Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]>C1COCC1.C(Cl)Cl>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:15]([CH3:14])[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Br)sc2c1
Reactant: CNCCN(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 0.1 %

Procedure:
Suspend 2-bromo-6-nitrobenzthiazole (5.00 g, 19.3 mmol) in THF (150 mL). Add N,N, N-trimethylethylene diamine (5.2 g, 40.0 mmol) and stir at room temperature for 6 h. Dilute with CH2Cl2, wash with saturated sodium bicarbonate (2×) and brine, and concentrate in vacuo to afford the crude title compound (5.79 mg, 100%). Carry the crude product on as is. 1H NMR (400 MHz, CDCl3): δ 8.50 (d, 1H, J=2.2 Hz), 8.19 (dd, 1H, J=8.8, 2.2 Hz), 7.49 (d, 1H, J=9.2 Hz), 3.73 (m, 2H), 3.27 (s, 3H), 2.64 (t, 2H, J=6.8 Hz), 2.33 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.C(N(CC)CC)C.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:5]1([O:4][CH2:3][CH2:2][O:1][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2nccs2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3nccs3)CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 16 h

Procedure:
To an ambient solution of tert-butyl 3-(2-hydroxyethoxy)-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (1.92 g, 6.11 mmol) in dichloromethane (20 mL) was added triethylamine (1.70 mL, 12.21 mmol), 4-dimethylaminopyridine (0.075 g, 0.611 mmol), and para-toluenesulfonyl chloride (1.28 g, 6.72 mmol). The reaction was stirred for 16 hours and was quenched by the addition of saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product, which was used without further purification. MS ESI(+) m/z 468.8 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[OH:18].CS(O)(=O)=O.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1>ClCCCl.CN1CCCC1=O.O.ClCCl.[OH-].[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[OH:18]
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(O)c(C(O)c2nc3ccccc3[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(O)c(C(OC2CCN(C)CC2)c2nc3ccccc3[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-[(1H-benzimidazol-2-yl)hydroxymethyl]-4-methylphenol (prepared according to procedure 561B) (360 mg), methanesulfonic acid (500 μL) and 1-methyl-4-piperidinol (500 mg) in 1,2-dichloroethane (20 mL) and N-methylpyrrolidinone (2 mL) is warmed at 90° C. for 2 h. After cooling at 0° C., the mixture is diluted with water and dichloromethane and concentrated sodium hydroxide slowly added up to pH 9. Organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 80/20/0.5) to afford 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol, melting at 151° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7](S([O-])(=O)=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Na+].[NH2-:17].[Na+].N>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:17])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [NH2-]
Reactant: Nc1cccc2c(S(=O)(=O)[O-])cccc12
Agent: N
Agent: [Na+]
Product: Nc1cccc2c(N)cccc12
Yield: 89.5 %

Procedure:
In a 200-ml autoclave were placed 29.2 grams (0.13 mole) of anhydrous sodium 1-aminonaphthalene-5-sulfonate, 13.2 grams (0.33 mole) of sodium amide and 110 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 200° C for 5 hours. The reaction pressure in the autoclave was 180 atm. during the reaction. After the ammonia was removed, 50 ml of methanol was added to the reaction mixture for solvolysis. The product was extracted with chloroform and the chloroform was distilled off to produce crude 1,5-diaminonaphthaline. The recrystallization thereof from ether gave 18.4 grams of 1,5-diaminonaphthalene having a melting point of 187° to 189.5° C. Yield was 89.1%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:28]1([NH:32][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:10][NH:11]3)=[CH:16][CH:15]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCC1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 125.6 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), cyclobutylamine (18.2 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 43.2 mg (92%) of the title compound as a TFA salt (1.5 H2O, 1.1 TFA, effective MW=561.92). 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.72 (2H, m), 8.13 (4H, m), 7.70 (1H, d, J=7.1), 7.58 (2H, m), 7.41 (2H, m), 7.27 (1H, s), 6.89 (1H, t, J=4.2), 2.84 (1H, m), 0.72 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 396.1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.CN([CH:28]=[O:29])C>>[C:17]([O:16][CH2:15][CH2:14][N:7]([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([CH:28]=[O:29])=[CH:10][CH:9]=1)(=[O:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Yield: 93 %

