Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][SH:18])[CH3:14].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:15][C:16]([C:17]1[S:18][C:2]2[CH:3]=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[OH:10])=[O:19])[CH3:14]
Reactant: CCOC(=O)c1cnccc1Cl
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2ccncc2c1O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a cooled (5° C.) stirred solution of ethyl 4-chloro-nicotinate (1.55 g, 8.4 mmol) and mercapto-acetic acid ethyl ester (2.6 ml, 23.4 mmol) in anhydrous DMF (30 ml), under an argon atmosphere, was added sodium hydride (21.7 mmol; 60% dispersion in oil, 868 mg) in portions over 20 minutes. Stirring was continued at 5° C. for 10 minutes, followed by 1.5 hours at room temperature. The reaction mixture was then quenched by the addition of water (5 ml), acidified by the addition of acetic acid (1 ml), and subsequently concentrated to provide a residue. The residue was partitioned between ethyl acetate (150 ml) and water (100 ml). The layers were separated and aqueous phase was extracted with DCM (100 ml). The combined organic phase was dried over sodium sulphate, filtered and evaporated to give a solid. The solid was triturated with diethyl ether:pentane (1:1, 15 ml) to afford the title compound as a yellow solid (1.5 g, 81%). LCMS (method B): RT=2.21 min, M+H+=224.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from Intermediate 2 and (3-acetylphenyl)boronic acid (Sigma Aldrich Company Ltd.) using the method of Example 1; mass spectrum (API+): Found 358 (MH+), C20H23NO3S requires 357; 1H-NMR (400 MHz, CDCl3): 1.42 (6H, d, J=7 Hz), 2.66 (3H, s), 2.99 (2H, m), 3.20 (1H, m), 3.35 (2H, m), 4.29 (2H, m), 7.32 (1H, m), 7.46 (2H, m), 7.56 (1H, m), 7.76 (1H, m), 7.92 (1H, m), 8.14 (1H, m).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[O:4].[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O>[F:25][C:2]([F:1])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:21][CH:22]=1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (18.98 g, 54.0 mmol) in anhydrous DMF (200 ml) was added to a suspension of NaH (2.592 g, 108.0 mmol) in anhydrous DMF (400 ml) at rt under N2. After stirring at rt for 1 hr, a solution of 1-(2-chloroethyl)pyrrolidine hydrochloride (9.184 g, 54.0 mmol) in anhydrous DMF (200 ml) was added and the reaction mixture was heated to 100° C. for 4 hr. The reaction mixture was cooled to rt, diluted with H2O (2000 ml), and extracted with EtOAc (4×250 ml). The combined extracts were washed with H2O (3×250 ml), dried over MgSO4, and concentrated in vacuo to give 21.15 g of yellow oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2) gave 10.503 g (43% yield) of yellow oil.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([NH:10][C:11](=[O:22])[C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=3[CH3:21])[CH:8]=2)[NH:3][CH:2]=1>CO.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:21])=[C:12]([CH:17]=1)[C:11]([NH:10][C:7]1[CH:8]=[C:9]2[N:1]=[CH:2][NH:3][C:4]2=[N:5][CH:6]=1)=[O:22]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc2[nH]cnc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)cc1C(=O)Nc1cnc2[nH]cnc2c1
Reaction time: 3 h

Procedure:
0.75 g of N-(3H-Imidazo[4,5-b]pyridin-6-yl)-2-methyl-5-nitro-benzamide in 20 ml methanol were hydrogenated over 10% palladium on charcoal at room temperature and atmospheric pressure. After 3 hrs conversion was complete as judged by HPLC/MS and the catalyst was filtered off. The filtrate was evaporated and the residue was used without further purification for the next steps.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>O.C(Cl)(Cl)Cl>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2cccc(CCNC(=O)CCCCl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.02 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride is dissolved in a water/chloroform mixture. Potassium carbonate is added and the mixture is agitated for 15 minutes in an ice bath. 0.022 mol of 4-chlorobutyryl chloride is then added dropwise. The agitation is maintained for half an hour at room temperature; then the chloroform phase is dried, and the residue is recrystallized in a toluene/cyclohexane mixture (1:1).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:18]1[CH2:30]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:18]1[CH2:30][F:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.2 h
Yield: 34.2 %

