Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH2:23][CH2:22][CH2:21][CH2:20][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19])=[O:10].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH2:23][CH2:22][CH2:21][CH2:20][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19])=[O:10])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCCCO)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Solvent: c1ccncc1
Product: CC(=O)OCCCNC(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In pyridine (20 ml) was dissolved N-(3-hydroxypropyl)N'-(2-fluoro-4-chlorophenyl)-3,4,5,6-tetrahydrophthalamide (1.5 g), followed by addition of acetic anhydride (10 ml). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 200 ml of ice-water and, after stirring, the precipitate was recovered by filtration and rinsed with water. After drying, it was recrystallized from ethyl acetate-n-hexane. Yield 0.9 g; m.p. 127°-128° C.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28](O)=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:26])([CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of methanesulfonamide (160 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A33. A solution of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B33. Solution B33 was added to Solution A33 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (25 mg, 20%) as a white solid: MS (ESI) M+1=384.3.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](OC)=O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1cccn1C
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccn3C)nc(=O)c1-2
Temperature: 25 °C
Yield: 36.9 %

Procedure:
Sodium spheres (1.0 g, 43.5 mmol) were dissolved in ethanol (50 mL) at reflux and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.2 g, 10 mmol), followed by methyl 1-methylpyrrole-2-acetate (3.06 g, 20 mmol) in ethanol (30 mL) were added. The reaction mixture was refluxed under argon overnight, cooled to room temperature and evaporated to dryness. The residue was dissolved in water, the solution was cooled and the resulting solid was collected by filtration to afford recovered starting material. The filtrate was chilled, a solid formed which was collected by filtration, slurried with water and acidified with 2N HCl. The mixture was cooled and the product was collected by filtration and dried at 110° C. in vacuo to afford 1.2 g of 1-cyclopentyl-3-ethyl-6-(1-methyl-2-pyrrolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 214.5°-216.5° C. Additional product (0.6 g) was also obtained by acidifying the filtrate with acetic acid, collecting the product by filtration and recrystallizing it from ethyl acetate.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][S:10][S:11](C)(=O)=O>O.C(O)C>[CH3:9][S:10][S:11][N:2]([CH3:1])[C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5]
Reactant: CSS(C)(=O)=O
Reactant: CN[C@@H](CS)C(=O)O
Solvent: O
Solvent: CCO
Product: CSSN(C)[C@@H](CS)C(=O)O
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of N-methylcysteine (Undhein, K., & Eidem, A., 23 Acta Chem. Scandinavica 3129-3133 (1970) (1.5 g, 11.1 mmol) in H2O (20 ml) was stirred at room temperature, under an atmosphere of argon, and treated with a solution of methyl methanethiol sulfonate (3.0 ml, 29.2 mmol) in ethanol (10 ml). The reaction mixture was stirred at this temperature for two hours and then diluted with H2O (100 ml) and washed with ether (4×40 ml). The aqueous layer was acidified to pH 2 and passed through an Amberlite IRA 93 (--OH form) column. The column was washed with water and the effluent was collected and evaporated to dryness under reduced pressure to give a white solid (1.2g, 60%), mp 194°-5° C. NMR (D2O, TMS ext. standard): δ2.2(3H, s), 2.5(3H, s), 3.2(2H,d), 3.7(1H,q).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Yield: 21.1 %

Procedure:
To a mixture of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.50 g, 2.5 mmol) in acetonitrile (25 mL) was added sodium carbonate (0.34 g, 6.25 mmol) and iodoethane (0.39 g, 2.5 mmol) and the mixture was refluxed for 1 h. Water (50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.12 g). The amine was converted to the fumaric acid salt and lyophilized from water. MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S-:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([S:28][CH3:27])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (56 mg, 0.13 mmol) in dry DMF (1 mL) at 60° C. was added sodium methanethiolate (9.9 mg, 0.14 mmol). The reaction was heated to reflux for 30 min and then cooled to room temperature. The reaction was quenched with 1M aq. NaOH and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (silica gel, 0–33% EtOAc in hexanes) to give 34 mg of the desired product as a colorless oil. MS (ESI) 403 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH:15]O.C(#N)C>O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7](=[O:15])[C@H:3]12
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)O
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)C(C(=O)O)N2C(=O)C(N)[C@H]2S1=O
Reaction time: 1 h