Procedure:
N,N-Di-(2-acetoxyethyl)aniline (A6) (126 g, 0.476 mol) was reacted with phosphorous oxychloride (80.3 g, 0.524 mol) in DMF as for A2 in Example 3. The product was distilled at 155°-175° C. (0.15 mm) to yield 130 g (93%) of A7 as an orange oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:36](=[O:45])[C:37]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]2[C:39]1=[O:40])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 25.8 %

Procedure:
In 100 ml of acetonitrile are dissolved 2.8 g of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 7.6 g of ethyl 2-bromo-8-phthalimidooctanoate, and 1.3 g of triethylamine is added to the solution. After heating at 80° C. for 3 days, the reaction solution is concentrated under reduced pressure, diluted with 200 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (10 ml) and oxalic acid (2.8 g) are added to the residue, and 200 ml of petroleum ether is added to the solution. After shaking, the resulting solution is allowed to stand. The supernatant is removed by decantation and 150 ml of water and 200 ml of ethyl acetate are added to the precipitate. The mixture is neutralized with sodium bicarbonate and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is separated and purified by silica gel column chromatography to give 1.5 g of tert-butyl 3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate from the first fraction.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C.[H-].[Na+]>CS(C)=O.O>[Br:23][C:21]1[CH:20]=[N:19][C:18]2[NH:24][C:4](=[O:3])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:16][C:17]=2[CH:22]=1
Reactant: CCOC(=O)CN(CCCN1CCOCC1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CN(CCCN2CCOCC2)Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)-(3-morpholin-4-yl-propyl)amino]acetic acid ethyl ester (11.8 g, 28.3 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 1.13 g, 28.3 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (7×250 mL). The combined organic layers were washed with H2O (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 96:4) gave the title compound (5.76 g, 55%) as an off-white powder: MS (ESI) m/e 369 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.Br[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C(OCC)C>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccs1
Reactant: Brc1cccc2ccccc12
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: c1csc(-c2cccc3ccccc23)c1
Reaction time: 0.5 h

Procedure:
2-Bromothiophene(1.45 ml, 0.015 m) in diethyl ether (20 ml) was added slowly to magnesium turnings (0.48 g, 0.02 m) and iodine (trace) in diethyl ether (10 ml). It was stirred for 30 min before being added to 1-bromonaphthalene (2.07 g, 0.01 m) and catalyst in diethyl ether (25 ml). The reaction was worked up the usual way yielding a brown oil (2.49 g). The brown oil was purified by column chromatography. Flash silica (104 g) eluted with petroleum ether (600 ml) and increased to 5% diethyl diethyl ether/petroleum ether separated a clear pale green oil (1.50 g, 71% yield); m/z 210 (M+); (Found: C, 80.26; H, 4.91; S, 15.10. C14H10S requires: C, 80.00; H, 4.76; S, 15.24); H NMR (CDCl3), δ7.17 (dd, J=3.2, 5.6 Hz 1H), δ7.23 (dd, J=<1, 3.2 Hz, 1H), δ7.41 (dd, J=<1, 5.6 Hz, 1H), δ7.45 (d, J=4.8 Hz, 1H), δ7.47 (d, J=4.8 Hz, 1H) δ7.48 (d, J=8 Hz, 1H), δ7.55 (dd, J=<1, 8 Hz, 1H), δ7.83 (d, J=8 Hz, 1H), δ 7.88 (dd J=3.2, 4.8 Hz, 1H), δ8.20 (dd, J=5.6, 4.8 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O.[CH3:34][O:35][C:36]1[C:37]([CH3:60])=[C:38]([C:51]([O:58][CH3:59])=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[CH2:39][C:40]1[CH:41]=[CH:42][C:43](O)=[C:44]([CH:49]=1)[C:45]([O:47][CH3:48])=[O:46].[OH-].[Na+]>C1C=CC=CC=1>[CH3:34][O:35][C:36]1[C:37]([CH3:60])=[C:38]([C:51]([O:58][CH3:59])=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:44]([CH:49]=1)[C:45]([O:47][CH3:48])=[O:46]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Reactant: OCc1ccncc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
4-Pyridinemethanol (0.232 g, 2.13 mmol), tri-n-butylphosphine (0.430 g, 2.13 mmol) and N,N,N′,N′-tetramethylazodicarboxamide (0.366 g, 2.13 mmol) were added to a benzene solution of methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (0.500 g, 1.33 mmol) and the solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous 2N sodium hydroxide solution (15 ml) and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:3) to obtain the titled compound (0.610 g, 1.31 mmol, 98%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[CH2:16]([O:18][C:19]1[N:24]=[N:23][C:22]([C:25]([O:27]CC)=O)=[C:21]([C:30]([F:33])([F:32])[F:31])[CH:20]=1)[CH3:17].[Br:34][CH2:35][Br:36].Cl>C1COCC1.[Cl-].[Na+].O>[Br:34][CH:35]([Br:36])[C:25]([C:22]1[N:23]=[N:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][C:21]=1[C:30]([F:31])([F:32])[F:33])=[O:27]
Reactant: BrCBr
Reactant: CCOC(=O)c1nnc(OCC)cc1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(F)(F)F)c(C(=O)C(Br)Br)nn1
Temperature: 0 °C

