Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[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.I[CH3:31]>CC#N.[Ag]=O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([O:28][CH3:31])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[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
Reactant: COC(=O)[C@H](O)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC(=O)[C@H](OC)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (610 mg, 1.45 mmol) in CH3CN (20 mL) are added iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol). After being stirred at room temperature for 16 h, additional iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol) are added and stirred for 3 days. The reaction mixture is filtered through celite pad and the filtrate is washed with brine. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (500 mg). HPLC retention time=1.20, 1.25 minutes (condition B): MS (m+1-Boc)=334. 1H-NMR (400 MHz, CDCl3) δ ppm 1.37, 1.41 (s, 9 H), 2.72-3.03 (m, 2 H), 3.43, 3.71 (s, 3H), 3.63-3.82 (m, 1 H), 4.27-4.41 (m, 1 H), 4.68-5.04 (m, 1 H), 7.28-7.40 (m, 4 H), 7.41-7.61 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[H-].[Na+].CS(O[CH2:15][CH3:16])(=O)=O>CN(C)C=O.O>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:15][CH3:16])[N:3]=1
Reactant: Brc1n[nH]c(Br)n1
Reactant: CCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Br)nc1Br
Temperature: 100 °C
Yield: 90.6 %

Procedure:
3,5-Dibromo-1H-1,2,4-triazole (2.5 g, 11.0 mmol, Eq: 1.00) was dissolved in dimethylformamide (31.8 ml) and sodium hydride (529 mg, 60% dispersion in mineral oil, 13.2 mmol, Eq: 1.2) was added slowly. Ethyl methanesulfonate (2.74 g, 2.27 ml, 22.0 mmol, Eq: 2) was added to the reaction and the mixture was heated in a microwave oven for 60 minutes at 100° C. The mixture was diluted with water and extracted 3× with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to give 3,5-dibromo-1-ethyl-1H-[1,2,4]triazole (2.54 g, 90.4%) as a white powder. MS: m/z=255.9 (M+H+)
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(CC)CC.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([NH:38][C:39]([NH:13][C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-[(2-thiophen-2-yl)thiazol-4-yl)ethan-amine hydrobromide salt, 8, and Et3N (0.42 mL, 3 mmol) in 10 mL DCM is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.445 g (96% yield) of the desired product which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-:10].[Cs+]>ClCCl.CCCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: [OH-]
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1cc(C)cc(O)c1
Yield: 96 %

Procedure:
Following general operating mode A, 3,5-dimethyliodobenzene (145 μL, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a white solid with a yield of 96% (eluent: dichloromethane/heptane 20:80).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=O.[CH3:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][S:19]([CH2:22][C:23](O)=[O:24])(=[O:21])=[O:20])=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][S:19]([C:22]2[C:23](=[O:24])[O:11][C:5]3[C:6]([CH:7]=2)=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:20])=[O:21])=[CH:26][CH:27]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3ccc(OC)cc3oc2=O)cc1
Yield: 43 %

Procedure:
A solution of 4-methoxysalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 43% yield of the title compound; m.p. 179-180° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1>C(#N)C.C(OCC)C>[ClH:24].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc(NC(=O)c2ccc(F)cc2)ccc1NC1=NCCC1

Procedure:
A mixture of 1.0 g (3.8 mmole) of product compound of Example 9 and 30.5 mmole of p-fluorobenzoyl chloride in 40 ml of acetonitrile was stirred at reflux for four hours, after which time thin-layer chromatography on silica gel (9:1 ethanol/concentrated aqueous ammonia) indicated no unreacted starting amine. The reaction mixture was then diluted eight-fold with diethyl ether. The resultant solid was collected and washed with three portions of ether, then dried in a high vacuum over 5A molecular sieves, giving the title compound as the hydrochloride salt. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10].[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([N:8]=[N+:9]=[N-:10])=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cccs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Temperature: 10 °C
Yield: 55.5 %

