Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.CC1O[N:29]=[C:28](C2C=CC=CC=2)[C:27]=1[CH2:37][O:38][C:39]1N=NC(C(O)=O)=C[CH:40]=1.NC1CCOCC1>>[O:38]1[CH2:37][CH2:27][CH:28]([NH:29][C:22]([C:3]2[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:12][O:13][C:14]=3[CH3:15])=[CH:7][C:2]=2[CH3:1])=[O:24])[CH2:40][CH2:39]1
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Agent: NC1CCOCC1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)NC1CCOCC1
Yield: 62 %

Procedure:
As described for example 11b, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid, was converted, using 4-amino-tetrahydropyran instead of thiomorpholine 1,1-dioxide, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 156 mg, 62%) which was obtained as a white solid. MS: m/e=409.3 [M+H]−.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C@H:29]([O:34][CH3:35])[C:30]([O:32]C)=[O:31])=[CH:24][C:23]=3[O:36][CH3:37])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].CO[2H]>>[C:30]([C@@H:29]([O:34][CH3:35])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:23]([O:36][CH3:37])[CH:24]=1)([OH:32])=[O:31]
Reactant: COC(=O)c1ccc(-c2ccc(OCCCOc3ccc(C[C@H](OC)C(=O)OC)cc3OC)cc2)cc1
Agent: [2H]OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C[C@H](OC)C(=O)O)ccc1OCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-{3-[2-methoxy-4-(2-methoxy-2-methoxycarbonyl-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylic acid methyl ester (Step B) by standard hydrolysis procedure C (NaOH). 1H-NMR (MeOD, 300.15 MHz):
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[Br:13]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:13][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]=2[CH:9]=1
Reactant: BrBr
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1Cc2cc(Br)ccc2O1
Reaction time: 16 h
Yield: 107.3 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-2-carboxylic acid (510 mg, 3.11 mmol) in glacial acetic acid (4 mL) is added bromine (497 mg, 3.11 mmol) dropwise. After 16 hours, the reaction is quenched with water (100 mL) and sodium bisulfite (1 g, 9.6 mmol) and extracted twice with EtOAc (100 mL). The extracts are concentrated in vacuo and dried under high vacuum to afford 5-bromo-2,3-dihydro-benzofuran-2-carboxylic acid (811 mg) as a solid. MS: 241 (M+H), 1H NMR [300 MHz, (CD3)2SO]: δ 13.05 (1H, s); 7.4 (1H, s); 7.25 (1H, d); 6.8 (1H, m); 5.25 (1H, q), 3.55 (1H, dd); 3.25 (1H, m).
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7](=[O:15])[CH:6]=1.Br[CH2:18][C:19](=[CH2:25])[C:20](OCC)=[O:21]>O1CCCC1.[Zn].C1(C=CC(O)=CC=1)O>[CH3:16][C:2]1([CH2:3][O:4][C:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7](=[O:15])[CH:6]=2)[CH2:25][C:19](=[CH2:18])[C:20](=[O:21])[O:1]1
Reactant: CC(=O)COc1cc(=O)oc2ccccc12
Reactant: C=C(CBr)C(=O)OCC
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(C)(COc2cc(=O)oc3ccccc23)OC1=O
Temperature: 0 °C
Reaction time: 36 h
Yield: 76.4 %

Procedure:
To a solution of 1a (0.655 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was reflued under nitrogen atmosphere for 36 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound (0.656 g, 76.4%) as a pale yellow crystal. mp: 161°-162° C.; IR(KBr) νmax : 1766, 1703, 1627; UV (CHCl3) λmax (log ε): 306 (3.79), 276 (4.01), 266 (4.05); 1H-NMR (CDCl3): δ1.64 (s, 3H, 5'-CH3), 2.88 (dt, 1H, 4'-H), 3.19 (dt, 1H, 4'-H), 4.08, 4.20 (two d, 2H, OCH2), 5.67 (s, 1H, 3-H), 5.75 (t, 1H, vinylic H), 6.38 (t, 1H, vinylic H), 7.12-7.33 (m, 2H, 6 and 8-H), 7.51-7.65 (m, 2H, 5 and 7-H). Anal. Calcd for C16H14O5 : C, 67.13; H, 4.93. Found: C, 67.14; H, 5.01.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:44]I>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11]([N:13]([CH3:44])[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][CH:19]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)N(C)c2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 118.5 %

