Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10](Br)([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1.[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:14]1([C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])([CH3:12])[CH3:11])[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Yield: 25.7 %

Procedure:
80 g (0.31 mole) of 2-bromo-prop-2-yl 4-chlorophenyl ketone, 26.9 g (0.39 mole) of 1,2,4-triazole and 53.8 g (0.39 mole) of potassium carbonate are heated under reflux in 350 ml of acetone for 6 hours. The mixture is allowed to cool and is filtered and the filtrate is concentrated in vacuo. The residue is taken up in methylene chloride and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from diisopropyl ether. 19.9 g (25.7% of theory) of 4-chlorophenyl 2-(1,2,4-triazol-1-yl)-prop-2-yl ketone of melting point 111° C. are obtained. ##STR19##
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].[H-].[Na+]>O1CCOCC1>[CH:13]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=2[O:8][CH3:9])[CH2:23][CH2:24]1)=[O:18])([CH3:15])[CH3:14]
Reactant: COc1c([N+](=O)[O-])ccnc1Cl
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(OC2CCN(C(=O)OC(C)C)CC2)ccnc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a solution of 2-chloro-3-methoxy-4-nitro-pyridine (102.3 mg, 0.543 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (110 mg, 0.587 mmol) in dioxane (3 mL), sodium hydride (60% dispersion, 32 mg, 0.8 mmol) were added. After stirring at 100° C. for 1 hour, mixture was purified by HPLC to give 4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a white solid (42.0 mg, 24%). 1HNMR (CDCl3, 400 MHz) δ 8.16-8.15 (d, J=5.4 Hz, 1H), 6.92-6.90 (d, J=5.8 Hz), 4.97-4.91 (m, 1H), 4.72-4.68 (m, 1H), 3.91 (s, 3H), 3.75-3.68 (m, 2H), 3.75-3.68 (m, 2H), 3.55 (m, 2H), 2.02-1.85 (m, 4H), 1.27-1.26 (d, J=6.2 Hz, 6H). Exact mass calculated for C15H21ClN2O4 328.12. found 329.2 (MH+).
Reaction SMILES: [Na+:1].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([O-:16])(=[O:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C1C=CC=CC=1>[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([Cl:19])(=[O:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+:1].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([O-:16])(=[O:14])=[O:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Agent: O=S(=O)([O-])CCCCOc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=S(=O)(Cl)CCCCOc1ccccc1

