Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH2:16])[C@@H:14]2[CH2:17][C@H:11]1[CH2:12][CH2:13]2.[N:19]1([S:24]([C:27]2[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:32]([C:30]2[S:31][C:27]([S:24]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)(=[O:26])=[O:25])=[CH:28][CH:29]=2)=[O:33])[C@@H:14]2[CH2:17][C@H:11]1[CH2:12][CH2:13]2
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1N
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 251 mg (1.0 mmol) of (5Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester (1) in 4 ml of tetrahydrofuran were added 257 mg (1.0 mmol) of 5 -(pyrrol-1-ylsulfonyl)thiophen-2-carboxylic acid and 13.5 mg (0.1 mmol) of 1-hydroxybenzotriazole. Under ice-cooling, 186 mg (1.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added thereto. The mixture was warmed to room temperature and stirred at 25° C. for 16 h. The mixture was diluted with water and extracted with toluene. The organic layer was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (toluene/ethyl acetate=6:1) to give 412 mg of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)-thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid methyl ester (I-la). Yield 83.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].S(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[C:10]([S:14]([Cl:13])(=[O:16])=[O:15])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1c[nH]c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
2-(4-chlorophenyl)imidazole (6 g., 0.034 mole) was added portionwise at room temperature with stirring to chlorosulfonic acid (30 ml.). The mixture was heated 2 hours at 100° and cooled to room temperature. Thionyl chloride (3 g.) was added and the mixture again heated for 2 hours at 100°. After cooling to room temperature the mixture was added cautiously to ice and water. A semi-solid separated and was extracted with ether. The ether layer was dried and concentrated to yield 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g., 0.005 mole).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 178 %

Procedure:
A mixture of (2S,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 6.6 mmol) and TFA (6 mL) in DCM (14 mL) was stirred at rt for 3 hours. The reaction was concentrated and dried to give 2 g of (2S,4R)4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as a TFA salt.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:15][C:14]=2[F:29])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:42][O:43][CH2:44][CH2:45][OH:46]>>[F:29][C:14]1[CH:15]=[C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:17]=[CH:18][C:13]=1[NH2:12].[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:15][C:14]=2[F:29])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:42][O:43][CH2:44][CH2:45][OH:46])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Nc1ccc(C#CCOC2CCCCO2)cc1F
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Yield: 69 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by column chromatography on silica gel (50% EtOAc/PE) as eluant), to give 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide as a white solid (69%) which was used directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.87 (br s, 1 H), 7.46-7.39 (m, 1 H), 7.31 (dd, J=12.2, 1.8 Hz, 1 H), 7.28-7.20 (m, 1 H), 7.14 (dd, J=8.3, 1.6 Hz, 1 H), 6.79 (ddd, J=8.8, 8.8, 4.7 Hz, 1 H), 4.80 (br s, 1 H), 4.46 (d, J=16.1 Hz, 1 H), 4.36 (d, J=16.0 Hz, 1 H), 3.84 (t, J=4.8 Hz, 2 H), 3.75 (ddd, J=11.5, 8.6, 3.3 Hz, 2 H), 3.55 (t, J=4.8 Hz, 2 H), 3.51-3.44 (m, 2 H), 1.76-1.60 (m, 2 H), 1.55-1.42 (m, 4 H). HRMS (EI+) calcd. for C23H23F3N2O5 464.1559 (M+), found 464.1558.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[S:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+].CI>CC#N.CCOCC>[C:23](/[N:22]=[C:20](\[S:21][CH3:32])/[NH:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:31])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[C@@H](NC(=S)NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CI
Product: CS/C(=N\C(=O)c1ccccc1)N[C@@H](C(=O)N1CCC(c2ccc(Cl)cc2)CC1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of (R)—N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamothioyl)benzamide (300 mg, crude) in CH3CN (2 mL) was added K2CO3 (275 mg, 2 mmol) followed by MeI (75 μL, 2 mmol). The reaction was stirred for 4 h at rt., diluted with Et2O (10 mL) and the solids were filtered through a plug of celite. The filtrate was condensed in vacuo to give (R,Z)-methyl N′-benzoyl-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamimidothioate (300 mg, m/z 473, M+1) as a foam, which was used in subsequent steps without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH3:13])[CH:5]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]=2[CH3:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(C)C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)cc2C)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 35.6 %

