Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:17]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:7][O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:59](O)=[O:60])=[O:56]>CN(C=O)C>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:59](=[O:60])[C@@H:58]([NH:57][C:55]([O:54][CH3:53])=[O:56])[CH:62]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:7][O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)(=[O:24])=[O:23])=[CH:30][CH:29]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@@H](CCCCN)COC(=O)c1cccnc1)S(=O)(=O)c1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COC(=O)c1cccnc1)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
The product of step B, (2S)-nicotinic acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (100 mg, 0.22 mmol) was dissolved in anhydrous DMF (2 mL) and treated with 0.062 mL (0.45 mmol) of triethylamine followed by EDC (100 mg, 0.56 mmol), HOBt (75 mg, 0.56 mmol) and (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (56 mg, 0.19 mmol). The mixture was stirred overnight at room temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The organic layer was separated and dried with Na2SO4, then evaporated to give 160 mg of crude oil. The residue was purified by flash chromatography with a mixture of eluents hexane/ethyl acetate (2/8). The title compound was obtained as a clear oil in 20% yield (25 mg).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O=[C:15]1[CH2:20][CH2:19][O:18][C:17](=O)[CH2:16]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOCC.[OH-].[Na+].C(Cl)Cl>[CH2:12]([O:11][C:9]([C:3]1([F:2])[CH2:4][CH2:5][N:6]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:7][CH2:8]1)=[O:10])[CH3:13]
Reactant: O=C1CCOC(=O)C1
Reactant: CCOC(=O)C1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1(F)CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 21 %

Procedure:
To a 250 mL RB were added compound B2(I) ethyl 4-fluoropiperidine-4-carboxylate, hydrochloride (1.25 g, 5.91 mmol, 1.0 eq), CH2Cl2 (20 mL), 4-oxotetrahydropyranone B2(II) (0.61 mL, 6.50 mmol, 1.10 eq), and glacial HOAc (0.340 mL, 5.91 mmol, 1.0 eq). After being stirred at rt for 5 to 10 min, sodium triacetoxyborohydride (2.02 g, 9.45 mmol, 1.60 eq) was added in one portion. A cloudy solution was obtained. After being stirred at rt for 12 h, the reaction mixture was diluted with 150 mL Et2O and 200 mL NaOH (1 M aqueous). The resulting suspension was stirred at rt for 1 h. The organic layer was collected, washed with 200 mL brine, dried over Na2SO4, filtered, and concentrated to afford 320 mg of the desired product, 4-fluoro-1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid ethyl ester B2(III) in 21% yield as a colorless oil. 1H NNR (400 MHz, CDCl3, ppm) δ 1.30 (t, J=7.08, 3H), 1.56-1.66 (m, 2H), 1.74-1.78 (m, 2H), 1.94-2.21 (m, 4H), 2.46-2.55 (m, 3H), 2.82-2.85 (m, 2H), 3.38 (ddd, J=1.52, 11.84, 11.84, 2H), 4.03 (dd, J=4.28, 11.08, 2H), 4.24 (q, J=7.05 Hz, 2H); 19F NMR (376 Hz, CDCl3, ppm) δ -166.94.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(N(CC)CC)C.[Br:21][CH2:22][C:23](Br)=[O:24].Cl>C(Cl)Cl>[Br:21][CH2:22][C:23]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])=[O:24]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reaction time: 3 h
Yield: 94 %

