Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:30])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([NH:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[C:26]([F:27])([F:28])[F:29])=[O:17])=[CH:6][CH:7]=1
Reactant: NC(c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C1CC[C@@H](C(=O)O)[C@H](c2ccc(Br)cc2)C1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)NC(c2ccc(Cl)cc2)C(F)(F)F)[C@H](c2ccc(Br)cc2)C1

Procedure:
A solution of (1R,2R)-2-(4-bromophenyl)-4-oxo-cyclohexane-carboxylic acid (100 mg, 0.300 mmol), 1-(4-chlorophenyl)-2,2,2-trifluoro-ethanamine (the faster eluting enantiomer on AD-H chiral column using MeOH/SF CO2; 62.8 mg, 0.300 mmol) and HOBT (45.9 mg, 0.300 mmol) in CH2Cl2 (5 mL) was reacted with EDC (115 mg, 0.600 mmol) and DMAP (36.6 mg, 0.300 mmol). The reaction was aged at rt until it was complete. The mixture was concentrated and purified on a silica gel column by eluting with 0-50% EtOAc/hexanes to afford the title compound. HPLC/MS: 488.1/490.0 (M+1); Rt=1.19 min (LC-2).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[NH:2][CH2:3][C:4]#[C:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C#CCN)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#CCNC(=O)Nc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-(3-aminoprop-1-ynyl)benzoate hydrochloride (see Example 1, Steps 1-3 above; 150 mg, 0.66 mmol) in THF (5 ml) was added 4-chlorophenyl isocyanate (102 mg, 0.66 mmol) and triethylamine (278 μL, 2.0 mmol). The reaction mixture was stirred for 30 min, diluted with ethyl acetate (50 ml), and sequentially washed with water (25 ml), 0.5M aqueous HCl (25 ml), saturated sodium bicarbonate (25 ml), and finally with brine (25 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo to provide methyl 4-[3-(3-(4-chlorophenyl)-ureido)prop-1-ynyl]-benzoate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].OO.O.S([O-])(O)=[O:18].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: O=S([O-])O
Reactant: CCOc1ccc(B(O)O)cc1F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g of the crude 3-fluoro-4-ethoxyphenyl boronic acid obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 23.6 g (208 mmol) of aqueous 30% hydrogen peroxide was added while being kept at about 35° C. in a warm bath. After addition and after stirring the reaction solution at a room temperature for 24 hours, the reaction solution was poured into 300 ml of water, then sodium hydrogen sulfite was added and stirred at a room temperature for one hour. The reaction solution was extracted with 300 ml of ethyl acetate and the extracted layer was washed with water and then with an aqueous saturated sodium chloride solution successively and, after dying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The concentrated residue was purified by silica gel column chromatography using a ethyl acetate/heptane mixed solvent as an eluent to obtain 17.6 g (113 mmol) of 3-fluoro-4-ethoxyphenol.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[S:23][C:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:20]=1)=O>CCCCCC.O1CCCC1.C(OCC)C>[CH2:15]([O:14][C:12](/[CH:11]=[CH:17]/[C:19]1[S:23][C:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:20]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1ccc(C(=O)OC(C)(C)C)s1

Procedure:
Sodium hydride (min 60% paraffinic dispersion, 1.88 g, about 47 mmol) was washed with anhydrous hexane in a nitrogen stream and suspended in anhydrous tetrahydrofuran. The obtained suspension was stirred under cooling with ice, followed by the gradual dropwise addition of a solution of ethyl diethylphosphonoacetate (10.53 g, 47 mmol) in anhydrous tetrahydrofuran. The obtained mixture was stirred at room temperature for 15 minutes. A solution of the t-butyl 5-formyl-2-thiophenecarboxylate (6.65 g, 31.3 mmol) prepared above in anhydrous tetrahydrofuran was gradually dropped into the resulting mixture under cooling with ice. The obtained mixture was stirred at room temperature for 30 minutes, diluted with diethyl ether, washed with a dilute alkali, diluted hydrochloric acid and an aqueous solution of common salt, dehydrated and evaporated in a vacuum to dryness. The residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=8:1) to give the objective compound. yield: 7.58 g
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:15])([F:14])[C:5]1[N:10]=[CH:9][C:8]([C@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]1[C:27]2[CH2:35][N:34]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=3)[CH2:33][CH2:32][C:28]=2[N:29]=[CH:30][N:31]=1>C(#N)C>[CH3:42][C:39]1[CH:40]=[CH:41][C:36]([N:34]2[CH2:33][CH2:32][C:28]3[N:29]=[CH:30][N:31]=[C:26]([NH:13][C@@H:11]([C:8]4[CH:9]=[N:10][C:5]([C:4]([F:14])([F:3])[F:15])=[CH:6][CH:7]=4)[CH3:12])[C:27]=3[CH2:35]2)=[N:37][CH:38]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4ccc(C(F)(F)F)nc4)c3C2)nc1
Temperature: 180 °C
Reaction time: 0.21 h

