Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].Cl>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: O=CCCCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
10 mg (0.011 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 16) were dissolved in 2 ml of dioxane/water, and 2.8 mg (0.022 mmol) of 6-oxohexanoic acid were added. The reaction mixture was subsequently stirred at 100° C. for 1 h. After cooling to RT, 0.75 mg (0.012 mmol) of sodium cyanoborohydride was added and the mixture was adjusted to a pH of 3 by adding 0.1 N hydrochloric acid. The reaction mixture was then stirred at 100° C. for a further hour. After cooling, another 2.8 mg (0.022 mmol) of 6-oxohexanoic acid were added and the reaction mixture was again stirred at 100° C. for 1 h. A further 0.75 mg (0.012 mmol) of sodium cyanoborohydride was added and 0.1 N hydrochloric acid was subsequently used to adjust the pH back to 3. The reaction mixture was then stirred at 100° C. for another 1 h. This procedure was then repeated for a third time. The reaction mixture was finally concentrated and the crude product was purified by means of preparative HPLC. This gave 6.4 mg (64% of theory) of the title compound in the form of a colourless foam.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.C(O)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16][CH2:15]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=Cc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of the compound prepared in Example 7 (2.00 g), tert-butyl piperidin-4-ylmethylcarbamate (2.72 g) and acetic acid (0.66 mL) in acetonitrile (60 mL) was stirred at room temperature for 30 minutes. Tetramethylammonium triacetoxyborohydride (9.12 g) was added and the reaction was stirred overnight. The reaction was then poured into a saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted three times with ethyl acetate. The combined organics were dried with anhydrous magnesium sulfate and concentrated to a white solid. The solid was triturated with hexane to obtain the title compound (3.90 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].Cl>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCCOc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OCCCC(=O)O)cc(OC)c1OC

Procedure:
7 g of the compound obtained in Step A are stirred at room temperature for 72 hours in a mixture of 100 ml of ethanol and 100 ml of 1M aqueous sodium hydroxide solution. Having been rendered acidic by 100 ml of 1M hydrochloric acid, the reaction mixture is extracted with dichloromethane. The organic fractions are dried over sodium sulphate and evaporated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: BrC1C(C)=CC(C)=CC=1C.C([Li])(C)(C)C.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:31])[CH3:25].[Cl-].[Na+]>O1CCCC1.CCCCC>[CH3:16][O:17][C:18]1[C:19]([CH:30]([OH:31])[C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccnc1
Reactant: CCOc1cccc(C=O)c1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C(O)c2ncccc2OC)c1
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of 2-bromomesitylene (9.16 ml, 60 m mol) in tetrahydrofuran (250 ml), a 1.64 M pentane solution of tert-butyl lithium (73 ml, 120 m mol) was added dropwise at −50° C. or below. After this mixture was stirred for 30 minutes, 3-methoxypyridine (5.0 g, 46 m mol) was added dropwise thereto at −50° C. or below and the resulting mixture was stirred at −20° C. for 2 hours. After the reaction mixture was cooled again to −50° C. or below, 3-ethoxybenzaldehyde (10.3 g, 69 m mol) was added dropwise thereto and the stirring was continued for another 30 minutes. After the addition of a saturated aqueous solution of sodium chloride (10 ml), the reaction mixture was returned to room temperature. After a saturated aqueous solution of sodium chloride (200 ml) was further added thereto, the organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 ml), and the extract was combined with the previous organic layer. After the combined organic layer was washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting solid was washed with hexane and then recrystallized from methanol (300 ml) to obtain the desired compound (7.0 g, 59%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][N:12]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:10][O:9][C:4]1[N:3]=[C:2]([N:26]2[CH2:25][CH2:24][CH:23]([N:12]([CH3:11])[C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:28][CH2:27]2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: COc1nc(C)cc(Cl)n1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(C)cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)n1
Yield: 71 %