Procedure:
2,4-Bis-benzyloxy-5-isopropenyl-N-(4-morpholin-4-ylmethyl-phenyl)-benzamide (0.1 g, 0.18 mmol) [Method A2 from (2,4-bis-benzyloxy-5-isopropenyl)-benzoic acid (Preparation B5) and 4-morpholin-4-yl-methyl-phenylamine] were dissolved in DMF (1 ml) and treated with 60% NaH in mineral oil (11 mg, 1.6 eq) and the reaction mixture was stirred for 15 minutes followed by the addition of methyl iodide (26 mg, 0.18 mmol). The reaction mixture was then stirred for 1 hour at room temperature, and subsequently diluted with EtOAc and water. The organic phase was separated, washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a solid (0.12 g). MS: [M+H]+ 563
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:26][OH:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccncc1)c1cccc(Br)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1

Procedure:
In analogy to example 1, step 2, from 3-(3-bromo-phenyl)-3-o-tolyl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=395.0 ([M+H]+, 1Br).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][N:9]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=O)[C:12]=2[CH:11]=[N:10]1>>[Cl:3][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([CH:8]=[CH:7][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[CH:11][C:12]=12
Reactant: O=c1[nH]cnc2c1cnn2CC(O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c1cnn2C=Cc1ccccc1
Temperature: 25 °C

Procedure:
POCl3 (14 g, 91 mmol) was added to 10 (2.56 g, 10 mmol) and the mixture was refluxed for 12 h and then cooled to room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[OH:42][C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.1 g, 0.27 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethyl amine (67.5 mg, 0.68 mmol) (Aldrich), followed by the addition of solution of 4-isocyanato-phenol (1.8 mL, 0.32 mmol) in toluene (from Example 78a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-hydroxy-phenyl)-amide as a white solid. (Yield 15 mg, 11%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[NH:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1>CN(C=O)C.O>[NH:28]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)=[N:29]1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Nc1cc[nH]n1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
To a solution of ethyl 4-chloroquinazoline-2-carboxylate (0.250 g, 1.05 mmol) in DMF (2.5 mL) at rt under argon were added potassium iodide (0.192 g, 1.16 mmol), DIEA (0.238 mL, 1.37 mmol), and 1H-pyrazol-3-amine (0.113 g, 1.37 mmol). The mixture was stirred at rt for 5 h and diluted with H2O (5 mL). The precipitate was collected by filtration, washed with H2O, and dried under high vacuum for several hours to afford ethyl 4-(1H-pyrazol-3-ylamino)quinazoline-2-carboxylate as a tan solid (0.190 g, 64%). 1H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.58 (s, 1H), 8.72 (d, 1H), 7.90 (d, 2H), 7.78 (s, 1H), 7.68 (m, 1H), 7.18 (s, 1H), 4.48 (q, 2H), 1.48 (t, 3H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[OH:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl>[Br:1][C:12]1[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([CH:11]=1)[CH2:9][OH:8]
Reactant: OCc1ccccc1O
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: OCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0°-5° C., 11.5 ml. of bromine in 100 ml. of carbon tetrachloride was added dropwise to a suspension of 24.8 g. of saligenin and 24 g. of calcium carbonate in a solvent mixture of 200 ml. of carbon tetrachloride and 220 ml. of methylene chloride. The reaction mixture was stirred for 24 hours at room temperature, then filtered, and the precipitate was washed with carbon tetrachloride. The CCl4 /CH2Cl2 phase was discarded. The solid substance was taken up in ethyl acetate/water, and the organic phase was separated, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from methylene chloride, thus obtaining colorless crystal flakes (24 g.). Melting point: 107°-109° C. (methylene chloride).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:8]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:9][N:10]([C:14]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=3[Cl:23])[C:11]=2[C:12]#[N:13])=[C:4]([F:30])[CH:3]=1>[Pt]=O>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([Cl:23])=[C:14]([N:10]2[C:11]([C:12]#[N:13])=[C:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([Br:1])=[CH:3][C:4]=3[F:30])[C:8]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:9]2)[CH:19]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Agent: O=[Pt]
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Yield: 96 %