Procedure:
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (500 mg, 2.55 mmol) and triethylamine (0.35 mL, 2.55 mmol) were stirred in DCM (10 mL). Bromoacetylbromide was added dropwise under a nitrogen atmosphere. Stirring was continued for 3 h. 2 M HCl (20 mL) was added and the reaction mixture extracted into DCM (3×50 mL). The combined DCM layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give the desired product as a cream solid (760 mg, 2.40 mmol, 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:14][C:13](=[O:15])[C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]([O:21][C:17](=[O:20])/[CH:18]=[CH:19]/[C:2]1[CH:3]=[N:4][C:5]2[NH:14][C:13](=[O:15])[C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1Nc2ncc(Br)cc2CN2CCC[C@@H]12
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A suspension of (S)-6-bromo-1,2,3,4,9,10a-hexahydro-3a,8,9-triaza-benzo[f]azulen-10-one (1.46 g, 5.17 mmol) in propionitrile (40 mL) and DMF (10 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with tert-butyl acrylate (3.0 mL, 20 mmol) and (i-Pr)2EtN (1.9 mL, 11 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (0.12 g, 0.53 mmol) and P(o-tol)3 (0.34 mg, 1.12 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight then allowed to cool. The resulting precipitate was isolated by filtration, dissolved in CH2Cl2, filtered through Celite and the solvent was removed in vacuo to give the title compound (0.68 g, 40%) as an off-white solid: MS (ESI) m/e 330 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([N:20]2[CH2:23][C:22]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21]2)[CH2:15][CH2:14]3)=[N:9][CH:10]=1)[CH3:4].[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38](O)=[O:39])=[N:35][CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([N:20]2[CH2:23][C:22]4([CH2:28][CH2:27][N:26]([C:38](=[O:39])[CH2:37][C:34]5[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=5)[CH2:25][CH2:24]4)[CH2:21]2)[CH2:15][CH2:14]3)=[N:9][CH:10]=1)[CH3:4]
Reactant: COc1ccc(CC(=O)O)nc1
Reactant: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4ccc(OC)cn4)CC3)C2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1c, 630 mg, 1.38 mmol) in dimethylformamide (5 mL) was added (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 230 mg, 1.38 mmol), HBTU (523 mg, 1.38 mmol) and triethylamine (1.20 mL, 8.5 mmol). The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residual DMF was azeotroped with toluene. The residue was partitioned between 50 mL of ethyl acetate and 50 mL 1N NaOH solution. The organic layer was collected, washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column (1-10% MeOH in CH2Cl2 in 20 minutes) to afford the desired product (554 mg, 79.4%) as an off-white foam. The solid was stirred in 50 mL of refluxing diisopropyl ether for 6 hours and filtered to afford a light-grey powder (490 mg, 71%). MS (ES+) 498.5 (M+H)+. 1H NMR (CDCl3) δ 1.28 (t, 3H), 1.53-1.77 (m, 4H), 1.77-2.01 (m, 1H), 2.03-2.22 (m, 1H), 2.65 (q, 2H), 2.76-2.94 (m, 1H), 2.95-3.18 (m, 5H), 3.30-3.54 (m, 4H), 3.69-3.86 (m, 5H), 3.88-4.04 (m, 1H), 7.14 (dd, 1H), 7.19-7.26 (m, 1H), 7.33 (d, 1H), 8.13-8.29 (m, 3H), 8.60 (s, 2H). [α]D20=+40.0 deg (c=10 mg/mL, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:5]2[N:6]=[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-hydroxyphenyl)pyrazine (coelenteramine) (c-5) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (303 mg, 1.09 mmol) was dissolved in pyridine (2 mL) and cooled to 0° C. To this was added acetic anhydride (133 μL, 1.40 mmol) and stirred for an hour after warming to room temperature. To the mixture was added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction. After separating the aqueous layer and organic layer, it was extracted 3 times with ethyl acetate. The organic layer was washed 3 times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (50 g, n-hexane/ethyl acetate=1/1) to give 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) as a pale yellow solid (337 mg, 96.7%). Rf=0.31 (n-hexane/ethyl acetate=3/2). Mp. 183.5-185.5° C. 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 4.07 (s, 2H), 6.42 (s, 2H), 7.12-7.17 (AA′BB′, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.27 (t, J=7.5 Hz, 2H), 7.33 (d, J=7.0 Hz, 2H), 7.90-7.95 (AA′BB′, 2H), 8.41 (s, 1H). IR (KBr, cm−1) 513, 596, 640, 654, 710, 746, 851, 910, 1016, 1136, 1167, 1198, 1217, 1373, 1423, 1452, 1466, 1493, 1508, 1535, 1630, 1746, 3148, 3289.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@H:24]([C:35](=[O:84])[NH:36][C:37]1[CH:38]=[N:39][N:40]([CH2:62][CH2:63][O:64][C:65]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:41]=1[NH:42][C:43]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].[OH-].[Na+]>C(Cl)Cl>[O:23]=[C:24]([C:35](=[O:84])[NH:36][C:37]1[CH:38]=[N:39][N:40]([CH2:62][CH2:63][O:64][C:65]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[C:41]=1[NH:42][C:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a stirred suspension of Dess-Martin reagent (845 mg) in methylene chloride (15 ml) was added tert-butyl [(3S)-3-hydroxy-4-oxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.5 g) and the mixture was stirred at room temperature for 30 minutes. 1N aqueous sodium hydroxide solution (8 ml) was added to the mixture with stirring for 30 minutes and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave an oil, which was purified by column chromatography on silica gel (ethyl acetate:methylene chloride=1:4) to give tert-butyl [3,4-dioxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.33 g).
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C>Cl>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[NH:18][CH:9]([P:10]([OH:15])(=[O:11])[OH:14])[P:4]([OH:8])(=[O:3])[OH:5]
Reactant: CCOP(=O)(OCC)C(Nc1nc2ccccc2[nH]1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(Nc1nc2ccccc2[nH]1)P(=O)(O)O

