Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24](O)=[O:25])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH:30][CH3:31].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:29][N:30]([CH3:31])[C:24]([C:22]1[N:23]=[C:17]2[CH:16]=[C:15]([NH:14][C:12]([C:11]3[N:10]([CH3:27])[N:9]=[CH:8][C:7]=3[C:5]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]2[N:21]=1)=[O:25]
Reactant: CNC
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
A mixture of ethyl 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (example 33, step d) (658 mg, 1.66 mmol) and lithium hydroxide hydrate (139 mg, 3.31 mmol) in methanol (20 ml) and water (5 ml) and tetrahydrofuran (10 ml) was stirred for 6 hours at 60° C. (soluble when heated). The mixture was neutralized using hydrochloric acid 2N (1.655 ml, 3.31 mmol) and the mixture was evaporated affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (776 mg, 77.4%) as a light brown solid which was used in the following reactions. A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (120 mg, 244 μmol), dimethylamine hydrochloride (99.4 mg, 1.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 359 μl, 609 μmol) and diisopropylethylamine (298 μl, 1.71 mmol) in tetrahydrofuran (7 ml) was stirred for 20 hours at 25° C. The solvent was evaporated, the residue was triturated with sodium bicarbonate solution, the precipitated solid was filtered off, washed with water and dried. The material was applied on silicagel and purified by flash chromatography over a 5 g silicagel column using dichloromethane/methanol 5% as eluent affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid dimethylamide (39 mg, 40.4%) as an off-white foam. MS: m/z=397.1 (M+H+)
Reaction SMILES: [OH-].[K+].FC(F)(F)C([N:7]1[CH2:22][CH2:21][C:10]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12](=[O:20])[CH2:11]2)[CH2:9][CH2:8]1)=O.Cl.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>O.CO>[C:33]([N:7]1[CH2:8][CH2:9][C:10]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12](=[O:20])[CH2:11]2)[CH2:21][CH2:22]1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc2N1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)N1CCC2(CC1)CC(=O)Nc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
KOH (0.65 g, 11.5 mmol) in water (3.0 mL) was added to 19b (1.20 g, 3.8 mmol) in methanol (15 mL) and stirred at rt overnight. The reaction was neutralized with conc. HCl (1 mL) and then concentrated. The crude reaction mixture was evaporated from toluene to remove water. The crude amine was taken up in dichloromethane (30 mL) and triethylamine (2.5 mL, 19.2 mmol) and pivaloyl chloride (0.9 mL, 7.7 mmol) were added. This was stirred at rt for 4 h and then water was added to quench the reaction. The aqueous layer was extracted with dichloromethane (3×) and the combined organics were dried (MgSO4), filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on Biotage using EtOAc/Hexanes (50-100%) to give 19c as a white solid (0.91 g, 79%). (M+H)+=301. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (s, 1H); 7.30 (d, J=7.3 Hz, 1H); 7.22 (t, J=7.7 Hz, 1H); 7.08 (t, J=7.6 Hz, 1H); 6.78 (d, J=7.8 Hz, 1H); 4.30 (m, 2H); 3.18 (m, 2H); 2.75 (s, 2H); 1.91 (m, 2H); 1.71 (m, 2H); 1.28 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(I)cc21
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of N-trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (80 mg, 0.19 mmol) in dichloromethane (3 mL) was treated with BBr3 (0.40 mL of a 1.0M solution in CH2Cl2, 0.40 mmol) and stirred overnight at 20 C. The excess BBr3 was quenched with water and the product mixture was diluted with ether (20 mL), washed with Na2CO3 (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 74 mg of a white solid. MS calculated for C13H13F3INO2+H: 400, observed: 400.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:3]1[N:2]([CH3:1])[C:6]([S:7]([CH3:8])=[O:19])=[N:5][N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2cccs2)n1C
Solvent: ClCCl
Product: Cn1c(-c2cccs2)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(2-thienyl)-4H-1,2,4-triazole (4.85 g, 2.29×10-2 mole) and CH2Cl2 (170 ml) was added portionwise m-chloroperoxybenzoic acid (4.95 g, 2.29×10-2 mole). After stirring at room temperature overnight the reaction was washed two times with saturated aqueous NaHCO3 and one time with saturated aqueous NaCl, and dried over anhydrous N2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure yielding an off-white solid which was purified by flash chromatography (40% acetone/EtOAc). Crystallization from EtOAc afforded small colorless plates: 2.78 g (53%), mp 10520 -107° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH2:17]([N:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]1[O:6][CH2:5][C:4]([OH:24])=[O:3])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Yield: 93 %

