Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH2:34][CH2:35][NH2:36].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:36][CH2:35][CH2:34][NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Temperature: 0 °C
Yield: 53.8 %

Procedure:
A solution of 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.11 mmol), N-2-pyridyl-1,2-ethanediamine (305 mg, 2.22 mmol) and triethylamine (0.310 mL, 2.22 mmol) in DMSO (4 mL) was stirred at 100° C. After 4 h the reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and dried to yield 5-amino-1-benzyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (285 mg, 54%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[N:4][CH:3]=1
Reactant: ClCc1cncc(Br)c1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CSCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 3-bromo-5-(chloromethyl)pyridine (from example 199, (1.2 g, 5.8 mmol) in acetonitrile (15 mL) was added K2CO3 (0.97 g, 7.0 mmol) followed by methyl 2-mercaptoacetate (0.57 mL, 6.4 mmol). The resulting solution was stirred at room temperature for 16 h. After this time, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water. The organic portion was dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to yield methyl 2-((5-bromopyridin-3-yl)methylthio)acetate (1.2 g, 80% yield). LCMS Method Y: retention time 1.66 min; [M+1]=276.0.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10](OC)[O:11]C>O>[CH:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCCCCCC(OC)OC)OC
Solvent: O
Product: O=CCCCCCCC=O

Procedure:
When the formation of the acetal is complete, the solution is neutralized under cold conditions and diluted with water. In the course of this, 1,1,8,8-tetramethoxyoctane separates out as a water-insoluble oil; it is separated off and the remaining solution is extracted with petroleum ether. The product phases are combined, freed from petroleum ether and fractionated in vacuo. This gives 322 g of 1,1,8,8-tetramethoxyoctane boiling at 147°-149° C./30, corresponding to 91.7% of theory.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[CH3:14].C(O)(=O)C>O>[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:6])=[CH:22][CH:23]=1)[CH3:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 90 °C

Procedure:
A round bottomed flask is charged with isatoic anhydride (5 g, 30.6 mmol) and (4-amino-phenyl)-acetic acid ethyl ester (6.05 g, 33.7 mmol). Acetic acid (11 ml) is added and the reaction is heated at 90° C. for 40 minutes and then allowed to cool to RT. The resulting suspension is diluted with distilled water to give a white precipitate. The precipitate is filtered, washed with water and vacuum dried to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([SH:6])[CH:3]([SH:5])[CH3:4].Cl[CH:8]([CH3:12])[C:9](=O)[CH3:10]>>[CH3:4][CH:3]1[CH:2]([CH3:1])[S:6][C:9]([CH3:10])=[C:8]([CH3:12])[S:5]1
Reactant: CC(S)C(C)S
Reactant: CC(=O)C(C)Cl
Product: CC1=C(C)SC(C)C(C)S1
Yield: 60 %

Procedure:
The procedure of Example 1(a) is followed using 2,3-butanedithiol and 3-chloro-2-butanone to give 2,3-dihydro-2,3,5,6-tetramethyl-1,4-dithiin, as a colorless liquid, b.p. 58°-60°/0.02 mm, yield 60%. NMR 1.34 (6d), 1.87 (6s), 2.7-3.2 (2m) (CDCl3). IR, 2950, 1600, 1435, 1365, 1150, 1060, 760, 680.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=3[N:1]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2n1
Temperature: 146.5 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.00 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.59 g, 3.00 mmol) in N,N-dimethylacetamide (8 mL) was added NaHSO3 (58.5 wt %, 0.59 g, 3.30 mmol) and p-TSA (0.22 g, 1.20 mmol). The reaction mixture was heated to 145-148° C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.50 g (49%).
Reaction SMILES: [SH:1][CH:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](SC)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].CS[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[SH:1][CH:2]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2([C:41]3[C:40]4[C:39](=[CH:3][CH:2]=[CH:33][CH:34]=4)[CH:44]=[CH:43][CH:42]=3)[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH2:20]2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CSc1ccc(-c2ccc(CC(NC(=O)C3(NC(=O)C(S)CC(C)C)CCCC3)C(=O)O)cc2)cc1
Product: CC(C)CC(S)C(=O)NC1(C(=O)NC(CC2(c3cccc4ccccc34)C=CC(c3ccccc3)=CC2)C(=O)O)CCCC1

