Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]2)[C@H:13]([F:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@@H:13]([F:24])[C@@H:14]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C[C@@H](F)[C@@H](C2(C(=O)O)CC2)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
1-Benzyloxycarbonyl-4-(S)-(1-ethoxycarbonylcyclopropyl)-3-(S)-fluoropyrrolidine (4.67 g, 13.92 mmol) was dissolved in ethanol (50 ml), and a 1 N sodium hydroxide aqueous solution (50 ml) was added dropwise to the resulting solution. The reaction solution was stirred at 40° C. for 1.5 hours and then ethanol was evaporated under reduced pressure. The resulting residue was mixed with water (50 ml) and washed with chloroform (100 ml), and the thus separated aqueous layer was acidified by adding dropwise 1 N hydrochloric acid and extracted with chloroform (200 ml×2) and then with diethyl ether (100 ml). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.94 g (92.1%) of the title compound as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[C:41]([CH3:49])[CH:40]=4)[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O.Cl>CCOC(C)=O.O1CCOCC1>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[C:41]([CH3:49])[CH:40]=4)[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(F)c(-c2ccc(C(=O)O)c(C)c2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6′-fluoro-4′-methoxy-3-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (55 mg, 0.074 mmol), lithium hydroxide monohydrate (31 mg, 0.74 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature overnight. LCMS trace of reaction aliquot indicated completion of reaction. Crude mixture was acidified by HCl (1N aq.). Volatiles were removed under reduced pressure. Pot residue was dissolved in a water/MeCN mixture and purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford a light yellow glass. This residue was dissolved in EtOAc and washed w/water (10 mL×2), separated, dried/Na2SO4, filtered and concentrated to afford the title compound. LCMS (ESI) calc.=729.16; found=730.15 (+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 8.10 (t, J=7.8 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.70 (s, 1.5H), 7.66 (d, J=8 Hz, 1H), 7.62 (s, 1.5H), 7.47-7.38 (m, 3H), 7.30-7.25 (m, 1H), 6.85 (dd, J=12.5, 3 Hz, 1H), 5.61 (d, J=8 Hz, 0.5H), 5.31 (d, J=8 Hz, 0.5H), 4.94 (d, J=4.5 Hz, 0.5H), 4.91 (d, J=4 Hz, 0.5H), 4.15 (d, J=16.5 Hz, 0.5H), 3.93 (d, J=16 Hz, 0.5H), 3.86 (s, 3H), 3.86-3.76 (m, 1H), 2.68 (s, 3H), 0.57 (d, J=6.5 Hz, 1.5H), 0.46 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:13]1([CH2:16][NH:17][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NCC2CC2)nc1
Yield: 95.5 %

Procedure:
Ethyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.68 mmol), cyclopropylmethylamine (0.28 mL, 3.22 mmol) and DIPEA (0.58 mL, 3.35 mmol) were dissolved in DMF (4 mL) and the reaction mixture was heated using a microwave reactor at 100° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and sat aq NaHCO3 (40 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (566 mg, 95.5%) as a yellow solid. LCMS (ES+): 222.1 [MH]+. HPLC: Rt 5.79 min, 92.9% purity.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([OH:3])=[O:2].[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1.C(O)C=C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:22]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:3])[CH:17]=[CH2:18]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c2ncccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOC(=O)c1cc([N+](=O)[O-])c2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a solution of 6-carboxy-8-nitroquinoline (5.7 g; 26 mM) in THF (70 ml) was added triphenylphosphine (8.9 g; 33.8 mM), allyl alcohol (2.3 ml; 33.8 mM) and DEAD (5.35 ml; 33.8 mM). After stirring at ambient temperature for 30 minutes, the mixture was extracted with ethyl acetate and purified by subjecting to flash chromatography, eluting with ethyl acetate/petroleum ether (40/60) to give 6-allyloxycarbonyl 8-nitroquinoline (4 g; 67.7%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][CH2:20][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:16]1[CH:4]=[CH:3][CH:2]=[CH:14][CH:13]=1
Reactant: C=CC(=O)OCC
Reactant: CC1=C2CCNCC2c2ccccc21
Solvent: CCO
Product: CC1=C2CCN(CCC(=O)OCc3ccccc3)CC2c2ccccc21

Procedure:
A mixture of 12.5 g of 1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 10 g acrylic acid ethyl ester are heated in 100 ml of ethanol for 3 hours at 80° C and then evaporated to dryness. The title compound is obtained as a colourless oil after distillation under a vacuum of 0.1 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6](Br)[C:7]=1[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:24])([F:25])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[C:7]=1[CH3:8]
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(Br)c1)CC2
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(-c3cccnc3)c1)CC2
Yield: 27.7 %

