Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:20]([OH:28])[CH2:21][C@@H:22]([CH3:27])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[CH2:37]([C@H:44]([CH2:48][C:49]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50])C(O)=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1.CO>[CH2:37]([C@H:44]([CH2:48][C:49]([N:51]1[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)=[O:50])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C@@H:20]([OH:28])[CH2:21][C@@H:22]([CH3:27])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
A mixture of 110 mg (0.215 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide [prepared as described in step (a) above], 2 ml of methanol and 2 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. The residue was mixed with benzene and the solvent was stripped from the mixture by distillation under reduced pressure. After this operation had been repeated three times, the final residue was dried in vacuo for 8 hours. The dried material was then suspended in 8 ml of anhydrous tetrahydrofuran, and 59.6 mg (0.215 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension. 0.042 ml (0.258 mmole) of 95% diethyl cyanophosphonate and 0.12 ml (0.86 mmole) of triethylamine were then added to the mixture, and the resulting mixture was stirred for 18 hours. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel (using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent), to afford 50 mg of the title compound as a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][CH2:33][CH2:34][C@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12>C1COCC1>[Cl:32][CH2:33][CH2:34][C@H:35]([N:47]1[C:43](=[O:53])[C:44]2[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:46]1=[O:48])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H](CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
Triphenylphosphine (5.25 g, 20.0 mmol) and diethyl azodicarboxylate (3.58 g, 20.0 mmol) were added to a solution of (1R)-3-chloro-1-phenyl-1-propanol (3.42 g, 20.0 mmol) and phthalimide (2.94 g, 20.0 mmol) in THF (100 mL). The reaction mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was triturated with pentane (3×50 mL). The combined pentane fractions were concentrated in vacuo and the crude product was purified by chromatography on silica using EtOAc/hexane (3:97) to give the desired product (4.40 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 1H, J=5.7 Hz), 7.81 (d, 1H, J=5.5 Hz), 7.70 (d, 1H, J=5.4 Hz), 7.69 (d, 1H, J=5.8 Hz), 7.55 (d, 2H, J=7.2 Hz), 7.38-7.28 (m, 3H), 5.64 (dd, 1H, J=6.8, 9.2 Hz), 3.56 (t, 2H, J=6.4 Hz), 3.11-3.02 (m, 1H) 2.85-2.75 (m, 1H); ESMS m/e: 300.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20]OC2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH2:43][OH:44]>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:44][CH2:43][C:34]2[CH:35]=[CH:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=2)[CH2:14][CH2:13]1
Reactant: OCc1ccc2ccccc2c1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc3ccccc3c2)CC1

Procedure:
Compound 25 was prepared in a similar manner to compound 7, substituting the commercially available 2-naphthylmethanol for 2-propanol in part C. MS (M+1)=462.41
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([N:8]2[N:12]=[N:11][C:10]([CH3:13])=[N:9]2)[CH2:4][C@H:3]1[N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([N:38]1[CH2:42][CH2:41][C@@H:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39]1)=[N:18][C:19]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N[C@@H:49]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:19]2[N:18]=[C:17]([N:38]3[CH2:42][CH2:41][C@@H:40]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH2:39]3)[N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[C@@H:3]2[CH2:4][C@H:5]([N:8]3[N:12]=[N:11][C:10]([CH2:13][CH3:49])=[N:9]3)[C@@H:6]([OH:7])[C@H:2]2[OH:1])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NS(C)(=O)=O)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NS(C)(=O)=O)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
The title compound is prepared using a procedure analogous to that of N-{(R)-1-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(5-methyl-tetrazol-2-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-methanesulfonamide (Example 67) by replacing (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-((R)-pyrrolidin-3-ylamino)-purin-9-yl]-5-(5-methyl-tetrazol-2-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 7) with (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48). MS (ES+) m/e 674 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[C:12]([CH:14]=[C:15]3[CH2:20][C@@H:19](O)[CH2:18][CH2:17][C@:16]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2)=[O:13].[CH2:23]([O:26][C:27](Cl)=[O:28])[CH:24]=[CH2:25]>O1CCCC1.N1C=CC=CC=1>[C:27]([C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][C:12](=[O:13])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:20]1)([O:26][CH2:23][CH:24]=[CH2:25])=[O:28]
Reactant: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C=CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCOC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reaction time: 6 h
Yield: 78 %

Procedure:
