Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(OC(N1CCC(C(Cl)=O)CC1)=O)C1C=CC=CC=1.COCCN>C(O)C.[Pd]>[CH3:22][O:21][CH2:20][CH2:19][NH:18][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:23]
Reactant: COCCNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: COCCN
Agent: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCNC(=O)C1CCNCC1

Procedure:
1-Benzyloxycarbonyl-4-[N-(2-methoxyethyl)carbamoyl]piperidine [5.76 g, m.p. 85°-86°, Analysis %: C, 63.9; H, 7.5; N, 8.4; Calculated: C, 63.7; H, 7.6; N, 8.8; prepared similarly to Preparation C but using toluene in place of chloroform and starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxyethylamine] in ethanol (75 ml) was hydrogenated over 5% palladium on charcoal at 50 p.s.i./50°. The catalyst was removed by filtration, and the filtrate evaporated to give 4-[N-(2-methoxyethyl)carbamoyl]piperidine as an oil which solidified on standing. I.r. and n.m.r. spectra were consistent with this structure and the product was used in Example 7 without further purification.
Reaction SMILES: [BH4-].[Na+].[OH-].[CH3:4][N+:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[N:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1>C(O)C>[CH3:4][N:5]1[CH2:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:7]=[C:6]1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1
Reactant: COC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)[n+](C)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1=CN=C(NCc2ccc(OC)c(OC)c2)N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 122.6 %

Procedure:
0.170 g (3 eq) of sodium borohydride is added to 0.400 g of 1-methyl-2-veratrylamino-5-methoxycarbonylpyrimidiniumhydroxide dissolved in 50 ml of ethanol. The mixture is stirred under argon at room temperature for three hours. After evaporation of the ethanol, the medium is extracted with dichloromethane and water. The organic phases are washed with a saturated sodium chloride solution and then dried over sodium sulfate. The oil resulting from evaporation of the organic phases, purified on silica gel under medium pressure (eluent: 15% MeOH/CH2 Cl2) gives 467 mg (yield: 98%) of the corresponding 1,6-dihydropyrimidine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[CH3:17][S:18]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Reaction time: 2 h
Yield: 103.1 %

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-(hydroxymethyl)cyclohexyl]carbamate (1.3 g, 5.68 mmol) in dichloromethane (10 mL) was added drop wise with methane sulfonyl chloride (0.52 mL, 6.75 mmol) at 0° C. Triethylamine (1 mL) was then added and the mixture stirred for 2 hours. The reaction mixture was quenched with ice and diluted in dichloromethane. Washed with a saturated solution of NaHCO3 and brine, dried and concentrated in vacuo to provide the title compound as brown solid (1.8 g). MS (M+1): 308.16
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([O:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][N:9]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([O:21][CH:22]([CH3:24])[CH3:23])[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)C(Cc1ccnc(OCCOc2ccc(Cl)cc2Cl)c1)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)OC(Cc1ccnc(OCCOc2ccc(Cl)cc2Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a suspension of ethyl 3-{2-[2-(2,4-dichlorophenoxy)ethoxy]-4-pyridyl}-2-isopropoxypropanoate (24 mg) in methanol (2 mL) was added 5N aqueous sodium hydroxide solution (0.4 mL), and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was diluted with water, and adjusted to pH 5 with 5N hydrochloric acid. After extracting with ethyl acetate (×2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified on a preparative TLC plate to give the title compound as a colorless solid (16 mg).
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[C:7]([CH:16]=[O:17])[C:6]=1[Cl:18])(=O)C.[OH-].[Na+]>CO>[Cl:18][C:6]1[C:5]([OH:4])=[C:10]([O:11][CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[CH:16]=[O:17]
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(Cl)c1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c([N+](=O)[O-])cc(C=O)c(Cl)c1O
Reaction time: 1 h

Procedure:
35.8 g of 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate are dissolved in 300 ml of methanol. After adding 145 ml of 1N sodium hydroxide solution the mixture is stirred at 23° for 1 hour. After evaporation of the methanol, the residue is diluted with ice-water, made acid with 2N hydrochloric acid and extracted twice with 400 ml of ethyl acetate each time. The organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde of m.p. 130°.
Reaction SMILES: [CH2:1]([O:8][C:9]1C=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=C[N:38](CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.P(Br)(Br)Br>>[CH2:1]([O:8][C:9]1[N:38]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Agent: BrP(Br)Br
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1

