Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11][CH:5]2[C:4](=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:6]=2[N:7]=1
Reactant: CC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(c(N3CCCCC3)n1)CCN(Cc1ccccc1)C2
Reaction time: 72 h

Procedure:
2-methyl-7-(phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one (Preparation 85, 19 g) and phosphorous oxychloride (150 ml) was heated for 1.5 h. The reaction mixture was concentrated and poured onto ice. Sodium carbonate was added to adjust pH to 10, and the product was extracted with chloroform. The organic extracts were concentrated and then purified by passing through a thick pad of florisil (5 cm diameter) the product was eluted with chloroform. Evaporation gave a dark red oil which was dissolved in ethanol (100 ml) and piperidine (25 ml) was added. After 72 h, the reaction mixture was concentrated in vacuo then dissolved in chloroform and basified with sodium hydroxide (2 M solution). The reaction mixture was dried and concentrated before purifying by flash chromatography on florisil eluting the product with petroleum ether (30-40) to give the title compound (12.5 g)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[S:9])[NH2:8])[CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>CC(C)=O.C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:9][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=2)[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1cc(C(N)=S)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1csc(-c2cc(C)on2)n1
Temperature: 55 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
5-Methyl-isoxazole-3-carbothioamide (1.0 g, 7.0 mmol) was dissolved in acetone (16 mL) and treated with ethyl bromopyruvate (1 mL, 1 equivalent) and 3.9 g of powdered 3 A molecular sieves. The reaction was stirred at 55° C. under a nitrogen atmosphere for 18 h. The mixture was filtered and evaporated to give 1.06 g of crude material. This material was dissolved in THF (25 mL), cooled to 0° C., and treated with 2,6-lutidine (1.5 mL, 3 equivalents). Trifluoroactetic acid (0.9 mL, 1.5 equivalents) was added and stirring was continued for 2 hrs under a nitrogen atmosphere. The reaction was poured into a 1 M solution of sodium bicarbonate and extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was removed by evaporation. The crude material was purified using chloroform:ethyl acetate (1:1) to give 876 mg (53%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:25]=NNC=5)=[CH:22][N:23]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[NH2:32][C:33]([C:35]1[S:36]C=C(B(O)O)[CH:39]=1)=[O:34]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:39]=[C:35]([C:33]([NH2:32])=[O:34])[S:36][CH:25]=5)=[CH:22][N:23]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: c1nc2c(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)ncc(-c3cn[nH]c3)n2n1
Reactant: NC(=O)c1cc(B(O)O)cs1
Product: NC(=O)c1cc(-c2cnc(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)c3ncnn23)cs1

Procedure:
This compound may be prepared using methods as described for Compound 46, using 2-(aminocarbonyl)thiophene-4-boronic acid. LCMS: Rt=0.93 (95%), m/z (ESI) 475 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][S:43]([CH3:45])=[O:44])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(=O)C.[ClH:53].CCOCC>O1CCOCC1>[ClH:53].[NH2:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][S:43]([CH3:45])=[O:44])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CS(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CS(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine sulfoxide is suspended in 100 parts by volume acetic acid and treated with 50 parts by volume 6 M HCl in dioxane. The resulting mixture is stirred at room temperature for two hours and then stripped of solvent under reduced pressure. Trituration of the residue with ether affords solid L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine sulfoxide hydrochloride. This compound is represented by the following formula. ##STR6##
Reaction SMILES: C1COCC1.[BH4-].[Na+].[C:8]([NH:27][C@H:28]([C@H:34]([OH:50])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:29](OCC)=[O:30])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(OCC)(=O)C>O>[C:8]([NH:27][C@H:28]([C@H:34]([OH:50])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:29][OH:30])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A THF suspension (2 mL) containing sodium borohydride (39.2 mg, 0.96 mmol) was heated to 60° C., and ethyl (2R,3R)-2-octadecanoylamino-3-hydroxyoctadecanoate (300.0 mg, 0.49 mmol) synthesized in the same manner as Example 17 was added for 2.5 hours. After completion of the dropwise addition, the mixture was further stirred at 60° C. for 24 hours. After ethyl acetate and water were added thereto, the reaction mixture was stirred at 60° C. for 1 hour. After the organic layer was separated, the obtained organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was removed in reduced pressure. It was confirmed that 219.4 mg of the title compound was contained (yield: 78%). HPLC analysis was carried out to find that anti-form:syn-form was 81:19 and the optical purity of the anti-form was 99% ee.
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5].[Cl:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[C:20]([F:31])=[CH:19][N:18]=3)=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5])[CH2:26]4)[C:20]([F:31])=[CH:19][N:18]=3)=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Reactant: C[C@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](CO)CN1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 80 °C

