Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[N+:15]([O-])([OH:17])=[O:16].Cl>C(OC(=O)C)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)N(C(C)=O)CC2
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN2
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of 1-acetyl-6-(methyloxy)-2,3-dihydro-1H-indole (2.0 g, 10.5 mmol) in acetic anhydride (150 mL) at 0° C. was added 70% nitric acid (1.03 g, 11.5 mmol) via a dropwise addition. After stirring the reaction at 0° C. for 2 hrs, the contents were allowed to warm to rt, the precipitate was filtered and washed with water. The filtrate was neutralized with 5.0 M NaOH, extracted with ethyl acetate (2×200 mL). The organic layers were combined, adsorbeded onto silica gel and purified by column chromatography (DCM to 2% MeOH/DCM). The derived residue was subsequently dissolved in methanol (200 mL), followed by the addition of 4M HCl(29 mL, 116 mmol). After heating at 60° C. for 3 hrs, the solvent was removed by rotary evaporation, the residue redissolved in THF (300 mL), washed with saturated NaHCO3 (300 mL) and the aqueous layer was extracted with THF (200 mL). The combined organic layers were filtered through a cotton plug, concentrated under reduced pressure, and placed under high vacuum for several hours to give 6-(methyloxy)-5-nitro-2,3-dihydro-1H-indole (1.1 g, 54% over two steps). ESIMS (M+H)+=195. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90 (t, J=8.42 Hz, 2 H) 3.58 (t, J=8.52 Hz, 2 H) 3.75-3.79 (m, 3 H) 6.10 (s, 1 H) 7.14 (s, 1 H) 7.65 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH3:17])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:18]([N:16]([CH3:17])[CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])=[CH:12][CH:11]=3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)C2c3ccccc3CCc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCN(C)C2c3ccccc3CCc3ccccc32)cc1)C(=O)O

Procedure:
3-(4-[2-([10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]-methyl-amino)-ethoxy]-phenyl)-2-ethoxypropanoic acid ethyl ester (example 10)(1.5 g, 3.07 mmol) was dissolved in ethanol (20 ml) and 20% sodium hydroxide (2 ml) was added. After 6 days ethanol was evaporated in vacuo, water (50 ml) and acetic acid (2 ml) were added and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue (1.4 g) was dissolved in acetone and neutralized with solution of hydrogen chloride in diethyl ether. The solvents were evaporated and the residue was triturated with diethyl ether yielding 1.15 g (74%) of the title compound as amorphous solid (hemihydrate). 1H NMR (250 MHz, DMSO-d6) δ10.50 (bs, 1H); 7.60 (bs)+7.10-7.50 (m, 10 H), 6.87 (d, J=7.9 Hz, 2H), 5.84 (bd, J=7.0 Hz, 1H), 4.49 (bs, 2H), 4.00 (t, J=5.6 Hz; +bm, 3H), 3.30-3,60 (m+m, 4H), 2.80-3.10 (s+bm, 7H), 1.07 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]1(=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCCl>[C:8]([CH:16]1[C:15](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:24])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)C1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Yield: 63 %

Procedure:
A mixture of 4-dimethylaminopyridine (664 mg, 5.44 mmol), triethylamine (7.6 ml 54.56 mmol), acetic anhydride (6.2 ml, 65.48 mmol in dry 1,2-dichloroethane (60,ml) was stirred at −20° C. and a solution of 1,3-indanedione (7.96 g, 54.56 mmol) in 1,2-dichloroethane was added dropwise in 1.5 h. The reaction mixture was stirred for 30 min, then washed with 10% hydrochloric acid (80 ml) and twice with water (80 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from methyl-tert-butylether (50 ml) to give 2-acetyl-1,3-indanedione 38(6.5 g 63%). Rf 0.27 (hexane-ethylacetate-acetic acid 20-5-0.5) MS C11H8O3 m/z (%) 189 [M+H]+ (100), 166 (72), 104 (20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:15]1(=O)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:13][O:14][C:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=C1CCC(=O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(-c3ccc(Cl)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of [2-(4-Chloro-phenyl)-thiazol-5-yl]-methanol (2 g, 8.8 mmol) in anhydrous THF (50 ml), at 0° C., under an atmosphere of nitrogen was added cyclopentane-1,3-dione (1.12 g, 11.4 mmol), followed by triphenylphosphine (2.99 g, 11.4 mmol). Diisopropylazodicarboxylate (2.2 ml, 11.4 mmol) was then added dropwise over a period of 5 minutes and the reaction allowed to warm to room temperature and stirred for 2 hours. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography to give 3-[2-(4-Chloro-phenyl)-thiazol-5-ylmethoxy]-cyclopent-2-enone (2.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]4OCC[O:21]4)[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][CH2:27][OH:28].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH:20]=[O:21])[N:12]([CH2:26][CH2:27][OH:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCBr
Reactant: Clc1ccc(-c2nc(-c3cccc(C4OCCO4)c3)n[nH]2)cc1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: O=Cc1cccc(-c2nc(-c3ccc(Cl)c(Cl)c3)nn2CCO)c1
Temperature: 25 °C