Procedure:
6-Benzyloxy-3-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one is prepared following preparation 15c from 2.50 g (7.14 mmol) 6-benzyloxy-3-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one (preparation 20a) and 0.67 mL (7.14 mmol) phosphorus tribromide.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][NH2:21])=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C[O-].[Na+].CO>C(OCC)(=O)C.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:30][C:29]([C:28]3[C:23]([NH2:22])=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:21][N:20]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1cccnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ncccc1-c1nnc(Cc2ccc(OCc3ccccc3)cc2)[nH]1
Reaction time: 14 h
Yield: 1.1 %

Procedure:
To a methanol (10 mL) solution of 4-benzyloxy-phenylacetic acid hydrazide (200 mg) described in Manufacturing Example 15-1 were added 2-amino-3-cyanopyridine (92 mg) and 28% sodium methoxide-methanol solution (30 mg), which was stirred for 14 hours under heating and reflux. Water and ethyl acetate were added to the reaction solution, and then the organic layer was extracted. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the titled compound (3 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1.Cl.[NH2:17][CH2:18][C:19]([NH2:21])=[O:20].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])(=[O:12])=[O:11])[CH:9]=1
Reactant: COc1ccc(CCCl)cc1S(=O)(=O)Cl
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CCCl)cc1S(=O)(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(2-chloro-ethyl)-2-methoxy-benzenesulfonyl chloride (5.78 g, 21.5 mmol) is dissolved in dioxane (72 mL). To this solution is added glycinamide hydrochloride (4.75 g, 42.9 mmol) and N,N-diisopropylethylamine (7 mL, 42.9 mmol) with stirring at room temperature for 24 h. The solution is diluted with ethyl acetate (100 mL) and washed with 1 M H3PO4 (2×50 mL), sat NaHCO3, (1×50 mL,) brine (1×50 mL). The organic phase is dried with Na2SO4, filtered and the volatiles concentrated to a white solid. The solid is collected on a buchner by vacuum filtration and washed with ether to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=3[CH3:29])=[C:11]([C:15]([O:17]C)=O)[NH:12]2)=[CH:8][CH:7]=1.O.[NH2:32][NH2:33]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=4[CH3:29])=[N:33][NH:32][C:15](=[O:17])[C:11]=3[NH:12][C:13]=2[CH:14]=1
Reactant: NN
Reactant: COCCOc1ccc2c(C(=O)c3cccc([N+](=O)[O-])c3C)c(C(=O)OC)[nH]c2c1
Solvent: CCO
Solvent: O
Product: COCCOc1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A yellow, homogeneous solution of methyl 6-(2-methoxyethoxy)-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate (1.546 g, 3.75 mmol) and hydrazine hydrate (0.982 mL, 13.13 mmol) in ethanol (55.1 mL) under nitrogen was refluxed overnight. The reaction was cooled to room temperature and concentrated in vacuo. It was dissolved in EtOAc (150 mL) and washed with water (40 mL) and brine (40 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 0-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.7461 g, 1.892 mmol, 50.4% yield) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[C:6]=2[CH:15]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[C:6]=3[CH:15]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: NCCCNc1nsc2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: NCCCNc1nsc2ccc(-c3ccccc3)cc12

Procedure:
A mixture of N1-(5-bromobenzo[d]isothiazol-3-yl)propane-1,3-diamine (100 mg, 0.35 mmol), phenylboronic acid (43 mg, 0.35 mmol), tetrabutylammonium bromide (115 mg, 0.35 mmol), sodium carbonate (110 mg, 1.05 mmol) and palladium (II) acetate (1 mg) in water (3 mL) was microwaved at 150° C. for 5 min. The reaction was diluted with methylene chloride and the mixture was washed successively with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product, N1-(5-Phenylbenzo[d]isothiazol-3-yl)propane-1,3-diamine, was carried forward without further purification. MW=238 confirmed by LC-MS, tr=2.73 min (Method B) MH+=237-239
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CO>C(Cl)(Cl)Cl>[Br:1][CH2:15][C:14]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (35 ml) in chloroform (150 ml) was added dropwise over 3 hours to a stirred mixture of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (150 g), chloroform (50 ml) and methanol (235 ml). When the addition was complete, the mixture was stirred at ambient temperature for a further 3 hours, then it was diluted with ice-cold water (750 ml). The product was extracted into dichloromethane (3×200 ml), and the combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (3×100 ml) and water (100 ml), dried (MgSO4), and the solvents removed in vacuo, to leave 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=1[NH2:29])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:16].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:25][C:20]1[CH:19]=[C:18]([NH:17][C:15]([C:14]2[CH:26]=[CH:27][C:28]3[N:29]=[C:4]([C:3]4[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=4[Cl:1])[NH:11][C:12]=3[CH:13]=2)=[O:16])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cccc(Cl)c1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-6-methylbenzaldehyde (107 mg) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (Example 5-1, step 6) (160 mg) in DMSO (1.5 mL) was added Yb(OTf)3 (80 mg). The solution was stirred at room temperature for 18 h then an additional 40 mg of Yb(OTf)3 was added the mixture was stirred at 70° C. for 24 h. The mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography using hexanes/ethyl acetate (5:1) and the product was isolated as a foam. MS (m/z) 390 (M+1), retention time=1.66 min, Method 10.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2)#[N:2]>O1CCCC1>[NH2:2][CH2:1][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2
Reactant: N#CC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Product: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Yield: 57.1 %

