Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[N:17]=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=3[CH2:12]2)=[O:10])[CH2:8][CH2:7][NH:6][CH2:5]1.[C:25]([C:28]1[CH:39]=[CH:38][C:31]2[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=2[CH:29]=1)(=O)[CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][O:2][CH2:3][C:4]1([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[N:17]=[CH:16][C:15]([C:21]([F:22])([F:24])[F:23])=[CH:14][C:13]=3[CH2:12]2)=[O:10])[CH2:8][CH2:7][N:6]([CH:25]([C:28]2[CH:39]=[CH:38][C:31]3[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=3[CH:29]=2)[CH3:26])[CH2:5]1
Reactant: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCNC1
Reactant: CC(=O)c1ccc2c(c1)n(C)c(=O)n2C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C(C)c2ccc3c(c2)n(C)c(=O)n3C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to general procedures described in Scheme 6: A mixture of (3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone VIc (50 mg, 0.146 mmol), 5-acetyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.146 mmol) and Ti(OiPr)4 (51 mg, 0.182 mmol) in THF (2.5 mL) was irradiated in a Microwave instrument at 100° C. for 30 min (Personal Chemistry Emrys™ Optimizer microwave reactor). The reaction mixture was cooled and NaBH(OAc)3 (93 mg, 0.438 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in 30 mL of ethyl acetate and washed with sat. NaHCO3. The organic layer was washed with brine (×3), then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to yield the desired final product as trifluoroacetic salt with purity greater than 95% (18.0 mg, 23.2% yield): 1H NMR (300 MHz, CD3Cl3): δ 8.71 (s, 1H), 7.72 (s, 1H), 7.29 (bs, 1H), 7.01 (bs, 1H), 6.92 (s, 1H), 5.23 (m, 2H), 4.87 (m, 1H), 4.73 (m, 1H), 4.10-3.86 (m, 4H), 3.71 (m, 1H), 3.40 (m, 3H), 3.32-3.24 (m, 6H), 3.12 (m, 3H), 2.91 (bs, 1H), 2.66 (d, 1H), 2.42 (s, 1H), 2.30 (s, 1H), 1.81 (m, 2H); MS (ESI) m/z: Calculated for C27H32F3N5O3: 531.3. found: 532.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][O:10][CH3:9]
Reactant: COCCBr
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccccc1I
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 2-iodo phenol (1 eq.) and 2-bromoethyl methyl ether (1.1 eq) in DMF (0.21M) at 0° C. was added Cs2CO3 (1.5 eq). The mixture was stirred at 50° C. for 6 h, cooled to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 10%, afforded the desired compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2ccccc2)c2nccn2CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: c1ccc(-c2cccn3ccnc23)cc1

Procedure:
Combine 9 g (46 mmol) of the product from Example 3 with 50 g of "activated" manganese dioxide in 200 ml of methylene chloride, and heat to reflux for 8 hr. Filter off the solids and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:19][O:18][N:17]([CH3:16])[C:12]([CH:10]1[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
To a solution of 1-Boc-azetidine-3-carboxylic acid (5.0 g, 24.9 mmol) in DMF (40 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.89 g, 29.8 mmol), EDC (5.55 g, 29.8 mmol), HOBt (3.36 g, 24.9 mmol) and DIPEA (9.82 mL, 54.7 mmol). The reaction was stirred at room temperature for 20 h. The reaction was diluted with water (150 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over MgSO4 and concentrated under vacuum to afford 4 as a clear colorless oil (6.06 g, 99%); 1H-nmr (400 MHz, CDCl3) δ 4.21-4.11 (m, 2H), 4.05 (t, J=8.0 Hz, 2H), 3.66 (s, 3H), 3.68-3.59 (m, 1H), 3.21 (s, 3H), 1.44 (s, 9H); m/z 189.1 [M−tBu].
