Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.O1CCOCC1>O>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:38]4[CH:37]=[CH:36][N:35]=[C:34]([O:33][CH3:32])[CH:39]=4)=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH3:25]
Reactant: COc1cc(B(O)O)ccn1
Reactant: CCN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCN(c2ccc(Nc3ccc(-c4ccnc(OC)c4)n4ncnc34)cc2)CC1
Temperature: 107.5 °C
Yield: 69.8 %

Procedure:
To a reaction vial (40 mL), is added 5-chloro-N-(4-(4-ethylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (110 mg, 0.3 mmol), potassium carbonate (207 mg, 1.5 mmol, 5 eq.), 2-methoxypyridin-4-ylboronic acid (70 mg, 0.45 mmol, 1.5 eq), PddppfCl2 (44 mg, 20%), dioxane (4.0 mL) and water (1.0 mL). The reaction mixture is degassed and filled with argon. The reaction is heated at 105-110° C. for 20 h. After cooling to rt, ethyl acetate (10 mL) is added to each reaction vial. The organic phase is filtered through a pat of celite and then is evaporated to give a residue that is purified by silica gel column chromatography (1-3% 2N NH3 in MeOH/DCM) to give the title compound as a light yellow solid (90 mg, yield, 69.8%). 1H NMR (300 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.60 (d, J=4.8 Hz), 7.58 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.12 (m, 4H), 2.50 (m, 4H), 2.36 (q, J=6.9, 2H), 1.04 (t, J=6.9 Hz, 3H); LCMS-ESI (m/z): calcd for C24H27N7O, 429; [M+H]+ found, 430.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][NH2:31])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:31][CH2:30][CH2:29][N:28]([CH2:32][CH3:33])[CH2:26][CH3:27])[N:13]=1
Reactant: CCN(CC)CCN
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCN(CC)CC)nc21
Yield: 80 %

Procedure:
The product of Example 44, and N,N-diethylethylenediamine were reacted by the procedure of Example 60 to afford 4-(2-chloro-phenyl)-2-(2-diethylamino-ethylamino)-8-(1-ethyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (371 mg, 80% yield. LC MS (m/e)=442 (MH+). Rt=1.77 min
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([CH:16]=O)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)(=[O:3])[CH3:2].CN(C[CH2:23][O:24][C:25](=[O:39])[C@H:26]([CH:28](C)[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:27])C>C1(OC)C=CC=CC=1>[CH3:2][C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([C:16]3[N:27]=[C:26]([C:25]([O:24][CH3:23])=[O:39])[CH:28]=[C:29]4[C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[NH:31][C:30]=34)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)=[O:3]
Reactant: CC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Reactant: CC(c1c[nH]c2ccccc12)[C@H](N)C(=O)OCCN(C)C
Solvent: COc1ccccc1
Product: COC(=O)c1cc2c([nH]c3ccccc32)c(-c2ccc3c(n2)C(=O)C(NC(C)=O)=CC3=O)n1
Temperature: 100 °C