Procedure:
To a stirred solution of diethylaminosulfur trifluoride (0.89 g, 5.53 mmol) in DCM (4 mL) at −78° C. under nitrogen was added a solution of (1,4-dibenzyl-piperazin-2-yl)-methanol (1.364 g, 4.61 mmol) in DCM (6 mL), dropwise over 0.2 h (internal temperature <−65° C.). Resulting solution was stirred at −78° C. for 1 h then warmed slowly to 20° C. and stirred thus for 16 h. The mixture was cooled in an ice-methanol bath then ice was added with stirring. The mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with DCM (3×30 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-25% diethyl ether in 40-60 petroleum ether) gave the title compound (0.471 g) as an oil. 1H NMR (CDCl3): 7.38-7.23 (10H, m), 4.93-4.64 (1H, m), 4.55 (1H, ddd), 4.03 (1H, d), 3.52 (3H, d), 2.91 (1H, d), 2.84-2.64 (2H, m), 2.56 (1H, s), 2.48-2.21 (3H, m).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:18])=[C:14]([CH2:16][OH:17])[CH:15]=1.N1C=CN=C1.[NH4+].[Cl-]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:18])=[C:14]([CH:15]=1)[CH2:16][O:17][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
TBDMS-Cl (10.6 g, 66.7 mmol) was added to a sol. of (5-bromo-2-chloro-phenyl)-methanol (12.8 g, 55.6 mmol) and imidazole (9.42 g, 138 mmol) in DMF (190 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and aq. sat. NH4Cl was added. The mixture was extracted with heptane (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 1:49) yielded the title compound (18.0 g, 96%). LC-MS: tR=1.22 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1.[OH-].[Na+].CN(C)C=O>O>[C:11]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[O:15][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(OCc2ccc(C#N)cc2)cc(C(C)(C)C)c1
Temperature: 120 °C
Yield: 12.4 %

Procedure:
A mixture of 5.1 g (25 mmole) of 3,5-di-t-butylphenol, 4.2 g (25 mmole) of alpha-bromo-p-tolunitrile, 1.0 g (25 mmole) sodium hydroxide and 75 ml of dimethylformamide was heated at 120° C. for about sixteen hours. The mixture was poured into 700 ml of water to give an oil which rapidly solidified. The solid was collected, rinsed with water, and recrystallized once from ethanol and twice from hexane to give 1.0 g of white crystalline 4-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile, m.p. 118°-121° C. Analysis: Calculated for C22H27NO: %C, 82.2; %H, 8.5; %N, 4.4; Found: %C, 82.7; %H, 8.6; %N, 4.1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[N:30]=[C:29]([NH2:31])[S:28][N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:31][C:29]2[S:28][N:27]=[C:26]([CH3:25])[N:30]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nsc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Product: Cc1nsc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3)cc2=O)n1
Yield: 12.1 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19) and 3-methyl-[1,2,4]thiadiazol-5-ylamine afforded 3-cyclopentyl-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionamide as a white solid (23.8 mg, 12.1%); ES+-HRMS m/e calcd for C21H23N5O3S [M+H+] 426.1595, found 426.1594. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.77 (m, 9H), 2.03 (m, 1H), 2.27 (m, 1H), 2.44 (s, 3H), 5.57 (dd, J=4.5, J=10.6 Hz, 1H), 5.76 (d, J=2.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 2H), 8.17 (d, J=2.8 Hz, 1H), 13.26 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18]2)=[O:16])=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](N)C2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)N2CCC[C@@H](NC(=O)c3ccccc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
Benzoyl chloride (0.15 g) was added to the aqueous solution of (R)-1-(p-methylbenzoyl)-3-aminopiperidine obtained in Example 13 (amount: 3 g), and the pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours. Chlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto, and then the mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.33 g, yield: 73%).
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[O:14][CH:15]=1.[CH:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[OH:36][CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7]#[C:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[O:14][CH:15]=1
Reactant: CCCCCCCCCCCC=O
Reactant: CC[Si](CC)(CC)c1cc(CCC=C(Br)Br)co1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(O)C#CCCc1coc([Si](CC)(CC)CC)c1
Reaction time: 2 h

