Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].CO[C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:24][O:23][C:21]1[CH:22]=[CH:16][C:17]([NH:18][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:19][CH:20]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 102 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6e (197 mg, 78%); mp: 147-149° C.; 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 8.24 (dd, J=4.9, 1.7 Hz, 1H), 7.55-7.48 (dd, J=7.7, 1.7 Hz, 1H), 7.17 (t, J=5.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.62-6.57 (m, 1H), 6.42-6.39 (m, 3H), 5.42 (s, 2H), 4.66 (d, J=5.4 Hz, 2H), 3.79 (s, 3H), 3.75 ppm (s, 6H) MS (ESI m/z): 475 [M+H]+. Yield: 78%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([OH:14])=O)[CH2:7]1.[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:12]([C@H:8]1[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])[CH2:7]1)=[O:14])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C[C@@H](C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)CC2=O)c(OC)c1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (20 g) prepared according to the same procedures as Preparation 5 in chloroform (200 ml) were sequentially added (S)-4-benzyl-2-oxazolidinone (15.2 g) and WSC.HCl (16.4 g), 4-(dimethylamino)pyridine (4.4 g) at room temperature, and the mixture was stirred for 3 hours. This reaction solution was washed with a 5 wt % aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/3), subjected to azeotropic drying with toluene, and dried under reduced pressure to give the titled compound (17.2 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.CCN(CC)CC.[NH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)Cl>[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:30][CH2:29]1
Reactant: NC1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirring solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100 mg, 0.35 mmol), Et3N (72 μL, 0.52 mmol), and CH2Cl2 (300 μL) under N2, was added 4-aminopiperidine (54 μL, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 98% CH2Cl2/2% MeOH to obtain the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349.3 retention time 2.22 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:24][C:25](S(C)(=O)=O)=[N:26][N:27]=5)[CH:21]=4)[N:16](C(OC(C)(C)C)=O)[CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH3:39].CCOC(C)=O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:24][C:25]([NH2:39])=[N:26][N:27]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5nnc(S(C)(=O)=O)s5)cc34)n2)CC1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CCN(c2cccc(-c3c[nH]c4ccc(-c5nnc(N)s5)cc34)n2)CC1
Temperature: 120 °C
Yield: 19 %

Procedure:
A sealed tube was charged with tert-butyl 3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (300 mg, 0.541 mmol) followed by ammonia in DMSO (10 mL). The reaction was heated at 120° C. for 4 h. Ice/H2O and EtOAc were added to the mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried, filtered and concentrated. The residue was purified with RP-HPLC to give 5-(3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (40 mg, 19%). MS (ESI, pos. ion) m/z: 392.1 (M+1); 1H-NMR (DMSO-d6, 300 MHz) δ 11.76 (1H, s), 10 (1H, brs), 8.8 (1H, s), 8.16 (1H, s), 7.5-7.67 (4H, m), 7.28-7.3 (1H, d), 6.75-6.79 (1H, d), 4.54-4.57 (2H, d), 3.6-3.65 (2H, d), 3.17-3.24 (4H, m), 2.91 (3H, s).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[O:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:20][C:7]1[CH:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:14]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:2])=[O:21]
Reactant: Oc1ccccc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccccc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 2-phenoxy-phenol as in Example 18 to afford 0.106 g (42%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C28H24O5 440, found 441 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][C:9]=2[CH3:20])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[C:12]4[N:11]([C:23](=[S:24])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][C:9]=2[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(c2cccc(Cl)c2)n2ncc(C(N)=O)c2NC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(c2cccc(Cl)c2)n2ncc3c(=O)[nH]c(=S)n(c32)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A mixture of 5.0 g of 7-(3-chlorophenyl)-4,5-dihydro-6-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 36) and 0.2 liters of dry tetrahydrofuran is stirred and cooled to -78° C. in a dry ice-acetone bath, then 1.43 g of sodium hydride (60 percent dispersion in mineral oil) is added in one portion. This mixture is stirred at -78° C. for 1.5 hours then 3.19 g of 1,1'-thiocarbonyldiimidazole is added and stirring is continued at -78° C. for 2 hours. The mixture is allowed to warm to room temperature and is stirred for 48 hours and then the reaction is quenched with 0.5 liters of water and neutralized with 5 percent aqueous hydrochloric acid. The crystalline solid that forms is collected, washed with ether and dried to give 4.0 g of the desired product as cream colored crystals, mp 289-291° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCCN1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.8 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 3.13 grams of 4-amino-1-n-butyl piperidine and 21.2 grams of sodium carbonate in 50 milliliters of water and 50 milliliters of chloroform. After stirring overnight at room temperature, the chloroform layer was separated, washed with water, dried and evaporated to give a brown solid which was triturated with ether to give 5.0 grams of the title compound as the hemihydrate. Melting point 190°-191°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[C:17]=3[O:19][CH3:20])[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:43]([O:47][C:48]([NH:50][NH2:51])=[O:49])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([O:47][C:48]([NH:50][NH:51][C:21]([C:16]1[C:17]([O:19][CH3:20])=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:11]=[C:10]2/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:22])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1c(C(=O)O)ccc2c1c(/C=C/c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1c(C(=O)NNC(=O)OC(C)(C)C)ccc2c1c(/C=C/c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 112 %