Procedure:
A solution of thiophene-2-carbaldehyde (650 mg, 5.8 mmol) and ethyl azidoacetate (6.89 grams, 53.4 mmol) in dry toluene (40 ml) was added to a cold (−5° C.) solution of sodium ethoxide (about 53 mmol) in ethanol (60 ml) during a time period of one hour, under nitrogen atmosphere. Stirring was continued for another hour while maintaining the temperature under 10° C. The reaction mixture was then cooled to 0° C. and acidified with HCl 0.1 M. After separation of the phases, the aqueous phase was extracted with ether (3×30 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 718 mg of pure 2-azido-3-thiophen-2-yl-acrylic acid ethyl ester (55% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].Cl.Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH:19]1[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([N:21]1[CH2:22][CH2:23][NH:18][CH:19]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)C1CNCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of 3,4,5-trimethoxybenzoyl chloride (10.9 g) in dichloromethane (100 ml) is added dropwise taking one hour, under ice-cooling while stirring, to a mixture of methyl piperazine-2-carboxylate dihydrochloride (10.24 g), triethylamine (18.7 g) and dichloromethane (200 ml). The reaction mixture is poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. Crystals obtained from the residue are recrystallized from ethyl acetate and hexane to afford methyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (9.6 g) as colorless needles, m.p. 113-114° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(I)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccc(C=O)cc2)ccn1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol, 0.05 equiv) was added to a deoxygenated mixture of tert-butyl 4-iodopyridin-2-ylcarbamate (1-1, 0.500 g, 1.56 mmol, 1 equiv), 4-formylphenyl boronic acid (351 mg, 2.34 mmol, 1.50 equiv), and aqueous saturated sodium carbonate solution (2.0 M, 2.3 mL, 4.7 mmol, 3.0 equiv) in dioxane (15 mL), and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled then concentrated. The residue was partitioned between half-saturated aqueous NaCl solution (100 mL) and EtOAc (100 mL). The organic layer was dried over sodium sulfate, and concentrated to give tert-butyl 4-(4-formylphenyl)pyridin-2-ylcarbamate (2-1) as an off-white solid. LRMS m/z (M+H) Calcd: 242.2 (minus t-Bu), 199.2 (minus Boc); found 243.0 and 199.0.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[N:24][NH2:25])[C:19](=[O:23])[NH:20]2)=[C:16]([Br:26])[CH:15]=1)=[O:13].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[N:24][NH:25][C:37](=[O:38])[CH2:36][C:34]3[CH:33]=[CH:32][C:31]4[O:27][CH2:28][CH2:29][C:30]=4[CH:35]=3)[C:19](=[O:23])[NH:20]2)=[C:16]([Br:26])[CH:15]=1)=[O:13]
Reactant: NN=C1C(=O)Nc2cc(C(=O)NCCCN3CCC[C@H]3CO)cc(Br)c21
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2c(c1)CCO2)NN=C1C(=O)Nc2cc(C(=O)NCCCN3CCC[C@H]3CO)cc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
(S)-4-Bromo-3-hydrazono-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide (0.22 g, 0.52 mmol) was added to a solution of (2,3-dihydro-benzofuran-5-yl)-acetic acid (0.93 g, 0.52 mmol), triethylamine (0.01 mL, 0.78 mmol) and HBTU (0.20 g, 0.52 mmol) in DMF (4 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (20% methanol in dichloromethane) followed by HPLC (10-100% acetonitrile/water) to give 0.040 g (13%) of (S)-4-bromo-3-[(2-2,3-dihydro-benzofuran-5-yl-acetyl)-hydrazono]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide. 1H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.37 (s, 1H), 7.24 (s, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.50 (t, J=12.7 Hz, 2H), 4.10 (bs, 2H), 3.88 (dd, J=3.9 Hz, J=12.2 Hz, 1H), 3.74-3.40 (m, 6H), 3.22-3.04 (m, 4H), 2.26-1.81 (m, 6H). Mass spectrum (LCMS, ESI pos.): Calcd for C27H30BrN5O5: 584.46. Found 584.1; (M+H).
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH2:9][CH2:10][C:11](ON2C(=O)CCC2=O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[C:43]2[N:44]=[C:45]([CH2:56][O:57][CH2:58][CH3:59])[N:46]([CH2:47][C:48]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])([CH3:50])[CH3:49])[C:42]=2[C:41]2[CH:40]=[CH:39][C:38]([OH:60])=[CH:37][C:36]=2[N:35]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:33][C:34]1[C:43]2[N:44]=[C:45]([CH2:56][O:57][CH2:58][CH3:59])[N:46]([CH2:47][C:48]([CH3:50])([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH3:49])[C:42]=2[C:41]2[CH:40]=[CH:39][C:38]([O:60][CH2:37][CH2:36][CH2:41][CH2:42][CH2:43][CH2:34][NH:33][C:11](=[O:12])[CH2:10][CH2:9][S:8][C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:37][C:36]=2[N:35]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)CCSC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Succinimido 3-(triphenylmethylthio)propanoate (246 mg, 0.553 mmol) was added to a 0° C. solution of N-{2-[4-amino-2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (280 mg, 0.553 mmol) in DMF (5 mL). The solution was stirred at 0° C. for 3 hours, then was diluted with ethyl acetate (100 mL) and washed with water (3×20 mL) and brine (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC on silica gel (gradient elution with 2-50% CMA in chloroform) to provide 0.22 g of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-(tritylthio)propanamide as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[Br:13][CH:14]([CH3:18])[C:15](Br)=[O:16]>C(=S)=S>[Br:13][CH:14]([CH3:18])[C:15]([C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][C:8]=1[Br:12])=[O:16]
Reactant: Brc1cccc(Br)c1
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc(Br)cc1Br
Yield: 76 %