Procedure:
2-{[1-(2-mercapto-4-methyl-pentanoylamino)-cyclopentanecarbonyl]-amino}-3-(4′-methylthio-biphenyl-4-yl)-propionic acid (from 4-methylthiophenyl-boronic acid; mp 187-189° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH:19]=O.C(O)(=O)C.[NH2:32][C@H:33]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:35]2[CH:47]=[C:48]([C:52]([F:55])([F:54])[F:53])[C:49]([CH3:51])=[CH:50][C:34]1=2.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[C:43]([O:42][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:33]([NH:32][CH2:19][C:18]2[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:16]([F:15])[CH:17]=2)[C:34]2[CH:50]=[C:49]([CH3:51])[C:48]([C:52]([F:55])([F:53])[F:54])=[CH:47][C:35]1=2)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
Add sodium triacetoxyborohydride (0.40 g, 1.89 mmol) to a mixture of 3-fluoro-5-trifluoromethyl benzaldehyde (0.096 mL, 0.69 mmol), acetic acid (0.030 mL, 0.625 mmol)) and (S)-tert-Butyl 5-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 13) (0.215 g, 0.63 mmol) in dichloroethane (3.0 mL). Stir the mixture at room temperature under an atmosphere of nitrogen for 20 h. Add a saturated solution of sodium bicarbonate, separate the layers and extract the aqueous layer with dichloromethane. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-30% ethyl acetate in hexane), to afford the title compound (0.32 g, 98%). MS (ES+): 521 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:22](Cl)(=[O:24])[CH3:23].CN(C1C=CC=CN=1)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH:5][C:22](=[O:24])[CH3:23]
Reactant: COc1ccc2cc(-c3ccc(N)c(OC)c3)ccc2c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(NC(C)=O)c(OC)c3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 2-methoxy-4-(6-methoxy-2-naphthyl)aniline (140 mg, 0.50 mmol, 1 eq) in 20 ml of dry dichloromethane are added acetyl chloride (64 μl, 71 mg, 0.91 mmol, 1.8 eq) and trace amounts of DMAP (dimethylaminopyridine). After stirring for 18 h at RT, the reaction mixture is stopped by adding a 2% sodium carbonate solution, the phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with a gradient of dichloromethane/methanol 10/0 to 9.8/0.2 yielded the desired product in a yield of 66%, 108 mg.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C:16]1([C:22](O)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[BH4-].[Na+].[Cl-].[Na+]>O1CCCC1.CO>[C:8]([O:12][C:13](=[O:14])[NH:15][C:16]1([CH2:22][OH:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Temperature: 0 °C

Procedure:
Neat 4-methylmorpholine (2.7 mL, 24.6 mmol) was added, via syringe, to a rapidly stirred, 0° C., solution of 4-tert-butoxycarbonylamino-tetrahydro-pyran-4-carboxylic acid (5.0 g, 20.4 mmol) and isobutyl chloroformate (3.2 mL, 24.5 mmol) in anhydrous tetrahydrofuran (200 mL) contained in a 1000 mL round bottomed flask. Precipitate immediately formed. The suspension was allowed to stir at 0° C. under N2 blanket for 20 minutes then a hand swirled, gas evolving, suspension of sodium borohydride (2.3 g, 61.3 mmol) in methanol (65 mL) was added, at as fast of a rate as possible while maintaining control of the concomitant reaction foaming. When observable gas evolution had ceased the opaque white reaction suspension was transferred to a separatory funnel containing saturated aqueous sodium chloride (500 mL) and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4), passed through a plug of silica gel, and evaporated to obtain 4.89 g of off white solid which was used without further purification. LRMS (ESI) m/z 232.2 [(M+H)+, calcd for C11H22NO4232.3].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([S:14][CH3:15])=[C:4](Cl)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH3:15][S:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:29]2[CH:28]=[N:27][CH:26]=[CH:25][CH:30]=2)=[N:3][C:4]=1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CSc1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Product: CSc1c(-c2cccnc2)nc(-c2cccnc2)nc1N1CCOCC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
A mixture of 4-(2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine (200 mg, 0.717 mmol.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (323 mg, 1.577 mmol, 2.2 eq), (PPh3)4Pd (165 mg, 0.2 mmol.), 2M Na2CO3 (2.1 ml, 4.302 mmol, 6.0 eq.) and dioxane (20 ml) was added to a reaction vessel which was then flushed with argon. The reaction mixture was stirred at 90° C. for 16 hrs, and then dried. The solvent was removed by evaporation. The mixture was partitioned between EA and water. The organic layer was collected, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography on silica gel (Hexane/EtOAc 2:3, few Et3N), recrystallized by (Hexane/EtOAc) to give a pale yellow solid 57.8 mg (22.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30](=O)[C:31]5[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]5[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=5)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc(Cc2ccc(Cc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1
Reaction time: 7 h
Yield: 81.1 %