Procedure:
A mixture of 1-(3,5-dibromo-4methylphenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline (D25, 0.51 g, 1 mmol), 3-pyridylboronic acid (0.12 g, 1 mmol), tetrakis (triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) and sodium carbonate (0.41 g, 4 mmol) in dimethoxyethane (30 mL) and water (3 mL) was heated under reflux, under argon, for 18 h. The mixture was cooled and poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel, eluted with ethyl acetate, and the eluted material was triturated with ether to give the title compound (0.14 g, 28%), m.p. 216-8° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[CH2:24]([O:26][C:27](=[O:46])[CH2:28][C@H:29]([NH2:45])[C:30]1[CH:35]=[C:34]([C:36]2([C:42]#[N:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[C:32]([Cl:44])[CH:31]=1)[CH3:25].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Cl:44][C:32]1[CH:31]=[C:30]([C@@H:29]([NH:45][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:46])[CH:35]=[C:34]([C:36]2([C:42]#[N:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Reactant: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C2(C#N)CCOCC2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (264.7 mg, 0.859 mmol), (S)-ethyl-3-amino-3-(3-chloro-5-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl)propanoate hydrochloride salt (from step 1 above) (314.3 mg, 0.842 mmol) and 1-hydroxybenzotriazole hydrate (27.4 mg, 0.179 mmol) was dissolved in a mixture of DMF/DCM (1:1) (8 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. Neat N,N′-diisopropylcarbodiimide (175 μL, 1.13 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in vacuo to give a pale yellow-cream gummy residue. LC-MS analysis of the crude residue shows the desired product: (3S)-ethyl 3-(3-chloro-5-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 627 (35ClM+H) and m/z 629 (37ClM+H); Calcd for C30H35ClN6O7: 627.09. The crude residue is used as such for the saponification with lithium hydroxide monohydrate (Step 3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[OH-].[Na+].[F:7][C:8]1[CH:9]=[C:10]([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH2:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1>C(O)C>[F:7][C:8]1[CH:9]=[C:10]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]3[NH:1][CH2:2][CH2:3][S:4]3)[CH2:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: NCCS
Reactant: O=Cc1ccccc1OCCN1CC=C(c2cccc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1cccc(C2=CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
8.09 g of cysteamine hydrochlorideare dissolved in 450 ml of ethanol, and 2.93 g of sodium hydroxide are added thereto. The mixture is stirred at room temperature for 10 minutes. A solution of 21.05 g of 2-{2-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethyloxy}benzaldehyde in 50 ml of ethanol is added to the mixture, and the mixture is further stirred at room temperature for 14 hours. The mixture is concentrated and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from n-hexane. 21.62 g of 2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine are obtained. Yield: 69%.
Reaction SMILES: ClC1C=C(C(COC)[C:10](OC)=[O:11])C=C(Cl)C=1.S(=O)(=O)(O)O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[O:26][C:27](=[CH2:31])[C:28]([OH:30])=[O:29]>[OH-].[Na+].O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[O:26][CH:27]([CH2:31][O:11][CH3:10])[C:28]([OH:30])=[O:29]
Reactant: C=C(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: COCC(C(=O)OC)c1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O

Procedure:
An emulsion of methyl 2-(3,5-dichlorophenyl)-3-methoxypropionate in sodium hydroxide (0.14 g) and water (2 ml) was stirred at ambient temperature for 2 hours when a clear solution was produced. The mixture was acidified with concentrated sulphuric acid (0.34 g), diluted with water then extracted with diethyl ether. The organic phase was separated, extracted with aqueous sodium hydrogen carbonate and the organic phase discarded. The basic aqueous extract was acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract was dried over magnesium sulphate and evaporated under reduced pressure to give a colourless oil, 0.50 g, containing a mixture of the required product and 2-(3,5-dichlorophenoxy)-acrylic acid in the ratio 2:1, which was used in the next Stage without further purification. 2-(3,5-Dichlorophenoxy)-3-methoxypropionic acid was characterised from its NMR spectrum.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:25][NH:26][CH3:27]>C(O)C>[ClH:23].[CH3:25][N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:27]
Reactant: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Product: Cl
Reaction time: 4 h

Procedure:
1.0 g of 3,4-dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone and 0 ml of a 33 percent solution of dimethylamine in ethanol are heated to boiling for 4 hours, whereupon the mixture is evaporated. The residue is taken up in ether and treated with an ethereal hydrogen chloride solution. The precipitated hydrochloride is filtered and dried. 3,4-Dichlorophenyl 4'-[(dimethylamino)methyl]-4-biphenylyl ketone hydrochloride, m.p. 223° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:5][CH:3]([CH3:4])[CH2:2][NH:1][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N)CNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,2-Diaminopropane (1.00 g, 13.5 mmol, 1.15 mL, 1.1 eq.) was placed in CH2Cl2 (30 mL) and cooled to 0° C. Mesyl chloride (1.40 g, 12.3 mmol, 0.95 mL, 1.0 eq.) was added over a period of five minutes followed by triethylamine (3.72 g, 36.9 mmol, 5.17 mL, 3.0 eq.). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain N-(2-amino-propyl)-methanesulfonamide as a clear, colorless oil (504 mg, 27%). 1H-NMR (CDCl3, 400 MHz) δ 3.17-3.03 (m, 2H), 2.98 (s, 3H), 2.88-2.80 (m, 1H), 1.12 (d, 3H, J=6.3 Hz).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[S:3]1.[CH3:13]CN(CC)CC.CI>CCO>[CH3:13][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc2sc(=S)[nH]c2c1
Solvent: CI
Solvent: CCO
Product: CSc1nc2cc(C#N)ccc2s1
Yield: 97.3 %