Procedure:
7-N-Acetyllavendamycin N-N-Dimethylaminoethyl Ester (Compound 19. Table l): 7-Acetamido-2-formylquinoline-5,8-dione (23) (prepared as described in Example 23) (317 mg, 0.13 mmol) was dissolved in 16 ml of dry anisole and heated to 80° C. b-methyltryptophan N,N-dimethylaminoethyl ester (41) (prepared as described in Example 41) (37.5 mg, 0.13 mmol) was added with stirring, and the stirred mixture was heated at 100° C. for 5.5 hr. The reaction mixture was allowed to cool to room temperature and the solid was filtered. The filtrate was distilled under vacuum to dryness. Ethyl acetate (3 ml) was added, and the mixture was stirred. Upon filtration 24.5 mg (a yield of 36%) of an orange solid was obtained.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH3:28])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:24])[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=2[C:14]([CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1>C(O)C.O.Cl>[OH:7][CH:8]([CH3:28])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:24])[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=2[C:14]([CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1
Reactant: CCCc1ccc(OCC(C)OC2CCCCO2)c2c(=O)cc(C(=O)O)oc12
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)O)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5-[2-(tetrahydropyran-2-yloxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid (0.12 g) in ethanol (3 ml), water (2 ml) and concentrated hydrochloric acid (1 drop) was stirred for 15 minutes at ambient temperature. The mixture was then extracted with chloroform (3×20 ml) and the chloroform extracts bulked, dried and evaporated in vacuo. The residue was crystallised from acetone giving 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid m.g. 134°-135° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].S(=O)(=O)(O)O.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)C>[CH2:29]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])[NH2:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)[C@@H](N)CCCNC(=N)N
Temperature: 140 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
A suspension of L-arginine free base (0.6 g, 3.5 mmol), sulfuric acid (0.31 ml, 7 mmol), and dodecanol (25 ml) were stirred together at 140° C. under nitrogen. After 6 hours, a clear light yellow solution resulted, and TLC indicated the reaction to be complete. The reaction mixture was diluted with diethyl ether (50 ml), and washed with water (3×25 ml). The combined aqueous extracts were washed with diethyl ether (2×25 ml), and basified with 1N KOH solution, upon which a white solid precipitated. Filtration of the suspension and washing of the filtrate with water (3× with 25 ml), acetone (3× with 25 ml) and diethyl ether (3× with 25 ml) gave arginine dodecyl ester. The yield was 86%. Melting point was 125-130° C. NMR gave the expected results for arginine dodecyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[O-2].[Mg+2].[Cl:24][CH2:25][C:26](Cl)=O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Cl)c2C1=O
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.0 g 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime (VIII) and 1.0 g magnesium oxide were suspended under stirring and argon atmosphere in 160 ml 1,4-dioxane. 2.7 ml Chloracetyl chloride were added in one portion and the white thick gel obtained was stirred 4 hours at r.t. and then 17 hours at reflux to give a lightly orange fluid suspension. 100 ml Dioxane were distilled off and the reaction mixture was cooled to room temperature. 180 ml Deionized water were added within 15 minutes and the suspension was stirred 1 hour at r.t. The precipitate was filtered off, washed with 50 ml deionized water twice and dried under vacuum at 80° C. for 18 hours. Crude product: 8.3 g as a light pink powder. This crude product was dissolved in 120 ml tetrahydrofuran at reflux and 0.83 g active charcoal Darco G 60 were added. The system was refluxed 1 hour, then filtered on 25 g Dicalit-Speedex and the filter cake was washed with three portions of 50 ml warm tetrahydrofuran. The filtrate was concentrated at 40° C. under reduced pressure. The residue was digested in 80 ml ethanol 1 hour at reflux, then stirred 16 hours at r.t. and finally 2 hours at 2° C. The precipitate (7-chloro-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzo-diazepin-6-one (IX)) was filtered off, washed with 2 portions of 25 ml cold tert-butyl methyl-ether and dried under vacuum 5 hours at 80° C. Crude product: 7.6 g as a light beige powder. m.p. 234-238° C.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[NH:23])OCC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>C(O)C.CO>[ClH:1].[NH2:25][C:19](=[NH:23])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: CCOC(=N)c1ccc(CCc2csc(NC(C)=O)n2)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(C(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 85 %

Procedure:
Ethyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzenecarboximidoate hydrochloride (300 mg) was dissolved in ethanol (6 ml). Then ammonium chloride (68 mg) and ammonia in methanol (1 ml) were added to the solution. The reaction mixture was refluxed for 5 hours under nitrogen atmosphere. After cooled to room temperature, the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with ethanol/diethyl ether to give N-[4-(2-{4-[amino(imino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide hydrochloride (234 mg) as a colorless solid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](O)(=[O:16])[CH2:11]CCCC>C(O)(=O)C>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:16])[CH3:11]
Reactant: CCCCCCCCO
Reactant: CCCCCC(=O)O
Solvent: CC(=O)O
Product: CCCCCCCCOC(C)=O

