Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:9]([C:17](=[O:22])[C:18](OC)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1([CH3:8])[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:18](=[O:19])[C:17](=[O:22])[N:9]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(C)(C)N(Cc1ccccc1)C(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)C(=O)N(Cc2ccccc2)C1(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of methyl 3-methyl-3-[[(methyloxy)(oxo)acetyl](phenylmethyl)amino]butanoate (6.9702 g, 22.68 mmol) in toluene (110 mL) was added 25% w/w NaOMe in MeOH (14 mL). The mixture was heated at 80° C. and stirred for 2 h. The solution was then cooled to room temperature and concentrated in vacuo to ca. ½ volume. The residue was partitioned between DCM (200 mL) and 1 N aq. HCl (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting white solid was triturated with hexanes and collected by vacuum filtration to afford methyl 2,2-dimethyl-4,5-dioxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (5.5965 g, 88%) as a white solid. LCMS: (M+H)+: 276.1.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl>ClCCl>[F:1][C:2]1[CH:21]=[C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2F)CC1
Agent: Cl
Solvent: ClCCl
Product: Fc1cc(N2CCOCC2)ccc1CN1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A 100 mL round-bottom flask, equipped with a magnetic stir bar, was charged with tert-butyl 4-(2-fluoro-4-morpholinobenzyl)piperazine-1-carboxylate (819 mg, 2.16 mmol) and dichloromethane (14 mL). The resulting solution was cooled to 0° C. Hydrochloric acid (3.2 mL, 4 N in dioxane) was added via syringe. The ice bath was removed and the resulting cloudy suspension was allowed to stir at room temperature overnight. After 20 h, the white suspension was transferred to a 250 mL Erlenmeyer flask and stirred with saturated aqueous sodium carbonate (30 mL), water (20 mL) and dichloromethane (30 mL) for 30 min. The layers were separated and the aqueous layer was extracted twice with dicholomethane (30 mL). The organic layers were washed with saturated aqueous sodium bicarbonate (30 mL), combined, dried over sodium sulfate and concentrated. The resulting yellow oil was chromatographed on a 24 g silica column with a gradient (100% dichloromethane to 90% dichloromethane/10% methanol containing 2M ammonia) to provide 4-(3-fluoro-4-(piperazin-1-ylmethyl)phenyl)morpholine as a yellow oil (580 mg, 96%). 1H NMR 400 MHz (CDCl3) δ 7.22 (t, J=8.5 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.56 (d, J=13 Hz, 1H) 3.90-3.80 (m, 4H), 3.49 (d, J=14.5 Hz, 2H), 3.20-3.10 (m, 4H), 2.92-2.88 (m, 4H), 2.44 (bs, 4H), 1.64 (s, 1H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:32]1(=[O:42])[N:36]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 10-undecene-1-ol (5.00 g, 29.36 mmol, 1 equiv), triphenylphosphine (7.70 g, 29.36 mmol, 1 equiv) and phthalimide (4.32 g, 29.36 mmol, 1 equiv) in dry tetrahydrofuran (THF, 30 mL) was stirred vigorously under argon. Diethyl azodicarboxylate (DEAD, 5.11 g, 29.36 mmol, 1 equiv) was diluted with THF (12 mL) and added dropwise by syringe. After; the addition, the reaction was stirred at room temperature for 4 hours. The solvent was evaporated under vacuum and ether (30 mL) was added to precipitate the triphenylphosphine oxide and hydrazine dicarboxylate which were removed by filtration. The precipitate was rinsed with ether (2×30 mL) and the combined filtrates were evaporated to afford a yellow solid. The yellow solid was triturated with warm hexanes (3×50 mL) and filtered. The combined hexanes were evaporated to give 1-phthalimidylundec-10-ene as a yellow wax.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1)#[N:14].C(=O)(O)[O-].[Na+]>CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][N:8]1[C:6]2=[N:7][C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[NH:10][C:9]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccc(Cl)nc21
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Temperature: 100 °C