Procedure:
To a solution of 4-isopropyl-2-methylbenzoic acid (80 mg, 0.45 mmol), 1-hydroxybenzotriozole (91 mg, 0.68 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol), triethylamine (0.3 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (69 mg, 0.45 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-2-methylbenzamide as a white solid (50 mg, 36%). LRMS (M+H+) m/z: calcd 312.18. found 312. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.45 (s, 1H), 8.00 (t, J=4.8 Hz, 1H), 7.20-7.06 (m, 3H), 5.85 (s, 1H), 4.25 (d, J=4.8 Hz, 2H), 2.91-2.82 (m, 1H), 2.29 (s, 4H), 2.12 (s, 2H), 2.10 (s, 1H), 1.17 (m, 1H) (d, J=6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41]([OH:43])=O)[CH:35]=[CH:34]3)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:41]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([NH:30][C:28]([C@H:9]1[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:44])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]1)=[O:29])[CH:40]=[CH:39]2)(=[O:43])[NH2:46]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3cc(C(=O)O)ccc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3cc(C(N)=O)ccc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-naphthoic acid (58 mg, 0.091 mmol) in methylene chloride (8 ml), HATU (35 mg, 0.091 mmol) was added followed by DIPEA (0.15 ml). The solution was stirred for 5 minutes and then ammonia in methanol (2M in methanol, 1.0 ml) was added and the mixture was stirred at rt for 3 hrs. The solvent was reduced to 4 ml and loaded onto a silica gel column and eluted with 5% Methanol/methylene chloride on a combifalsh machine to give a white solid. 49 mg, 84.5%. (ES+) m/z Calcd: [(M+H)+]: 635. found: 635.
Reaction SMILES: Cl[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:15][CH2:16][CH3:17])[CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1.[ClH:19].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>>[Cl:19][C:31]1[CH:32]=[CH:33][C:28]([CH2:26][NH:14][C:12]([C:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:2][N:20]4[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]4[C@@H:26]([OH:27])[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[S:18][C:6]=3[N:7]([CH2:15][CH2:16][CH3:17])[CH:8]=2)=[O:13])=[CH:29][CH:30]=1
Reactant: CCCn1cc(C(N)=O)c(=O)c2cc(CCl)sc21
Reactant: O[C@@H](c1ccccc1)[C@H]1COCCN1
Reactant: Cl
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3[C@@H](O)c3ccccc3)sc21

Procedure:
Analogous to the procedures described in Example 15, N-(4-chlorobenzyl)-2-(chloromethyl-7-propyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 13) is treated with (S)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 9) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:21].O>O1CCOCC1>[I:11][C:10]1[C:3]2[C:2]([NH2:21])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:9]=1
Reactant: N
Reactant: O=[N+]([O-])c1cccc(-n2cc(I)c3c(Cl)ncnc32)c1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2-c1cccc([N+](=O)[O-])c1
Yield: 97 %

Procedure:
A solution of 4-chloro-5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.25 mmol), NH3.H2O (3 mL) and dioxane (6 mL) in a sealed tube was heated to 120° C. in a microwave reactor for 40 min. The yellow precipitate was collected by filtration to provide 5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (69) (460 mg, 97%). LC-MS (ESI): m/z (M+1) 382.
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=CC=1.[N+:39]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][O:47][C:48]([NH:50][CH:51]=N)=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40].FC(F)(F)S([O-])(=O)=O>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([N:30]2[CH2:36][CH2:35][CH2:34][N:33]([CH:51]=[N:50][C:48]([O:47][CH2:46][C:45]3[CH:53]=[CH:54][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[O:49])[CH2:32][CH2:31]2)=[O:29])[CH2:11]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=C(N=CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Following a procedure similar to that described in Preparation 4, but using 2.10 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in Preparation 2(i)] and 0.93 g of N-(4-nitrobenzyloxycarbonyl)formamidine, 2.38 g of the trifluoromethanesulfonate of the title compound were obtained. The salt was treated by the same procedure as described in Preparation 4(ii), to give 1.90 g of the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[N:27][N:26]=4)=[CH:20][CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:41][N:42]([CH3:49])[CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>CS(C)=O>[CH3:41][N:42]([CH3:49])[CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][C:5]1[N:10]=[C:9]([C:11]2[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:27][N:26]=4)=[CH:20][CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Reactant: CN(C)CC(C)(C)CN
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A resealable pressure vial was charged with N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (100 mg, 0.180 mmol) and N1,N1,2,2-tetramethylpropane-1,3-diamine (0.12 ml, 0.73 mmol) and DMSO (1.2 ml, 0.15 M). The reaction vessel was sealed and the mixture was stirred at 70° C. for 16 hrs. The reaction was cooled to RT and diluted with 3 ml of DMSO. The solution was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure N-(4-(3-(2-(3-(dimethylamino)-2,2-dimethylpropylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine as a yellow solid. MS m/z=597 [M+H]+. Calc'd for C36H36N8O: 596.72.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[CH:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][C:44]=1[CH2:53][CH2:54][O:55][CH2:56][C:57]([NH2:59])=[NH:58]>CN(C=O)C.ClCCl>[NH:58]=[C:57]([NH:59][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH2:56][O:55][CH2:54][CH2:53][C:44]1[CH:45]=[CH:46][C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=1
Reactant: N=C(N)COCCc1ccc2ccccc2c1
Reactant: O=C(O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N=C(COCCc1ccc2ccccc2c1)NC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, 3-chloro-2-pyrazinecarboxylic acid (Tyger, 250 mg), TBTU (532 mg), and diisopropylethylamine (1.34 ml) were added to a solution of 2-(2-naphthalen-2-yl-ethoxy)-acetamidine hydrochloride (417 mg) in DMF (5 ml). The reaction mixture was stirred for 2 h at r.t., diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The obtained, crude title compound (567 mg) was used without further purification in the next step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCCCC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Yield: 88 %

