Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=3[O:16][CH2:17][C@@H:9]12)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:15]2[O:16][CH2:17][CH:9]3[NH:8][CH2:13][CH2:12][CH2:11][CH:10]3[C:14]=2[CH:21]=1
Reactant: COc1ccc2c(c1)[C@H]1CCCN(Cc3ccccc3)[C@@H]1CO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C1CCCNC1CO2

Procedure:
A solution of 1.5 g of trans-4-benzyl-9-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 30 ml of ethanol is hydrogenated at 300 kPa pressure in the presence of 0.5 g of 10% palladium on charcoal until one mole of hydrogen is consumed. The reaction mixture is filtered, evaporated to dryness to give 9-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C:25]([OH:28])([CH3:27])[CH3:26])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=12)=O>ClCCCl>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:29][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=23)[C:25]([OH:28])([CH3:26])[CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)(O)[C@@H](N)C(=O)NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)(C)O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (R)-2-amino-N-cyclopentyl-3-hydroxy-3-methylbutanamide (49.4 mg, 0.246 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. 1-tert-Butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Following reaction, the mixture was concentrated to afford the title compound. [M+H] calc'd for C25H36N4O6, 489; found, 489.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH:12]1[CH2:15][CH2:14][CH2:13]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CNC1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC2)cc1

Procedure:
The title compound was prepared from 4-fluoronitrobenzene and azetidine hydrochloride according to Method AE and was isolated as a yellow solid (69%) after trituration in water, and then in Et2O, δH (DMSO-d6) 8.10-7.99 (2H, m), 6.48-6.35 (2H, m), 4.04 (4H, t, J 7.5 Hz), 2.47-2.31 (2H, m). LCMS (ES+) 178.9 (M+H)+, RT 2.71 minutes (Method 3).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][N:10](C=O)C>ClCCl>[C:9]([C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)#[N:10]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)nc1
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1
Yield: 78 %

Procedure:
A mixture of 6-bromo-3-picoline (3 g, 17.4 mmol) and cuprous cyanide (2.3 g, 26.1 mmol) in DMF (60 mL) was heated at reflux for 1.5 h. The reaction mixture was diluted with dichloromethane, washed with aqueous ammonia, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:n-hexane, 1:9) to give the title compound (1.6 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36](=[O:37])[C:35]([C:38](O)=[O:39])=[CH:34][N:33]([CH:41]([CH3:43])[CH3:42])[C:32]2=[O:44])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:38]([C:35]2[C:36](=[O:37])[N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[C:32](=[O:44])[N:33]([CH:41]([CH3:43])[CH3:42])[CH:34]=2)=[O:39])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=238-240° C.; LCMS m/z=585 (M+1); 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J=6 Hz), 7.73-7.67 (m, 2H), 7.55 (s, 1H), 7.45-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.17 (d, 1H, J=8 Hz), 6.31 (d, 1H, J=4.5 Hz), 4.78 (p, 1H, J=6 Hz), 3.95 (s, 6H), 2.09 (s, 3H), 1.43 (d, 6H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([Cu])#[N:11].N>CN1C(=O)CCC1>[NH2:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[C:10]#[N:11]
Reactant: Cc1cccc(Br)c1N
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: Cc1cccc(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9].O1CCCC1.[CH3:21][NH:22][C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:26]=[C:25]([CH3:35])[N:24]=1>C(N(CC)CC)C>[F:34][C:31]([F:32])([F:33])[CH2:30][O:29][C:27]1[CH:26]=[C:25]([CH3:35])[N:24]=[C:23]([N:22]([CH3:21])[C:12]([N:11]([CH3:15])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])=[O:13])[N:28]=1
Reactant: CN(C(=O)Cl)S(=O)(=O)c1ccccc1Cl
Reactant: CNc1nc(C)cc(OCC(F)(F)F)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(F)(F)F)nc(N(C)C(=O)N(C)S(=O)(=O)c2ccccc2Cl)n1