Procedure:
5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3) (74 mg, 0.4 mmol), 2-cyanophenylboronic acid pinacol ester (179 mg, 1.2 mmol), sodium bicarbonate (200 mg, 2.4 mmol), and bis(tri-t-butylphosphine)palladium(0) (61 mg, 0.12 mmol) were added to a microwave vial and purged with nitrogen. Dioxane (1.2 mL) was added, the vessel was sealed and the suspension was heated at 100° C. for 12 minutes in a microwave reactor. The cooled reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (4-1). MS (M+H)+: observed=251.1, calculated=251.3.
Reaction SMILES: CN1C(NCCCNC2C=CC([N+:19]([O-:21])=[O:20])=CC=2)=CC(=O)N(C)C1=O.[CH3:25][N:26]1[C:31]([NH:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+]([O-])=O)=[CH:40]C=2)=[CH:30][C:29](=[O:47])[N:28]([CH3:48])[C:27]1=[O:49]>>[CH3:25][N:26]1[C:31]([NH:32][CH2:33][CH2:34][NH:35][CH2:36][C:37]2[CH:38]=[CH:43][C:42]([N+:19]([O-:21])=[O:20])=[CH:41][CH:40]=2)=[CH:30][C:29](=[O:47])[N:28]([CH3:48])[C:27]1=[O:49]
Reactant: Cn1c(NCCCNc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Reactant: Cn1c(NCCNCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Product: Cn1c(NCCNCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O

Procedure:
The same procedure as in Example 2 was repeated with the exception that 1,3-dimethyl-6-(piperazin-1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) was replaced with 0.45 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), in order to obtain 1,3-dimethyl-6-[2-(4-nitrobenzylamino)ethylamino]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: N[C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:15].C(#N)C.[I:19]CI.N(OCCC(C)C)=O>CCCCCCC.C(OCC)(=O)C>[Cl:15][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:13][CH3:14])[C:2]=1[I:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(OC)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(Cl)c(I)c(OC)c1
Temperature: 70 °C
Yield: 66.6 %

Procedure:
To ethyl 4-amino-3-chloro-5-methoxybenzoate (15.8 g, 68.8 mmol) were added acetonitrile (40 mL) and diiodomethane (22.2 mL, 275 mmol) in that order, and then the mixture was stirred at 70° C. and isoamyl nitrite (13.9 mL, 103 mmol) was added dropwise over a period of 10 minutes. The mixture was then stirred at 70° C. for 40 minutes. After returning the mixture to room temperature, the solvent in the mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=8/1 then 5/1) to obtain the title compound (15.6 g, 45.8 mmol).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33]([N:16]2[CH2:17][CH:18]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)=[O:34])[CH:26]=[CH:25]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.022 g (0.067 mmol) of 3-(SR)-(4-phenyl piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.016 g (0.1 mmol) of indole-7-carboxylic acid in 2 mL of CH2Cl2 and 0.037 mL (0.27 mmol) of triethylamine was added 0.022 g (0.087 mL) of BOP-Cl [Bis-(2-oxo-3-oxazolidinyl)phosphinic chloride] and the reaction mixture was stirred at rt for 5 h. The reaction mixture concentrated and purified by chomatography (silica, acetone: hexanes, 1:3 to 1:2) to give the title compound. 1H NMR (CDCl3) δ; 10.02 (bs, 1H), 7.79 (bs, 1H), 7.02-7.53 (m, 11H), 6.62 (bs, 1H), 4.15-4.19 (m, 2H); Mass Spectrum (CI) m/e=482 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]1[NH:27][N:26]=[N:25][N:20]=1
Reactant: N#CCCCOc1ccccc1OCc1ccc2ccccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCc2ccc3ccccc3n2)c(OCCCc2nnn[nH]2)c1
Yield: 17.2 %

Procedure:
A mixture of 8.7 g of 4-[2-(2-quinolylmethyloxy)phenoxy]butyronitrile, 5.3 g of sodium azide and 4.4 g of ammonium chloride is heated with 25 ml of dry dimethylformamide at 140° C. for 20 hours. The reaction mixture is poured onto ice, basified with 1N sodium hydroxide and extracted 2 times with ethyl acetate. The aqueous fraction is acidified with acetic acid. The product is filtered and washed with water. The crude product is crystallized from acetonitrile to give 1.7 g of pure product of M.P. 137°-140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[CH:10][N:9]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.O>[CH:24]1([C:21]2[CH:22]=[CH:23][C:15]([NH:14][C:11]3[CH:10]=[N:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH:27]4[CH2:29][CH2:28]4)=[N:13][CH:12]=3)=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])[CH2:26][CH2:25]1
Reactant: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2C2CC2)nc1
Temperature: 110 °C