Compound 43 was prepared from 7-oxo-DHEA (2) (1.0 mmol) and allylchloroformate (4.0 mmol) in tetrahydrofuran-pyridine mixture at 0-5° C. After stirring 6 hours only 30% conversion had occurred; from the mixture the product was isolated in 78% yield (based on 30% conversion) by column chromatography. M.p. 159-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][C:6]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:8][C:7]=1[C:25]([O:27]CC)=[O:26].C1COCC1.[OH-].[Na+].Cl>CCOC(C)=O.O.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][C:6]1[C:10]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:9]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[S:8][C:7]=1[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#Cc2ccccc2)c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(N2CCOCC2)c(C#Cc2ccccc2)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a suspension of ethyl 3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylate (0.041 g, 0.082 mmol in THF (2.00 mL, 24.6 mmol) and methanol (0.37 mL, 9.1 mmol) was added 1.000 M of sodium hydroxide in water (1.684 mL, 1.684 mmol) and the resulting biphasic mixture was stirred at room temp for 2 days. The pH was carefully adjusted to 3.0 via addition of 1N HCl (monitored in real time with a pH meter), and the reaction mixture was transferred to a separatory funnel. The mixture was diluted with EtOAc (40 mL) and water (15 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (eluent: 0-5% MeOH:DCM) afforded 3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylic acid (30 mg, 78% yield). LCMS: (FA) ES+ 472, 473, 474; 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 7.55-7.50 (m, 2H), 7.43-7.34 (m, 5H), 7.21 (dd, J=8.3, 2.0 Hz, 1H), 4.39 (s, 2H), 3.81-3.68 (m, 4H), 3.56-3.42 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][S:11]([OH:14])(=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][S:11]([Cl:17])(=[O:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)CCOCc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 2-(benzyloxy)ethanesulfonic acid (4.0 g) was added thionyl chloride (13.5 ml) dropwise at ambient temperature for 15 minutes and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added dropwise N,N-dimethylformamide (0.072 ml) at ambient temperature. The mixture was stirred at the same temperature for 20 minutes and refluxed for 1 hour. After cooling down to room temperature, the mixture was evaporated under reduced pressure to give 2-(benzyloxy)ethanesulfonyl chloride (4.1 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[N:26]1([C:24]2[N:25]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:21]=[N:22][CH:23]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1cncc(N2CCc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: c1ccc2c(c1)CCN2c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 90 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 1-(6-chloropyrazin-2-yl)indoline (88) 423 mg, 0.185 mmol, 0.9 eq) in DME (7 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional minutes was performed. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(indolin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 134 in 12 mg quantity. The compound 134 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.06 (s, 2H), 8.59 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.44 (m, 1H), 8.16 (s, 1H), 7.41 (m, 1H), 6.99 (m, 1H), 4.21 (m, J=8.53, 2H), 3.33 (m, J=341.82, 2H); MS m/z 313.9 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:11]=1>CO>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])[O:14][N:13]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2OC)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1noc(CCCCC(=O)O)n1
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Add 2 N sodium hydroxide (20 mL) to a solution of 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid methyl ester (4.00 g, 13 mmol) in methanol (100 mL) at room temperature under nitrogen and stir the mixture for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL) and wash with diethyl ether (200 mL). Adjust the aqueous layer to pH 1 with 2 N HCl and collect the solids by vacuum filtration to afford 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid (3.65 g, 99%). APCI mass spectrum m/z 275 [C14H16N2O4—H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18].Cl.[OH-].[Na+]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCCC[C@@](O)(c1ccccc1Oc1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1ccccc1Oc1cccc(F)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxy pentyl)piperidine-1-carboxylate (0.50 g, 1.03 mmol) in MeCN (60 mL) was added 2 N aq HCl (60 mL) slowly at rt. The resulting solution was stirred at rt overnight, then basified to pH=10 with 10 N aq NaOH. The mixture was evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH2Cl2 (4×10 mL), and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under vacuum to give (S)-1-(2-(3-fluorophenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (0.40 g, quantitative) as a free amine.
Reaction SMILES: [CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:32])[C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:10]=2)[CH3:2].[N:46](OCCC(C)C)=[O:47]>C1COCC1>[CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:32])[C:23]3[C:24]([CH3:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:33](=[O:41])[C:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[N:46][OH:47])[CH:10]=2)[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)Cc3ccccc3)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Solvent: C1CCOC1
Product: CCCCC(CC)Cn1c2ccc(C(=O)C(=NO)c3ccccc3)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
The mixture of 1-[11-(2-Ethylhexyl)-5-(2,4,6-trimethylbenzoyl)-11H-benzo[a]carbazol-8-yl]-2-phenyl ethanone (1.20 g, 2.03 mmol) and isoamyl nitrite (0.50 g, 4.26 mmol) in THF (6 ml) is bubbled with HCl gas for 1 minute. After stirring at room temperature for 4 hours, the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the crude is purified by column chromatography on silica gel eluting with a mixed solvent of n-hexane and CH2Cl2 (1:1) to obtain an off-white resin (0.69 g, 50%). The structure is confirmed by 1H-NMR spectrum (CDCl3) δ [ppm]: 0.79-0.90 (m), 1.19-1.45 (m), 2.19 (s), 2.28 (m), 2.42 (s), 4.75 (m), 6.97 (s), 7.35-7.41 (m), 7.57 (d), 7.63 (d), 7.70-7.79 (m), 7.98 (d), 8.35 (s), 8.63 (d), 8.72 (s), 9.54 (d).