Procedure:
Dissolve 2,2,6,6-tetramethylpiperidine (19.3 g, 136 mmol) in dry THF (300 mL). Cool the solution to 0° C., and slowly add n-BuLi (2.5M Hexanes; 50 mL, 125 mmol). Stir the mixture at 0° C. for ten minutes, and then cool to −78° C. Add this solution via canula to a mixture of ethyl 6-ethoxy-4-(trifluoromethyl)pyridazine-3-carboxylate (15.0 g, 56.8 mmol; prepared essentially as described by Guillaume et al. (1995) Synthesis 8:920-922) and dibromomethane (23.6 g, 136 mmol) in dry THF (300 mL) at −78° C. Stir the mixture at −78° C. for 30 minutes. Quench the reaction with water (200 mL) and allow it to warm to room temperature. Add brine (100 mL) and 3N HCl (100 mL). Extract with EtOAc (3×300 mL). Dry the combined organic extracts over sodium sulfate and evaporate. Chromatograph on silica eluting first with hexane followed by hexane/EtOAc (95/5) to yield the title compound. LC/MS (MH+) 392.87.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.NN.[C:30](Cl)(=[O:32])[CH3:31]>CO.C(Cl)Cl.N1C=CC=CC=1.[Ni]>[C:17]([C:16]1[C:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[C:12]([C:19]2[CH:20]=[C:21]([NH:25][C:30](=[O:32])[CH3:31])[CH:22]=[CH:23][CH:24]=2)[CH:13]=[N:14][CH:15]=1)#[N:18]
Reactant: N#Cc1cncc(-c2cccc([N+](=O)[O-])c2)c1Nc1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Ni]
Agent: NN
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(1H-indol-5-ylamino)-5-(3-nitrophenyl)nicotinonitrile 151 (9 mg, 0.025 mmol) in MeOH (1 mL) were added hydrazine (20 uL) and Raney-Nickel (2-5 mg). The mixture was stirred for 2 h then filtered through celite and the filtrate was concentrated to give the crude reduced product which was then dissolved in CH2Cl2 (1 mL) and pyridine (20 uL), and acetyl chloride (20 uL) was added. After stirring for 1 h, the reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (4 mg). MS: 366.0 (M+H), HPLC retention time: 1.61 min.(a).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: O=C(O)c1ccncc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and isonicotinic acid as brown solid (36%). MS 409 (MH+).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9](=[O:10])[O:11][CH3:12])=[CH:26][CH:25]=1
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.83 h
Yield: 79 %

Procedure:
0.14 ml of triethylamine and 0.08 ml of methyl chloroformate were added to a solution of 250 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in Example 3(b)] in 5 ml of methylene chloride cooled in an ice-water bath and the resulting mixture was stirred at the same temperature for 50 minutes. The temperature of the reaction mixture was then elevated to room temperature and the mixture was stirred for a further 30 minutes. At the end of this time water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was; washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate to give 243.1 mg (yield 79%) of the title compound as a solid having a melting point of 142°-144° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C:7](=O)[C:8](=O)[CH3:9])([CH3:4])([CH3:3])[CH3:2].IC1C=CN=C(OC)C=1C=O.C(OC(C1[NH:30][C:31]([C:35]2[C:36]([O:42][CH3:43])=[N:37][CH:38]=[CH:39][C:40]=2[I:41])=[N:32]C=1C)=O)C>>[I:41][C:40]1[CH:39]=[CH:38][N:37]=[C:36]([O:42][CH3:43])[C:35]=1[C:31]1[NH:30][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])=[C:8]([CH3:9])[N:32]=1
Reactant: CCOC(=O)c1[nH]c(-c2c(I)ccnc2OC)nc1C
Reactant: CC(=O)C(=O)C(=O)OC(C)(C)C
Agent: COc1nccc(I)c1C=O
Product: COc1nccc(I)c1-c1nc(C)c(C(=O)OC(C)(C)C)[nH]1
Yield: 47 %