Procedure:
In a schlenck tube, a mixture of 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid (0.55 mmol, 0.200 g), cyclopropylboronic acid (0.71 mmol, 0.061 g), K3PO4 (1.86 mmol, 0.395 g), PCy3 (0.05 mmol, 0.015 g) and Pd(AcO)2 (0.03 mmol, 0.006 g) in a mixture of toluene/water 6:1 (6 ml) was heated at 110° C. for 72 hours, under argon atmosphere. The crude mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and the solvent removed. The crude mixture was purified by reverse phase chromatography eluting with a gradient of 100% water to 100% MeOH/AcN 1:1 affording 0.016 g (71% of yield).
Reaction SMILES: [NH4+].[Cl-].[CH3:3][O:4][C:5](=[O:18])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[I:17]>O.CO.[Fe]>[CH3:3][O:4][C:5](=[O:18])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[I:17]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)COc1ccc(N)cc1I
Temperature: 90 °C
Yield: 26.1 %

Procedure:
NH4Cl (4.49 g, 84.00 mmol) in water (105 ml) was added to a suspension of Fe (powder, 2.85 g, 51.00 mmol) in water (18 ml), the treated with (2-iodo-4-nitro-phenoxy)-acetic acid methyl ester (5.06 g, 15.00 mmol) in MeOH (105 ml). The reaction was heated at 90° C. for 28 h, filtered and extracted with brine/EtOAc (3×). The organic phase was washed with brine, dried over Na2SO4 and evaporated to give 1.2 g of (4-amino-2-iodo-phenoxy)-acetic acid methyl ester, MS: 308.1 (MH)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[O:44])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:26])[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c12

Procedure:
Prepared by a 2-step process from 3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (obtained from Example 5, Step D) and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (prepared as in Example 19, Step C) according to the method of Example 21, Steps A and B. The crude material was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 25 mg (68% for 2-step process) of the desired product. LRMS (ESI pos) m/e 475.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.42 (d, 1H), 8.33 (d, 1H), 8.24 (d, 1H), 7.99 (dd, 1H), 7.64 (m, 2H), 7.46 (m, 1H), 7.34 (d, 1H), 7.28 (m, 2H), 6.26 (d, 1H), 2.75 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.6, −127.6.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[S:37][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[CH:34][N:35]=1
Reactant: Cc1ncc(CCl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (627 mg; compound B50) is reacted with 5-(chloromethyl)-2-methyl-1,3-thiazole (273 mg; compound D18) in the presence of potassium carbonate (405 mg) in DMF (10 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 1/1 (v/v)] as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C@@H:11]2[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([C:19]([N:21]3[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]3)=[O:20])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:28]1[C:30]([NH2:33])([C:31]#[N:32])[CH2:29]1.Cl>>[C:31]([C:30]1([NH:33][C:16]([C@@H:14]2[CH2:15][C@@H:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)(=[O:10])=[O:9])[CH2:12][C@H:13]2[C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[O:18])[CH2:28][CH2:29]1)#[N:32]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2cccc(Br)c2)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: N#CC1(N)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 117 step 7 using (1R,2R,4S)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (example 188 step 3) and 1-amino-cyclopropyl cyanic hydrochloride. Light yellow foam (89%). MS (EI): 532.1 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Cl:11][C:12]1[C:17]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: NCCOc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Clc1nccnc1NCCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A mixture of 2-phenoxyethylamine (2.65 g, 19.3 mmol), 2,3-dichloropyrazine (2.88 g, 19.3 mmol) and K2CO3 (2.67 g, 19.3 mmol) in acetonitrile (8 mL) was stirred in a sealed tube for 12 h at room temperature, and for a further 9.5 h at 80° C. The reaction mixture was diluted with ether, filtered, and concentrated. The residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 2.36 g (49%) of the title compound as a yellowish oil that solidified on standing: mp 51-53° C.; HRMS m/z calcd for C12H12ClN30 (M)+ 249.0669, found 249.0659. Anal. (Cl2H12ClN30) C, H, N.
Reaction SMILES: [O:1]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C@@H:2]1[CH2:3][OH:4].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[O:1]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C@@H:2]1[CH:3]=[O:4]
Reactant: COC(=O)c1cccc([C@@H]2O[C@H]2CO)c1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([C@@H]2O[C@H]2C=O)c1