Procedure:
To a solution of 5-(3,4-Dichloro-phenyl)-3-(3-[1,3]dioxolan-2-yl-phenyl)-1H-[1,2,4]triazole (mixture of tautomers) (400 mg, 0.31 mmol) in acetonitrile (5 ml) was added 2-bromoethanol (156 μl, 2.21 mmol) and BEMP on poystyrene resin support (2.3 mmol/g, 960 mg). This mixture was shaken at r.t. until the starting material had been consumed (5 d), then aminomethyl polystyrene (1.1 mmol/g, 147 mg) was added and the mixture shaken for a further 2 h at r.t. The mixture was then filtere, washed with acetonitrile and evaporated to afford an isomeric mixture of alkylated acetals which were chromatographically separated over SiO2 (Merck 230-400 Mesh) eluting with EiOAc/nHexane (1:4). The purified isomer was dissolved in THF (3 ml) and treated with 4N HCl (0.3 ml) at r.t. for 3 h, then the mixture was adjusted to pH 9 with NaHCO3, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried, filtered and evaporated to afford the title aldehyde as a off white semi-solid (33 mg, 9% yield), MS: m/e=361 (M+H+). The position of alkylation on the triazole ring was assigned by 1H-NMR, nOe spectroscopy.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([I:26])[CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[O:27][CH3:28])[CH2:2][CH3:3].ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([I:26])[CH:17]=3)[N:12]=2)=[CH:7][C:6]=1[O:27][CH3:28])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1OC
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1OC
Yield: 80 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 80% yield, as creamy solid. 1H-NMR (CDCl3) 8.48 (d, 1H, J=1.98 Hz); 8.04 (dd, 1H, J=8.46, 1.98 Hz); 7.7 (dd, 1H, J=8.43, 2.01 Hz); 7.65 (d, 1H, J=1.95 Hz); 7.07 (d, 1H, J=8.49 Hz); 6.97 (d, 1H), J=8.46 Hz); 5.63 (s, 1H); 4.06 (t, 2H, J=6.8 Hz); 4.02 (s, 3H); 1.94-1.87 (m, 2H); 1.06 (t, 3H, J=7.41 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C@H:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH2:18][OH:19])[CH:13]=[CH:12][C:11]=2[N+:27]([O-])=O)[CH:5]=1)[CH3:2].[CH2:30](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:15][C:14]([NH:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)[CH2:18][OH:19])=[CH:13][CH:12]=[C:11]3[N:27]=[CH:30]2)[CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCOc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](CO)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
(2R)-2-({6-[(5-ethoxy-1H-pyrazol-3-yl)amino]-5-nitropyridin-2-yl}amino)-2-(5-fluoropyridin-2-yl)ethanol (Intermediate 27, 0.2 g) was dissolved into ethanol (20 mL) with Pd—C (50 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.06 g of the title compound MS (electrospray): 384 (M+1) for C18H18FN7O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.20 (d, 1H) 8.15 (s, 1H) 7.50 (d, 1H) 7.30 (dd, 1H) 6.40 (d, 1H) 5.85 (s, 1H) 5.00 (m, 1H) 4.00 (d, 2H) 3.80 (m, 2H) 1.00 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:9][C:5]1[N:4]=[C:3]([CH:10]=[N:19][NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([NH2:1])=[N:7][C:6]=1[Cl:8]
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: Nc1nc(Cl)c(Cl)nc1C=NNc1ccccc1