Procedure:
94 mg of 3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid and 34.4 mg of hydrazine carboxylic acid tert-butyl ester were condensed in the manner as described in Example 127, to afford 126.9 mg of the title compound as pale yellow crude crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=1>CO.C1COCC1.[Ni]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NCCN2CCCC2)c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(NCCN2CCCC2)c1

Procedure:
4-Nitro-3-(2-pyrrolidin-1-yl-ethylamino)-benzoic acid methyl ester (xiii) (1.30 g, 4.42 mmol) was shaken in MeOH/THF 1:1 (40 mL) in presence of Raney nickel under 1.1 bar H2 at rt for 40 min. The catalyst was filtered off and washed with MeOH. The filtrate was evaporated to give the title compound as an oil (tR 2.05 min (conditions 8), MH+=264).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][NH:9][N:8]=1)=[O:6].[CH3:15]I>O1CCCC1>[CH3:3][O:4][C:5]([C:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]([CH3:15])[N:8]=1)=[O:6]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A mixture of sodium hydride (167 mg, 6.96 mmol) in tetrahydrofuran (15 mL) cooled to 0° C. was treated with a solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.0 g, 5.8 mmol) in tetrahydrofuran (10 mL). This mixture was stirred at 0° C. for 1 h. It was then treated with methyl iodide (0.54 mL, 8.7 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was cooled to 0° C. and was then quenched with a saturated aqueous ammonium chloride solution and diluted with ethyl acetate (200 mL). This solution was washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was slurried in 40% ethyl acetate/petroleum ether and cooled in the freezer for 15 min. At this time, the solids were collected by filtration to afford 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (889 mg, 82.8%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ8.93 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:9][C:4]2[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-chloropyridin-3-amine (1.535 g, 7.399 mmol, Asymchem Laboratories, Morrisville, N.C.) was dissolved in pyridine (20 mL), and 4-acetylbenzenesulfonyl chloride (2.436 g, 11.14 mmol) was added. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (110 C-115 C) and stirred under nitrogen for 2 hours. The reaction was then cooled to room temperature, concentrated, and poured into a biphasic solution of water (40 mL) and DCM (50 mL). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter plug (DCM to 20:1 DCM/MeOH) to afford 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide. MS (ESI positive ion) m/z: 389 (M+1, 79Br), 391 (M+1, 81Br). Calcd. for C13H10BrClN2O3S: 388 (79Br), 390 (81Br).
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]1=O.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1.C[Li]>CO>[CH2:20]([C@@H:3]1[N:2]([CH3:1])[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH2:16][CH2:17][CH3:18]
Reactant: C1CCOC1
Reactant: CN1C(=O)CC[C@H]1COc1cccnc1
Agent: [Li]C
Solvent: CO
Product: CCCC[C@H]1CC[C@@H](COc2cccnc2)N1C
Temperature: -78 °C
Reaction time: 44 h