Procedure:
The title compound is prepared analogously to Example 5 from (2S,3S)-2,3-epoxy-3-(3-methoxycarbonylphenyl)-propanol; colourless oil; IR (methylene chloride): 2910, 2780, 1705, 1590, 1570, 1415, 1270, 1235 cm-1 ; Rf =0.36 (hexane/ethyl acetate 3:2).
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]([F:33])([F:32])[C:29]([NH2:31])=[O:30].[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[O:24]1[CH:25]=[CH:26][C:22]([C:13]2[C:14]([O:20][CH3:21])=[C:15]([C:10]([CH2:9][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[N:31][C:29](=[O:30])[C:28]([F:33])([F:32])[F:27])=[O:8])=[CH:11][CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:23]1
Reactant: NC(=O)C(F)(F)F
Reactant: COC(=O)c1c(CS(=O)c2ccccc2)ccc(-c2ccoc2)c1OC
Agent: [Rh]
Agent: [Mg+2]
Agent: [O-2]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1c(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)ccc(-c2ccoc2)c1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 38.5 %

Procedure:
A mixture of methyl 6-(benzenesulphinylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 216, 0.920 g), trifluoroacetamide (0.56 g), magnesium oxide (0.40 g), iodobenzene diacetate (1.20 g) and rhodium (II) acetate dimer (0.030 g) in DCM (20 mL) was stirred at room temperature for 22 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate and cyclohexane with a gradient of 10-40% to give methyl 3-(furan-3-yl)-2-methoxy-6-{[S-phenyl-N-(trifluoroacetyl)sulphonimidoyl]methyl}benzoate (0.46 g) as a colourless gum.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:11]([CH:27]=[CH2:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@H:11]([CH2:27][CH3:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of (6) (0.663 g, 1.52 mmol) in EtOAc (5 ml) was added a small spatula tip of 10% Pd(C) and placed on Parr shaker under hydrogen at 45 PSI. The mixture was shaken under hydrogen overnight. After addition of more EtOAc the mixture was filtered through celite, and concentrated in vacuo to yield (2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidine (7) (0.575 g, 86%) as a white crystalline solid. MS m/z 438.1 (M+H); retention time=6.841 min, method [10].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([CH3:45])=[C:23]([NH:22][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(C)c(C(=O)O)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)o1
Yield: 82.8 %

Procedure:
In the same manner as in Example 259 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (85 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (62 μL, 0.72 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (170 mg, 81%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[S:4][C:3]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(-c2cccc(Cl)c2)sc1C(=O)O
Yield: 84.4 %

Procedure:
Methyl 3-amino-5-(3-chlorophenyl)-2-thiophenecarboxylate (1.0 g), 2M sodium hydroxide (2 mL) and methanol (10 mL) were heated at 70° C. for 2 days. The methanol was evaporated off and the residue was acidified with 2M hydrochloric acid. Extraction into ethyl acetate followed by drying (MgSO4) and evaporation of the solvent gave the sub-title acid (0.8 g).
Reaction SMILES: [CH3:1][NH2:2].[OH-].[Na+].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:2][CH3:1])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)c1ccc(F)cc1
Yield: 94 %

Procedure:
To a solution of 30 mL MeNH2 (40% wt in H2O) was added 139 mL of 1N NaOH. To this was added 130 mL of CH2Cl2 followed by 4-fluorobenzoyl chloride (22 grams, 139 mmol) while the mixture was rapidly stirred. After 1 hour the organic layer was separated, washed with H2O, dried over Na2SO4 and solvent removed under vacuum to yield 20 grams (94% yield) solid. 1H NMR (500 MHz, DMSO) δ: 2.78 (d, 3, J=5), 7.28 (t, 2, J=9), 7.91 (m, 2), 8.46 (br s, 1). 13C NMR (125 MHz, DMSO) δ: 26.13, 114.95, 115.13, 129.49, 129.56, 130.87, 130.90, 162.67, 164.64, 165.46.