Procedure:
2.5 g (5.96 mmol) of 1-(benzimidazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are dissolved in 25 ml of 1N hydrochloric acid and heated at 100°-110° for 26 hours. In the course of the reaction, the product separates out in the form of a fine white precipitate. It is filtered while hot and washed with water and then with methanol. 0.23 g (13% of the theoretical yield) of 1-(benzimidazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 265° (decomposition) is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:29])=[C:5]([N+:30]([O-])=O)[CH:4]=1)#[N:2]>CO.[Pd]>[NH2:30][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[C@@H:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:11](=[O:28])[N:10]1[CH3:29]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2N)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 5.5 h

Procedure:
Under argon, (4R)-4-(4-cyano-2-nitrophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (6.0 g, 11.3 mmol) was dissolved in methanol (420 ml). 10% Palladium on activated carbon (5.5 g) was then added, and the mixture was hydrogenated at RT and atmospheric pressure for 5.5 h (strictly monitored by HPLC). The reaction mixture was then filtered through kieselguhr and the filter residue was washed with methanol (1000 ml). The filtrate was concentrated and the crude product was subjected to flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 2:1). The title compound was obtained as a solid (2.28 g, 40% of theory).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[CH:13][C:12]=2[CH3:18])=[C:6]([CH3:19])[CH:5]=1.N#N.[OH-].[Na+]>O.N1C=CC=CC=1>[CH3:18][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH3:17])[C:11]=1[C:7]1[C:8]([CH3:10])=[CH:9][C:4]([OH:3])=[CH:5][C:6]=1[CH3:19]
Reactant: COc1cc(C)c(-c2c(C)cncc2C)c(C)c1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1cncc(C)c1-c1c(C)cc(O)cc1C
Temperature: 140 °C

Procedure:
To stirring pyridine (3 mL) was slowly added concentrated hydrochloric acid (3.3 mL). The reaction flask was then fitted for distillation, and water was distilled from the mixture until the temperature rose to 210° C. After cooling to 140° C., 4 (0.241 g, 1.00 mmol) was added to the above mixture, and the reaction flask was fitted with a reflux condenser connected to a N2 source. The yellow mixture was stirred and refluxed for 3 h at 210° C. The resulting reaction mixture was then diluted with warm water (3 mL) and slowly poured into hot water (20 mL). The resulting yellow solution was cooled to room temperature and neutralized with dilute NaOH solution to pH ˜7. The resulting colorless precipitate was then collected by filtration and washed with water to give 0.208 g (91.6%) of analytically pure product as a colorless solid: mp>270° C. (decomp.); 1H NMR (500 MHz, DMSO-d6): δ 9.245 (s, 1H), 8.337 (s, 2H), 6.579 (s, 2H), 1.841 (s, 6H), 1.729 (s, 6H); 13C NMR (125 MHz, DMSO-d6): δ 156.400, 148.191, 147.630, 134.949, 131.015, 127.197, 114.493, 19.359, 16.098; MS (ESI): m/z 228.4 [(M+H)+,100]; Anal. Calcd. For C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.14; H, 7.58; N, 6.18.
Reaction SMILES: Cl.O=[C:3]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH3:20])[CH2:8][CH2:7]1.[H][H].Cl.[OH-].[Na+]>O.[Pd]>[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]3)[CH2:7][CH2:8]1)[CH3:20]
Reactant: [H][H]
Reactant: CCOc1ccccc1N1CCN(CCC(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOc1ccccc1N1CCN(CCCc2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
2.0 Grams of 6-{1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril monohydrochloride and 0.4 g of palladium black were suspended in 100 ml of water and the suspension was catalytically hydrogenated under 3 atmospheric pressure of hydrogen gas at 80° C. Then 5 ml of concentrated hydrochloric acid was added to the reaction mixture and further catalytically hydrogenated. The catalyst was removed by filtration and to the filtrate thus obtained was neutralized by adding 10N-NaOH aqueous solution, then extracted with chloroform. The chloroform was removed by distillation and the residue thus obtained was purified by column chromatography. Recrystallized from ether to obtain 6-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 0.8 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.I[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH4+].[OH-]>CCOCC.[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2cc(Br)cn2)cc1
Temperature: 130 °C
Yield: 68.4 %