Procedure:
To a solution of compound 21 (2.0 g, 6.15 mmol) in methanol (20 mL) and water (5 mL) was added potassium carbonate (1.3 g, 9.4 mmol) and the resulting reaction mixture was allowed to stir at reflux for 2 hours. The reaction mixture is poured onto 1N HCl and extracted with dichloromethane (3×100 mL) and the combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 1.7 g of 22 as a white solid (1.83 g theoretical, 93% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])[CH:7]=1.[O:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)=[CH:23][C:18]=2[CH2:17][CH2:16][CH2:15]1.BrC1C=CC(Cl)=C(CN)C=1>>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH:27]=[CH:28][C:24]([C:22]3[CH:21]=[CH:20][C:19]4[O:14][CH2:15][CH2:16][CH2:17][C:18]=4[CH:23]=3)=[N:25]2)=[CH:7][C:6]=1[CH2:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)NCc1cc(Br)ccc1Cl
Reactant: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Agent: NCc1cc(Br)ccc1Cl
Product: CC(=O)NCc1cc(-n2ccc(-c3ccc4c(c3)CCCO4)n2)ccc1Cl

Procedure:
N-[(5-bromo-2-chlorophenyl)methyl]acetamide (i.e. the product of Step B) (0.58 g, 2.2 mmol) was reacted with 3-(3,4-dihydro-2H-1-benzopyran-6-yl)-1H-pyrazole (i.e. the product of Step A of Synthesis Example 1) (0.40 g, 2.0 mmol) using a procedure analogous to Step B of Synthesis Example 1 to provide the title product, a compound of the present invention, as a solid (0.09 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:32][CH:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1>C(O)C>[C:40]([O:39][C:37]([N:35]1[CH2:36][CH:33]([NH:32][C:20]([C:17]2[N:16]=[C:15]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11][C:12]([OH:14])=[O:13])[O:19][N:18]=2)=[O:22])[CH2:34]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 80 °C

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (480 mg, 1.42 mmol) and triethylamine (1 ml, 7.18 mmol) in ethanol (8 ml) was treated with tert-butyl 3-amino-1-azetidinecarboxylate (Preparation 78) (300 mg, 1.74 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 18 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (90:10) to afford the title compound contaminated with starting amine. The solid was dissolved in ethyl acetate and washed with hydrochloric acid (0.5M) (2×), water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a sticky foam.
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18]/[C:8](/[CH3:10])=[C:2](/[CH3:1])\[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C(/C)NCc1ccccc1
Reaction time: 6 h
Yield: 104.8 %

Procedure:
A solution of ethyl 2-methylacetoaceate (1-004-01) (115.34 g) and benzylamine (85.73 g) in toluene (1.6 L) was azeotropically dehydrated in an oil bath at 145° C. for 8 h under nitrogen atmosphere. Benzylamine was added to the reaction mixture and the reaction mixture was dehydrated again. After 6 h, the reaction mixture was distilled under atmospheric pressure to remove about 600 mL of the solvent, and evaporated under reduced pressure to give ethyl 3-benzylamino-2-methylcrotonate (1-004-02) (195.66 g).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](I)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[Li+].C([Mg]Cl)(C)C.[O:35]1[CH2:38][C:37](=[O:39])[CH2:36]1>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[C:25]([C:37]4([OH:39])[CH2:38][O:35][CH2:36]4)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(C2(O)COC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (0.973 g, 2.00 mmol) in anhydrous tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride complex (1.30 M solution in tetrahydrofuran, 1.76 mL, 2.20 mmol) at −40° C. The reaction mixture was stirred for 1 hour at −40° C., after which oxetan-3-one (0.432 g, 6.00 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. After quenched with saturated ammonium chloride solution (10 mL), the mixture was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (5 mL); dried over sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title compound as an amorphous solid (0.336 g, 39%): 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.2 Hz, 1H), 6.60 (d, J=12.3 Hz, 1H), 5.01 (d, J=6.9 Hz, 2H), 4.84 (d, J=7.0 Hz, 2H), 3.86 (s, 1H), 3.52 (s, 2H), 2.05-1.94 (m, 3H), 1.78-1.55 (m, 12H), 1.54 (s, 9H).
Reaction SMILES: [C:1](Cl)([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.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH2:35][CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH2:35][CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=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
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCON=C(C(=O)OCC)c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 125.1 %

Procedure:
3.98 g of trityl chloride were slowly added under an inert atmosphere to a mixture of 3.16 g of the product of Step A, 6 ml of dimethylformamide, 12 ml of methylene chloride and 1.89 ml of triethylamine cooled to -15° C. and the mixture stood at 10° C. for 30 minutes and then 3 hours at room temperature. 13 ml of N hydrochloric acid were added to the mixture which was stirred and decanted. The organic phase was washed with N hydrochloric acid, then with water and was extracted with methylene chloride. The extracts were dried and evaporated to dryness to obtain 7.89 g of raw ethyl 2-(2-tritylamino-4-thiazolyl)-2-ethoxyiminoacetate having a syn configuration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.[NH:10]([C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)CCC>[NH:10]([C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CCCCO
Product: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
4-Aminophenol (0.73 g, 7.8 mmol) and concentrated hydrochloric acid (1.30 ml, 7.1 mmol) were added to 4-anilino-5-bromo-2-chloropyrimidine (Method 1; 3.0 g, 7.1 mmol) in n-butanol (30 ml), and the mixture was heated at 100° C. for 12 hours. The solid which precipitated out on cooling was filtered off and washed with n-butanol and diethyl ether to give the product (0.80 g, 32%). MS (MH+): 357, 359.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=1.[C-:20]#[N:21].[Na+].CC(C)=O>C(O)C>[Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:20]#[N:21])[CH:8]=1
Reactant: [C-]#N
Reactant: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: N#CCc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1