Procedure:
A mixture of 4-chloro-2-methoxy-6-methylpyrimidine (300 mg, 1.8987 mmol, 1 eq), benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (470 mg, 1.8987 mmol, 1 eq) and K2CO3 (523 mg, 3.796 mmol, 2 eq) in acetone (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, filtration over Celite was carried out and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% methanol/dichloromethane). The desired product was in the form of a light-yellow solid. Yield: 71% (500 mg, 1.3513 mmol)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Br:15][C:16]1[CH:17]=[C:18](/[C:22](/[C:30]2[C:31]([C:36]#[N:37])=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:23]\S(C(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[C:30]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccnc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ncccc32)cc1
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
Butyllithium (2.5 M in hexanes, 0.947 mL) was added dropwise to a solution of 4-bromoanisole (483 mg, 2.58 mmol) in anhydrous THF at −78° C. under an atmosphere of argon. The mixture was stirred at that temperature for 30 min and then a solution of N-[(1E)-(3-bromophenyl)(2-cyanopyridin-3 -yl)methylene]-2-methypropane-2-sulfinamide (Example 2, 840 mg, 2.15 mmol) in THF (10 mL) was added dropwise. Stirring was continued for 3 h at −78° C., and then for 1 h at −25° C. The reaction was quenched by the addition of water, the mixture was diluted with ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (20 mL) and to this was added 2 M hydrochloric acid in diethyl ether (2.5 mL). The mixture was stirred at room temperature for 22 h and then concentrated. The residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. Purification by column chromatography using a gradient of increasing concentration of ethyl acetate in dichloromethane (0-50%) and finally 5% of 2 M ammonia in methanol in ethyl acetate-dichloromethane (45:50) gave 115 mg (14% yield) of the title compound. 1H NMR (CDCl3) δ 8.62 (dd, 1H), 7.88 (dd, 1H), 7.46 (t, 1H), 7.37 (m, 2H), 7.26 (m, 1H), 7.21 (m, 2H), 7.14 (t, 1H), 6.81 (m, 2H), 3.78 (s, 3H); MS (ESI) m/z 394, 396 [M+1]+.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.F[C:35](F)(F)C(O)=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C.C[O-].[Na+].Cl>C(Cl)Cl>[C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(=[O:5])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: O=C(O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (81 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (3 mL), triethylamine (0.25 mL, 1.79 mmol), and acetic anhydride (0.085 mL, 0.90 mmol), and the resulting mixture was stirred at r.t. for 16 h. The mixture was concentrated to dryness, and the residue was dissolved in MeOH (3.6 mL) and treated with NaOMe (3.6 mL, 1.79 mmol, 0.5 M in MeOH) for 1 h at r.t. 1 M HCl was added until pH was about 3-4, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 37 mg of the title compound as an off-white solid. MS: (+) m/z 395.38 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([C:14]1[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Benzyl bromide (41 g, 240 mmol), 4-formylbenzeneboronic acid (28 g, 186.7 mmol), palladium tetrakis triphenyl phosphine (7.9 g, 6.84 mmol) and potassium carbonate (84.7 g, 613 mmol) were combined in tetrahydrofuran (620 mL) and heated at 80° C. under nitrogen for 8 hours. The resulting suspension was allowed to cool to ambient temperature and stirred overnight. The reaction mixture was poured into 10% citric acid (50 mL) and extracted with ethyl acetate (3-fold 50 mL). The combined organic extracts were washed with brine (100 mL) and dried (magnesium sulphate) and the solvent removed in vacuo. The resulting oil was purified by column chromatography on silica gel eluting with ethyl acetate:heptane, (0:1 changing to 1:5, by volume) to give the title compound as a colourless oil, 83% yield, 30.45 g.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)[C:8]=2[CH:23]=1)(=[O:3])[CH3:2].[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C([BH3-])#N.[Na+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][CH2:35][C:33]4[CH:32]=[CH:31][C:28]5[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=5[N:34]=4)[CH2:20][CH2:21]3)[C:8]=2[CH:23]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 7 %

Procedure:
6-Acetyl-4-[2-(4-aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one (Intermediate 87), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 7% yield.
Reaction SMILES: COC([O:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:8][CH:7]=1)=O.N>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:23][CH:24]=1
Reactant: CCCCCCCCCCOC(=O)c1ccc(OC(=O)OC)cc1
Agent: N
Solvent: CCO
Product: CCCCCCCCCCOC(=O)c1ccc(O)cc1

Procedure:
Quantities: compound 22 (16.53 g, 0.049 mol), ethanol (200 ml), aqueous ammonia (35% w/v, 100 ml).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:34][C:30]1[CH:29]=[C:28]([N:6]2[C:7]3[N:14]([CH3:15])[C:13](=[O:16])[CH:12]=[C:11]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:8]=3[C:9](=[O:10])[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]2=[O:37])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc([N+](=O)[O-])c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a suspension of toluene-4-sulfonic acid 3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 12 (21 g) obtained in Step 6 in tetrahydrofuran was added stannous chloride dihydrate (45 g), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was alkalified with saturated aqueous sodium hydrogen carbonate, an insoluble inorganic product was filtered off by suction using celite as a filtration aides, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=9:1) to give toluene-4-sulfonic acid 1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 13 (15 g, 74%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([S:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]2[CH:33]=[C:34]([CH3:36])[CH:35]=[C:27]2[NH:26]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([S:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:30]([C:29]3[N:25]([CH3:24])[NH:26][C:27]4=[CH:35][C:34]([CH3:36])=[CH:33][C:28]=34)=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc2[nH]n(C)c(C(=O)Cl)c-2c1
Reactant: Cc1ccc(Sc2ccc(CN)cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2ccc(CNC(=O)c3c4cc(C)cc-4[nH]n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To a stirred mixture of 4-(4-methylthiophenoxy)benzylamine (124 mg, 0.505 mM), triethylamine (61 mg, 0.60 mM) and toluene (20 ml) was added dropwise a solution (10 ml) of 2,5-dimethylcyclopenta[1,2-c]-pyrazole-3-carbonyl chloride(100 mg, 0.503 mM) in toluene at 0°-10° C., and the mixture was stirred for 3 h at the room temperature. The mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with saturated sodium hydrogen carbonate solution, water, saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-[4-(4-methylthiophenoxy)benzyl]-2,5-dimethylcyclopenta[1,2-c]pyrazole-3-carboxamide (138 mg, 67%) as colorless crystals, m.p. 138.0° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([NH:11][CH2:12][CH3:13])[C:6]([O:8]CC)=O)(=[O:3])[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-]#N.[Na+]>>[C:1]([NH:4][CH:5]([NH:11][CH2:12][CH3:13])[C:6]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CCNC(NC(C)=O)C(=O)OCC
Reactant: NCc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Product: CCNC(NC(C)=O)C(=O)NCc1ccccc1