Procedure:
To a stirred solution of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine dihydrochloride (44 mg, 0.17 mmol) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) in acetonitrile (1.1 mL) was added 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (30 mg, 0.1 mmol). The reaction was capped and heated in the microwave for 10 hours at 180° C. The reaction mixture was quenched with excess water and allowed to stir for 10-15 minutes. The precipitated product was filtered, washed with water and dried in vacuum oven to obtain the title compound as a light tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH:6]=[C:5]2[CH:17]=[O:18].[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[C:27]([CH3:39])=[C:26]([F:40])[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:25]=[C:26]([F:40])[C:27]([CH3:39])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[CH:6]=[C:5]4[CH:17]=[O:18])[CH:29]=2)[CH2:20][CH2:21]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Temperature: 60 °C

Procedure:
To a mixture of the product of Example 59 step ii) (3.17 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3.3 g) [prepared as described in WO06110173] and potassium carbonate (2.86 g) in DMF (40 mL) was added Pd-118 (0.20 g) and the mixture heated at 60° C. under nitrogen for 11 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate, filtered and evaporated. The residue was purified (SiO2, eluting with 3:2 ethyl acetate:isohexane) to give the sub-title compound (4.24 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].Cl[CH2:12][CH:13]1[O:15][CH2:14]1.C(O)C.[OH-].[K+]>O>[O:15]1[CH:13]([CH2:12][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:1][CH2:2][CH3:3])[CH2:14]1
Reactant: ClCC1CO1
Reactant: CCCc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1ccccc1OCC1CO1

Procedure:
To a solution of 27.2 parts of 2-propylphenol and 56 parts of 1-chloro-2,3-epoxypropane in 30 parts of ethyl alcohol, heated under reflux, was added a solution of 13.2 parts of potassium hydroxide in 50 parts of ethyl alcohol and 6 parts of water over 15 minutes and the mixture obtained was heated under reflux for a further 2 hours. The mixture was poured into 1,000 parts of water and extracted with ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulphate, filtered and evaporated to yield a yellow oil. The oil was distilled at the water pump to yield 31.0 parts of 1,2-epoxy-3-(2-propylphenoxy)propane, boiling point 155°-158° at 15 mm.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH3:8][C:9]1[N:10]=[C:11]([S:14]([N:17]2[CH2:22][CH2:21][NH:20][C:19](=O)[CH2:18]2)(=[O:16])=[O:15])[S:12][CH:13]=1.[N:24]1([CH2:33][C:34](O)=[O:35])[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:8][C:9]1[N:10]=[C:11]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:34](=[O:35])[CH2:33][N:24]3[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]3=[O:26])[CH2:19][C:18]2=[O:4])(=[O:16])=[O:15])[S:12][CH:13]=1
Reactant: Cc1csc(S(=O)(=O)N2CCNC(=O)C2)n1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C(O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: Cc1csc(S(=O)(=O)N2CCN(C(=O)Cn3cc(C)c(=O)[nH]c3=O)CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
To 3 mL of DMF, were added 0.30 g (0.8 mmol) of 4-(4-methyl-thiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt, 0.147 g (0.8 mmol) of (thymin-1-yl)-acetic acid and 0.458 g of PyBOP. The reaction mixture was stirred for 4 hours at room temperature. Almost of the solvent was removed in vacuo and the residue was dissolved in methylene chloride. The solution was washed with saturated sodium bicarbonate solution, water, 1N HCl, water and brine sequencially. The organic layer was concentrated and column chromatographed on silicagel to give 0.19 g (56%) of the title compound.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[C:12]([C:15]1[C:16](=[S:26])[S:17][S:18][C:19]=1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)([OH:14])=[O:13].[O-]CC.[Na+].[CH2:31](I)[CH2:32][CH2:33][CH3:34]>C(O)C.C(OCC)(=O)C>[CH2:31]([O:13][C:12]([C:15]1[C:16](=[S:26])[S:17][S:18][C:19]=1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:14])[CH2:32][CH2:33][CH3:34]
Reactant: O=C(O)c1c(-c2cnccn2)ssc1=S
Reactant: CCCCI
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCOC(=O)c1c(-c2cnccn2)ssc1=S
Temperature: 50 °C
Yield: 25.6 %