Procedure:
To a solution of 2-thioxo-2,3-dihydrobenzothiazole-5-carbonitrile (260 mg, 1.35 mmol) in EtOH (10.8 mL) was added Et3N (137 mg, 1.35 mmol) and methyliodide (192 mg, 1.35 mmol). The mixture was heated at reflux for 1 h. The volatiles were evaporated and the residue was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 2-methylsulfanylbenzothiazole-5-carbo-nitrile 271 mg (97%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=2)[CH:19]=[O:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:22][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([CH:19]=[O:20])[CH:21]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(N2CCN(Cc3ccccc3)CC2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C=O
Yield: 70 %

Procedure:
0.5 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde are dissolved in 5 ml of NMP at 20° C. under nitrogen with stirring, and 0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate are added. The mixture is stirred at 110° for 4 hours and cooled to 15°. 30 ml of water and 30 ml of ethyl acetate are added to the mixture, the phases are separated, and the aqueous phase is extracted with 30 ml of ethyl acetate. Combined organic phases are washed with 2×30 ml of water and freed from solvent under reduced pressure. The yellow oil which remains (0.7 g) is chromatographed on 10 g of silica gel (MTB ether/heptane 5:1) and gives 0.45 g of product (70%; yellowish oil), MS 382 (M+), 296, 263, 199, 149, 119, 91 (100%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC.C(OC)(C)(C)C>[N:7]1([C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrC1=NOCC1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: COC(C)(C)C
Product: C1CCN(C2=NOCC2)C1
Temperature: 120 °C

Procedure:
3-(Pyrrolidin-1-yl)-4,5-dihydroisoxazole III-59 was prepared in 1 step according to the following procedure: 3-bromo-4,5-dihydroisoxazole III-18 (1.0 equiv) was dissolved in n-butanol (0.64 M) followed by the addition of pyrollidine (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is the sealed and heated in an oil bath to 120° C. for 18 h after which it allowed to cool and then transferred to a separatory funnel with excess water and tert-butylmethyl ether. The aqueous layer was washed with tert-butylmethyl ether (2×) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrate to provide a orange solid that was purified using flash silica gel chromatography (gradient ethyl acetate/hexanes) to provide III-59 as a white solid. [M+H]+=345.4 m/z. Activity: C
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=[CH:15][C:3]=12.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.CCN(C(C)C)C(C)C>C(O)CCC>[C:34]([O:33][C:32]([NH:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:3]=23)[CH2:26]1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 140 °C
Yield: 86.7 %

Procedure:
A mixture of ethyl 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.5 g, 4.3 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (1.0 g, 5.0 mmol) and DIPEA (0.84 g, 6.5 mmol) in 1-butanol (10 mL) was heated to 140° C. for 14 h, then allowed to cool. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with EtOAc and washed with aq. NaHCO3. The organic extract was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 20-100% EtOAc in hexanes, to give the sub-title compound (1.9 g, 86%). LCMS calc. for C27H36N5O5 (M+H)+: m/z=510.3. Found: 510.2.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>CN(C)C=O>[CH2:16]([NH:18][C:19]([N:3]1[CH2:2][CH2:1][C:7]2[CH:8]=[CH:9][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4]1)=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CCNCC2
Solvent: CN(C)C=O
Product: CCNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1

Procedure:
3.4 G. of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide are dissolved in 50 ml. of dimethylformamide while warming at 60° C. and the solution is then rapidly cooled with an icebath. As soon as a temperature of 20° C. is reached, 1.18 ml. of ethylisocyanate are added dropwise while stirring, and the mixture is subsequently stirred at 25° C. for 0.5 hour. The solution is then concentrated in vacuo on a bath at 80° C. and the crystalline residue is digested with ether. There is obtained 3-ethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Reactant: NCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2×18 mL). The combined organic extracts were washed with H2O (2×10 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography using 40% EtOAc in hexane as an eluting solvent to afford the title compound I-4a (93 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>CN1C(=O)CCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: NC(CO)CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
The product of example 3 (90 mg, 0.2 mmol) was dissolved in NMP (1 mL) and serinol (91 mg, 1.0 mmol) was added. The solution was heated to 65° for 48 h, diluted with EtOAc (75 mL) and washed with 10% aq citric acid (2×), H2O, and satd aq NaCl, dried (Na2SO4), concentrated and purified by prep hplc to afford 46 mg (50%). LC MS m/z=460 (MH+), Rt=1.37 min