Procedure:
0.96 gram (0.005 mole) of 3-amino-5,6-dichloropyrazinaldehyde, 0.54 gram (0.005 mole) of phenylhydrazine and 20 milliliters of ethanol were heated with stirring and refluxed for 10 minutes to obtain a 5,6-dichloro-3-[(2-phenylhydrazono)methyl]pyrazinamine product as a solid. The reaction mixture was allowed to cool and the solid product recovered by filtration and recrystallized from ethanol to obtain 0.71 gram (50 percent yield) of purified product as yellow flakes, m.p. 277°-278° C. (dec.). Elemental analyses were as follows:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCNCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a mixture of β-alanine ethyl ester hydrochloride (2.69 g, 17.5 mmol), benzaldehyde (1.68 mL, 16.6 mmol) and sodium sulfate in DCM (30 mL) was added diisopropylethylamine (3.35 mL, 19.3 mmol) and the resulting mixture stirred at ambient temperature for 4 hours. The reaction mixture was filtered and the filtrate concentrated under vacuum to a clear oil. The oil was re-dissolved in methanol (30 mL) and cooled to 0° C., and then sodium borohydride (662 mg, 17.5 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated under vacuum and the resulting residue dissolved in DCM and washed with 10% aqueous citric acid, then dried over sodium sulfate and concentrated under vacuum to afford 2.45 g (71%) of 3-benzylamino-propionic acid ethyl ester as a clear oil. LCMS (Method I, ESI): RT=1.49 and 0.31 min, m+H=208.3; 1H NMR (400 MHz, CDCl3) δ: 7.32 (s, 3H), 7.25 (m, 2H), 4.14 (q, 2H), 3.68 (s, 2H), 2.90 (t, 2H), 2.55 (m, 2H), 1.25 (t, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](OC)[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].O.P([O-])(O)(O)=[O:21].[Na+].P(=O)(O)(O)O.S(=O)(=O)(O)O>O.O1CCOCC1>[OH:21][CH:3]1[CH2:4][C:5](=[O:1])[C:6]([CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: COC(=O)CCCC#CCC(OC)c1ccco1
Reactant: O=P([O-])(O)O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCC#CCC1=CC(O)CC1=O
Temperature: 50 °C
Yield: 72 %

Procedure:
A stirred solution of 25.0 g of methyl 8-(2-furyl)-8-methoxy-5-octynoate, 5.52 g of sodium dihydrogen phosphate monohydrate, 45.6 g of 86% phosphoric acid, 300 ml of dioxane and 200 ml of water was heated under reflux for 44 hours. The resulting solution, which contained a mixture of the 3- and 4-hydroxy isomers, was cooled to 50° C. and treated dropwise with 15 ml of concentrated sulfuric acid. This solution was stirred under reflux for 12 hours, cooled and partitioned with brine and ether. The organic layer was separated, washed with brine, dried and concentrated. The resulting oil was chromatographed on a silica gel column with chloroform progressively enriched in ether. The appropriate fractions were combined and concentrated, giving 6.4 g of the desired product which was recrystallized from ether, giving tan crystals, mp 65°-71° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH:23]1[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH2:27][CH2:28][CH:23]([C:15]2[N:14]([CH2:13][CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc3ccccc3n2CCN2C(=O)c3ccccc3C2=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCn1c(C2CCCNC2)nc2ccccc21

Procedure:
tert-Butyl 3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (129A) (4.36 mmoles max, crude mixture) was added to a 20 mL scintillation vial equipped for stirring. CH2Cl2 (3 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir at room temperature for 72 hrs. The reaction was concentrated and dried in-vacuo affording 2-(2-(2-(piperidin-3-yl)-1H-benzo[d]imidazol-1-yl)ethyl)isoindoline-1,3-dione (129B) as a mixture that was used without further purification. ESI-MS: m/z 375.3 (M+H)+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][C:22]([C:25](O)=[O:26])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62](=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([NH:70][C:25]([C:22]2[N:23]=[CH:24][N:20]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=2)=[O:26])=[CH:68][CH:69]=1)=[O:71]
Reactant: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(N)cc2)c(=O)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(=O)c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (51 mg, 0.65 mmol) in N,N-dimethylformamide (0.8 mL) at 25° C. was treated with 1-hydroxybenzotriazole hydrate (19.3 mg, 0.14 mmol) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (54 mg, 0.14 mmol). The resulting mixture was cooled to 0° C. and then treated with the hydrochloric acid salt of N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-(4-amino-phenyl)-acetamide (62 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.65 mmol). The reaction was stirred at 0° C. for 1 h and then at 25° C. for 4.5 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×15 mL) and a saturated aqueous sodium chloride solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–00 mesh, 93:7 dichloromethane/methanol) afforded 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (4-{[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-amide (67.9 mg, 68%) as a pale yellow solid: FAB-HRMS m/e calcd for C45H41N8O4F (M+Na)+ 799.3133, found 799.3113.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.O>[Si:26]([O:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC1CC(O)CNC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CNC1=O
Reaction time: 15 h
Yield: 85.8 %