Procedure:
6-amino-2,2-dimethylpenam-3-carboxylic acid (1.06 g.) was suspended in water (6 cc), and sodium tungstate dihydrate (10 mg.) was added thereto. To the stirred mixture was added, dropwise, 30% hydrogen peroxide (0.8 cc) while cooling in an ice bath over a period of 20 minutes, and the mixture was stirred for 1 hour at the same temperature. To this mixture was added, dropwise, cooled acetonitrile (90 cc), and the precipitate was collected by filtration and dried under reduced pressure to yield a pale yellowish powder (0.85 g.) of 6-amino-2,2-dimethylpenam-3-carboxylic acid-1-oxide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[N:7][CH:8]=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[CH2:10][NH:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]3)=[CH:4][CH:5]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: ClCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCc3ccc(NCc4ccc(Cl)c(Cl)c4)nc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
A mixture of 5-(chloromethyl)-N-(3,4-dichlorobenzyl)pyridin-2-amine (0.1 g, 0.332 mmol), 6-hydroxyquinolin-2(1H)-one (0.048 g, 0.298 mmol) and Cs2CO3 (0.864 g, 2.65 mmol) in DMF (3.3 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and the resulting suspension was filtered. The filter cake was stirred in methanol for 1 h, filtered, washed with methanol, and dried to yield 6-((6-(3,4-dichlorobenzylamino)pyridin-3-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.033 g, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (1H, s), 8.06 (1H, d, J=2.01 Hz), 7.85 (1H, d, J=9.54 Hz), 7.46-7.63 (3H, m), 7.08-7.37 (5H, m), 6.39-6.62 (2H, m), 4.91 (2H, s), 4.49 (2H, d, J=6.02 Hz). LCMS: R.T.=3.15; [M+H]+=426.00.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(#N)C.[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[CH2:49]Br)[C:44]#[N:45]>C(OCC)(=O)C>[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[CH2:49][N:16]1[CH:17]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:14]=[CH:15]1)[C:44]#[N:45]
Reactant: N#Cc1ccc(CBr)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCCc1cn(Cc2ccc(C#N)cc2Br)cn1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To 4-[4-(tert-butyldimethylsilanyloxy)butyl]-1-trityl-1H-imidazole (3.95 g, 7.95 mmol) is added acetonitrile (300 mL). To this solution is added 3-bromo-4-bromomethylbenzonitrile (2.14 g, 7.78 mmol). The solution is stirred at 40° C. for 18 h. The solvent is then removed in vacuo and methanol (300 ml) is added. The solution is heated to 55° C. and stirred for 1.5 h. Saturated sodium bicarbonate is then added and stirred for 10 min. The organic solvent is removed in vacuo, and the crude product extracted into ethyl acetate and washed with water. The organic solvent is removed in vacuo to give the crude product. Chromatography (silica gel, 1:0 to 1:1 to 0:1 hexanes:ethyl acetate) gives the pure product. MS (ESI) m/z 448, 450 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[F:11][C:4]1[CH:3]=[C:2]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[O:12])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-n2ccccc2=O)cc1F
Temperature: 150 °C
Yield: 49.4 %