Procedure:
To a 5 mL reaction vial equipped with stir bar was added approximately 200 μL of 3-butyl-1-(butyl-4-sulfonyl)imidazolium trifluoromethanesulfonate (1.9 M). Added next via syringe was 1-octanol (60 μL, 0.38 mmol) followed by hexanoic acid (48 μL, 0.38 mmol). The resulting monophase was allowed to stir at room temperature for a period of 7 days at which time the oil was washed with toluene (5×2 mL). Shorter reaction times using higher reaction temperatures also afforded excellent conversion of acid to ester. Reaction of 1-octanol and acetic acid resulted in 89% conversion to n-octyl acetate at 40° C. for a period of 72 h whereas 83% conversion was observed at 40° C. for 48 h. The collected organic washes were concentrated in vacuo to afford 76 mg of n-octyl hexanoate. GC analysis of the crude product revealed only trace amounts of starting material in the organic washes. Purification of the crude colorless oil by bulb-to-bulb distillation afforded the desired compound in 72 mg (0.31 mmol, 82% yield) as a clear and colorless oil (bp 130° C./3 mm Hg (air bath temp)). 1H NMR (300 MHz, CDCl3); δ 4.04, J=6.6, 2H), 2.27 (t, J=7.4, 2H), 1.63-1.58 (m, 4H), 1.30-1.25 (m, 14H), 0.87-0.80 (m, 6H). 13C NMR (75.5 MHz, CDCl3); δ 174.10, 64.47, 34.42, 31.84, 31.39, 29.26, 28.72, 26.00, 24.78, 22.70, 22.38, 14.13, 13.96. IR (thin film) 2956, 2929, 2858, 1739, 1466, 1173 cm−1. GC ((HP-1 methyl siloxane; f=1.0 mL/min) 100° C. (2 min), 10° C./min, 275° C. (10 min)) 11.05 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[CH2:17][C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:20][C@@H:18]([CH3:19])[CH2:17][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)cc1F
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Yield: 39.4 %

Procedure:
The title compound was prepared from 2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (1.39 g, 6.78 mmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.423 g, 8.12 mmol), triphenylphosphine (2.129 g, 8.12 mmol) and DIAD (1.578 ml, 8.12 mmol) using the method of Example 34(c) affording 0.70 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.95 (d, 3H), 3.22 (m, 1H), 4.01 (m, 2H), 7.02 (d, 1H), 7.78 (m, 1H), 7.81 (m, 1H), 7.88 (d, 1H).
Reaction SMILES: [NH3:1].CO.[NH2:4][C:5]1[N:13]=[C:12]([S:14][CH2:15][C:16](OC)=[O:17])[N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([OH:27])[N:9]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:4][C:5]1[N:13]=[C:12]([S:14][CH2:15][C:16]([NH2:1])=[O:17])[N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([OH:27])[N:9]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Reactant: N
Solvent: CO
Product: NC(=O)CSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 89 %

