Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>>[ClH:7].[ClH:15].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:25]1[CH2:24][CH2:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])[CH2:27][CH2:26]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(CN2CCN(c3ccccc3Cl)CC2)cc(OC)c1OC
Product: Cl
Yield: 111.3 %

Procedure:
4.33 g of 3,4,5-trimethoxybenzyl chloride and 3.93 g of N-(2-chlorophenyl)-piperazine and 3.5 g of K2CO3 are reacted and processed according to example 2. 5.0 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2-chlorophenyl)-piperazine dihydrochloride is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: NS(N)(=O)=O
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a solution of 1-pyridin-4-ylpiperazine (1.23 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-pyridin-4-ylpiperazine-1-sulfonamide as a white solid. A mixture of 4-pyridin-4-ylpiperazine-1-sulfonamide (0.260 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.438 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.350 g) in dioxane (10 ml) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1N>>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[C:13]1[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:12]=1[Cl:11].[CH3:10][O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:12]=1[Cl:11]
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: COc1ccc(Cl)c(Cl)c1
Product: COc1cc(Cl)c(Cl)cc1-c1cc(Cl)c(Cl)cc1Cl
Product: COc1ccc(Cl)c(Cl)c1-c1cc(Cl)c(Cl)cc1Cl

Procedure:
2-Methoxy-2',4,4',5,5'-pentachlorobiphenyl was prepared from 3,4-Dichloroanisole (35 g, 200 mmol) and 2,4,5-trichloroaniline (2.95 g, 15 mmol) according to the procedure in Example 2A. The excess dichloroanisole was removed by distillation and the residue was then filtered through silica gel (heptane eluent) and further purified [Chromatotron®, 4 mm silica gel, cyclohexane, 20 mL/min] to give 2-methoxy-2',4,4',5,5'-pentachlorobiphenyl (700 mg) and 2-Methoxy-2',4',5,5',6-pentachlorobiphenyl (1.2 g). Mass spectrum: m/z at 354 for C13H7Cl5O.
Reaction SMILES: CC([S@]([NH:7][C@:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[F:25])([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:7][C@@:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[F:25])([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: Cc1cccc([C@](CF)(C[C@H](O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc([C@](N)(CF)C[C@H](O)C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-methyl-N-((2S,4S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (2.0 g, 5.16 mmol) in DCM (20 mL) and MeOH (10 mL) was added hydrogen chloride, 4.0m solution in 1,4-dioxane (12.91 ml, 51.6 mmol) and stirred at rt for 15 min. The reaction went to completion, concentrated, diluted with DCM and washed with 1N NaOH. The organic phase was separated, dried over Na2SO4, filtered and concentrated to afford (2S,4S)-4-amino-1,1,1,5-tetrafluoro-4-(2-fluoro-3-methylphenyl)pentan-2-ol. This amino-alcohol was dissolved in THF (12 mL) followed by the addition of benzoyl isothiocyanate (0.764 ml, 5.68 mmol) and the resulting mixture was stirred at rt for 40 min. The reaction went to completion then triethylamine (0.862 ml, 6.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hcl (1.089 g, 5.68 mmol) were added and the resulting mixture was heated at 70° C. for 1 h. The reaction went to completion. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-20% EtOAc/hexanes to afford a white solid as N-((4S,6S)-4-(2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.69 g, 4.10 mmol, 79% yield). MS m/z=412.9 [M+H]+. Calculated for C20H17F5N2O2S: 412.12.
Reaction SMILES: [NH2:1][OH:2].[C:3](Cl)(=[O:7])[C:4]([CH3:6])=[CH2:5].Cl.NO.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:3]([NH:1][O:2][C:3](=[O:7])[C:4]([CH3:6])=[CH2:5])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)Cl
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)NOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,O-dimethacryloylhydroxylamine was prepared by the reaction of hydroxylamine with methacryloyl chloride in pyridine medium. Hydroxylamine hydrochloride (10 g; 0.144 mol) was dissolved in 50 ml pyridine (0.632 mol) and 25.4 g (0.243 mol) methacryloyl chloride was dropwise added. Temperature of the reaction mixture was kept below 45° C. After completed addition of methacryloyl chloride, the mixture was stirred at ambient temperature for 2 hours. Then, the mixture was diluted with 100 ml chloroform and 21 ml hydrochloric acid (0.245 mol) was slowly dropwise added in order to transfer pyridine to its hydrochloride. The organic layer was separated, washed four times with 100 ml water, and then dried over MgSO4. Chloroform was evaporated in vacuum and the oily residue was dried in vacuum of an oil pump. The product crystallized during drying, the crystals were filtered and twice recrystallized from the mixture diethyl ether-light petroleum. The yield was 7.0 g (34%) N,O-dimethacryloylhydroxylamine, m.p. 55° C., elemental analysis: calculated C--56.70, H--6.55, N--8.28%; found C--56.74, H--6.22, N--8.34%.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[C:5]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:19])[C:3]1[C:8]([C:9]([Cl:23])=[O:10])=[CH:7][N:6]=[C:5]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1
Reactant: O=C(O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 10 ml of dichloromethane, 467 mg of 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylic acid are admixed with two drops of N,N-dimethylformamide and cooled to 0° C. Following the dropwise addition of 167 μl of oxalyl chloride, the reaction mixture is stirred at room temperature for three hours and then concentrated by evaporation. This gives the crude product 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carbonyl chloride.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:55]>CC(C)=O.O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH:29][C:30]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:55]
Reactant: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h