Procedure:
4-Bromopyrazole (1.5 g, 10 mmol) and 4-iodotrifluoromethoxybenzene (3.0 g, 10.3 mmol) were stirred DMF (8 mL) and treated with potassium phosphate (6.3 g, 30 mmol) and CuI (0.5 g, 2.6 mmol). The solution was stirred and heated to 130° C. for 30 min, then it was cooled to ambient temperature and poured into 1 N NH4OH (50 mL). The solid precipitate was isolated by filtration, re-dissolved in ether, filtered and concentrated to a tan solid. Recrystallization from EtOH gave an off-white solid (2.1 g): mp 63-65° C.; LCMS 308.6 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cccnc32)cc1

Procedure:
(24.1 mg, 54%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.9 mg, 0.12 mmol) and 4-methoxybenzenesulfonyl chloride (48.2 mg, 0.23 mmol); HRMS-FAB+ for C20H21N3O3S: calculated MH+:384.13818; found:384.13811.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:30]=[C:29]3[C:17]([C:18](=[O:32])[C:19]4[N:28]3[C:27](=[O:31])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=4)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:11]1([C:14]2[CH:30]=[C:29]3[C:17]([C:18](=[O:32])[C:19]4[N:28]3[C:27](=[O:31])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=4)=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)-n2c(nc4ccccc4c2=O)C3=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccc(N3CCNCC3)cc2-n2c1nc1ccccc1c2=O
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
To a solution of 9-(4-t-butyloxycarbonylpiperazinyl)indolo[2,1-b]quinazoline-6,12-dione (Example 52, 40 mg, 925 μmol) in 1 mL of methylene chloride was added 1 mL of trifluoroacetic acid (TFA). After 30 min, saturated sodium bicarbonate was added. The aqueous layer was separated and extracted with 3×50 mL of chloroform, dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to give 37 mg of crude product. Silica gel chromatorgraphy using (95:5) methylene chloride:methanol as eluent gave 24 mg (77%) of the title compound: mp 214° C. (dec); 1H NMR(DMSO-d6) δ 2.5 (s, 4H), 3.5 (s, 4H), 6.88-6.94 (dd, 1H), 7.62-7.66 (d, 1H), 7.68-7.75 (m, 1H), 7.90-7.94 (m, 2H), 7.95-7.98 (m, 1H), 8.26-8.31 (d, 1H).
Reaction SMILES: CN1CCOCC1.[C:8]([NH:12][C:13]([C:15]1[N:16]=[C:17]([O:23][CH3:24])[S:18][C:19]=1[C:20](O)=[O:21])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([N:12]1[C:20](=[O:21])[C:19]2[S:18][C:17]([O:23][CH3:24])=[N:16][C:15]=2[C:13]1=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1nc(C(=O)NC(C)(C)C)c(C(=O)O)s1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1nc2c(s1)C(=O)N(C(C)(C)C)C2=O

Procedure:
3.75 g (37.1 mmol) of N-methylmorpholine, 1.20 g (10 mmol) of 4-N,N-dimethylaminopyridine and 8.70 g of a 50% strength solution (13.7 mmol) of propanephosphonic anhydride in CH2Cl2 were added in succession to a solution of 2.6 g (10 mmol) of 4-tert-butylaminocarbonyl-2-methoxythiazole-5-carboxylic acid in 100 ml of CH2Cl2 at -5° C. The mixture was refluxed for 6 hours, after which the solvent was removed and the residue was taken up with ethyl acetate. The solution was extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution, washed with water and dried over MgSO4. After removed of the solvent, the crude product was purified by chromatography over silica gel (eluant: 1:1 cyclohexane/ethyl acetate) and 1.20 g (50%) of product of melting point 63°-66° C. were obtained in this manner (Active ingredient Example No. 4.014)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][NH:21][C:22]([NH2:24])=[S:23].N.O>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]3[N:24]=[C:22]([NH:21][CH3:20])[S:23][CH:13]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: CNC(N)=S
Agent: N
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
A 1.43 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride and 495 mg of 1-methylthiourea were stirred in 30 ml of ethanol at 70° C. for 30 minutes. After cooling, 10 ml of aqueous ammonia was added to stir at room temperature for 10 minutes. Water was added to extract with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off, thus yielding 1.47 g (89.1%) of 4-[4-(4-chlorobenzyloxy)phenyl]-2-methylaminothiazole. Recrystallization from ethyl acetate afforded crystals of m.p. 158°-159° C.