Procedure:
By the procedure of Example 1, Step I, 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carbonitrile (from Step F) was hydrogenated in the presence of platinum oxide catalyst to give a 96% yield of the title compound as a tacky, orange oil; nearly homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 461, 463 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.89 (t, J=7.2 Hz, 3H), 1.33 (m, 2H), 1.58 (m, 2H), 2.58 (t, J=7.7 Hz, 2H), 3.94 (s, 2H), 6.69-6.75 (m, 2H), 7.03 (dd, J≈8, 8.5 Hz, 1H), 7.2-7.3 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:24]3[CH2:28][O:27]C(C)(C)[O:25]3)[CH:23]=2)=[N:4][N:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:12]1([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:38][CH2:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)=[N:3][N:4]=[C:5]3[C:18]2[CH:23]=[C:22]([CH:24]([OH:25])[CH2:28][OH:27])[CH:21]=[N:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OCC(c2cncc(-c3nnc(Cl)c4c(-c5ccccc5)cccc34)c2)O1
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCC(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 100 °C
Yield: 5.1 %

Procedure:
To a solution of 4-chloro-1-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-phenylphthalazine (1.00 g, 2.39 mmol) in toluene (5 mL) was added pyridin-2-ylmethanamine (5.00 mL, 48.5 mmol) the contents were heated at 100° C. for 12 h. The reaction mixture was diluted with DCM (200 mL) and washed with 1.5N HCl (2 ×20 mL). The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by preparative HPLC (Condition 18 as described in general methods) to obtain 1-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)ethane-1,2-diol (55.0 mg, 5.11%) as a white solid. The racemic product (50 mg) was resolved into individual enantiomers by chiral SFC (Condition 29 as described in general methods).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([S:10]([N:13]([CH2:27][C:28](Cl)=[O:29])[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=2)[O:17][C:16]([CH3:26])([CH3:25])[CH2:15]1)(=[O:12])=[O:11])[CH3:9]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(Cl)Cl>[CH2:8]([S:10]([N:13]([CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=2)[O:17][C:16]([CH3:25])([CH3:26])[CH2:15]1)[CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:29])(=[O:11])=[O:12])[CH3:9]
Reactant: Nc1ccncc1
Reactant: CCS(=O)(=O)N(CC(=O)Cl)C1CC(C)(C)Oc2ccc(F)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N(CC(=O)Nc1ccncc1)C1CC(C)(C)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
141 mg of p-aminopyridine and a spatula tipful of DMAP dissolved in 6 ml of pyridine are treated with a solution of 655 mg of [ethanesulfonyl-(6-fluoro-2,2-dimethylchroman-4-yl)amino]acetyl chloride in 6 ml of methylene chloride. The mixture is stirred at RT for 4 h and then concentrated in vacuo. The product is partitioned between EA and water and the organic phase is washed with water. After removing the solvent in vacuo, 600 mg of the product are obtained as a colorless foam (m.p. 195° C.).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:13]([NH:31][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
In the first process step, glucose (a) is reacted with octadecylamine (b) to give N-octadecyl-β-D-glucopyranosylamine (c) which, in the second process step, is acylated with oleoyl chloride to give N-octadecyl-N-oleyl-β-D-glucopyranosylamide (I).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[C:16](C)[CH:17]=[CH:18][CH:19]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/[C:25](C)=[O:26])=N\O.C(=O)C1C=CC=C(OC)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:26][CH3:25])[CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(-c2nc(CI)c(-c3ccccc3)o2)c1
Reactant: CC(=O)/C(C)=N/O
Agent: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc(CI)c(C)o2)c1

Procedure:
Analogous to the building block synthesis of 4-iodomethyl-5-phenyl-2-m-tolyloxazole, diacetylmonoxime and m-anisaldehyde gave 4-iodomethyl-2-(3-methoxyphenyl)-5-methyloxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[C:10]1=[O:31].O.C(O)(C(F)(F)F)=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(S(C)(=O)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.4 %

