Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=1.O>CN(C=O)C>[CH3:29][O:28][C:24]1[N:23]=[C:22]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1cccc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2cccc(OC)n2)CC1
Yield: 10.9 %

Procedure:
Diisopropylethylamine (2.16 mL, 12.7 mmol) was added to a solution of ethyl piperidine-4-carboxylate (2.00 g, 12.7 mmol) and 2-chloro-6-methoxypyridine (1.48 mL, 12.7 mmol) in DMF (10 mL), and the mixture was stirred while irradiated with microwaves at 150° C. for 3 hours using Initiator® manufactured by Biotage Japan Ltd. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=90/10] to obtain the title compound (365 mg, yield: 11%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[S:6]1)=O.[NH3:15]>CO>[C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[S:6]1)(=[O:2])[NH2:15]
Reactant: N
Reactant: COC(=O)C1CNc2ccccc2S1
Solvent: CO
Product: NC(=O)C1CNc2ccccc2S1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
580 mg of 2(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazine are dissolved in 3 ml of a 6N ammonia solution in methanol and the solution is stirred at 50° C. for 16 h. Purification by chromatography over 50 g of silica gel gives 2(R,S)-carbamoyl-3,4-dihydro-2H-1,4-benzothiazine: Rf (Y)=0.19.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1)[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[CH3:12][O:11][C:10]1[C:9]([CH3:13])=[CH:8][C:4]([C:5]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[C:29]([NH:28][CH2:26][CH3:27])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[O:7])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: CCNc1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc(C)c(OC)c(C)c2)CC1
Reaction time: 1 h

Procedure:
3,5-Dimethyl-4-methoxybenzoic acid (I, PREPARATION 3, 0.36 g) is added to a solution of 1,1'-carbonyldiimidazole (0.33 g) in tetrahydrofuran (4 ml) at 20°-25°. After one hour of stirring, 4-[3-(ethylamino)-2-pyridinyl]piperazine (II, International Publication No WO 87/01706 based on International Patent application No PCT/US86/01797, PREPARATION A-47, 0.42 g) in tetrahydrofuran (6 ml) is added and the solution is stirred for 18 hours. The mixture is diluted with dichloromethane and a saturated aqueous sodium bicarbonate solution. The phases are separated, the organic phase is washed with water, then with saline and the phases are separated. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (230-400 mesh), the product eluted with chloroform, the appropriate fractions are pooled and concentrated to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[C@@H:20]([NH2:27])[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:27][C@@H:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:19]([F:18])([F:28])[F:29])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 336105-46-5) as starting materials, MS (EI): m/e=392.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N)(C)C>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)N
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(F)cc3)c2c1O
Yield: 35.3 %

Procedure:
To a solution of 7-Bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (124.9 mg, 0.39 mmol) in THF (5.6 mL) was added trimethylsilylacetylene (0.11 mL, 0.78 mmol), PdCl2(PPh3)2 (55.1 mg, 0.078 mmol), CuI (29.9 mg, 0.156 mmol) and isopropylamine (0.34 mL, 2.42 mmol). The reaction mixture refluxed for 16 h with stirring. After cooling to r. t. the mixture was diluted with EtOAc (20 mL), filtered and the filter cake washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2 gave the title compound as white solid (57 mg): MS (m/z) 415.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH:14]=[O:15])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(#N)C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]([O:28][C:29](=[O:50])[C@H:30]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1)[NH:31][C:32](=[O:41])[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40])([CH3:27])[CH3:26]>CC(O)C.N1C=CC=CC=1>[CH:25]([O:28][C:29](=[O:50])[C@H:30]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([NH:49][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH2:11][N:12]([CH:14]=[O:15])[CH3:13])[CH:9]=[CH:10][C:2]=2[NH:1][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:47][CH:48]=1)[NH:31][C:32](=[O:41])[C:33]1[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=1[Cl:39])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Reactant: CCOC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)Nc1ccc(CN(C)C=O)cc1C(=O)Nc1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)C)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To 2.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)-benzoic acid, there were added 10 mL of acetonitrile and 3.9 mL of pyridine to form a slurry and the latter was cooled to 10° C. To this slurry, there was dropwise added 2.76 mL of ethyl chloro-formate over 5 minutes and then stirred for one hour. After the confirmation of the disappearance of the starting material by HPLC, 1.46 mL of 2-propanol was added to the reaction liquid so that the unreacted ethyl chloroformate was thus decomposed at 25° C. To this reaction liquid, there was added 3.80 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine isopropyl ester and the resulting mixture was stirred overnight. Subsequently, 30 mL of 2-propanol was dropwise added to the mixture, followed by the stirring of the mixture at 10° C. for 3 hours. The solid separated was isolated through filtration under reduced pressure, washed with 10 mL of 2-propanol and then dried at 60° C. for 18 hours under reduced pressure to thus give 4.35 g of the intended product as a white crystalline solid.
Reaction SMILES: [C:1]([C:3]1([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:8][CH2:7][N:6]([S:9]([NH:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.C(O)C.O>[NH2:2][CH2:1][C:3]1([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:4][CH2:5][N:6]([S:9]([NH:12][CH2:13][CH3:14])(=[O:10])=[O:11])[CH2:7][CH2:8]1
Reactant: CCNS(=O)(=O)N1CCC(C#N)(CC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-cyano-4-(cyclopropylmethyl)-N-ethylpiperidine-1-sulfonamide (I-9) (83 mg, 0.306 mmol) in ethanol (1 mL) was added to 1M sodium hydroxide in 95% ethanol-water (15 mL) and the solution degassed with nitrogen. Raney Nickel (50% slurry in water) (220 mg) was added and the black suspension shaken under hydrogen pressure (40 psi) at room temperature for 12 h. The catalyst was filtered off and wahed with 95% ethanol-water. The filtrate was evaporated in vacuo then partitioned between water and DCM. The organic phase was separated and the aqueous phase re-extracted with DCM twice. The combined organic phase was dried (MgSO4) and the solvent removed in vacuo to leave 4-aminomethyl-4-(cyclopropylmethyl)-N-ethylpiperidine-1-sulfonamide (I-10) that was used in the next step without further purification. 1H NMR (500 MHz, CD3OD): δ 3.21-3.11 (m, 4 H), 3.02 (q, J=7.2 Hz, 2 H), 2.69 (s, 2 H), 1.63-1.53 (m, 4 H), 1.31 (m, 2 H), 1.15 (t, J=7.2 Hz, 3 H), 0.65 (m, 1 H), 0.48 (t, J=6.4 Hz, 2 H), 0.07 (m, 2 H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[F:16][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:17](=[O:19])[CH3:18])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[I:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of amine 96 (16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with TEA (9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled to 0–5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0–5° C. under N2. The resulting reaction mixture was subsequently stirred at 0–5° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (aryl iodide 101, 17.36 g, 96.5% yield) as a white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3). C12H12FIN2O3, LCMS (EI) m/e 379 (M++H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[C@H:11]([CH2:36][CH3:37])[CH2:10]1)(C(C)(C)C)(C)C.Cl.CCOC(C)=O>C(O)C.C([C@H]1[C@@H](C2N3C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=CC3=NN=2)C[C@H](O)C1)C>[CH2:36]([CH:11]1[CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:13][CH:9]([OH:8])[CH2:10]1)[CH3:37]
Reactant: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC1CC(O)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reaction time: 1 h