Procedure:
To a stirred solution of compound 1C (0.355 g, 1.54 mmol) in 5 mL of DMF at room temperature was added imidazole (401 mg, 5.89 mmol) and then t-butyldimethyl chlorosilane (401 mg, 2.31 mmol). After 15 h, the reaction mixture is diluted with 25 mL water and extracted four times with 20 mL portions of ether. The combined organic extracts were washed three times with water, once with saturated NaCl. The organic layer was dried over MgSO4, and then filtered and evaporated under reduced pressure. Purification by silica gel chromatography (2:1 EtOAc/CH2Cl2) provided the title compound (455 mg, 86%) as a white solid. MS [M+H]+: found 345.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[NH:21]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=2)=[N:2][N:23]=[N:22]1
Reactant: N#Cc1ccc(Oc2ncccc2C(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Oc1ccc(-c2nnn[nH]2)cc1
Reaction time: 24 h
Yield: 29.2 %

Procedure:
A mixture of 14.5 g of 2-(4-cyanophenoxy)nicotinic acid, 3.97 g of ammonium chloride, 4.96 g of sodium azide and 120 ml of dimethylformamide is allowed to stand at 100° C to 110° C for 24 hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated. To the residue is added a dilute hydrochloric acid, and the crystals are filtered off and recrystallized from methanol to give 5 g of 2-[4-(5-1H-tetrazolyl)phenoxy]-nicotinic acid melting at 225° C to 230° C with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](OC)=[O:11].O.O.[I-].[Li+].[BH4-].[Na+].Cl>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][OH:11]
Reactant: CCCCC(C(=O)OC)c1ccc(Br)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CCCCC(CO)c1ccc(Br)cc1Br
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 16.5 parts of methyl 2,4-dibromo-α-butylbenzeneacetate, 11.5 parts of lithium iodide dihydrate and 180 parts of acetonitrile is stirred till all solid enters solution. Then there are added portionwise 3.6 parts of sodium borohydride. Upon completion, the whole is heated to reflux and stirring is continued overnight at reflux temperature. After cooling, the reaction mixture is acidified with a diluted hydrochloric acid solution and poured onto water. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 15 parts (100%) of 2,4-dibromo-β-butylbenzeneethanol as a residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([O:28][CH3:29])[CH:5]([NH:20]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.Cl>O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([O:28][CH3:29])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@H](OC)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (200 mg, 0.461 mmol) is treated with 4M HCl in dioxane (3 mL). After being stirred at room temperature for 1 h, the reaction mixture is concentrated. The residue is used for a next step without further purification. HPLC retention time=1.26, 1.33 minutes (condition A): MS (m+1)=334.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[NH:15][C:14]([CH3:21])=[C:13]3[C:22]#[N:23])[CH:10]=2)[NH:5][N:4]=1)=[O:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:13]([C:22]#[N:23])=[C:14]([CH3:21])[NH:15][C:16]([CH3:20])=[C:17]3[C:18]#[N:19])[CH:10]=2)[NH:5][N:4]=1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C=O)c3c2)C(C#N)=C(C)N1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(CO)c3c2)C(C#N)=C(C)N1
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a suspension of 4-(3-formyl-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (200 mg, 0.66 mmol) in MeOH was added NaBH4 (50 mg) at rt. After 1 hr, the reaction was diluted with brine, extracted with EtOAc, washed with water, and dried. Concentration followed by purification through flash chromatography afforded 1,4-dihydro-4-[3-(hydroxymethyl)-1H-indazol-5-yl]-2,6-dimethyl-3,5-pyridinedicarbonitrile (100 mg, 50%) as a yellow solid (Cpd. No. 144, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=9.55 (s, 1H), 7.68 (s, 1H), 7.52 (d, 1H), 7.26 (d, 1H), 5.24 (t, 1H), 4.78 (d, 2H), 4.55 (s, 1H), 2.03 (s, 6H) ppm.