Procedure:
2.628 g of the product of Example 34 in resin form were dissolved at room temperature in 5.2 ml of acetone and 10.4 ml of a molar solution of sodium bicarbonate in water were added thereto all at once. The mixture stood at 20° C. for 1 hour and was then vacuum filtered. The recovered precipitate was rinsed twice with 2 ml of a 1-1 water-acetone mixture and with 2 ml of distilled water and was dried at 40° C. under reduced pressure to obtain 1.612 g of the syn isomer of raw sodium 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-vinyloxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]12[C@:11]([OH:14])([C:12]#[CH:13])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:15][CH2:16][C:17]3[C@@H:23]([C@H:6]1[CH2:5][CH2:4]2)[CH2:22][CH2:21][C:19](=O)[CH:18]=3.C([C@]12CC[C@@H]3C4CC=C(OC)CC=4CC[C@H]3[C@@H]1CC[C@@H]2O)C.[Cl-].O[NH3+].C([C@]12CC[C@@H]3[C@@H]4C(CC[C@H]3[C@@H]1CC[C@@H]2O)=CC(=[N:68][OH:69])CC4)C>N1C=CC=CC=1>[CH3:1][CH2:2][C@@:3]12[C@:11]([OH:14])([C:12]#[CH:13])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:15][CH2:16][C:17]3[C@@H:23]([C@H:6]1[CH2:5][CH2:4]2)[CH2:22][CH2:21]/[C:19](=[N:68]\[OH:69])/[CH:18]=3
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=NO)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: [Cl-]
Agent: [NH3+]O
Solvent: c1ccncc1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C/C(=N/O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Hungarian Patent No. 165356 describes the synthesis of dl- as well as d-norgestrel. The starting material of the synthesis is the racemic or the optically active 13-ethyl-3-methoxygona-2,5(10)-diene-17β-ol, which is reacted with hydroxylammonium chloride in pyridine at 100° C. Then the obtained 13-ethyl-3-(hydroxyimino)-gon-4-ene-17β-ol is oxidized at position 17, followed by ethinylation of the oxo group at position 17, to give the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime, or norelgestromin. Although the synthesis of the intermediates, the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime and norelgestromin, are described, the identification and the purity (the quality requirements) as well as the pharmacological activity of these compounds are not provided.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([P:9](OCC)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>>[Cl:1][C:2]([Cl:20])([PH:9]([C:11]1([Cl:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: CCOP(=O)(c1ccccc1)C(Cl)(Cl)C(=O)OC(C)C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)OC(=O)C(Cl)(Cl)[PH](=O)C1(Cl)C=CC=CC1
Reaction time: 48 h

Procedure:
To 10.14 g of 1-methylethyl 2,2-dichloro-2-[(ethoxy)phenylphosphinyl]acetate at 60° C. and under a nitrogen atmosphere was added 6.24 g of phosphorus pentachloride in 1 g portions over a 72 hour period. The mixture was stirred an additional 48 hours after addition. Volatile reaction products were distilled at 45°-50° C./0.75 mm Hg leaving 1-methylethyl 2,2-dichloro-2-[(1-chloro)phenylphosphinyl]acetate as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11](O)[CH2:10]2)=[N:6][CH:7]=1.ClC1C(C2C=CC=C(NCC3C=CC=C(F)C=3)N=2)=CC(F)=[N:35]C=1.N[C@@H]1CC[C@H](O)C1.C(N(CC)CC)C>CN1C(=O)CCC1>[NH2:35][C@@H:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10]1
Reactant: O[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Agent: N[C@@H]1CC[C@H](O)C1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N[C@@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Preparation of (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentanol: To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100° C. for 18 hr, and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, 50 mL of 1 M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.71 (d, J=14.09 Hz, 1 H) 1.75-1.91 (m, 2 H) 1.97-2.05 (m, 1 H) 2.10-2.16 (m, 1 H) 2.61 (br. s., 1 H) 4.03-4.18 (m, 1 H) 4.39 (tt, J= 4.84, 2.59 Hz, 1 H) 4.55 (d, J= 5.09 Hz, 2 H) 5.19 (br. s., 2 H) 6.41 (d, J= 8.22 Hz, 1 H) 6.55 (s, 1 H) 6.90-7.02 (m, 2 H) 7.05-7.18 (m, 2 H) 7.24-7.34 (m, 1 H) 7.43-7.55 (m, 1 H) 8.07 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:13]N1C(=O)CCC1=O>CN1C(=O)CCC1.O>[Br:13][C:10]1[C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2nc(Cl)sc2c1Br
Yield: 120.6 %