Procedure:
To a solution of (R)-3-bromo-2-methylpropan-1-ol (0.006 mL, 0.055 mmol) and (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)-pyrimidin-4-amine, 12a, (0.020 g, 0.055 mmol) in CH3CN (2 mL) was added K2CO3 (0.023 g, 0.165 mmol). The reaction mixture was heated at 80° C. at for 24 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 135.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([CH3:36])[CH2:35][O:34][CH2:33]4)=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@H:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([CH3:36])[CH2:35][O:34][CH2:33]4)=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:41]3[CH2:42][CH2:43][O:38][CH2:39][CH:40]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1C(O)c1ccc(C3(C)COC3)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C3(C)COC3)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from ((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-(3-methyloxetan-3-yl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:12]=[C:13]4[S:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:14]4=[CH:15][C:16]=3[C:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:18]=2[CH:19]=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([C:26]1[CH:25]=[C:24]2[C:29]([S:30][C:13]3[C:14]2=[CH:15][C:16]2[C:17]([CH2:20][CH3:21])([CH2:22][CH3:23])[C:18]4[CH:19]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=4[C:11]=2[CH:12]=3)=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CCC1(CC)c2cc(OC)ccc2-c2cc3sc4ccccc4c3cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(CC)c2cc(OC)ccc2-c2cc3sc4ccc(C(C)=O)cc4c3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (100 mL) in which were dissolved 2-methoxy-12,12-diethyl-6,12-dihydro-6-thia-indeno[1,2-b]fluorene (6.60 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. Dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[OH:26][C:27]1[CH:69]=[CH:68][C:30]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[CH:43]=[CH:42][C:41]([C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)([C:51]5[CH:56]=[CH:55][C:54]([N:57]6[CH2:61][CH2:60][CH2:59][CH2:58]6)=[CH:53][CH:52]=5)[O:40][C:39]=4[CH:38]=3)=[CH:33][CH:32]=2)=[CH:29][CH:28]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4[CH:43]=[CH:42][C:41]([C:62]5[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=5)([C:51]5[CH:56]=[CH:55][C:54]([N:57]6[CH2:61][CH2:60][CH2:59][CH2:58]6)=[CH:53][CH:52]=5)[O:40][C:39]=4[CH:38]=3)=[CH:35][CH:36]=2)=[CH:68][CH:69]=1)=[O:4]
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 25.1 %

Procedure:
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-octanoyl chloride (0.30 g, 0.7 mmol) was added to a solution of 6-[4′-(hydroxy)biphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[2,1-b]pyran (0.40 g, 0.7 mmol) in DCM (30 mL) containing pyridine (2 mL) under N2 at 0° C. with stirring. The mixture was stirred at room temperature for 1 h, poured into HCl (2 M, 100 mL), extracted with DCM (3×50 mL), washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (60% in hexanes) as eluent and the solvent removed under reduced pressure. The residue was dissolved in Et2O, hexane was added and the solvent reduced. The resulting precipitate was filtered to give the title compound (0.17 g, 25%) as a colourless powder, mp 144-145° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:48][C:49]([C:51]1[C:52]2[CH:53]=[CH:54][N:55]=[CH:56][C:57]=2[CH:58]=[CH:59][CH:60]=1)=[NH:50]>CN(C=O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:50]=[C:49]([C:51]3[CH:60]=[CH:59][CH:58]=[C:57]4[C:52]=3[CH:53]=[CH:54][N:55]=[CH:56]4)[N:48]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 110 °C
Yield: 26.4 %

Procedure:
4-[(Difluoromethyl)oxy]benzoic acid (Aldrich; 121 mg, 0.642 mmol) was stirred in DMF (1 ml) with HATU (244 mg, 0.642 mmol) and DIPEA (0.28 ml, 1.605 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 100 mg, 0.535 mmol) in DMF (1 ml). The resulting mixture was heated to 110° C. for 2 hrs in a Biotage Initiator microwave. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-100% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated under vacuum to provide a crude material, which was further purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound as a white solid (48 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=O>C(O)(C)C>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[N:20]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=2)=[CH:31][CH:32]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(Br)cc3)nc2-c2ccc(Cl)cc2)cc1
Yield: 63.6 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (30 mL), 2,4'-dibromoacetophenone (720 mg, 2.58 mmol) was added. After heating the reaction mixture at 80°-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (810 mg) was chromatographed (silica gel, hexane/ethyl acetate, 6/4) to give 4-(4-bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (400 mg, 64%) as a pale yellow solid: mp 145°-48° C. Anal. Calc'd. for C22H16N2SO2BrCl: C, 54.17, H, 3.31, N, 5.74, S, 6.57. Found: C, 54.41, H, 3.33, N, 5.50, S, 6.52.
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]([C:15]3[C:16](=[O:22])[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])C(C)=CC=1.Cl.ON.C(N(CC)CC)C>CCO.O>[NH2:3][C:8]1[CH:9]=[C:10]([C:15]2[C:16](=[O:22])[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=2)[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccc(-c2ccnn(C)c2=O)cc1-n1c(C)ccc1C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccnn(C)c2=O)cc1N
Yield: 51.5 %

