Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
To a solution of 2.389 g of 2-chloro-4-trimethylsilanylethynyl-pyridine (11.39 mmol) in THF (90 ml) were added 11.39 ml of a 1 M TBAF solution in THF at −78° C. and the reaction mixture was stirred for 45 min at 0° C. Then saturated NH4Cl solution was added and the THF was removed under reduced pressure. The aqueous mixture was extracted with diethylether and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The remaining residue was purified by column chromatography (pentane/diethylether 100:0 to 4:1) to give 2-chloro-4-ethynyl-pyridine (1.427 g, 91%) as an off-white solid. 1H-NMR (CDCl3, 300 MHz: δ 3.36 (s, 1H), 7.27 (dd, J=5 and 1 Hz, 2H), 7.40 (br s, 1H), 8.37 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]([CH:4]1[CH:9]([C:10]([NH:12][C@H:13]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH2:8][CH:7]=[CH:6][CH2:5]1)([OH:3])=[O:2].C(Cl)Cl.C(O)(=O)C>[OH-].[Na+].CO.O>[C:1]([C@@H:4]1[C@H:9]([C:10]([NH:12][C@H:13]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH2:8][CH:7]=[CH:6][CH2:5]1)([OH:3])=[O:2]
Reactant: C[C@H](NC(=O)C1CC=CCC1C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](NC(=O)[C@@H]1CC=CC[C@@H]1C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The phenylmethyl ester product from part (a) (1.2 g., 2.31 mmole) is dissolved in a solution of 10% sodium hydroxide (5 ml.) and methanol(5 ml.) and stirred at room temperature for 3 hours. The reaction mixture is diluted with water and washed with diethyl ether. Upon acidification of the aqueous layer with potassium bisulfate and saturation with sodium chloride, the diacid product is extracted into ethyl acetate and dried (MgSO4). The ethyl acetate solution is concentrated and the residue is triturated with hexane and diethyl ether to give 400 mg. of 1-[N-[(6-carboxy-3-cyclohexen-1-yl)carbonyl]-L-alanyl]-L-proline as a white solid; m.p. softens at 98°, 125°-130°. TLC (Rf 0.44 silica gel, methylene chloride:methanol:acetic acid; 8:1:1). [α]D =-76.7° (c=1.4, methanol).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:33]([NH:35][C@H:36]([C:40]([O:42]C)=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[CH2:18][C:19](=[O:21])[OH:20])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[OH-].[Na+]>CO>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:33]([NH:35][C@H:36]([C:40]([OH:42])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])[CH2:18][C:19](=[O:20])[OH:21])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](N)CCCNC(=N)N)C(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Two grams (g) of BOC-Arg-Gly-Asp-D-Phe-Val-OMe (SEQ ID NO 1) were first dissolved in 60 milliliters (ml) of methanol to which was added 1.5 ml of 2 N sodium hydroxide solution to form an admixture. The admixture was then stirred for 3 hours at 20 degrees C. (20C). After evaporation, the residue was taken up in water and acidified to pH 3 with diluted HCl and extracted with ethyl acetate. The extract was dried over Na2SO4, evaporated again and the resultant BOC-Arg-Gly-Asp-D-Phe-Val-OH (SEQ ID NO 2) was stirred at 20C for 2 hours with 20 ml of 2 N HCl in dioxane. The resultant admixture was evaporated to obtain H-Arg-Gly-Asp-D-Phe-Val-OH (SEQ ID NO 3) that was subsequently dissolved in a mixture of 1800 ml of dichloromethane and 200 ml of dimethylformamide (DMF) followed by cooling to 0C. Thereafter, 0.5 g of dicyclohexylcarbodiimide (DCCI), 0.3 g of 1-hydroxybenzotriazole (HOBt) and 0.23 ml of N-methylmorpholine were added sequentially with stirring.
Reaction SMILES: [CH3:1][C:2]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:13][CH2:12]1)[CH2:3][C:4]([O:6]C)=[O:5]>Cl>[CH3:1][C:2]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:15][CH2:16]1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Agent: Cl
Product: CC(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)(CC(=O)O)c1ccccc1

Procedure:
A suspension of 1.5 g (0.0027 mol) of methyl 2-methyl-2-phenyl-5-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate in 60 ml of 6N hydrochloric acid is refluxed for 25 hours. After cooling the precipitate is filtered off and washed with water and ethyl acetate.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[C:9](Cl)(=[O:11])[CH3:10]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:9]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CC(C(=O)O)C1
Temperature: 0 °C