Procedure:
n-Butyl lithium (a 2.5M solution in tetrahydrofuran; 0.42 ml, 1.04 mmol) was added dropwise to a solution of 4-(4,4-dibromo-3-butenyl)-2-triethylsilylfuran (200 mg, 0.51 mmol) in tetrahydrofuran (8 ml) at -78° under argon. After 2 hours, a solution of 1-dodecanal (102 mg, 0.56 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 14 hours, while the cooling bath attained room temperature. The mixture was quenched with water and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave a residue, which was purified by a silica column with 15% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH2:12][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
With cooling with ice, 4.00 g (0.10 mol) of 65% oily sodium hydride was added to a DMF solution (200 ml) of 7.51 g (0.05 mol) of 4′-methoxyacetophenone and 8.77 g (0.06 mol) of diethyl oxalate, and stirred overnight at 100° C. in a nitrogen atmosphere. Aqueous 2 N hydrochloric acid solution was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water, dried and then concentrated under reduced pressure. Thus concentrated under reduced pressure, the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 12.52 g (yield: 100%) of ethyl 4-(4-methoxyphenyl)-2,4-dioxobutyrate as a yellow solid.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].CN(C=O)C.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][OH:22]>C1COCC1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][O:22][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CBr
Reactant: OCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)COCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 4.80 g, 120 mmol) in THF, at 0° C., was added a THF solution (15 ml) of bromoacetic acid (6.11 g, 44 mmol). Mixture was stirred at room temperature 0.5 hr, then a DMF solution (15 ml) of alcohol 1 (5.84 g, 40 mmol) was added dropwise. Mixture was stirred at room temperature for 17 hrs then quenched with H2O and extracted twice with ether. Aqueous layer was acidified to pH 2-3 and extracted with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated to give pure compound 2 as a pale yellow oil (6.93 g, 85%) used for next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)Cl>[Br:22][C:6]1[CH:5]=[C:4]2[C:9](=[N:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: c1cnc2c(c1)CCN2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Brc1cnc2c(c1)CCN2
Temperature: 25 °C

Procedure:
The bromination may be carried out by any of the procedures known for such a reaction. The bromination may be carried out, for example, by mixing 7-azaindoline, p-toluene sulphonic acid monohydrate and 1,3-dibromo-5,5-dimethylhydantoin in methylene chloride and stirring the mixture at for example ambient temperature for a period of time, for example 3 hours. Extraction and purification gives 5-bromo-7-azaindoline.
Reaction SMILES: C([O:5][C:6](=[O:13])[CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])(C)(C)C.C(O)C.O.[NH4+].[OH-]>>[C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:13])=[O:5])(=[O:12])[CH3:11]
Reactant: CC(=O)NCCC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NCCC(=O)O
Yield: 116.4 %