Procedure:
To a mixture of (R)-3-(3,5-Dichloro-4′-methanesulfonyl-biphenyl-4-ylmethyl)-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one (0.12 g) in THF (6 mL), add water (6 mL) and TFA (2 mL). Stir the mixture at room temperature for 12 hours. Dilute the reaction mixture with ethyl acetate and wash with sodium bicarbonate (Sat.) and water. Separate the organic and dry over sodium sulfate, filter and concentrate. Purify the crude mixture on silica gel column with 50% ethyl acetate in hexane to 100% ethyl acetate to afford 0.088 g of the titled product. MS (m/z): 497 (M+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[N:3]1[CH:7]=[CH:6][NH:5][NH:4]1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([S:19][CH2:20][CH2:21][CH3:22])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([S:19][C:13]1[CH:12]=[C:11]([N:5]2[CH:6]=[CH:7][N:3]([C:2]([F:9])([F:8])[F:1])[NH:4]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[CH2:21][CH3:22]
Reactant: FC(F)(F)N1C=CNN1
Reactant: CCCSc1cc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cc(N2C=CN(C(F)(F)F)N2)ccc1C#N
Temperature: 25 °C
Yield: 38.2 %

Procedure:
1.06 g (7.7 mmol) of 3-trifluoromethyl-1H-triazol, 1.38 g (6.5 mmol) of 4-chloro-2-n-propylthiobenzonitrile and 1.07 g (7.7 mmol) of potassium carbonate were stirred in 10 ml of N,N-dimethylformamide at 150° C. for 2 hours. The resulting reaction mixture was cooled to the room temperature and poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, then washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.78 g of 2-propylthio-4-(3-trifluoromethyl-1H-triazolyl)benzonitrile (yield 38.2%) as a milk-white powder (m.p. 143-144° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][NH2:27])[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: Cc1cccc(NN)c1
Product: Cc1cccc(NNC(=O)c2ccncc2Nc2ccc(I)cc2F)c1

Procedure:
was synthesized according to the procedure for General Method 1, outlined above, starting with 0.44 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.63 mmol of 3-methyl-phenylhydrazine. LC/MS [6.05 min; 463 (M+1)]
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Ic1ccccn1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccn2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (99 mg, 0.52 mmol) and 2-iodopyridine (0.07 mL, 0.66 mmol) according to the general procedure IC to give 69 mg (50%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.09 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.62-8.60 (m, 1H), 7.70-7.64 (m, 1H), 7.54-7.49 (m, 3H), 7.25-7.18 (m, 3H), 3.67 (s, 3H), 2.99-2.94 (t, 2H, J=7.8 Hz), 2.67-2.61 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 150.0, 143.5, 141.6, 136.1, 132.2, 128.4, 127.1, 122.6, 120.2, 89.2, 88.4, 51.6, 35.2, 30.8; EI-MS calcd for C17H15NO2 (M+): 265. found: 265.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([C:33]([F:36])([F:35])[F:34])[C:27]([C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[N:26]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([C:37]([F:42])([F:43])[C:38]([F:40])([F:41])[F:39])[C:28]=2[C:33]([F:35])([F:36])[F:34])=[O:31])=[CH:13][C:6]=1[C:7](=[O:8])[NH:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
95.3 mg (0.45 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide, 3.7 mg (0.03 mmol) of N,N-dimethylpyridine-4-amine are dissolved in 2.5 ml of ethyl acetate. The solution is cooled to 0° C. using an ice bath and admixed with 158 μl (0.91 mmol) of N-ethyldiisopropylamine. 100 mg (0.30 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride are suspended in 2.5 ml of ethyl acetate and then added to the cooled reaction solution. The reaction mixture is heated for four hours at 50° C. and then stirred for 16 hours at room temperature. The reaction solution is diluted with 10.0 ml of ethyl acetate. The organic phase is washed three times with 1M hydrochloric acid, twice with 1M sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and filtered and solvent is removed under reduced pressure on a rotary evaporator. This gives 151 mg of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (97%) as white solid.