Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[OH:11].[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:8])=[CH:4][C:3]=1[OH:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Cl)c(O)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 46 %

Procedure:
The title compound is prepared from 4-chloro-3-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=342/344 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]([CH3:12])(O)[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C(O)=O.C1(C=CC(O)=CC=1)O>C(OC(=O)C)(=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH2:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(C)(O)C1=O
Agent: Oc1ccc(O)cc1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: C=C1NC(=O)N(CCCC)C1=O
Temperature: 120 °C

Procedure:
3-n-Butyl-5-methyl-5-hydroxyhydantoin (5.1 g 0.027 mole) was added to an ice-cold solution of 80% formic acid (50 ml) in acetic anhydride (60 ml) containing a small amount of hydroquinone (0.1 g) and the mixture heated on an oil-bath at 120° C. for 15 minutes. The mixture was then cooled to room-temperature and the solvents removed on the rotary evaporator under reduced pressure, yielding an oil which readily crystallised. The title product was crystallised from ethyl acetate-light petroleum (b.p. 40°-60° C.) to yield the product as prisms, m.p. 73° C. Yield=4.3 g=94%.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)Nc3ccc(F)cc3)c(=O)n12
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 25 minutes. After stirring for 5 minutes, 9.78 g (0.088 mol) of 4-fluoroaniline dissolved in 80 ml of chloroform are dropped to the above solution at -13° C. during 30 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 18.3 g (77%) of the named compound as yellow crystals after recrystallization from n-propanol, m.p.: 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH3:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:4]1[CH:3]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:7]=[N:6][CH:5]=1
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Reactant: CS(=O)(=O)Cl
Product: Cn1c(-c2cncc(NS(C)(=O)=O)c2)cc2ccccc21

Procedure:
2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100) and methanesulfonyl chloride are processed according to the methods described in Example 225a and 225c to give methanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.15 (s, 3H), 3.77 (s, 3H), 6.71 (s, 1H), 7.06-7.13 (m, 1H), 7.23 (ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.79 (t, J=2.2 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 10.18 (s, 1H). HRMS: (ESI) m/z 302.0966 [(M+H)+ Calcd for C15H16N3O2S 302.0958].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:55][CH2:56][CH2:57][N:51]([CH3:50])[CH2:52][CH2:53]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCCN(C)CC4)c3)c2C)c1
Yield: 42 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1-methylhexahydro-1H-1,4-diazepine (30.4 μL., 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [48.3 mg (42%)]. LC-MS m/z 757.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CC1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.1 %

Procedure:
To a mixture of 2-(piperidin-4-yl)-acetic acid ethyl ester (211.4 mg, 1.234 mmol, Oakwood,) in N,N-dimethyl formamide (5.0 mL) was added 1,1′-carbonyldiimidazole (216 mg, 1.332 mmol Aldrich). After it was stirred at rt for 4 days under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give [1-(imidazole-1-carbonyl)-piperidin-4-yl]acetic acid ethyl ester (293.3 mg, 1.10 mmol, 89.6%) which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][CH:2]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:34])=[CH:25][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.69 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (322 mg, 1.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (487 mg, 2.54 mmol) and 1-hydroxy-1H-benzotriazole (259 mg, 1.69 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (650 mg, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH:8]=[C:9]3[C:14](=[CH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:17]=[C:16]2[C:7]([CH:8]=[C:9]3[C:14](=[CH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2cc3c(cc2c1)CCCC3
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cc3c(cc2c1)CCCC3
Reaction time: 5 h
Yield: 97.8 %

Procedure:
A mixture of 4 mg (17.62 mmol) of 1,2,3,4-tetrahydro-7-nitroanthracene (John D. Scribner and James A. Miller; J. Chem. Soc., 5377 (1965)) and 0.5 g of palladium-on-carbon catalyst in 200 ml of methanol was shaken with hydrogen at 50 p.s.i. for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 3.4 g (97%) of 7-amino-1,2,3,4-tetrahydroanthracene. To a solution of 3.2 g (16.24 mmol) of the latter in 50 ml of dry tetrahydrofuran was added 2.7 g (26.7 mmol) of triethylamine followed by 3 g (24.9 mmol) of trimethylacetylchloride. After stirring at room temperature overnight, the solvent was removed and the residue was triturated with warm water to give 4.52 g (99%) of 7-trimethylacetylamino-1,2,3,4-tetrahydroanthracene, crystallized from methanol into colorless crystals of melting point 202°-204° C. and providing the following analysis:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21](O)=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N:25](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([NH2:25])=[O:22])=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)O)[nH]c23)cc1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(N)=O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a mixture of 7-{[(4-methylphenyl)sulfonyl]amino}-1H-indole-2-carboxylic acid (105 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (58 mg) and N,N-dimethylformamide (5 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (80 mg) at 4° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (69 mg, yield 66%) as pale-yellow crystals. melting point 312-313° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:36][C:6]1[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:29])[N:11]2[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1-phenethyl-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.063 mmol), β-alanine (560 mg, 6.3 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (10-85% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:35]([NH2:36])=[CH:34][N:33]=[CH:32]2)[CH2:27][CH2:26]1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:36][C:35]2[N:31]([CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:32]=[N:33][CH:34]=2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1cncn1C1CCOCC1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Solvent: CN1CCCC1=O
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncn1C1CCOCC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 19.5 %