Procedure:
The compound 11 obtained above (220 mg, 0.518 mmole) was dissolved in 4 ml of a mixture of acetic acid-water-tetrahydrofuran (65:35:10) and the solution was heated with stirring at 40°-45° C. for one and half hours. Then, the reaction mixture was treated following the procedure similar to that of Example 4, to yield the title compound 12 (156 mg, 88%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.OO.C([O-])(O)=[O:32].[Na+]>CO.OS(O)(=O)=O.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:21][CH:22]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: O=C([O-])O
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 61 %

Procedure:
To a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (2.00 g, 5.43 mmol) in MeOH (40 mL) were added an aqueous solution of, 30-40% by weight, H2O2 (5.0 mL) and a few drops (10-12) of conc. H2SO4. The resultant mixture was stirred for 24 h. Reaction mixture was neutralized with saturated aqueous NaHCO3 and then diluted with EtOAc (200 mL). Reaction mixture was washed with water (2×30 mL), brine (1×30 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (9:1 to 4:1) as an eluent to give 1.180 g (61%) of the title compound (233) as a white foam. The 1H NMR and mass spectral data are consistent with the data reported in Example 41 (Step 1).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:27][OH:28])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Br)c2C1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Br)c2C1=O
Yield: 86 %

Procedure:
17.85 g (56.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile were stirred with 10.3 g (97.7 mmol) of sodium carbonate and 8 g (115.1 mmol) of hydroxylamine hydrochloride in 300 ml of ethanol and 60 ml of water at 50° for 1 hour and at 75° for 20 minutes. After dilution with 50 ml of water the suspension was suction filtered and the crystals were dried. There were obtained 16.95 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime of m.p. 265°-266°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C(CC(C)(C)C)(C)C>[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:23][CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)CC(C)(C)C
Product: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 127.9 %

Procedure:
Add 6-chloronicotinamide (7.03 g, 44.90 mmol) to a stirred solution of 4-(2-benzylamino-ethyl)-phenol (10.10 g, 44.43 mmol), potassium carbonate (15.35 g, 111.1 mmol), dimethylacetamide (138 mL), and isooctane (16 mL). Using a Dean-Stark trap, heat the reaction to reflux under nitrogen for 6 h. Cool the reaction mixtures to room temperature, filter off the solids, and concentrate most of the solvent off on a rotary evaporator. Take the residue up in ethyl acetate (200 mL) and add 1N hydrochloric acid (200 mL). Stir for 15 minutes and filter off the precipitate washing with ethyl acetate. Dissolve the solid in 400 mL of boiling 1:1 methanol/water. To this solution add 5N sodium hydroxide (35 mL) and allow the solution to cool to room temperature. Filter and wash with water to yield 19.74 g (83%) of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.15 (dd, 1H), 7.34-7.24 (m, 7H), 7.06 (d, 2H), 6.93 (d, 1H), 6.08 (br s, 2H), 3.82 (s, 2H), 2.92 (t, 2H), 2.84 (t, 2H), 1.33 (br s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[C:5]([O:12][CH3:13])[CH:4]=1)[CH3:2].CCN=C=NCCCN(C)C.[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:29][C:27](=[S:28])[NH:26][N:25]=2)=[C:5]([O:12][CH3:13])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)O)c(OC)c1
Reactant: NNC(N)=S
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-ethyl-2-methoxybenzoic acid (example 18b) (1 g, 6.1 mmol) in pyridine (6 mL) was added EDCI (1.2 g, 6.3 mmol) and the suspension was stirred at r.t. for 2 h. Then thiosemicarbazide (547 mg, 6 mmol) was added and the reaction was stirred at r.t. for 24 h. The mixture was evaporated to dryness and then diluted with water. A white solid was collected and washed with water. The solid was suspended in aq. NaHCO3 (1M, 20 mL) and heated at reflux for 2 days. The suspension was filtered hot and the aqueous solution was cooled in ice and acidified to pH 3 with conc. HCl. The solid was collected washed with water and dried to give 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione as a white powder (55%). MS (M+H, 236).