Procedure:
A 1.24 g (6.0 mmol) sample of 3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as in Example 22b above, was dissolved in mL of THF and cooled to -78° C. To this solution was added 6.0 mL (12 mmol) of 2 M methyl lithium, and the solution was warmed to room temperature, then stirred for 44 hours. Two mL of methanol were added, and the mixture concentrated under vacuum. Another 10 mL of methanol was added, followed by 65.6 mg of NaBCNH3 and a trace of bromocresol green indicator. HCl (4M) was added slowly until the solution remained a yellow color, then the reaction mixture was stirred for 1 hour. The mixture was then adjusted to basic pH with satd NaHCO3, concentrated, and extracted with ethyl acetate. The extract was dried, concentrated and chromatographed on silica gel to give 86 mg of title compound. MS (DCI/NH3) m/e: 248 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.33-8.31 (m, 1H), 8.23-8.19 (m, 1H), 7.23-7.19 (m, 2H), 4.11-4.04 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.77 (m, 1H, 2.46 (s, 3H), 2.40-2.27 (m, 1H), 2.05-1.20 (m, 10H), 0.92 (t, J=6.0 Hz, 3H).
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: Cn1ccc2cc(Br)ccc21
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
2,6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:6]=[C:7](SC)[NH:8][CH:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)#[N:5].C[O-].[Na+]>CO>[C:4]([NH:6][C:7]1[NH:2][N:3]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([CH3:18])[N:8]=1)#[N:5]
Reactant: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Reactant: NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1N=C(NC#N)NN=C1c1ccccc1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Hydrazine hydrate (4.55 g) was added to a solution of 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (5.43 g) in methanol (20 ml), and the mixture was allowed to stand at room temperature for 1 hour. After addition of catalytic amount of sodium methoxide to the solution, the mixture was allowed to stand at room temperature for 2 hours with occasional shaking. The resultant preapitates were collected, washed successively with methanol, water and methanol and dried. Thus obtained product was dissolved with dimethylformamide (25 ml), the solution was filtered by suction and then water (25 ml) was added thereto little by little. After cooling, the resultant precipitates were collected by filtration, washed successively with ethanol, water and ethanol, and dried to give 3-cyanoamino-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (2.37 g), m.p. 244.5°~245° C. (decomp.).
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31]C(=O)[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>CO.ClCCl>[CH3:7][O:6][C:1]1([O:4][CH3:5])[CH2:29][CH2:28][CH:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: COC(OC)OC
Reactant: O=C1CCC(OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC1(OC)CCC(OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
529 mL of trimethyl orthoformate and 32 mg of p-toluene sulfonic acid were added to a solution of 4-benzyloxy cyclohexanone in 20 mL of dry methanol and the mixture was stirred overnight. 20 mL of saturated aqueous sodium bicarbonate solution and 20 mL of dichloromethane were added, the aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried and evaporated to dryness to yield 1.50 g of the desired product, which was used without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[CH3:34][S:31]([NH:30][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[O:3][C:4]([C:7]3[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:5][N:6]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(C)(=O)=O)c3)o2)cc2ccccc21
Temperature: 80 °C
Yield: 53.4 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.281 g, 0.883 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.321 g, 1.723 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-(methylsulfonamido) phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 24 (0.221 g, 54% yield) as solid. MS (ES) m/z 469 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.C([O:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH:21]=1)C.Cl>C1COCC1.CCOCC>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:22]2[CH2:23][CH2:24][CH2:25][C:20](=[O:19])[CH:21]=2)=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCc1ccc(Br)cc1
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(C2=CC(=O)CCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a suspension of magnesium (1.477 g, 60.8 mmol) in THF (56 mL) was added 1-bromo-4-octylbenzene (15.00 g, 55.7 mmol). After stirring for about 6 h the reaction mixture was added with filtering to a solution of 3-ethoxycyclohex-2-enone (7.10 g, 50.6 mmol) in THF (28.0 mL) at 0° C. Following the addition the reaction mixture was allowed to warm to room temperature. After 1 h 1N HCl was added until a pH of 1 was obtained. The reaction mixture was diluted with Et2O and the organic layer was separated, washed with NaHCO3, and brine, dried with (Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/Hep) to provide 3-(4-octylphenyl)cyclohex-2-enone (9.5 g, 33.4 mmol, 65.9% yield) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5].[O:20]1C2C=CC=C(C(O)=O)C=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:16]2[CH:17]=[CH:18][CH:2]=[C:3]([C:4]([NH:6][C:7]3[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=3)=[O:5])[C:15]=2[O:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Product: O=C(Nc1c[nH]nc1C(=O)O)c1cccc2c1OCCO2

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid as the starting acid to give 4-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid (340 mg) as a white solid. (1H NMR (300 MHz, DMSO-d6) δ 13.5 (s, 2H), 11.2 (s, 1H), 8.4 (s, 1H), 7.7 (d, 1H), 7.1 (d, 1H), 7.0 (t, 1H), 4.5 (s, 2H), 4.4 (s, 2H)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]([OH:19])=[O:18])[N:3]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:19])[CH3:26]
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(=O)O)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 73 by refluxing in ethanol in the presence of concentrate sulphuric acid, mp. 177.5° C.