Procedure:
A scalemic mixture enriched in 1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1.55 g, 2.87 mmol) was suspended in ethanol (30 mL). Concentrated HCl (0.3 mL, 3.65 mmol) was added dropwise. After about 1 h., the suspension was sonicated until all solid went into solution. EtOAc (250 mL) was added and the organics were washed with saturated aqueous NaHCO3 (2×30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduce pressure. The residue was purified using silica gel chromatography eluting with 30-80% EtOAc in DCM to give a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (1.09 g, 90%): LC/MS (Table 1, Method b) Rt=1.99 min; MS m/z: 426 (M+H)+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.C(OCC)C.[CH3:15][Sn:16](Cl)([CH3:18])[CH3:17].[Cl-].[NH4+].CC1C=CC(C2C=CC(C)=CC=2)=CC=1>O1CCCC1.O>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([Sn:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: Cc1ccc(-c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
41.4L of 1.0M p-tolylmagnesium bromide in diethyl ether (41.4 mol) was added dropwise, maintaining the temperature below -5° C., over 4 hours to a solution of 546 g (2.79 mol) of trimethyltin chloride in tetrahydrofuran (4 L) under nitrogen at -10° C. The suspension was allowed to warm slowly to room temperature over 12 hours then saturated ammonium chloride solution (1 L) was added followed by sufficient water (approximately 1 L) to dissolve the precipitate. The solution was extracted with ether-hexane (1:1) (1×4 L, 3×2 L). The combined organic phases were washed with brine, dried over magnesium sulfate and the solvents removed under vacuum. Purification by flash chromatography on silica gel eluting with hexane/ethyl acetate (95:5) gave a pale yellow oil containing white crystals of 4,4'-dimethylbiphenyl which were removed by filtration to leave 711.3 g (100%) of product. 1H NMR (300 MHz, CDCl3): 0.30 (s, 9H), 2.34 (s, 3H), 7.19 (d, 7.7 Hz, 2H), 7.40 (d, 7.7 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[F:1])[CH:9]=1)=[O:27]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(F)cnn1C
Yield: 58 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-difluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 21 mg (58% yield) of Compound 37: LCMS m/z (%)=377 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.50 (s, 1H), 8.24 (m, 1H), 7.98 (s, 1H), 7.64 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.06 (ddd, J1=11.4 Hz, J2=8.6 Hz, J=2.8 Hz, 1H), 6.99 (dd, J1=9.6 Hz, J2=9.6 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −119.93 (m, 1F), −127.63 (m, 1F) −177.41 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N:20]([CH:23]([CH2:29][CH2:30]Br)[C:24](OCC)=[O:25])=[N+:21]=[N-:22].[I-].[Na+]>C(#N)C>[N:20]([CH:23]1[CH2:29][CH2:30][N:8]([C@H:7]([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[C:24]1=[O:25])=[N+:21]=[N-:22]
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)OC(C)(C)C)N1CCC(N=[N+]=[N-])C1=O
Temperature: 60 °C
Yield: 18.9 %