Procedure:
4-Phenoxybutyl sulfonyl chloride (16) was synthesized as described in 12.1 using 15 (1.0 g, 4.37 mmol) and thionyl chloride (1.55 g, 13.0 mmol) in benzene (40 mL)/DMF (4 mL). Purification by flash column chromatography on silica gel afforded 15 (0.434 g, 40% yield) as a white solid (m p 65-67° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene was added aniline (2 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N′-phenyl-urea as a light yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1C.[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH2:18][S:19][CH3:20])[NH2:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][O:13][C:14](=[O:21])[CH:15]([NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)[CH2:17][CH2:18][S:19][CH3:20]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)[C@@H](N)CCSC
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CCSC)Nc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
1 g of 4-fluoro-3-methylnitrobenzene, 0.694 g of L-methionine methyl ester and 1.09 ml of triethylamine were added to a solution of 5 ml of N-methylpyrrolidinone. The reaction medium was heated at 90° C. for 7 hours and, after cooling to room temperature, was poured into an ice water mixture. The reaction medium was then extracted with ethyl acetate and the organic phase was dried and concentrated to dryness. After purification by chromatography on a column of silica, 4-methylsulfanyl-2-(4-nitrophenylamino)butyric acid methyl ester (28) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[CH3:36][NH:37][CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:37]([CH3:38])[CH3:36])=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNC
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B, Step 2 starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid and dimethylamine hydrochloride. LCMS (M+H)+: m/z=487.3.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][CH:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][CH:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49].Br[CH2:64][CH2:65][F:66]>>[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:64][CH2:65][F:66])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: FCCBr
Reactant: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1NC1c2ccccc2CC1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino 2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 2969, 2932, 2907, 2877, 1608, 1563, 1545, 1483, 1447, 1392, 1353, 1207, 1177, 1123, 1042 cm−1; OAMS supporting ions at: ESI+ 483.2; MS (EI) m/z 482 (M+); HRMS (FAB) calcd for C27H32CLFN4O+H1 483.2327, found 483.2324. [α]25D=−79 (c 0.52, methylene chloride); Anal. Calcd for C27H32ClFN4O: C, 67.14; H, 6.68; N, 11.60. Found: C, 67.19; H, 6.90; N, 11.63.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[Se:9][C:5]=2[C:4](=[O:14])[NH:3][N:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:15][N:3]1[C:4](=[O:14])[C:5]2[Se:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[N:1]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nnc2c1[se]c1ccccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc2c([se]c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 3H-benzo[b]1,2,3-triazino[4,5-d]selenophen-4-one (200 mg, 0.8 mmol) in acetone (50 mL) was added sequentially potassium carbonate (400 mg, 1.6 mmol), iodomethane (0.1 mL, 0.9 mmol) and a catalytic amount of PEG-400 was added at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using hexane-chloroform (70:30) as eluents to give the product as a off-white solid (120 mg, 47%), mp 190-192° C. IR (neat) νmax 3431, 1673, 1220, 1021 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56-8.58 (1H, m, H-9), 7.98-8.01 (1H, m, H-6), 7.58-7.66 (2H, m, H-7,8), 4.13 (3H, s, —NCH3); 13C NMR (100 MHz, CDCl3): δ 155.5, 152.8, 142.3, 135.3, 130.4, 129.8, 126.4, 126.2, 126.0, 37.8; LC-MS (positive ion mode): m/z 286, 288 (M+Na)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1(=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([C:34]1([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C2(O)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A solution of (4S)-4-benzyl-3-[2-(4-methoxyphenyl)acetyl]-1,3-oxazolidin-2-one (2.5 g, 7.68 mmol) in dry methylene chloride (50 mL) was cooled to −78° C. and treated with diisopropylethylamine (1.09 g, 8.45 mmol) followed by titanium tetrachloride (0.88 mL, 8.06 mmol). The resulting reaction was warmed to 0° C. where it was stirred for 1 h, during which time the reaction turned dark purple. The reaction was then re-cooled to −78° C. and was treated with another portion of titanium tetrachloride (0.88 mL, 8.06 mmol) followed by a solution of cyclohexanone (0.91 mL, 8.83 mmol) in methylene chloride (10 mL). After addition, the reaction was warmed to 0° C. where it was stirred for 2 h, after which time the reaction was carefully quenched with the addition of a saturated aqueous solution of sodium bicarbonate and the mixture was stirred at 0° C. for 30 minutes. The reaction was filtered to remove the titanium salt that had precipitated, and the layers of the filtrate were then separated. The aqueous layer was washed with methylene chloride (3×30 mL). The solid precipitate was then collected and stirred vigorously in a 2N aqueous solution of hydrochloric acid (50 mL) for 20 minutes, after which time, the remaining product was extracted from the aqueous layer with methylene chloride (3×60 mL), and the combined organic extracts (from the filtrate and the liberated salt) were dried over magnesium sulfate and concentrated in vacuo. The product was purified via Biotage™ Horizon chromatography (FLASH 40 M, silica, gradient from 10% ethyl acetate/hexane to 45% ethyl acetate/hexane) to yield 2.67 g (82%) (4S)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetyl]-1,3-oxazolidin-2-one as a colorless foam. MS (ESI) m/z 406; [α]D25=+109° (c=0.010 g/mL, EtOH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccccc2)c1

Procedure:
A mixture of 1564 g. (10.2 mole) of methyl 3-hydroxybenzoate, 1407.6 g. (10.2 mole) potassium carbonate and 1285.2 g. (10.2 mole) benzyl chloride in 5 . of acetone is heated at reflux for 22 hours. The reaction mixture is then cooled, filtered and the filtrate evaporated. The residue is crystallized in a small volume of pentane to give a quantitative yield of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[H-].[Na+].[CH3:23]I.Cl>C1COCC1.O1CCOCC1>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:2][O:1][CH3:23])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=1
Reactant: CI
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COCc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of Example 417A (142 mg, 0.5 mmol) in THF (3 mL) at room temperature was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol) and methyl iodide (0.30 mmol), stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine (3-aminophenyl)carbamic acid tert-butyl ester (0.156 g, 0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and dichloromethane (8 mL). Stir at room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL 1N aq.). Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography on a Biotage® silica cartridge eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the free base of the title compound. Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title compound as a white solid: mp 124-5° C.; mass spectrum (ion spray): m/z=306.2 (M+1), 1H NMR (CDCl3): 7.06 (t, J=8.0 Hz, 1H), 6.86 (bs, 1H), 6.51-6.48 (m, 1H), 6.42 (bs, 1H), 6.30-6.27 (m, 1H), 3.60 (bs, 1H), 3.30 (bs, 1H), 2.80 (bd, J=11.8 Hz, 2H), 2.31 (s, 3H), 2.19-2.02 (m, 4H), 1.89 (bs, 2H), 1.52 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:17]=3[C:16]=2[CH3:25])(=[O:14])=[O:13])=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:6]=1)=O.O1CCOCC1.C(=O)([O-])O.[Na+].[C:41]([NH2:44])(=[S:43])[CH3:42]>C(O)C>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[S:19][C:15]([S:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]4[N:44]=[C:41]([CH3:42])[S:43][CH:2]=4)=[CH:6][C:7]=3[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:13])=[O:14])=[C:16]([CH3:25])[C:17]=2[CH:23]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2S(C)(=O)=O)sc2ccc(F)cc12
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)cs1
Reaction time: 2 h
Yield: 42.6 %