Procedure:
15 g of aluminium chloride are added with caution, at 0° C., to 25 g of 1,3-dibromobenzene in 250 ml of carbon disulphide, and 22.86 g of 2-bromopropionyl bromide are then run in slowly. The mixture is maintained at reflux for 8 hours, then the carbon disulphide is evaporated off under vacuum and the reaction medium is poured onto crushed ice. The product is extracted twice with heptane, dried, evaporated to dryness and then is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent, to give the expected product.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.Cl.O>CC(O)=O>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 14 (45.06 g, 62.6 mmol, 1 eq.), in AcOH (338 mL) was added 1N HCl (188 mL) over 1 min. The reaction mixture was heated at 40° C. for 2 h. After cooling down to r.t., water (676 mL) was added. The reaction mixture turned into a suspension and was stirred at r.t. for 15 min. The solid was collected by filtration and the product cake was washed with water (2×100 mL) then dried in vacuum for 30 min to afford a crude hydrochloride salt of 15 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][OH:14]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCOc1ccc(Br)cc1
Yield: 78.2 %

Procedure:
To a sol. of 4-bromophenol (40 g, 231 mmol) in EtOH (140 mL) was added NaOH (10.2 g, 254 mmol). The resulting mixture was stirred at 70° C. for 30 min until the whole amount of NaOH had dissolved. A sol. of 2-bromoethanol (17.3 mL, 231 mmol) in EtOH (40 mL) was added dropwise at 70° C. The sol. rapidly turned milky. The mixture was heated to reflux overnight. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc. The mixture was washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5→1:4→1:3→1:2→EtOAc) yielded the title compound (39.2 g, 78%) as a pale brown oil that crystallized when placed at −18° C. Rf=0.3 in (EtOAc/heptane 1:1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.CCN(C(C)C)C(C)C.[Cl-].[CH:28]1([O:34][C:35]([C:37]2[N:38]=[C:39]([CH:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)[S:40][CH:41]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([CH2:12][C:13]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:35]([O:34][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:36])[N:38]=3)[CH2:47][CH2:46]2)=[O:15])[N:4]=1
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (348 mg, 65%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=1[CH3:34]>>[CH3:34][C:28]1[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:21]1[N:20]=[C:19]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)[CH:24]=[CH:23][N:22]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1cc(O)ccc1N
Product: Cc1cc(O)ccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 49.7 %

Procedure:
Using procedure of example 1, compound 1f (4.0 g) was reacted with 4-amino-3-methylphenol (2.66 g) to provide 1.7 g (50%) of compound 79. 1H NMR (400 MHz, DMSO) δ 12.20 (s, 1 H), 9.18 (s, 1 H), 8.45 (s, 1 H), 8.35 (d, 1 H), 8.22 (d, 1 H), 8.18 (d, 1 H), 7.15 (m, 1 H), 7.00 (m, 1 H), 6.65 (d, 1 H), 6.60 (dd, 1 H), 2.15 (s, 3 H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH3:26])=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-(5-benzylbenzofuran-2-yl)-3-fluorobenzaldehyde (0.559 g, 2 mmol) in THF at 0° C. was added methyl-magnesium bromide (1.4M solution in toluene/THF=3:1, 2.40 mL, 3 mmol) dropwise over 5 min. The mixture was allowed to stir for 20 min at 0° C., treated with NH4Cl, extracted with EtOAc, dried over MgSO4, and evaporated. The crude product was purified by flash chromatography (EtOAc/hexanes) to give 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanol. 1H NMR (300 MHz, CDCl3) δ ppm 7.98 (t, J=8.0 Hz, 1H), 7.38-7.46 (m, 2H), 7.10-7.34 (m, 9H), 4.77-5.04 (m, 1H), 4.08 (s, 2H), 1.85 (d, J=3.8 Hz, 1H), 1.46-1.60 (m, 3H). MS (ESI) m/z: Calculated; 346.1 Observed: 347.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:27][CH2:24][CH2:25][CH3:26])[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CCCN
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and propylamine in DME. ES-MS m/e (%): 264 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[OH2:15]>O1CCOCC1>[O:12]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=1)[CH:11]=[O:15]
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Reactant: O
Solvent: C1COCCO1
Product: O=CC(=O)c1cccc(OC(F)(F)F)c1
Yield: 98 %

Procedure:
To a solution of 1-(3-(trifluoromethoxy)phenyl)ethanone (5.0 g, 24.6 mmol) dissolved in 1,4-dioxane (75 mL) and water (4 mL) was added SeO2 (4.38 g, 39.4 mmol) in one portion. The mixture was refluxed overnight. The mixture was filtered to remove the black precipitate. The filtrate was concentrated and purified by column chromatography (1:5 Ethyl Acetate/Pentane) to give 2-oxo-2-(3-(trifluoromethoxy)phenyl)acetaldehyde as a yellow oil (5.3 g, 98% yield).