Procedure:
A 28% ammonia/methanol solution was added to 6-amino-9-benzyl-8-hydroxy-2-(methoxycarbonylmethyl)thiopurine (75 mg, 0.22 mmol). The solution was heated in autoclave for 6 hours and then the solvent was removed in vacuo. To the residue was added methanol and the resulting crystals were filtered to give the subject compound (64 mg, yield 89%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Product: CC(C)(C)c1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(3-tert-Butyl-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-tert-butyl-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.58-2.63 (m, 4H), 3.48-3.60 (m, 4H), 3.73 (s, 2H), 5.40 (s, 1H), 6.72-6.76 (m, 1H), 6.84-6.86 (m, 1H), 7.20-7.22 (m, 1H), 7.85 (s,1H), 10.80 (br s, 1H), 12.65 (br s, 1H). Mass spectrum (ES) MH+=343.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(OC)cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.96 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (1.06 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([Br:18])=[CH:7][CH:8]=2)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O>O>[Br:18][C:6]1[CH:5]=[C:4]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]4[S:28][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=4)=[CH:14][C:15]=3[C:3]2([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:8][CH:7]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CS(C)=O
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3nc4ccccc4s3)cc21
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (49.35 g., 0.15 mol.), 2-amino-thiophenol (20 ml. 0.187 mol., 1,25 eq.), and DMSO (110 ml) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 ml.) filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g., were then reslurried in hot ethanol, (600 ml), cooled and filtered to get the benzothiazole product, 45.69 g., m.p. 133.6–135° C. An additional 6.6 g., m.p. 134.6–135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery was 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Calculated for C24H20BrNS: C, 66.37; H, 4.64; Br, 18.40; N, 3.23; S, 7.37%. Found: C, 66.46; H, 4.52, Br, 18.54; N, 3.14; S, 7.19%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[CH3:23][O:24][NH2:25].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:25]([O:24][CH3:23])[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CON
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (150 mg) was dissolved in methanol (3.0 ml) and O-methylhydroxylamine hydrochloride (420 mg) and sodium methoxide (270 mg) were added. The mixture was stirred at room temperature for 12 hrs. and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to dryness. Then, 4N hydrochloric acid ethyl acetate solution (3 ml) was added to the residue and the mixture was stirred at room temperature for 12 hrs. Water was added to wash the reaction mixture, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 6-chloro-2-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=4[F:36])=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:28]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:27]=1[O:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[C:17]([O:37][CH3:38])[CH:18]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C)CC1
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To a solution of 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (305 mg, 0.58 mmol) in CH2Cl2 (1 mL) was added 0.4 mL of TFA. The reaction mixture was stirred for 1.5 h and the solvents were removed under reduced pressure. The crude product was treated with NaBH(OAc)3 (381 mg, 1.80 μmmol) and formaldehyde (0.5 mL, 37% in H2O). The stirring was continued for 12 h. The reaction was quenched with sat. aqueous NaHCO3. 15% NaOH was added until PH=14. The product was extracted with EtOAc. Removal of the solvent in vacuo gave the crude product, 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinoline, (240 mg, 93%), which was used directly in the next reaction.
Reaction SMILES: CCN(C(C)C)C(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[OH2:45]>C(#N)C>[OH:45][C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reaction time: 1 h

Procedure:
DIPEA (7.421 g, 10.00 mL, 57.42 mmol) was added to a suspension of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (1 g, 1.918 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 1 hour then water (5 mL) was added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the desired product (880 mg, quantitative yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]([CH3:16])=[CH:15][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:20][O:18][C:17]([C:10]1[C:11]2[CH:15]=[C:14]([CH3:16])[O:13][C:12]=2[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:8][CH:9]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(C(=O)O)ccc(OC3CCCC3)c2o1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(C)cc12
Temperature: 5 °C
Yield: 102.5 %

Procedure:
To a suspension of 7-cyclopentyloxy-2-methylbenzo[b]furan-4-carboxylic acid (40.0 g, 0.153 moles) and potassium carbonate (42.0 g, 0.184) in acetone (400 mL) added dimethyl sulfate (24.0 g, 0.307 moles) and refluxed for 4-5 hrs. acetone (305 mL) was distilled off and reaction mixture was cooled to 5° C., ice cold water (500 mL) was and the solid separated was filtered, washed with water (2×100 mL0 and dried to get off white solid (43.0 g).
Reaction SMILES: C([N:4]1[C:9]2[CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=3[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:33])([CH3:32])[CH2:5]1)(=O)C.C([O-])(O)=O.[Na+]>CCO>[CH3:32][C:6]1([CH3:33])[CH2:5][NH:4][C:9]2[CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=3[NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH:12]=[CH:13][C:8]=2[O:7]1
Reactant: CC(=O)N1CC(C)(C)Oc2ccc(NC(=O)c3cccnc3NCc3ccc(F)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc2O1
Temperature: 0 °C

Procedure:
N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide (250 mg, Example 52) was dissolved in EtOH (10 mL) and treated with conc. HCL (0.5 mL) at 60° C. for 16 h. The mixture was cooled to 0° C. and sat. NaHCO3 (aq) was added. The mixture was extracted with EtOAc (3×50 mL) and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (50% EtOAc/hexanes). M+H 407.3; Calc'd for C23H23FN4O2: 406.18.