Procedure:
Into 4.0 mL of chloroform was dissolved 200 mg of Compound 19, and 194 mg of benzyltrimethylammonium tribromide was added, followed by 1 hour of stirring at room temperature. The reaction was terminated by adding water to the reaction solution and then the solvent was once removed by evaporation. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was washed with methanol to obtain 201 mg of N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide as a colorless solid. The thus obtained N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide (150 mg) was dissolved into a mixed solution of 1.5 mL of dioxane and 1.5 mL of ethanol, and 53 mg of sodium hydrogen carbonate and 26 mg of thioacetamide were successively added, followed by 2 hours of stirring under heating and refluxing. The reaction was terminated by adding water to the reaction solution and then the solvent was removed by evaporation under reduced pressure. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 61 mg of the title compound as light yellow powder.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: O=C1CN(c2cncc(Cl)n2)CCN1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C1CN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CCN1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 4-(6-chloropyrazin-2-yl)piperazin-2-one (132) (33 mg, 0.184 mmol, 0.9 eq) in DME (8 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.409 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-2-one 133 in 9 mg quantity. The compound 133 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.84 (s, 1H), 8.95 (d, J=2.07, 1H), 8.64 (d, J=1.95, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H, 7.53 (m, J=2.92, 1H), 6.56 (m, J=1.70, 1H), 4.18 (s, 2H), 3.89 (m, J=5.36 2H); MS m/z 294.9 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.CN(C1NC=NN=1)C.CN1CCOCC1.CN(C(O[N:56]1[N:64]=[N:63][C:58]2C=[CH:60][CH:61]=[N:62][C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:63][CH2:58][C:57]1[NH:62][C:61]([CH3:60])=[N:64][N:56]=1)=[O:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)c1nnc[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)[nH]1
Reaction time: 1 h
Yield: 52.2 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), methyl-4H-1,2,4 triazole-3-yl-methylamine hydrogen chloride (7.80 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12.6 mg, 0.024 mmol, 51.2% yield): LCMS=526.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (2 H, d, J=8.28 Hz), 7.49-7.76 (8 H, m), 5.18 (1 H, s), 4.35-4.61 (2 H, m), 4.26 (1 H, s), 2.41 (3 H, br. s.); HPLC peak RT=2.3 min (Method E).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1Cl)[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8]2=[O:21]>CN(C=O)C.COCCO>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[N:2]([CH3:3])[CH3:1])[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8]2=[O:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: CNC
Solvent: CN(C)C=O
Solvent: COCCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N(C)C)cc21
Reaction time: 7 h
Yield: 88 %

Procedure:
13 g of dimethylamine were dissolved in a mixture of DMF (20 cm3) and methyl cellosolve (20 cm3). 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid were added and the mixture was heated, whilst stirring, in an autoclave at 120°-130° C. for 7 hours. After cooling, the solution was concentrated to dryness in vacuo and the residue was taken up in 20 cm3 of water. The solid was filtered off and recrystallised from methyl cellosolve (30 cm3). 3.9 g of 6-chloro-7-dimethylamino-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 210° C., were obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[CH2:23]([NH:22][C:20]1[CH:19]=[CH:18][C:17]([S:30][C:31]2[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(NCc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (105 mg, 0.50 mmol) was reacted with the product from Example 44c (161 mg, 0.50 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (68 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.83 (sext, J=7.35 Hz, 2H) 2.97 (dd, J=7.35 Hz, 2H) 4.29 (m, 2H) 6.15 (d, J=6.99 Hz, 1H) 6.51 (d, J=8.46 Hz, 2H) 6.93 (d, J=8.46 Hz, 2H) 7.22-7.38 (m, 8H) 7.78 (d, J=8.83 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 9.66 (s, 1H) 10.90 (br s, 1H) 14.21 (br s, 1H); MS (ESI+) m/z 493 (M+H−TFA)+.