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12](OC)=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O=C1C2C(C(OCC)=O)=CC=CC=2NC(C2C=CC=CN=2)C1C1C=CC=CN=1.O.[NH2:57][NH2:58]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:4]1[NH:5][C:6]2[C:11]3[C:2](=[N:57][NH:58][C:12](=[O:13])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccn1)C(c1ccccn1)N2
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccccn1)C(c1ccccn1)N2
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccn1)C2c1ccccn1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of methyl 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (68 mg, 0.19 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for 4 hr. Then the mixture was cooled to room temperature and solvent was removed in vacuum to give crude product. The crude product was purified by pre-HPLC to give 8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (24 mg, yield 37%) as a light yellow solid. 1H-NMR (400 MHz, DMSO) δ 5.42-5.43 (d, J=5.2 Hz, 1H), 5.56-5.57 (d, J=5.2 Hz, 1H), 7.30-7.32 (d, J=8.0 Hz, 1H), 7.37-7.39 (d, J=8.0 Hz, 1H), 7.63-7.66 (t, J=6.6 Hz, 1H), 7.68-7.70 (m, 2H), 7.78-7.80 (d, J=7.2 Hz, 1H), 7.87-7.89 (d, J=8.0 Hz, 1H), 8.11-8.16 (m, 2H), 8.66-8.67 (d, J=4.8 Hz, 1H), 8.74-8.76 (d, J=5.6 Hz, 1H); LC-MS (ESI) m/z: 342(M+1)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C([O:7][C:8](=O)[CH:9]([F:15])[C:10](OCC)=[O:11])C.CC[O-].[Na+]>CCO>[F:15][C:9]1[C:8]([OH:7])=[N:1][C:2]([OH:3])=[N:4][C:10]=1[OH:11]
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(O)c(F)c(O)n1
Temperature: 25 °C

Procedure:
To a heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1.96 g, 10.67 mmol) in EtOH (11 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21.34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCl to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1.45 g, 93%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH:26]1([C:29]2[S:33][C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[N:31][N:30]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.O>CS(C)=O>[CH:26]1([C:29]2[S:33][C:32]([NH:34][C:35]([N:2]3[CH2:7][CH2:6][C:5](=[CH:8][C:9]4[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=5)[CH:10]=4)[CH2:4][CH2:3]3)=[O:36])=[N:31][N:30]=2)[CH2:28][CH2:27]1
Reactant: O=C(Nc1nnc(C2CC2)s1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nnc(C2CC2)s1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine hydrochloride (0.100 g; Example 1a, Step 5), phenyl 5-cyclopropyl-1,3,4-thiadiazol-2-ylcarbamate (0.085 g, 1.2 equiv), and triethylamine (0.045 mL, 1.2 equiv) in dimethyl sulfoxide (1 mL, 0.3 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 10-30% ethyl acetate/dichloromethane over 30 minutes as the eluent to give the title compound as a white foam. 0.057 g, 42% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.98-1.07 (2H, m), 1.09-1.18 (2H, m), 2.15-2.25 (1H, m), 2.46 (2H, t, J=5.5 Hz), 2.60 (2H, t, J=5.5 Hz), 3.66 (2H, t, J=5.8 Hz), 3.76 (2H, t, J=5.9 Hz), 6.40 (1H, s), 6.95-7.04 (3H, m), 7.09 (1H, d, J=7.8 Hz), 7.37 (1H, t, J=7.8 Hz), 7.89 (1H, dd, J=8.6, 2.7 Hz), 8.43 (1H, dd, J=1.6, 0.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]([CH2:18][C:19](=[O:21])[NH2:20])[C:15]([OH:17])=[O:16])[C:8]2=[O:13])([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]([CH2:18][C:19](=[O:21])[NH2:20])[C:15]([OH:17])=[O:16])[C:8]2=[O:13]
Reactant: [H][H]
Reactant: NC(=O)CC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)CC(C(=O)O)N1C(=O)c2cccc(N)c2C1=O

Procedure:
A mixture of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-carbamoylpropanoic acid (7.5 mmol) and 10% Pd/C (200 mg) in 20 ml of dimethylformamide is treated with 60 psi of hydrogen in a Parr shaker to afford 2-(4-amino-1,3-dioxoisoindolin-2-yl)-3-carbamoylpropanoic acid.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=2)[N:11]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(CCNc1ccc([N+](=O)[O-])c(N)n1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-6-aminopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methyl{2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:23]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.C(N)(C)C.[CH3:52][C:53]([OH:57])([C:55]#[CH:56])[CH3:54]>>[OH:57][C:53]([CH3:54])([CH3:52])[C:55]#[C:56][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:23]=1
Reactant: CC(C)NCc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Solvent: CC(C)N
Product: CC(C)NCc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 39 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((isopropylamino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with isopropylamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a brown solid (16 mg, 39%).