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([S:14](=[O:20])(=[O:19])[NH:15][CH:16]3[CH2:18][CH2:17]3)[CH:10]=[C:9]2[C:21]([O:23]CC)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CO.O>[CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([S:14](=[O:20])(=[O:19])[NH:15][CH:16]3[CH2:17][CH2:18]3)[CH:10]=[C:9]2[C:21]([OH:23])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(S(=O)(=O)NC2CC2)c(C)n1CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(S(=O)(=O)NC2CC2)cc(C(=O)O)n1CC1CCCCC1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a solution of compound 3a (8.0 g, 22.0 mmol) in MeOH (200 mL) was added a solution of LiOH (4.2 g, 100 mmol) in water (50 mL) and the solution was warmed to 50° C. overnight, cooled to rt and concentrated. The residue was diluted with water and acidified to pH˜4 with 4N aq. HCl and the solution was extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=2/1) to give compound 3b (6.0 g, 80%) as a white solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([S:19]([N:22](C(OCC(C)C)=O)[C:23]3[C:28]([O:29][CH3:30])=[N:27][C:26]([CH3:31])=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:6].[Cl-].[NH4+]>CO>[CH3:6][N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([S:19]([NH:22][C:23]3[C:28]([O:29][CH3:30])=[N:27][C:26]([CH3:31])=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:4]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(N(C)C)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(N(C)C)cc1
Yield: 61.4 %

Procedure:
Sodium methoxide (0.115 g) was added to a solution of 2-[4-(N,N-dimethylamino)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.212 g) in methanol (10 ml) and the mixture was stirred and heated under reflux for 90 minutes. The reaction mixture was cooled, poured into saturated aqueous ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×30 ml). The organic extracts were combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with ether to give 2-[4-(N,N-dimethylamino)phenyl] -N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (104 mg) as a solid, m.p. 183°-184.5° C.; 1H NMR (d6 -DMSO): 2.2 (s, 3 H), 2.95 (s, 6 H), 3.8 (s, 3 H), 6.7 (br s, 2 H), 7.3-7.5 (m, 4 H), 8.37 (dd, 1 H), 8.7 (dd, 1 H), 10.1 (br s, 1 H); mass spectrum (+ve FAB, DMSO/methanol/NBA): 400 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>C(O)C.O.O1CCOCC1.O>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(C)n1cc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of ethyl 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (266 mg, 1.06 mmol) and lithium hydroxide (102 mg, 4.25 mmol) in ethanol:water:dioxane (1:1:1, 6 mL) was warmed to 40° C. and stirred overnight. The mix cooled to RT, diluted with water (25 mL) and washed with ether (20 mL). The aqueous phase made acidic with 3N HCl (pH˜2) and extracted with ethyl acetate (2×15 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (199 mg, 84% yield) as a white solid. MS (ESI) m/z: 223.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5]([CH3:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19]>CC(C)=O>[CH3:1][O:2][C:3](=[O:10])[C:4](=[N:8][O:9][CH2:17][CH2:18][CH3:19])[C:5]([CH3:7])=[O:6]
Reactant: CCCI
Reactant: COC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCON=C(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 13.6 g of 2-hydroxyiminoacetoacetic acid methyl ester in 70 ml of acetone is added under ice cooling 20.8 g of potassium carbonate. To the mixture is added dropwise 17.0 g of n-propyl iodide in the course of 30 minutes. At the end of the dropwise addition, the mixture is stirred at room temperature for 2 hours. Acetone is evaporated under reduced pressure. To the residue is added 250 ml of water, and the mixture is subjected to extraction with methylene chloride. The extract is washed with water twice, dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to yield 2-(n-propoxyimino)acetoacetic acid methyl ester as a pale yellow oily product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14]I)[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][N:25]=[N+:26]=[N-:27])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CI)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 90 %

Procedure:
To a stirred solution of the 3'-O-t-butyldimethylsilyl-5'-iodo-5'-deoxythymidine (10.8 g, 20 mmol) prepared according to the method of Example 25 in dry DMF (50 ml) was added sodium azide (3.9 g, 60 mmol) and the mixture heated at 0° C. for 12 hours. Then the reaction mixture was diluted with ethyl acetate (200 ml) washed with water (2×50 ml) and brine (50 ml) and then dried with sodium sulfate. The title compound was purified by flash chromatography using 50% ethyl acetate in hexance in 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>C(O)C.N1CCCCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1CCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (60.9 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2CO)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 5-chloro-N-methyl-N-(p-toluenesulfonyl)anthranilic acid (5.20 g (15.3 mmol)) in chloroform (20.0 ml), thionyl chloride (2.00 g (27.4 mmol)) was added with stirring at room temperature. The resulting mixture was heated at 50° C. for 2 hours with stirring and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (20.0 ml) and added dropwise to a solution of sodium borohydride (90%, 1.30 g (30.9 mmol) in water (20.0 ml) under cooling with ice. After one hour's stirring at room temperature, water (100.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.40 g (88%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15](OCC)=[O:16])[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[N:6]2[N:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=[C:2]2[NH:1][CH:20]=1)=[O:24])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C(=O)O)n[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C(=O)O)nn2c1=O
Temperature: 120 °C
Yield: 29.9 %

Procedure:
To a solution of 5-amino-1H-pyrazole-3-carboxylic acid (600 mg, 4.7 mmol, 1 eq) in acetic acid (30 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (1.1 g, 5.2 mmol, 1.1 eq). The mixture was heated at 120° C. for 4 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol to afford the expected compound as grey powder (353 mg, 30% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([C:22]([O:24]C)=[O:23])[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=2)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].[OH-].[Na+]>O1CCOCC1.Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=2)[C:22]([OH:24])=[O:23])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1nc(-c2cc(C(=O)OC)cc(C(=O)OC)c2)cnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1nc(-c2cc(C(=O)O)cc(C(=O)OC)c2)cnc1N
Yield: 36.9 %

Procedure:
A mixture containing dimethyl 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzene-1,3-dicarboxylate (1.1 g, 3.2 mmol) and aqueous sodium hydroxide (3 mL of a 1N solution) was heated in dioxane (100 mL) at 95° C. for 3 h. The mixture was diluted with 1 N aqueous hydrochloric acid (300 mL) and extracted with ethyl acetate (3×300 mL) and saturated ammonium chloride solution and dried over sodium sulfate. Filtration, concentration and purification by reverse phase HPLC gave the product as a yellow solid (0.39 g, 37% yield). 1H NMR (400 MHz, d6-DMSO): δ 8.83 (s, 1H), 8.78 (d, 1H), 8.70 (d, 2H), 8.39 (t, 1H), 7.69 (br, 2H), 6.47 (br, 1H), 3.87 (s, 3H), 2.79 (d, 3H). MS (EI) for C15H14N4O5: 331 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([C@H:6]([CH3:19])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([CH2:17][CH3:18])[CH:8]=1)[NH2:5].[C:21]([O:25][C:26]([NH:28][C@@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([C@H:6]([CH3:19])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([CH2:17][CH3:18])[CH:8]=1)[NH:5][C:37](=[O:38])[C@@H:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:27]
Reactant: CCn1cc([C@@H](C)[C@@H](N)C(=O)OC)c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Solvent: ClCCl
Product: CCn1cc([C@@H](C)[C@@H](NC(=O)[C@@H](Cc2ccccn2)NC(=O)OC(C)(C)C)C(=O)OC)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of (αR,βR)-5-chloro-1-ethyl-β-methyltryptophan methyl ester (1.24 g) and N-t-butoxycarbonyl-3-(2-pyridyl)-D-alanine (1.12 g) in dry methylene chloride (30 ml) which was cooled on an ice bath, was added a solution of N,Nα-dicyclohexylcarbodiimide (0.9 g) in dry methylene chloride (5 ml). The mixture was stirred overnight at room temperature. After removal of the solvent, the crude residue was taken up with a mixture of ethyl acetate and water, filtered, and the organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and solvent was evaporated off to give Nα -[N-t-butoxycarbonyl-3-(2-pyridyl)-D-alanyl](αR,βR)-5-chloro-1-ethyl-β-methyltryptophan methyl ester (2.29 g). To this compound was added trifluoroacetic acid (10 ml) and the mixture was stirred for 30 minutes on an ice bath. After evaporation of the solvent, the crude residue was dissolved in chloroform (50 ml), washed with saturated sodium bicarbonate solution, treated with active charcoal, dried over magnesium sulfate, and the solvent was evaporated off to give an oil (1.43 g). The crude material was dissolved in ethanol (10 ml) and saturated alcoholic ammonia (10 ml) was added. The resulting mixture was allowed to stand for 3 days at room temperature and concentrated in vacuo. The crude residue was chromatographed on silica gel (70 g) (chloroform and 50:1 mixture of chloroform and methanol as eluent) to give an oil (0.56 g) which was crystallized from ethanol to afford (3R,6R)-3-[(R)-1-(5-chloro-1-ethylindol-3-yl)ethyl]-6-(2-pyridylmethyl)piperazine-2,5-dione (0.34 g).