C:30]3[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A solution of 13.8 g (0.123 mole) of potassium tert.-butylate in 65 ml of dimethyl sulfoxide was added dropwise in the course of 30 minutes to a solution of 22.6 g (0.06 mole) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate (about 85% strength) and 7.86 g (0.06 mole) of 4-cyanobenzaldehyde in 190 ml of dry dimethyl sulfoxide at room temperature. Stirring was continued for 1 hour, after which the mixture was poured onto 1 liter of ice water and acidified with a little dilute hydrochloric acid, and the resulting crystals were filtered off under suction. Recrystallization from ethanol gave 9.2 g (49%) of the title compound of melting point 157° C.
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:28]([CH3:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.[OH-].[Na+]>CO>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH:28]2[CH3:29]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
A solution of ethyl 4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenyl carbonate (0.45 g, 1.02 mmol) in methanol (5.0 mL) was treated with a 1 N sodium hydroxide (5.1 mL) solution, and heated at 75° C. for 14 hours. After cooling to room temperature, the methanol was evaporated in vacuo. The resulting aqueous mixture was acidified with a 1 N hydrochloric acid solution, diluted with a saturated, aqueous, sodium chloride solution (100 mL), and extracted with dichloromethane (5×15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a white solid. The solid was purified by filtration through a short column of silica gel, eluting with ethyl acetate, to yield the title compound as a homogeneous, white, crystalline, solid (0.34 g, 89%), m.p. 188° C.;