Procedure:
N-(5-Cyano-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide(4.85 g, 15.5 mmol) was dissolved in 100 mL of dry tetrahydrofuran (THF), and the mixture was stirred while cooling in an ice bath. Borane-THF complex (40 mL, 1.0M) was added to the cold, stirring solution, and the reaction mixture was stirred under nitrogen for 15 hours at room temperature. The reaction mixture was quenched by addition of 20 mL of 20% HCl and 60 mL of methanol. The solvents were removed under reduced pressure, and the aqueous residue was treated dropwise with 1M NaOH until basic. The residue was extracted with EtOAc and the combined organic layers were dried (MgSO4) and evaporated. The crude product was acidified with dilute HCl in EtOH and recrystallized from EtOAc to yield 2.8 g of N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide as a hydrochloride salt. MS: 317 (M+H)+.
Reaction SMILES: CC(C)(C)C([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)=O>FC(F)(F)C(O)=O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][NH2:5])=[O:15])=[CH:9][CH:10]=1
Reactant: CC(C)(C)C(=O)NNC(=O)c1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (10 ml) was added to 4iodo-benzoic acid N′-(2,2-dimethyl-propionyl)-hydrazide (Intermediate 13) (1 g, 2.76 mmol) and stirred at room temperature for 2 hours. The trifluoroactic acid was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The desired product was obtained as a white solid (0.55 g, 2.1 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][C@@H:26]4[C@@H:30]([OH:31])[CH2:29][CH2:28][NH:27]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][C@@H:26]4[C@@H:30]([OH:31])[CH2:29][CH2:28][N:27]4[CH3:44])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OC[C@H]5NCC[C@@H]5O)ccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OC[C@@H]5[C@@H](O)CCN5C)ccn34)c12
Reaction time: 0.5 h

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(((2R,3S)-3-hydroxypyrrolidin-2-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0095 mmol; Example 38 in MeOH (1 mL) was added HCHO (as a 35% aqueous solution) (7.7 mg, 0.095 mmol) and NaBH(OAc)3 (10 mg, 0.048 mmol). The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. Purification by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) provided the final product (3 mg). MS (ES+APCI) m/z=540 (M+H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=2)[CH2:5][CH2:4]1>O1CCCC1.CO>[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=2)[CH2:5][CH2:4]1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCC2CC2)c1
Yield: 78 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 4.8 eq) of sodium hydroxide and methyl 3-[2-cyclopropylmethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 426 mg of 3-[2-cyclopropylmethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=64° C.). Yield=78% over the two steps
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.C(=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)=[CH:35][CH:36]=1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2ccc(OC)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 4-anisaldehyde (16.7 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(4-Methoxybenzyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 10 as a colorless oil (18.7 mg, 59%). LRMS 366.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:24]Br>>[CH3:20][C:21]1[CH:28]=[C:27]([CH:26]=[C:23]([CH3:24])[CH:22]=1)[CH2:29][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(C)cc(C)c2)c(=O)[nH]c1=O
Yield: 67.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (265 mg, yield: 67.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[N:24]=[CH:25][NH:26][C:27](=[O:29])[CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:34]C([Si](Cl)(C)C)(C)C.[H-].[Na+].CI.[N+](CC)(CC)(CC)CC.[F-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[N:24]=[CH:25][N:26]([CH3:34])[C:27](=[O:29])[CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2cc(=O)[nH]cn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Agent: [H-]
Solvent: CI
Product: C[C@@H](c1ccc(-c2cc(=O)n(C)cn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with (i) TBSCl, (ii) NaH, MeI and (iii) Et4NF. LC-MS Method 2 tR=0.87, m/z=452.15; 1H NMR (CD3OD) 1.20 (m, 2H), 1.49 (d, 3H), 1.83 (m, 2H), 2.15 (m, 1H), 2.22-2.41 (m, 2H), 3.07 (m, 1H), 3.38 (t, 2H), 5.50 (m, 1H), 6.88 (d, 1H), 7.01 (m, 4H), 7.21 (m, 2H), 7.79 (m, 2H), 7.90 (s, 1H).