Procedure:
To a solution of D-alanine tert-butylester (1.28 g) and N,N-diisopropylethyamine (1.22 ml) in acetonitrile (15 ml), was added a solution of ethyl 2-azido-4-bromobutanoate (1 g) and sodium iodide (0.02 g) in acetonitrile (5 ml). The mixture was heated at 60° C. for 60 h and then concentrated under pressure to give a brown oil. This oil was partitioned between DCM and water. The separated organic layer was washed further with water and dried (over magnesium sulphate), and concentrated under reduced pressure. The residual brown oil was purified using Biotage™ chromatography (silica, eluting with cyclohexane;ethyl acetate 3:1) to give the title compound (0.204 g) as a mixture of two diastereoisomers.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16][N:15]=1.O>CCCCCC.O1CCCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[N:15][NH:16]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc2cnncc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C2NN=Cc3ccccc32)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
5.53 ml of a 1.6 M solution of butyllithium in hexane are added dropwise at -78° C. within 20 min. to a solution of 1.48 g of 1-bromo-4-fluoro-benzene in 5 ml of tetrahydrofuran. The resulting white suspension is stirred for a further hour. A solution of 1 g of phthalazine in 5 ml of tetrahydrofuran is added dropwise at -78° C. within 10 min. The reaction mixture is left to warm to room temperature, treated with 50 ml of water and extracted 3 times with 50 ml of dichloromethane each time. The organic phases are combined washed with 50 ml of water and 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate, filtered, the filtrate is concentrated and the residue is chromatographed on 100 g of silica gel with the eluent hexane/ethyl acetate 1:1. 1.49 g (86%) of (RS)-1-(4-fluoro-phenyl)-1,2-dihydro-phthalazine are obtained as a yellow oil. MS: 227 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O-:12].[Na+].N1C=CC=NC=1.O>CO>[Cl:10][C:4]1[C:5]([Cl:9])=[C:6]([O:12][CH3:11])[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)c(Cl)c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1cncnc1
Product: COc1nc(C)nc(Cl)c1Cl

Procedure:
A solution containing 38 g (0.17 mol) of 2-methyl-4,5,6-trichloropyrimidine in 200 ml of methanol was cooled in an ice bath to 10° C.-15° C. and sodium methoxide as a 25 percent solution in methanol was added slowly with stirring until the starting pyrimidine could no longer be detected by GLC analysis. Water was then added and the resulting mixture was extracted with methylene chloride. Removal of the solvent and other volatiles from the extract by evaporation under reduced pressure left the title compound as a white powder melting at 77° C.-78° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[O:9][C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])=[N:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:9][C:5]([CH2:4][O:3][CH3:2])=[N:6][N:7]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: COCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(COC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B33) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (223 mg; compound C10) and HBTU (232 mg) in DCM (15 ml) in the presence of DIPEA (0.36 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 3/2 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Br[CH2:34][CH3:35].[C:36](OCC)(=O)[CH3:37]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:36][CH3:37])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][CH2:34][CH3:35])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CCc1cn(CC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (62 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and bromoethane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over anhydrous sodium sulfate. After concentration, the residue was purified via column chromatography to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-ethyl-1H-indol-3-yl]propanoate (D120) (79 mg). δH (CDCl3, 400 MHz): 1.14 (3H, t), 1.25 (3H, t), 1.45 (6H, d), 2.71 (2H, t), 3.12 (2H, t), 4.15 (2H, q), 4.20 (2H, q), 4.72 (1H, m), 6.97 (1H, s), 7.07 (1H, d), 7.20 (1H, t), 7.55 (1H, dd), 7.76 (1H, dd), 8.08 (1H, dd), 8.26 (1H, d); MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: C([OH:5])(C)(C)C.[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=1)=[CH2:7].S([O-])([O-])=O.[Na+].[Na+].[OH2:27]>>[OH:27][C@H:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=1)[CH2:7][OH:5]
Reactant: CC(C)(C)O
Reactant: O
Reactant: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)C(=O)Nc1ccc([C@@H](O)CO)cn1
Temperature: 5 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
A suspension of AD-Mix-B® (1.40 g) in water (5 ml) and t-butanol (5 ml) was cooled to 5° C. and N-(5-vinyl-pyridin-2-yl)-2,2-dimethylpropionamide (0.204 g, 1.0 mmol) was added. The mixture was stirred at 5° C. for 18 hours. The reaction mixture was then treated with sodium sulfite (3.0 g), stirred for 30 minutes and then extracted with dichloromethane. The dichloromethane extract was washed with water and brine and then dried and evaporated to afford 0.230 g (96%) of the title product as colorless crystals. mp 105-106° C. 1H NMR (CDCl3): δ=8.21 (br, 1 H); 8.10 (m, 2 H); 7.61 (d of d, 1 H); 4.70 (m, 1 H); 3.64 (m, 1 H); 3.57 (m, 1 H); 1.25 (s, 9 H). MS (Cl): m/z=239 (M+H+).