Procedure:
To a solution of 3-hydroxycyclobutanecarboxylic acid (100 mg, 0.86 mmol) in DCM (10 mL) was added DMAP (1.0 mg, 0.086 mmol). The solution was cooled to 0° C., followed by the addition of acetyl chloride (0.14 mL, 2.6 mmol). The reaction was heated at 45° C. for 4 hours, then cooled to rt and diluted with DCM (20 mL). The mixture was washed with water (10 mL), followed by washing with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtained the crude product which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[CH2:11]>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][C:12]([CH2:10][CH2:11][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:13][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=Cc1ccncc1
Solvent: CC(=O)O
Product: c1ccc2c(CCc3ccncc3)c[nH]c2c1

Procedure:
Indole (5.85 g, 50 mmol) was dissolved in glacial acetic acid (25 ml) together with 4-vinylpyridine (5.80 g, 55 mmol). The reaction mixture was boiled under reflux for 6 h. For working up, the glacial acetic acid was distilled off. Saturated NaHCO3 solution (75 ml) and water (15 ml) were then added to the mixture. The mixture was extracted with ethyl acetate (1×100 ml, 3×15 ml). (The insoluble oil remaining between the phases contained only polar impurities.) The organic phase was dried over Na2SO4 and then evaporated. The residue was recrystallized twice from ethyl acetate (30 ml each time). The product Ind-14 was obtained as a pale yellow solid in a yield of 7.06 g (31.8 mmol, 63%, m.p.: 154-158° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.25 g, 0.67 mmol) was dissolved in THF (10 ml). To this was added diisopropylethylamine (0.33 ml, 1.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.06 ml, 0.74 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 20% heptane, 80% ethyl acetate) to give the title compound (57 mg, 20% yield) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+].[Br-]>>[CH2:19]([O:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCC(=O)OC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [K+]
Product: CCCCOc1cc(-c2ccccc2)c(OCC(=O)O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared as an off white solid (0.167 g, 85%) from (5′-butoxy-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 92-94° C.; 1H NMR (DMSO-d6) δ 0.92 (t, J=7.5 Hz, 3H), 1.38-1.49 (m, 2H), 1.65-1.74 (m, 2H), 3.64 (s, 2H), 4.02 (t, J=6.6 Hz, 2H), 6.87 (s, 2H), 7.33-7.39 (m, 2H), 7.39-7.44 (m, 4H), 7.57-7.61 (m, 4H), 12.30-12.55 (bs, 1H); IR (KBr) 3420, 3060, 2930, 2860, 2770, 2590, 1725, 1590, 1570, 1460, 1420, 1360, 1260, 1235, 1215, 1195, 1075, 1050, 1010, 925, 760, 750, 700, and 620 cm−1; mass spectrum [(+) ESI], m/z 394 (M+NH4)+; Anal. Calcd. for C24H24O4: C, 76.57; H, 6.43; N, 0.00, Found: C, 76.33; H, 6.55; N, -0.04.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]2[C@:45]3([C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]3)[CH2:44][C@@H:43]([C:52](Cl)=[O:53])[O:42][C:39]2=[CH:40][CH:41]=1>>[CH2:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:52]([C@@H:43]2[CH2:44][C@@:45]3([C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]3)[C:38]3[C:39](=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=3)[O:42]2)=[O:53])[CH2:5][CH2:6]1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCN1CCN(CC=Cc2ccccc2)CC1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCN(CC=Cc4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a chilled mixture (less than -5° C.) of 4-(2-aminoethyl)-1-cinnamylpiperazine (10.0 g, 40.8 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (6.20 g, 40.8 mmol) and N,N-dimethylformamide (55.0 ml, 710 mmol) was added over 30 minutes a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1, 11.1 g, 37.1 mmol) in N,N-dimethylformamide (100.1 ml, 1.29 mol). After stirring the mixture for 15 hours at 25° C., the solvent was evaporated. The residue was chromatographed on silica gel, eluted with a mixture of AcOEtAcOEt/MeOH (9:1), and evaporated in vacuo to dryness to give a colorless oil of the desired compound (17.5 g, 92.6%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].Cl.[CH3:28][O:29][NH:30][CH3:31].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([N:30]([O:29][CH3:28])[CH3:31])=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)O)cc2OCC3)n(C(C)C)n1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (4.00 g, 11.3 mmol) and N-methoxymethanamine hydrochloride (1.32 g, 13.6 mmol) in N,N-Dimethylformamide (100 mL) was added N-Ethyldiisopropylamine 7.9 mL, 45.3 mmol) followed by HBTU (4.72 g, 12.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS analysis of the reaction mixture showed no more starting material. The solvent was removed and the residue was diluted with DCM, washed with NaHCO3 sat. aq., dried over Na2SO4, filtered and concentrated. The resulting oil was purified on silica gel (0→10% MeOH/DCM) to give 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-N-methoxy-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17](=[O:26])[CH2:18][S:19][CH2:20][C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].ClC1C=CC=C(C(OO)=[O:35])C=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17](=[O:26])[CH2:18][S:19]([CH2:20][C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:35])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(N)=Nc1nc(-c2ccc(CNC(=O)CSCc3ccco3)o2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(N)=Nc1nc(-c2ccc(CNC(=O)CS(=O)Cc3ccco3)o2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[5-{(furan-2-yl)methylthio}acetamidomethylfuran-2-yl]thiazole (1.5 g) and 3-chloroperbenzoic acid (0.9 g) in a mixture of tetrahydrofuran (30 ml) and N,N-dimethylformamide (10 ml) was stirred for 1.5 hours at ambient temperature. To the reaction mixture was added a solution of water and ethyl acetate and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and isopropyl ether to give 2-(diaminomethyleneamino)-4-[5-{(furan-2-yl)methylsulfinyl}acetamidomethylfuran-2-yl]thiazole (1.5 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=1.CCN(C(C)C)C(C)C.F[C:44]1[C:52]2[C:51]([NH2:53])=[CH:50][C:49]([C:54]3[CH:62]=[C:61]([F:63])[CH:60]=[C:59]4[C:55]=3[CH:56]=[CH:57][N:58]4S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)=[CH:48][C:47]=2[N:46](S(C2C=CC=CC=2)(=O)=O)[N:45]=1>CN(C)C=O.CS(C)=O>[F:63][C:61]1[CH:60]=[C:59]2[C:55]([CH:56]=[CH:57][NH:58]2)=[C:54]([C:49]2[CH:48]=[C:47]3[C:52]([CH:44]=[N:45][NH:46]3)=[C:51]([NH:53][C:31]([C:29]3[N:30]=[C:26]([CH3:25])[S:27][CH:28]=3)=[O:33])[CH:50]=2)[CH:62]=1
Reactant: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reactant: Cc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)Nc2cc(-c3cc(F)cc4[nH]ccc34)cc3[nH]ncc23)cs1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 10.2 %