Procedure:
Utilizing the procedure for converting 40a to 41a, 127 (0.10 g, 0.19 mmol) gave 128 (29 mg, 39%) as a fluffy solid after flash chromotography (silica, 10:1.2:1.2 ethanol/H2O/NH4OH).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][C@H:18]1[O:58][C@@H:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C@H:31]2[CH2:55][CH2:54][C@@:53]3([CH3:56])[C:33](=[CH:34][CH2:35][C@@H:36]4[C@@H:52]3[CH2:51][CH2:50][C@@:49]3([CH3:57])[C@H:37]4[CH2:38][CH2:39][C@@H:40]3[C@H:41]([CH3:48])[CH2:42][CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:32]2)[C@H:21]([OH:59])[C@@H:20]([OH:60])[C@H:19]1[OH:61].[C:62](O)(=[O:80])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]/[CH:70]=[CH:71]\[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>C(Cl)(Cl)Cl>[C:62]([NH:16][CH2:17][C@H:18]1[O:58][C@@H:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C@H:31]2[CH2:55][CH2:54][C@@:53]3([CH3:56])[C:33](=[CH:34][CH2:35][C@@H:36]4[C@@H:52]3[CH2:51][CH2:50][C@@:49]3([CH3:57])[C@H:37]4[CH2:38][CH2:39][C@@H:40]3[C@H:41]([CH3:48])[CH2:42][CH2:43][CH2:44][CH:45]([CH3:46])[CH3:47])[CH2:32]2)[C@H:21]([OH:59])[C@@H:20]([OH:60])[C@H:19]1[OH:61])(=[O:80])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]/[CH:70]=[CH:71]\[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CN)[C@H](O)[C@H](O)[C@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NC[C@H]1O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 3 h
Yield: 55.1 %

Procedure:
A solution of dicyclohexylcarbodiimide (106 mg.) in chloroform (5 ml.) is added to a solution of 6-(5-cholesten-3β-yloxy)hexyl 6-amino-6-deoxy-1-thio-β-D-galactopyranoside (309 mg.) and oleic acid (131.5 mg.) in chloroform (20 ml.). After 3 hours at room temperature, the reaction mixture is filtered and washed with water (20 ml.) and methanol (25 ml.). The organic layer is dried and evaporated in vacuo to a syrup which is crystallized from methanol to give the title compound (238 mg., 55%); m.p. 160°-163° C., [α]D27 -5.0° C. (C 1.0, chloroform).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:3]=1.[C:19]([CH2:22][C:23](=O)[CH3:24])(=O)[CH3:20]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[C:3]3[C:2](=[N:1][C:19]([CH3:20])=[CH:22][C:23]=3[CH3:24])[N:7]([CH:8]3[CH2:10][CH2:9]3)[C:6](=[O:11])[CH:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cc(-c2cccc(Cl)c2)cc(=O)n1C1CC1
Product: Cc1cc(C)c2c(-c3cccc(Cl)c3)cc(=O)n(C3CC3)c2n1

Procedure:
Starting compounds: 6-amino-4-(3-chlorophenyl)-1-cyclopropyl-2(1H)-pyridone and acetylacetone
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc2oc(-c3ccccc3)cc2c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of 2-phenylbenzofuran-5-amine (210 mg, 1.00 mmol) in pyridine (5 mL) at room temperature was added isobutyryl chloride (120 μL, 1.10 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate solution followed by saturated aqueous potassium carbonate solution. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:2 v/v) to afford 134 mg (48%) of the title compound (LCMS RT=6.81 min, MH+ 280.1)
Reaction SMILES: ClCCl.[C:4]([C:6]1[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]([O:20]C)[C:9]([F:19])=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]=1[CH3:12])#[N:5].BrB(Br)Br.O>[Cl-].[Na+].O>[C:4]([C:6]1[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:25])[CH3:27])=[C:8]([OH:20])[C:9]([F:19])=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]=1[CH3:12])#[N:5]
Reactant: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(F)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A dichloromethane (60 ml) solution of N-(5-cyano-2-fluoro-3-methoxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-70) (2.02 g, 5.93 mmol) was cooled at −78° C., a dichloromethane solution of 1 N tribromoborane (17.8 ml, 17.8 mmol) was dropwise added, followed by stirring at −78° C. for 15 minutes. Afterwards, this was heated up to −12° C., and stirred for 30 minutes. The reaction liquid was put into cold water (100 ml), saturated brine (50 ml) was added, the intended product was extracted with ethyl acetate (300 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (1.70 g, 88%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C:23]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH2:28]([C:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24](=[O:25])[NH:26][CH3:27])[CH2:30][CH3:31])[CH3:29]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=425.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1F

Procedure:
From 3-chloro-2-fluorobenzoic acid and (4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=433.2, tR (minutes, Method D)=0.83