Procedure:
To the solution of 2-chloro-6-methoxy-benzothiazole (200 mg, 1.0 mmol, 1.0 eq) in 5 mL of NMP was added N-bromosuccinimide (213 mg, 1.20 mmol, 1.2 eq) at room temperature. The reaction mixture was stirred at 75° C. for >24 hours with subsequent addition of NBS in small batches for reaction progress, thereafter the mixture was diluted with water (ca. 100 mL) and aqueous layer extracted with ethyl acetate (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure. Purification on ISCO using gradient 0%-50% ethyl acetate-hexane gave 336 mg of product as off white fluffy powder in 60% yields structure of which was confirmed by H+NMR. LC/MS (m/z) [279.9] (MH+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>C(OCCO)C>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Solvent: CCOCCO
Product: COc1ccc2c(Nc3ccc4[nH]ccc4c3)c(C#N)cnc2c1
Temperature: 120 °C

Procedure:
Using an analogous procedure to that described in Example 141, 1.0 g (4.57 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile, 724.8 mg (5.48 mmol) of 5-aminoindole and 528.3 mg (4.57 mmol) of 5-aminoindole in 35 mL of 2-ethoxyethanol was heated at 120° C. for 2 hr. The work up gave 1.38 g of the product as a greenish gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 314.9 HRCIMS: calcd 314.117 for C19H14N4O (M+), obsd 314.1135.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([CH2:14][S:15][CH2:16][CH3:17])=[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([CH2:14][S:15][CH2:16][CH3:17])=[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCSCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution mixture comprising 50 ml of a 10% sodium hydroxide aqueous solution and 150 ml of methanol, 3.9 g of methyl 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoate was added, and the mixture was stirred at room temperature for 30 minutes. Methanol was distilled off under reduced pressure, and a dilute hydrochloric acid was added to the residue for acid precipitation. The mixture was extracted with ethyl acetate, and the extract was dried. Then, the solvent was distilled off to obtain 3.5 g of the desired product. Melting point: 172°-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:29]3[CH2:30][CH2:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28]3)=[O:27])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added 1,2,3,4-tetrahydroisoquinoline (50 mg, 0.38 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](Br)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(=O)CC(C)=O.P(Br)(Br)Br.[CH:30]([Si:33]([C:40]#[CH:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>C(#N)C.C(N(CC)CC)C.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>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:41]#[C:40][Si:33]([CH:30]([CH3:32])[CH3:31])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1cc(Br)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: BrP(Br)Br
Solvent: CCN(CC)CC
Solvent: CCOC(=O)CC(C)=O
Solvent: CC#N
Product: Cc1cc(C#C[Si](C(C)C)(C(C)C)C(C)C)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 1-(4′-nitrophenyl)-5-bromo-3-methylpyrazole (prepared as described for Example 19 except using ethyl acetoacetate instead of ethyl trifluoroacetoacetate and using PBr3 in acetonitrile and refluxing for 72 hr for the halogenation step) (100 mg, 0.35 mmol) in triethylamine (5 mL) was added Pd(PPh3)4 (20 mg, 0.017 mmol) and CuBrSMe2 (8 mg, 0.036 mmol), followed by triisopropylsilylacetylene (72 mg, 0.39 mmol). The mixture was heated to 70° C. for 1 hour and cooled to room temperature. The solid was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane/acetate, 4:1) to give the title compound (127 mg, 95%). mp: 71-73° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].O1CCCC1.C(N(CC)CC)C.[CH2:40]([NH:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:59]([N:58]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 93.8 %

Procedure:
Lithocholic acid (81) (7.1 g, 18.8 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) Isobutylchloroformate (2.6 g, 2.6 mL, 18.8 mmol) was added followed by the addition of triethylamine (3.84 g, 5.3 mL, 38 mmol) and dioctadecylamine (9.8 g, 18.77 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL) The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 82 (15.5 g) in 93% yield. This was used as such for the next step.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 440 [M+1]+.