Procedure:
HATU (0.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (0.2 ml) and added to 2-methyl-1,3-thiazole-4-carboxylic acid (0.1 mmol) also in DMF (0.2 ml). DIPEA (0.05 ml 0.3 mmol) was added and the mixture was left to stand for 5 mins. 3-Fluoro-6-{6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-amine (0.1 mmol) was dissolved in DMF (0.2 ml) and to this was added the acid containing mixture. The solution was shaken for 5 minutes and left to stand at room temperature overnight. A further portion of HATU (0.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (0.2 mL) and added to further 2-methyl-1,3-thiazole-4-carboxylic acid (0.1 mmol), also in N,N-Dimethylformamide (DMF) (0.2 mL). DIPEA (0.3 mmol) was added and the mixture left to stand for 5 mins, then the resultant solution was added to the vessel containing the reaction mixture. Solutions were shaken for 5 minutes and then placed in the oven at 40° C. for 1 hour. DMF was removed by vacuum centrifugation (not to dryness) and the residue was dissolved in chloroform (0.3 ml). The solution was loaded onto aminopropyl SPE cartridge (500 mg) that had been preconditioned with MeOH followed by chloroform (2 ml each). The column was eluted with 10% MeOH in EtOAc (5 ml) and the fractions obtained were blown down under a stream of nitrogen. The residue was dissolved in DMSO (0.5 ml) and purified by Mass Directed AutoPrep on an Xbridge column using Acetonitrile/Water as eluent with an ammonium carbonate modifier. The solvent was evaporated in vacuo using the Genevac. The residue was dissolved in isopropanol (0.3 ml) and NaOH (2M, aqueous, 0.3 ml) was added. The solution was left for 32 hours at room temperature, then heated at 40° C. overnight. The reaction mixture was neutralised using 2 M, aqueous HCl and then blown down under a stream of nitrogen. The residue was dissolved in DMSO (0.5 ml) and purified by Mass Directed AutoPrep on an Xbridge column using Acetonitrile/Water with a formic acid modifier. The solvent was evaporated by vacuum centrifugation to give the title compound (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) 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 (76 mg, yield 99%).
Reaction SMILES: [NH2:1][C:2]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH2:18](C(CC)(CC)C([O-])([O-])[O-])[CH3:19].C(O)(=O)C>ClC(Cl)C>[OH:17][CH2:16][C:2]1([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:14][O:15][C:18]([CH3:19])=[N:1]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CC(=O)c1ccc(CCC(N)(CO)CO)cc1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(CCC2(CO)COC(C)=N2)cc1
Temperature: 80 °C