Procedure:
Using ethyl 2-acetamido-2-(ethylamino)acetate (0.90 g, 4.79 mmol), benzylamine (0.62 g, 5.75 mmol), and NaCN (0.03 g, 0.51 mmol) gave an oily residue which was purified by flash column chromatography on SiO2 gel (3% MeOH/CHCl3) to give the desired product as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH:15]C(=O)C)[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:15])[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)NC1CCc2cccc(N)c2C1=O
Temperature: 60 °C

Procedure:
245 mg of the compound prepared in (3) above was dissolved into 40 ml of 3N hydrochloric acid and heated at 60° C. for 1 hour while stirring. After cooling to 0° C., the reaction solution was neutralized with sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate. The residue obtained after the removal of the solvent was recrystallized in ethyl acetate and hexane to obtain 150 mg of the title compound.
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[CH:48]1[C:55]2[C:54]([CH3:56])=[N:53][N:52]([CH2:57][CH3:58])[C:51]=2[C:50](=[O:59])[N:49]1[C:60]1[CH:61]=[C:62]([CH3:70])[C:63]2[N:64]([C:66]([CH3:69])=[N:67][N:68]=2)[CH:65]=1>CCCCCCC.CCO.CO>[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[C@@H:48]1[C:55]2[C:54]([CH3:56])=[N:53][N:52]([CH2:57][CH3:58])[C:51]=2[C:50](=[O:59])[N:49]1[C:60]1[CH:61]=[C:62]([CH3:70])[C:63]2[N:64]([C:66]([CH3:69])=[N:67][N:68]=2)[CH:65]=1
Reactant: CCn1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)C2c1ccc(F)cc1F
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CCCCCCC
Solvent: CCO
Solvent: CO
Product: CCn1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)[C@@H]2c1ccc(F)cc1F

Procedure:
The title compound (34 mg, 48% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: Gilson PLC 2020; column: Chiralpak AD-H, 20×250 mm; mobile phase: heptane/EtOH/MeOH 80:10:10; flow: 12 mL/min; temperature: 38° C.; detection UV: 220 nm) of the racemic mixture of 4-(2,4-difluorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-ethyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 181).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])=[C:6](I)[C:5]([C:14]#[N:15])=[N:4]1)[CH3:2].[CH2:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[C:17]#[CH:18].C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])=[C:6]([C:18]#[C:17][CH2:16][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([C:14]#[N:15])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C#N)c(I)c1CC(C)(C)O
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCn1nc(C#N)c(C#CC[Si](C)(C)C)c1CC(C)(C)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-iodo-1H-pyrazole-3-carbonitrile (900 mg, 2.81 mmol), propargyltrimethylsilane (0.8 mL, 5.6 mmol), copper(I) iodide (107 mg, 0.562 mmol), dichlorobis(triphenylphosphine)palladium(II) (197 mg, 0.281 mmol), triethylamine (1.2 mL, 8.4 mmol) and acetonitrile (14 mL) were combined and then heated at reflux for five hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and then filtered through a layer of silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with a gradient of 0 to 80% ethyl acetate in hexanes) to provide 1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-(3-trimethylsilylprop-1-ynyl)-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])C=CC=CC=1.[CH2:17]([OH:19])[CH3:18]>>[CH3:18][CH2:17][O:19][C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: CCO
Product: CCOC(=O)Nc1ccccc1
Yield: 93 %

Procedure:
Following the same procedures as in Example 8, a total amount of N,N'-diphenyl urea crystal was reacted with 50.00 g of ethyl alcohol. After the reaction, the reaction mixture was analyzed to obtain a 93% yield for N-phenylethyl carbamate and a 95% yield for aniline.