Procedure:
(6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (120.1 mg, 0.3454 mmol) and 3-tetrahydropyran-4-ylimidazol-4-amine (75 mg, 0.314 mmol) (prepared according to a procedure similar to Preparation 10) were suspended in NMP (1 mL) and stirred at 100° C. for 19 hours. The reaction was cooled to ambient temperature and purified by passing the crude reaction mixture through a 10 g SCX-2 cartridge (pre-washed with MeOH). The cartridge was washed with DCM/MeOH mixtures then the product eluted with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo and the material was purified by fractionlynx. The clean fractions were freeze-dried to give title compound 2-amino-6-fluoro-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a beige solid (21.1 mg, 19% Yield). MS (ES+) 346.1.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH:12][CH3:13].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[CH3:8][O:9][CH2:10][CH2:11][N:12]([CH3:13])[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A stirred solution of triethylamine (2.4 ml, 17.23 mmol) and N-(2-methoxyethyl)methylamine (1.5 g, 16.85 mmol) in DCM (20 ml) was cooled in an ice/water bath. A solution of 4-nitrobenzenesulphonyl chloride (3.2 g, 14.45 mmol) in DCM (20 ml) was added dropwise. The reaction was stirred for one hour the cooling bath was removed and the mixture stirred for further 3 hours. The reaction mixture was washed with 1M hydrochloric acid (40 ml), water (30 ml) and then brine. The volatiles were evaporated to give the title compound (3.8 g). M/z: 245.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][C:13]([O:15]CC)=[O:14])=[O:2].[OH-].[Na+].O>O1CCOCC1>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14])=[O:2]
Reactant: CCOC(=O)Cc1[nH]c2ccccc2c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(CC(=O)O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.7 %

Procedure:
Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1,4-dioxane (100 ml) and added 36% aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCl and extracted with ethyl acetate (250+150 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford 10.3 g (73% over two steps) of (3-formylindolyl)acetic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:29])[NH:9][C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[N:16]=2)=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:30]I>C1COCC1>[C:3]([O:7][C:8](=[O:29])[N:9]([CH3:30])[C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[N:16]=2)=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)OC(C)(C)C)s3)n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(Nc2nccc(-c3ccc(N(C)C(=O)OC(C)(C)C)s3)n2)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% disersion in mineral oil) (21.4 mg, 0.535 mmol) was added to a solution of [5-(2-m-tolylamino-pyrimidin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester (186 mg, 0.486 mmol) in anhydrous THF (5 mL) at ice bath temperature. After 15 minutes, MeI was added and the mixture was removed from the ice bath. Additional NaH (7.7 mg, 0.19 mmol) and MeI (9.0 uL, 0.145 mmol) were added after 5 hours and the reaction was stirred 3 days. The reaction was quenched by addition of a few drops of water and was concentrated to dryness and taken to the next step without further purification. MS: m/z 397 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)c2cccnc2c1OCc1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-bromo-8-hydroxy-[1,6]-naphthyridine-7-carboxylate (7.73 g, 27.4 mmol), 4-methoxybenzyl chloride (5.15 g, 32.9 mmol), and Cs2CO3 (10.7 g, 32.9 mmol) in DMF (150 mL) was stirred in an oil bath at 50° C. overnight. Additional quantity of 4-methoxybenzyl chloride (0.6 g), and Cs2CO3 (1 g) was added, and the mixture heated at the same temperature for 8 hour. The resulting mixture was filtered and concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in boiling ethyl acetate (150 mL), hexane was added until solution turn cloudy. The resultant slurry was stirred at room temperature overnight. The solid precipitated was collected by filtration to provide methyl 5-bromo-8-[(4-methoxybenzyl)oxy]-[1,6]-naphthyridine-7-carboxylate.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C(OCC)C>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:10]=1[F:9])[CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C=CCCBr
Reactant: O=Cc1ccc(F)cc1F
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a stirred suspension of magnesium turnings (16.9 gm) in dry diethyl ether (1.5L) was added (argon atmosphere) a crystal of iodine and 4-bromobutene (2 ml). Soon after the reaction was initiated the remaining 4-bromobutene (101 gm) in dry diethyl ether (500 mL) was added at such a rate to maintain gentle reflux. After complete addition, the mixture was heated to reflux for 1 hour. 2,4-Difluorobenzaldehyde (100 gm) in dry diethyl ether (400 mL) was then added dropwise with a gentle reflux. The mixture was now heated for 2 hours and allowed to cool to room temperature. The entire contents of the flask were poured on 6L ice-water containing 200 ml concentrated HCl. The organic phase was separated, washed with water, saturated NaHCO3, water and dried (Na2SO4). Removal of ether in vacuo provided crude 5-hydroxy-5-(2,4-difluorophenyl)pentene as an oil (136.5 gm) which was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: Fc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-fluoro-1H-indole and iodobenzene: ESMS m/e: 212.0 (M+H)+.
Reaction SMILES: [OH2:1].[OH-].[Li+].Cl.[CH2:5]1[CH2:9][O:8][CH2:7][CH2:6]1>O.CO>[CH3:9][C:5]1[CH2:6][CH2:7][C@H:6]([C:7]([OH:1])=[O:8])[CH2:5][CH:9]=1
Reactant: C1CCOC1
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1=CC[C@@H](C(=O)O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Methyl-cyclohex-3-(S)-enecarboxylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (3.34 g, 13.2 mmol) in THF (25 mL), water (2.5 mL) and methanol (2.5 mL) was treated with lithium hydroxide monohydrate (2.8 g, 66.2 mmol) and warmed to 50° C. with stirring. After 1 h, the reaction mixture treated with 1M HCl (about 25 mL). The mixture was extracted with hexanes:ethyl acetate (200 mL: 15 mL), dried over sodium sulfate, filtered and concentrated to 2.4 g of a white semi-solid. The residue was redissolved in hexanes:dichloromethane (100 mL, 95:5), washed with water, dried over sodium sulfate, filtered and concentrated to 1.68 g (91% yield) of (1S)-4-methyl-cyclohex-3-enecarboxylic acid as a white powder.