Procedure:
To 18 parts of N-[(2-chlorophenyl)sulfonyl]N-methylcarbamyl chloride in 300 parts of tetrahydrofuran containing 10 parts of triethylamine is added 22 parts of 2-methylamino-4-(2,2,2-trifluoroethoxy)-6-methylpyrimidine. After stirring at reflux for 10 hours, the precipitated salts are filtered off and the filtrate is concentrated to yield N-[N-[4-(2,2,2,-trifluoroethoxy)-6-methylpyrimidin-2-yl]-N-methylaminocarbonyl]-2-chloro-N-methylbenzenesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([O:10][CH3:11])[O:8][CH3:9].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:11][O:10][CH:7]([O:8][CH3:9])[CH2:6][N:5]([CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[F:1])[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: COC(CNCc1ccccc1F)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccccc1F)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C

Procedure:
N-(2-fluorobenzyl)-2,2-dimethoxyethanamine (BB; 33.0 g, 0.154 mol) were dissolved in 200 mL of dichloromethane and pyridine (50.2 g, 0.417 mol) was added. At 0° C. a solution of p-toluene sulphonyl chloride (58.0 g, 0.201 mol) in dichloromethane (500 mL) was added drop wise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M aqueous hydrochloric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (2H, m), 7.43-7.39 (m, 1H), 7.29-7.21 (m, 3H), 7.12-7.08 (m, 1H), 6.99-6.95 (m, 1H), 4.52 (s, 2H), 4.39-4.37 (t, 1H, J=5.2 Hz), 3.26-3.24 (m, 8H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[N:14][C:15]([CH:18]=O)=[N:16][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:21]O.C1(S(Cl)(=O)=O)C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]#[N:21])=[N:16][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NO
Reactant: CCCCC[C@H]1CC[C@H](c2cnc(C=O)nc2)CC1
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2cnc(C#N)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.0 g of trans-5-(4-pentylcyclohexyl)-2-pyrimidinecarboxaldehyde are dissolved in 150 ml of pyridine under a nitrogen atmosphere, treated with 3.9 g of hydroxylamine hydrochloride and stirred at room temperature for 2 hours. Thereafter, the mixture is treated with 18.3 g of benzenesulphonyl chloride, the temperature rising to about 50° C. Subsequently, the mixture is stirred at a bath temperature of 70° C. for 6 hours, then cooled, poured into 500 ml of ice/water and 100 ml of concentrated hydrochloric acid and extracted with ether. The extract is washed with dilute hydrochloric acid, washed neutral with water, dried over sodium sulphate and evaporated. The crude product obtained is chromatographed on a column of 275 g of silica gel with hexane/20% ether. The almost pure fractions (in accordance with thin-layer chromatography) are combined and recrystallized three times from hexane. There is obtained pure trans-5-(4-pentylcyclohexyl)-2-pyrimidinecarbonitrile; m.p. 83.5° C.
Reaction SMILES: [CH2:1](I)I.[Cl:4][C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1>C(Cl)Cl.[Zn]>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:9]2[CH2:1][C@H:10]2[C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: ICI
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Agent: [Zn]
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of zinc dust (6.54 g, 0.1 mole) and cuprous chloride (1 g, 0.01 mole) in methylene chloride (30 mL) is stirred and heated to reflux under a nitrogen atmosphere for 30 min. After the mixture is cooled to room temperature, methylene iodide (13.4 g, 0.05 mole) is added to the mixture which is then refluxed for an additional hour. After cooling to 0° C., trans-4-chlorocinnamic acid (9.1 g) is added. The reaction is allowed to warm to room temperature over 2 hours and then refluxed for 3 days. The reaction is quenched at 0° C. by the addition of 30 ml of diethyl ether and 30 ml of ice cold 10% H2SO4 solution. The mixture is filtered washed with ether. The organic layer is dried over MgSO4 and concentrated to provide the desired product as a white solid. 1H NMR (CDCl3) 7.25 (d, J=7 Hz, 2H), 7.05 (d, J=7 Hz, 2H) , 2.58 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.37 (m, 1H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:4][N:3]=1.O=P(Cl)(Cl)[Cl:31].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cncc(-c2nnc(O)c3c(-c4ccccc4)cccc23)c1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-(4-hydroxy-5-phenylphthalazin-1-yl)nicotinate (3.50 g, 9.42 mmol) in toluene (35 mL) was added POCl3 (26.4 mL, 283 mmol) followed by N,N-dimethylbenzenamine (1.5 mL, 9.42 mmol). The resulting mixture was heated in a sealed tube at 100° C. for 12 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated NaHCO3 (2×50 mL) solution. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield ethyl 5-(4-chloro-5-phenylphthalazin-1-yl)nicotinate (3.50 g) as a yellow solid with LC-MS purity of 47% which was taken for the next step without further purification. LCMS (Condition 12): retention time 0.97 min, [M+1]=390.0.
Reaction SMILES: [OH-:1].[K+].C(N[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11])(=O)C>O>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[OH:1]
Reactant: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 94.6 %