Procedure:
In a 3-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 34.39 g of 1,4-bis(4-(4-nitrobenzoyl)phenylmethyl) benzene was dissolved in 1000 milliliters of dichloromethane, and a solution of 37.8 g of titanium tetrachloride in 50 milliliters of dichloromethane was added dropwise for 1 hour with ice cooling. Subsequently, a solution of 41.46 g of triethylsilane in 50 milliliters of dichloromethane was added for 1 hour. 30 minutes after the end of the dropwise addition, stirring was carried out for 7 hours with ice cooling. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was neutralized with an aqueous solution of sodium carbonate and then washed with water. After removing off dichloromethane by a rotary evaporator, the solution was dissolved in chloroform, treated with an alumina column, and removed off the solvent from the solute. By recrystallizing the concentrate from an ethyl acetate solvent, 26.48 g of 1,4-bis(4-(4-nitrophenylmethyl)phenylmethyl)benzene was obtained as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH:18]=O)[CH2:10][C@H:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[OH:30])[CH2:23]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:27]2[CH2:28][CH2:29][C:24]3([CH2:22][CH2:23]3)[C@H:25]([OH:30])[CH2:26]2)[CH2:10][C@H:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CCC=O)C(=O)CCN1C(=O)OC(C)(C)C
Reactant: O[C@@H]1CNCCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 0.418 g (1.47 mmol) of (R)-2-methyl-5-oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (example IC) in 10.5 ml dichloromethane was slowly added to a suspension of 0.241 g (1.47 mmol, 1 eq.) of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2), 0.205 ml (1.47, 1 eq.) of triethylamine, 0.168 ml (2.94 mmol, 2 eq.) of acetic acid and 0.353 g (1.62 mmol, 1.1 eq.) of sodium triacetoxyborohydride in 55 ml dichloromethane. After 30 min, the reaction mixture was slowly added to a solution of sat. aq. sodium hydrogencarbonate, followed by extraction with dichloromethane (3 times). The organic phases were washed with a solution of sat. aq. sodium hydrogencarbonate and with 10% aq. sodium chloride solution. The combined organic phases were dried over Na2SO4 and evaporated to give 0.541 g (88%) of the title compound as white foam. MS: 396.3 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:13]([CH2:19][N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(CCc2ccccc2)C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N(CCc1ccccc1)Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-{4-bromo-2-[(methoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-phenyl)-acetic acid methyl ester in THF and MeOH was added lithium hydroxide, and the reaction was stirred overnight at room temperature. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were concentrated and purified by preparative HPLC to give the title compound. M+H=498.
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:12]=[N:11][C:5]3[N:6]=[C:7]([NH2:10])[N:8]=[CH:9][C:4]=3[CH:3]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: Nc1ncc2cc(Br)cnc2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)cc(-c2cnc3nc(N)ncc3c2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A mixture of 6-bromopyrido[2,3-d]pyrimidin-2-amine (1.0 g, 4.46 mmol), 3,5-dimethoxyphenylboronic acid (1.2 g, 6.70 mmol), PdCl2(dppf) (364 mg, 0.446 mmol) and potassium carbonate (1.8 g, 13.39 mmol) in 1,4-dioxane/water (4 mL/1 mL) was degassed with nitrogen for 5 min and stirred at 110° C. for 30 min under microwave. The reaction mixture was cooled to RT, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to afford 6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-amine as a yellow solid (400 mg, 31%). MS (ES+) C15H14N4O2 requires: 282. found: 283 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C@H:10]1[CH2:14][N:13](C(OC(C)(C)C)=O)[C@H:12]([C:22](=[O:29])[NH:23][C:24]2([C:27]#[N:28])[CH2:26][CH2:25]2)[CH2:11]1>C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:22]([NH:23][C:24]2([C:27]#[N:28])[CH2:26][CH2:25]2)=[O:29])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(F)cc2Cl)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: O=CO
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccc(F)cc3Cl)CN2)CC1
Yield: 99 %

Procedure:
The reaction of the amide 11A with formic acid yielded (2S,4R)-4-(2-chloro-4-fluorophenylthio)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide as a light yellow viscous oil (99%). MS ISP (m/e): 340.2/342.0 (100/25) [(M+H)]+, 230.2/232.0 (94/40).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:29][CH2:30][CH2:31][C:32](=O)[CH2:33][CH2:34][CH3:35].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C.C(N(CC)CC)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH:32]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:30][CH3:29])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Reactant: CCCC(=O)CCC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCC(CCC)N1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
The compound (57.7 mg) obtained in Example 32-2 was dissolved in methanol (1.73 ml) and then added with 4-heptanone (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (30.7 μl), sodium cyanoborohydride (13.8 mg), and triethylamine (76.5 μl). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 7 days. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then the whole was separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (27.7 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20]([CH3:27])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:30]=[C:31]1[O:35][CH:34]([O:36][CH2:37][CH2:38]C2C=CC=CC=2)[CH:33]([NH:45][C:46](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:47])[CH2:32]1>>[CH2:37]([O:36][CH:34]1[CH:33]([NH:45][C:46]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]2[CH:19]=[C:20]([CH3:27])[C:21]([O:25][CH3:26])=[C:22]([CH3:24])[CH:23]=2)[CH3:15])=[O:47])[CH2:32][C:31](=[O:30])[O:35]1)[CH3:38]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: COc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(C)c(OC)c(C)c1
Yield: 81 %

Procedure:
Prepared from 1-[2-(4-methoxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 174 mg (81% yield) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 1.04 (t, 0.45H), 1.27 (t, 2.55H), 1.34-1.45 (m, 3H), 1.95-2.45 (m, 10H), 2.78-2.84 (m, H), 3.60-3.90 (m, 8H), 4.50-4.70 (m, 2H), 4.90-4.94 (m, H), 5.45 (d, 0.85H), 5.61 (d, 0.15H), 6.99 (d, H), 7.15 (d, H), 7.45 (s, 2H); retention time on analytical HPLC: 10.09 min; LC-MS: m/z=476 (M+H+).