Procedure:
Anhydrous hexamethylphosphotriamide (5 cc) and 4-carboxy-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (1.28 g) (prepared as described in Example 32) are added to a solution of dry sodium ethoxide (0.34 g) in anhydrous ethanol (5 cc). The suspension obtained is heated to a temperature of about 50° C, the resulting solution is cooled to a temperature of about 20° C and then butyl iodide (1.7 g) is added. The reaction mixture is then maintained at a temperature of about 50° C for 7 hours. An insoluble material is filtered off and the filtrate is evaporated to dryness under reduced pressure (20 mm Hg). The oil obtained is treated with ethyl acetate (2 cc) and the product which crystallises is filtered off and washed with diethyl ether (2 cc). After drying, 4-butoxycarbonyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (0.4 g), melting at 127° C, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]3[CH2:15][C:16](=[O:22])[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:23]([N:25]([CH2:41][CH3:42])[CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=1[CH3:40])=[O:31])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]3[C:15](=[CH:38][C:35]4[NH:34][C:33]([CH3:40])=[C:32]([C:30](=[O:31])[NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:41][CH3:42])[CH2:23][CH3:24])[C:36]=4[CH3:37])[C:16](=[O:22])[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: COc1ccc(NC(=O)c2cccc3c2CC(=O)N3)cc1Cl
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(C(=O)Nc4ccc(OC)c(Cl)c4)c32)c1C
Yield: 93.1 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)amide (1 g, 3.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (1 g, 3.58 mmol) to give 1.7 g (85%) of the title compound as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.278 g, 0.73 mmol) (from example 120, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.029 g, 0.73 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.044 mL, 0.73 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (83 mg, 34%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-2.14 (m, 4H), 2.71-3.14 (m, 4H), 3.43-3.75 (m, 3H), 4.01-4.78 (m, 2H), 5.65 (s, 1H), 6.78-7.14 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N+:17]([O-])=O)=[CH:13][N:12]([CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:11]1=[O:29])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:20][C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:11]1=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c([N+](=O)[O-])cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Yield: 67.9 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-5-nitro-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (173 mg, 0.34 mmol) in methanol (5 mL) was added 10% palladium/carbon (36 mg) in a nitrogen atmosphere, followed by stirring at room temperature for 1 hr in a hydrogen atmosphere. After removal of the palladium/carbon by filtration through celite, the filtrate was concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/1/1) and dried in a vacuum to afford 109 mg of the compound as a colorless oil (yield 66%).
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[F:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CCF)c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Yield: 93 %

Procedure:
Compound 9c was synthesized by a procedure similar to that described for 9a using commercially available 3-fluoropropiophenone (8c, 5.0 g, 0.033 mol), TBDMSOTf (8.3 mL, 36.1 mmol), and Et3N (7.3 mL) in CH2Cl2 (50 mL). After purification, 8.1 g (93%) of 9c was isolated as colorless oil: 1H NMR (CDCl3) δ 7.38-7.10 (m, 2H), 7.00-6.87 (m, 1H), 5.26 (q, 1H, J=6.9 Hz), 1.75 (d, 3H, J=6.9 Hz), 1.00 (s, 9H), −0.02 (s, 6H); 13C NMR (CDCl3) δ 164.5, 161.2, 149.2, 142.4, 129.4, 121.4, 114.3, 114.0, 112.8, 112.5, 107.1, 105.9, 26.0, 18.5, 11.9, −3.9. C15H23FOSi.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:30]=[N:29][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[O:26]1[CH:31]=[N:28][N:27]=[C:25]1[C:22]1[N:23]=[CH:24][C:19]2[NH:18][C:17]3[N:29]=[CH:30][C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:9][CH:10]=4)=[CH:15][C:16]=3[C:20]=2[CH:21]=1
Reactant: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1nnc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)o1
Yield: 10.9 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbhydrazide (53.8 mg, 0.134 mmol) and trimethoxymethane (1.21 mL, 11.0 mmol) in DMF (0.81 mL) was heated at 120° C. for 24 h. The mixture was cooled, treated with trimethoxymethane (1.0 mL) and a few drops of acetic acid and heated under reflux for 48 h. The mixture was allowed to cool, treated with saturated aqueous sodium bicarbonate solution, and the resultant white precipitate collected by filtration and washed with water. The filtrate was extracted with DCM, 20% methanol in DCM, and the combined organic phases dried over sodium sulfate, combined with the isolated solid and concentrated in vacuo. The resultant residue was purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a light-yellow flaky solid (6.0 mg, 27%). 1H NMR (DMSO-D6, 400 MHz): 12.77-12.69 (s, 1H), 9.41 (s, 1H), 9.26 (d, J=2.2 Hz, 1H), 9.18 (s, 1H), 9.08 (s, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=7.69 min, M+H+=411.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][C:8]2=[O:13])[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][C:8]3=[O:13])[CH2:3][CH2:2]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C1COCCN1C1CCNCC1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH2:47][CH2:48][NH:49][CH2:50][CH:51]=2)=[CH:42][CH:41]=1>C(#N)CC.O>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:50][CH2:51][C:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)=[CH:47][CH2:48]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CC=C(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (45.3 mg, 27%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 2H), 7.23-7.41 (m, 7H), 7.03 (d, J=2.0 Hz, 1H), 6.19 (s, 1H), 4.72 (s, 2H), 3.86 (s, 2H), 3.43 (s, 2H), 3.03 (d, J=2.8 Hz, 2H), 2.58-2.65 (m, 2H), 2.44 (br. s., 2H). [M+H] calc'd for C26H25ClN4O, 445. found, 445.