Procedure:
To a solution of 10.96 g of 4-bromo-2-fluoro-benzoic acid in 40 ml of DMSO was added subsequently 6.67 g of 2-hydroxypyridine, 1.10 g of 8-hydroxyquinoline, 1.43 g of Cu(I)I and 7.61 g of K2CO3 and the mixture was heated to 150° C. for 18 h. The suspension was diluted with water, filtered, the residue was washed with AcOEt, triturated with MeOH, filtered and dried to give 5.77 g of the title compound 35e. MS: 234.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:10][CH2:11]1)[CH3:5])=[O:54]
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1ccnc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (0.077 g, 0.20 mmol), EDCI (0.043 g, 0.22 mmol) and HOBT (0.030 g, 0.22 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (0.038 g, 0.22 mmol) followed by DIPEA (42 μL, 0.24 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 2-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.062 g, 57%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.0 Hz), 1.06 (m, 1H), 1.22 (m, 1H), 1.57 (m, 2H), 1.81 (m, 3H), 2.11 (br t, 1H), 2.36 (s, 6H), 2.53 (br t, 1H), 2.75-2.88 (m, 3H), 3.20-3.33 (m, 2H), 3.71 (s, 3H), 3.82 (m, 1H), 3.90 (m, 2H), 6.63 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.0 Hz), 6.96 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.98 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=3.0 Hz), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.3, 18.9, 19.1, 29.6, 30.4, 30.9, 39.9, 43.8, 47.0, 51.9, 55.5, 59.2, 60.0, 114.4, 119.9, 124.2, 125.1, 148.0, 149.0, 149.3. ES-MS m/z 536 (M+H), 558 (M+Na). Anal. Calcd. for C30H38N5O2Cl.0.2 CH2Cl2: C, 65.58; H, 7.00; N, 12.66. Found: C, 65.64; H, 7.15; N, 12.79.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14]([O:16][CH2:17][CH2:18]O)[CH3:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:15][CH2:14][O:16][CH2:17][CH3:18])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CC(=O)C(=O)O
Reactant: CCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A toluene solution (1 L) contaning pyruvic acid (440 g, 5.0 mol), 2-ethoxyethanol (450 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 100 to 105° C.) to give 2-ethoxyethyl pyruvate (544 g, yield: 68%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (7.927 mmol) of 2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile are initially charged in 15 ml of DMF, 2.13 g (8.720 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.99 g (23.781 mmol) of sodium bicarbonate are added and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the precipitated solid is filtered off, washed with MTBE and dried under high vacuum. This gives 3.87 g (100% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[N:12]1([C:18]2[C:23](=[O:24])[NH:22][CH:21]=[C:20]3[CH2:25][N:26]([CH2:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[C:27](=[O:28])[C:19]=23)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(#N)C>[CH3:5][O:4][CH2:3][CH2:2][N:22]1[C:23](=[O:24])[C:18]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:19]2[C:27](=[O:28])[N:26]([CH2:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:25][C:20]2=[CH:21]1
Reactant: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 4.8 %

Procedure:
A solution of 1-bromo-2-methoxyethane (32.0 mg, 0.231 mmol), potassium carbonate (159 mg, 1.153 mmol) and 7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (90 mg, 0.231 mmol, see Example 15) were suspended in acetonitrile (50 ml) in a round-bottomed flask. The suspension was stirred at about 120° C. for about 12 h. The obtained crude material was purified by preparative HPLC to give the title compound (5 mg, 0.011 mmol, 4.84% yield).
Reaction SMILES: [OH:1][NH:2][CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[C:27](OC(=O)C)(=[O:29])C>C1COCC1.C(O)=O>[CH:27]([N:2]([CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[OH:1])=[O:29]
Reactant: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a preformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2×5 ml) was added and evaporated in vacuo. The residue was taken in CH2Cl2-methanol (6 ml, 9:1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered off and rinsed with CH2Cl2-methanol (9:1). The residue was purified on silica gel (eluant:CH2Cl2—MeOH 4%) to give the title compound as a light orange solid (220 mg, 61%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:19](=[O:27])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[C:19](=[O:27])[C:18]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Solvent: CC(=O)O
Product: O=c1c(I)c(OCc2ccccc2)ccn1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
N-Iodosuccinimide (2.64 g, 11.74 mmol) was added to a solution of intermediate D1 (3.0 g, 11.74 mmol) in acetic acid (40 ml). The reaction mixture was stirred at room temperature for 1 hour, after which it was concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM as eluent) and finally recrystallized from diethyl ether to yield intermediate D6 (4.12 g, 92%) as a solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenyl glyoxal (3.85 g) and 2-(4-carbomethoxyphenyl) ethanamine (3.4 g), and crystallised from hexane m.p. 75-77.5. τ(CDCl3) 7.66 (2H, broad, replaceable by D2O), 5.9-6.5 (6H, m), 6.15 (3H,s), 5.3 (1H,m), 2.75 (2H,d,J=8 Hz), 2.3-2.6 (4H,m), 2.03 (2H,d,J=8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:30])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:38]1([CH2:41][NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:40][CH2:39]1>C(O)C>[CH:43]1([N:42]([CH2:41][CH:38]2[CH2:39][CH2:40]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:30])=[O:9])[CH:3]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 160 °C

Procedure:
A solution of tert-butyl 3-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate (Intermediate 34, 140 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg, 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent reduced to one tenth of the volume in vacuo. The solid formed was triturated with water and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate which was used directly without any further purification. The residue was redissolved in DCM (4.5 ml) and treated with TFA (0.5 ml). After stirring at RT for 2 hours the solvent was removed in vacuo to give the title compound as an off-white solid.