Procedure:
To a suspension of 1-[4-(3-amino-4-hydroxy-3-hydroxymethyl-butyl)-phenyl]-ethanone (1 mmol) in anhydrous dichloroethane (2 mL) is added triethylorthoacetate (1.1 mmol) and acetic acid (0.05 mmol). The resulting mixture is heated at 80° C. for 12 hours. After concentration, the residue is purified by flash column chromatography (EtOAc) to give 1-{4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-ethanone as an oil; MS: (ES+): 262.1 (M+1)+.
Reaction SMILES: [I-:1].[I-].[I-].[CH2:4]([N:7]([C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[S+:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2)[CH2:8][CH2:9][CH3:10])[CH2:5][CH3:6].[CH2:25]([N:28](C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)[CH2:29][CH2:30]C)[CH2:26]C.C(N(C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)CCC)CC.C(NCC)C>>[I-:1].[CH2:25]([N:28]([C:19]1[CH:18]=[CH:17][C:16]2[C:21]([CH:20]=1)=[S+:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([N:7]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6])[CH:24]=1)[N:15]=2)[CH2:29][CH3:30])[CH3:26]
Reactant: CCCN(CCC)c1ccc2nc3ccccc3[s+]c2c1
Agent: [I-]
Solvent: CCNCC
Product: CCCN(CCC)c1ccc2nc3ccc(N(CC)CC)cc3[s+]c2c1

Procedure:
This compound was obtained following isolation of 3-(N,N-dipropylamino)-phenothiazin-5-ium triiodide and subsequent treatment with diethylamine. Precipitation from dichloromethane by addition of diethyl ether yielded purple lustrous crystals. Mass spectrometry: C22H30N3OS requires m/z=368; found m/z=368 (I− not detected by mass spectrometry).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]([OH:19])=[O:18])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[C:10]1([C:8]2[O:9][C:5]3[C:4]([C:17]([OH:19])=[O:18])=[CH:3][CH:2]=[CH:16][C:6]=3[CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1cc(Cl)cc2cc(-c3ccccc3)oc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Temperature: 40 °C

Procedure:
1.46 g of 5-chloro-2-phenylbenzofuran-7-carboxylic acid are dissolved in a mixture of 15 ml of ethyleneglycol monomethylethers and 15 ml of methanol. 500 mg of 10% palladium-carbon and 1.6 g of ammonium formate are added to the solution and the solution is heated at 40° C. for 1.5 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate. The solution is washed successively with 10% hydrochloric acid and water, dried and evaporated to remove solvent to give 2-phenylbenzofuran-7-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15](=O)[NH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:25]>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15]([Cl:25])=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2nc(NCc3ccccc3Cl)ncc12
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccccc1CNc1ncc2c(Cl)nccc2n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
2-(2-Chloro-benzylamino)-6H-pyrido[4,3-d]pyrimidin-5-one 8 (3.00 g, 10.5 mmol) was dissolved in POCl3 (30 mL) and stirred at 90° C. for 15 h. The reaction mixture was carefully poured into ice water and the pH was adjusted to 8 adding 2 N NaOH solution. The precipitate formed was filtered off and dried in vacuo. The product was purified by crystallization from diethyl ether to yield in a colorless solid (3.18 g, 10.4 mmol, 100%).