Procedure:
The product of Step D, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran is reacted with sodium cyanide by heating to reflux in a solvent mixture of acetone and ethanol. Evaporation provides the desired product, 2-bromo-5-chloro-3-(3-cyanomethylphenyl)benzofuran.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][C:12]=1[NH:19][C:20](=[O:38])[CH2:21][CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl.C(OCC)(=O)C>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[NH:19][C:20](=[O:38])[CH2:21][CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CNS(=O)(=O)CC)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reaction time: 1 h
Yield: 42.5 %

Procedure:
180 μl (1.90 mmol) of ethanesulfonyl chloride and then 213 mg (1.75 mmol) of 4-N,N-dimethylaminopyridine were added to a solution of 700 mg (1.59 mmol) of N-[2-t-butyl-5-(aminomethyl)phenyl]-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 26A) in 15 ml of methylene chloride, whilst cooling in an ice-salt bath, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 38 g of silica gel, using a 3:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 360 mg of the title compound as a foam-like substance.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>CC(C)=O>[CH2:1]([O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OCc2ccccc2)c1
Yield: 873.2 %

Procedure:
160 ml (1.3 mmol) of benzyl bromide and (1.3 mmol) of potassium carbonate are added to a solution of 2 g (1.3 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 20 ml of acetone. The mixture is stirred at reflux for 6 hours and then evaporated. 50 ml of 1N aqueous solution of sodium hydroxide are added and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue obtained is precipitated from 1 heptane/ethyl acetate mixture (95/5). 2.75 g of 2-benzyloxy-4-methoxybenzaldehyde are obtained in the form of a white powder with a yield of 86%.
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:39]([C:41]1[N:42]=[C:43]([C:54]([O-])=[O:55])[N:44]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:45]=1)#[N:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[C:12]([NH:13][C:54]([C:43]3[N:44]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:45]=[C:41]([C:39]#[N:40])[N:42]=3)=[O:55])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1cccnc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1cccnc1C1=CCCCC1
Yield: 69.1 %

Procedure:
A solution of 365 mg (2.10 mmol) of 2-cyclohex-1-enyl-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 1.46 g (3.14 mmol) of PyBroP, 704 mg (2.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 1.09 mL (6.28 mmol) of DIEA at RT for 3 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 615 mg (69%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.86 (br s, 1H), 8.69 (dd, 1H, J=8.0, 1.6 Hz), 8.37-8.34 (m, 1H), 7.78 (s, 1H), 7.22-7.17 (m, 1H), 6.05 (sept, 1H, J=1.6 Hz), 5.93 (s, 2H), 3.68-3.63 (m, 2H), 2.45-2.39 (m, 2H), 2.37-2.30 (m, 2H), 1.91-1.77 (m, 4H), 1.00-0.95 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[CH:34]([F:36])[F:35])=[CH:4][C:5](=[O:26])[N:6]([CH:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[CH:34]([F:36])[F:35])=[CH:4][C:5](=[O:26])[N:6]([CH:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
79 mg (0.15 mmol) of tert-butyl 4-[(2-{5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) (Example 14.1E) were hydrolysed with TFA according to General Method 2. Yield: 54 mg (76% of theory)
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:12]=3[N:35]3[CH2:36][CH2:37][C@H:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccccc2F)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2F)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 10 h

Procedure:
2-Cyclopropyl-7-fluoro-6-(2-fluorophenyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-175) (147 mg, 0.47 mmol) was dissolved in dimethyl sulfoxide (3 ml), then at room temperature, triethylamine (99 μl, 0.71 mmol) and (3S)-3-(dimethylamino)pyrrolidine (78 μl, 0.62 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 10 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[C:5]2=[CH:16][N:17]([CH2:19]C)[N:18]=[C:4]2[N:3]=1.[K+].[Br-]>>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[C:5]2=[CH:16][N:17]([CH3:19])[N:18]=[C:4]2[N:3]=1
Reactant: CCn1cc2c(nc(N)n3nc(-c4ccco4)nc23)n1
Agent: [Br-]
Agent: [K+]
Product: Cn1cc2c(nc(N)n3nc(-c4ccco4)nc23)n1

Procedure:
5-Amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (Compound 35) yield 65%, -yellow solid m.p. 249-250° C. (EtOAc-light petroleum); IR (KBr): 3430-2950, 1680, 1655, 1620, 1550, 1450 cm−1; 1H NMR (DMSO-d6) δ 1.46 (t, 2H, J=7); 4.30 (d, 2H, J=7); 6.72 (m, 1H); 7.18 (m, 1H); 7.93 (bs, 2H); 7.93 (s, 1H); 8.62 (s, 1H).