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].Cl[C:23]1[C:24]2[S:31][CH:30]=[CH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)CC)C.ClC1C2C=CSC=2N=CN=1>CC(O)(C)C>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[O:6][C:5]=2[CH:3]([NH:2][C:23]2[C:24]3[S:31][CH:30]=[CH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2ccsc12
Agent: Cl
Agent: Clc1ncnc2sccc12
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 49.8 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2, 50 mg, 0.166 mmol), 4-chlorothieno[3,2-d]pyrimidine (36.8 mg, 0.215 mmol), triethylamine (0.046 ml, 0.331 mmol) were reacted in 2-methylpropan-2-ol (1 ml) at 50° C. for 24 hrs and at 80° C. for 27 hrs. 4-Chlorothieno[2,3-d]pyrimidine (5.7 mg, 0.033 mmol), triethylamine (0.09 ml, 0.066 mmol) were added and the mixture reacted at 90° C. for 4 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (33 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2].S(=O)(=O)(O)[OH:16].[Al].C(O)(=O)C(C(C(O)=O)O)O>O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:16])[CH:9]=[CH:8][C:7]=1[NH2:12])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOCCc1ccccc1[N+](=O)[O-]
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCCc1cc(O)ccc1N
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
58.5 g (0.3 mole) of 1-(β-ethoxyethyl)2-nitrobenzene was added at a temperature of 90° C. to a solution of 100 ml of concentrated sulphuric acid diluted in 1 liter of distilled water. 17 g of aluminium powder was added using a spatula and with vigourous stirring. Stirring was maintained for 40 minutes and then 70 g of tartaric acid was added. Stirring was continued for a further 15 minutes with the temperature maintained at 90° C. and then the reaction medium was cooled and the suspension filtered through sintered glass. The filtrate was neutralised with 20% ammonium hydroxide at a temperature below 20° C. A pinkish beige precipitate was obtained. The precipitate was taken up in 0.5 l of refluxing ethyl acetate, hot filtered and dry concentrated. It was recrystallised again from ethyl acetate to obtain beige crystals of the expected product which had a melting point of 102° C.
Reaction SMILES: [C:1]([NH:4][C:5]([CH3:12])([CH:9]([CH3:11])[CH3:10])[C:6]([OH:8])=[O:7])(=O)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:2][C:1]1[O:7][C:6](=[O:8])[C:5]([CH3:12])([CH:9]([CH3:11])[CH3:10])[N:4]=1
Reactant: CC(=O)NC(C)(C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1=NC(C)(C(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Acetamido-2,3-dimethylbutyric acid (16 g) is dissolved in THF (200 mL) and dicyclohexylcarbodiimide (DCC, 21.0 g) is added. The mixture is allowed to stir for 16 hours at 25° C. At the end of this time the mixture is filtered and evaporated to dryness. The residue is dissolved in CH2Cl2 (10 mL) and filtered again. Evaporation of the filtrate gives the crude product which is purified by distillation at 0.65 mmHg, having bp 50° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])CCC)[CH2:8][CH2:7]2.[C:19]([NH2:22])(=[O:21])[CH3:20].[OH-].[NH4+]>>[CH2:16]([NH:12][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([NH:22][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:17][CH3:18]
Reactant: CC(N)=O
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: [NH4+]
Agent: [OH-]
Product: CCCNC1CCc2cccc(NC(C)=O)c2C1
Temperature: 180 °C

Procedure:
To 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (500 mg, 1.6 mMol) were added acetamide (5 gm) and cuprous iodide (340 mg, 1.8 mMol), and the mixture was heated at 180° C. for four hours. The dark reaction mixture was then poured into a slurry of ice and ammonium hydroxide. This mixture was extracted well with dichloromethane, and the combined extracts were washed with water, dried over sodium sulfate and concentrated in vacuo to give a dark viscous residue. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the title compound as a dark, viscous oil (130 mg, 31%). The maleate salt was formed and crystallized (ethanol/diethyl ether) to give tan crystals (m.p.=132°-133° C.).