Procedure:
2,3-Dioxo-butyric acid tert-butyl ester (0.293 g, 1.54 mmol) and 4-iodo-2-methoxy-pyridine-3-carbaldehyde (0.405 g, 1.54 mmol) were reacted as described for the synthesis of 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester to give the title material (0.303 g, 47%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 1.58 (s, 9H) 2.46 (s, 3H) 3.85 (s, 3H) 7.64 (d, J=5.31 Hz, 1H) 8.00 (d, J=5.31 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
As shown in Reaction Scheme 5, methyl 3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-carboxylate (0.64 g, 1.6 mmol) was suspended in THF (10 mL), MeOH (10 mL) and water (5 mL), and LiOH (0.39 g, 16.2 mmol) was added. The reaction mixture was heated at 50° C. until dissolution was achieved, and then the mixture was stirred for 3 days at rt. The reaction mixture was brought to pH 4 with 1N HCl and was extracted with EtOAc (3×25 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. This yielded 0.518 g (84%) of the desired product as an off-white solid. LC/MS m/z 383.3 (MH+), retention time 3.83 min. 1H NMR (400 MHz, DMSO-d6) δ 7.18 (t, 1H), 7.59-8.00 (m, 8H), 8.70 (t, 1H), 10.50 (bs, 1H), 12.95 (bs, 1H).
Reaction SMILES: C([O:9][N:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[C:25]([O:33][CH3:34])[CH:24]=1)[C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=O)C1C=CC=CC=1>[NH4+].[OH-].CO>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([N:10]([OH:9])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[O:20])=[CH:18][CH:17]=1
Reactant: C#CCOc1ccc(CCN(OC(=O)c2ccccc2)C(=O)Cc2ccc(Cl)cc2)cc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1ccc(CCN(O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzoyloxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (0.3 g, 0.6 mmol) is dissolved in 2 ml 10% NH4OH/MeOH and stirred at room temperature overnight. The solvent is removed under vacuum and the crude product is purified by flash chromatography (ethyl acetate:hexane, 1:2) to yield 2-(4-chloro-phenyl)-N-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as a solid.
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([N:19]([CH2:25][C:26]3[CH:31]=CC=C[CH:27]=3)[C@H](C)C(O)=O)(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)CCCC.C(Cl)(=O)[C:33]([Cl:35])=[O:34].CN(C=O)C>ClCCl>[CH3:31][CH:26]([CH3:27])[C@@H:25]([NH:19][S:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([S:6][CH3:1])[S:8][C:9]=2[CH:15]=1)(=[O:17])=[O:18])[C:33]([Cl:35])=[O:34]
Reactant: CCCCCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H](C)C(=O)O)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2s1
Temperature: 0 °C

Procedure:
(2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl) benzylamino]propionic acid (157 mg, 0.328 mmol) prepared in Example 33 was dissolved in dichloromethane (2 mL) and cooled down to 0° C. Oxalylchloride (0.114 mL, 10 equi.) and DMF of catalytic amount were added and the reaction solution was refluxed for 3 hours at RT. After reaction, the solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure to give (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic chloride. The compound was then dissolved in THF (1 mL) to obtain acid chloride THF solution. Hydroxyamine hydrochloride salt (0.23 g, 10 equi.) and NaHCO3 (0.33 g, 12 equi.) were dissolved in THF/H2O (3 mL/3 mL) and cooled down to 0° C. to give a hydroxyamine solution. The above acid chloride THF solution was slowly added to the hydroxyamine solution at 0° C. After 1 hour, the solvent was removed from the reaction solution. Then, the product was extracted with ethylacetate 10 mL), washed with H2O and 0.1N HCl, dried over MgSO4, distilled under reduced pressure and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)benzylamino]propionamide (163 mg, 100%).