Procedure:
To a solution of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2-methyl-2H-pyridazin-3-one (1.05 g, 3.57 mmol) in EtOH (20 ml) and water (10 ml) was added hydroxyl amine hydrochloride (2.49 g, 35.79 mmol) and triethyl amine (1.0 ml, 7.16 mmol). The mixture was heated at reflux for 24 hours. The solvent was evaporated to dryness under reduced pressure and the rsidue was partitioned between water and EtOAc. The organic layer was separated and washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/1:1) gave 0.396 g (51%) of 4-(3-amino-4-methyl-phenyl)-2-methyl-2H-pyridazin-3-one as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH:21]=[CH:22][C:23]=1[CH3:24].[C:33](Cl)(Cl)=[O:34]>C(=S)=S>[CH3:31][C:28]1[C:33](=[O:34])[C:30]2[C:25](=[CH:26][C:27]=1[CH3:32])[C:20]1[C:21](=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=1)[CH:29]=2
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(-c2ccc(C)c(C)c2)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: S=C=S
Product: CC1=C(C)C(=O)C2=Cc3cc(C)c(C)cc3C2=C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
35.6 g of anhydrous aluminium chloride are added in portions to a solution of 20 g of biphenyl according to (a) and 14 g of phosgene in 130 ml of carbon disulfide at -10° C. to 0° C. in the course of 2 hours. After stirring at room temperature for 15 hours, the mixture is refluxed for 2 hours, poured onto ice-water and extracted with 1.5 l of chloroform. The residue from the organic phase (22.9 g) is separated by column chromatography on silica gel. Elution with methylene chloride/toluene=13:7 gives 9.8 g of 1,2,6,7-tetramethyl-fluorenone (Rf value 0.62) and 10.04 g of 2,3,6,7-tetramethyl-fluorenone (Rf value 0.41).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19](=[N:21][OH:22])[NH2:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:30](Cl)(=O)[O:31]C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[NH:20][C:30](=[O:31])[O:22][N:21]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC(Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12)=NO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1
Reaction time: 1 h

Procedure:
A solution of 2-(6-fluoro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)-N′-hydroxyacetimidamide (0.040 g, 0.13 mmol) and triethylamine (0.025 mL, 0.198 mmol) in CHCl3 (1 mL) was treated with phenyl carbonochloridate (0.018 mL, 0.19 mmol) and stirred for 1 h. The reaction mixture was washed with water (30 mL) and dichloromethane (30 mL). The organic solution was dried with Na2SO4, evaporated under vacuum. The crude product was purified by HPLC to provide the title product. M/e+ 329 for C16H11F2N4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.0, 2.2 Hz, 1H), 7.77 (dd, J=9.9, 4.7 Hz, 1H), 7.69 (m, 2H), 7.62 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H) ppm.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Mercapto-4-phenoxy-5-sulfamylbenzoic acid (0.6 g) is suspended in water (20 ml) and the pH is adjusted to 8 by addition of 1 N sodium hydroxide. Benzyl bromide (0.35 g) is added to the resulting solution, and the reaction mixture is stirred for 2 hours at room temperature. After cooling, the precipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is dissolved in hot water (60 ml) and the solution acidified by addition of 1 N hydrochloric acid. After cooling, the precipitated 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration and recrystallized from aqueous ethanol to yield the desired compound with a melting point of 234°-236° C., after drying in vacuo.
Reaction SMILES: S(Cl)(Cl)=O.S1C=CC=C1CC(O)=O.S1C=CC=C1CC(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52]>C1(C)C=CC=CC=1.C(O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)=[S:55])=[CH:40][CH:39]=1
Reactant: O=C(Cc1cccs1)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)Cc1cccs1
Agent: O=C(O)Cc1cccs1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4cccs4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-thienyl)acetic acid (40 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-thienyl)ethanoyl isothiocyanate was prepared using the resultant 2-(2-thienyl)ethanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-thienyl)ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 57%).