Procedure:
A solution of KOH (73.4 g,) in H2O (330 mL) was added to 3-acetamido-4,6-dichloro-2-nitrobenzoic acid 1-5 (38.1 g, 0.130 mol). The resulting brown solution was heated to reflux for 18 h (bath temp 130° C.). The reaction was cooled and extracted with ether. The aqueous layer was then acidified to pH 2 with concentrated HCl and extracted into EtOAc (×4). The combined organic layers were washed with brine (×3), dried over Na2SO4, filtered and concentrated to provide 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid 1-6 as a brown solid (31.0 g, 95%). 1H NMR (400 MHz, d6-DMS) 57.88 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[N:32][S:33][CH:34]=2)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH:20][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:31]=[N:32][S:33][CH:34]=3)=[CH:26][CH:25]=2)[CH:11]=1
Reactant: BrCc1ccc(-c2csnn2)cc1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(-c2csnn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A solution of 0.800 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of methanol were added 1.08 g of 4-(4-bromomethylphenyl)-1,2,3-thiadiazole and 0.710 g of sodium hydrogencarbonate, and the mixture was stirred at 70° C. for 1 hour. The reaction solution was concentrated, and was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to give 0.830 g of N-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH3:32])(=[O:41])=[O:40]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-methylbenzene-1-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C1CCC(N=C=NC2CCCCC2)CC1.[C:31](=S)=[S:32]>C(OCC)C>[F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:12]=[C:31]=[S:32])=[CH:9][CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: S=C=S
Reactant: NCc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)c1ccc(CN=C=S)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
4.7 g of 4-pentafluoroethylbenzylamine was added dropwise to a mixture of 4.8 g of DCC, 20 ml of carbon disulfide and 50 ml of diethyl ether with stirring at -10° C. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[C:15]([C:2]2[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: COc1cc(O)c(C=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(O)c(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water (4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). The reaction mixture was heated under reflux for 15 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane, to give 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde as a white solid (2.2 g, 73%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:19]3[S:24][C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:22]([CH3:32])[C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:39](O)(=[O:43])[C@H:40]([CH3:42])[OH:41]>>[OH:41][C@@H:40]([CH3:42])[C:39]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:23]2[S:24][C:19]3[C:18]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[N:17][C:16]([C:13]4[CH:14]=[N:15][C:10]([NH:9][CH3:8])=[N:11][CH:12]=4)=[N:21][C:20]=3[C:22]=2[CH3:32])[CH2:27][CH2:28]1)=[O:43]
Reactant: C[C@H](O)C(=O)O
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)c(C)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with L-lactic acid via General Procedure B to give 24.5 mg of 389 after reverse phase HPLC purification. MS (Q1) 513.3 (M)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][O:9][C:10]([C@@H:12]([NH:20][C:21]([C@@H:23]([NH2:28])[CH2:24][C:25]([OH:27])=[O:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]>>[CH3:1][C:2]([CH2:3][CH2:4][NH:28][C@H:23]([C:21]([NH:20][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])[CH2:24][C:25]([OH:27])=[O:26])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C

Procedure:
3,3-Dimethylbutyraldehyde and the acid salt of aspartame or the N-protected aspartame are reacted for a time and at a temperature sufficient to produce neotame. Generally, the time ranges from about 1 to about 24 hours, preferably from about 2 to about 4 hours after addition of the 3,3-dimethylbutyraldehyde is complete. If the 3,3-dimethylbutyraldehyde is added to the reaction mixture all at once, then the time sufficient to produce neotame preferably ranges from about 6 to about 24 hours. Generally, the temperature sufficient to produce neotame according to the present invention ranges from about 20° C. to about 60° C., preferably from about 22° C. to about 40° C.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]#[N:29])=[O:22])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Yield: 67.8 %

Procedure:
In a similar manner to Example 2, 2-tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (90.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (70.0 mg) were used to obtain (2S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (85.2 mg).