Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(NC(C)C)(C)C.CO>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Solvent: CC(C)NC(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
10 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.04 mM) at room temperature. And then 8.5 μl of benzoyl chloride (0.07 mM) and 19.1 μl of diisopropylamine (0.11 mM) were added thereto and the mixture was stirred for 2 hrs at 0° C. The reaction was stopped by adding methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with ethyl acetate and hexane (1:2) as an eluant to give 12 mg of 3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (i) (yield: 87%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22]#[N:23])([CH3:9])[CH3:8].[CH2:28](I)[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:28]([N:12]1[C:11]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[C:10]([CH:7]([CH3:9])[CH3:8])[C:15](=[O:16])[NH:14][C:13]1=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(Oc2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Potassium carbonate (9.3 mg, 0.0067 mmol, 1.0 eq.) was added to 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzonitrile (103) (23 mg, 0.0.08 mmol, 1.2 eq.) in 1.0 mL DMF. The reaction mixture was stirred at room temperature for 10 minutes, and n-butyl iodide (7.6 μL, 0.0.067 mmol) was added. The reaction mixture was filtered and purified by reverse phase HPLC (MeCN/water) to give a white powder (3.8 mg, 17%). LC-MS shows 342.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.37 (br, 1H), 7.28 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 3.42 (t, 2H), 2.71 (m, 1H), 2.42 (s, 3H), 1.60 (m, 2H), 1.28 (m, 2H), 1.17 (d, 6H), 0.88 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].CS(O)(=O)=O.O[CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:19]1=[O:33].O>CN(C)C=O>[CH3:1][C:2]([C:5]1[CH:9]=[CH:8][N:7]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:19]2=[O:33])[N:6]=1)([CH3:4])[CH3:3]
Reactant: O=C1C(O)CCN1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc[nH]n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccn(C2CCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(1,1-dimethylethyl)1H-pyrazole (0.22 g, 1.8 mmol) in N,N-dimethylformamide (20 mL) under nitrogen at room temperature was added 60% sodium hydride in mineral oil (90 mg, 2.16 mmol). After the addition, the mixture was stirred at room temperature for ˜15 minutes, and 3-hydroxy-1-[3-(trifluoromethyl)phenyl]-2-pyrrolidinone methanesulfonate (0.5 g, 1.8 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight and then poured into water (˜100 mL). The aqueous layer was extracted twice with ethyl acetate (˜30 mL each; brine solution was added to separate the two layers). The organic extracts were combined, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by column chromatography (silica gel, ˜20% ethyl acetate/80% hexanes) to give the title compound, a compound of this invention, as a yellow solid (300 mg) melting at 76–78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+]>>[Cl:21][C:9]1[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1nc(-c2ccccc2)c2cccc(Cl)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1nc(-c2ccccc2)c2cccc(Cl)c2n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To 1.24 g of 8-chloro-4-phenyl-2(1H)-quinazolinone (compound No. IV-4) was added 6.65 g of phosphorus oxychloride, followed by stirring at 95° C. for 1 hour. The resulting reaction solution was poured into 200 ml of ice water and sodium bicarbonate was added thereto, thereby adjusting the pH 9. Then, precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 1.07 g of the titled compound. Mp.154.4.° C. 1H NMR (CDCl3): 7.52-7.65 (4H, m), 7.76-7.80 (2H, m), 8.02-8.08 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][C@H:10]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[Si:26]([O:25][C@H:10]1[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][NH:12][CH2:11]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of (+/−)-(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (13 g, 28.0 mmol) and Pd/C (5% on carbon, 1.786 g, 0.839 mmol) in methanol (250 mL) was hydrogenated at 30 psi overnight. The mixture was filtered through Celite and the filtrate was concentrated in vacuo and further dried under high vacuum at 40° C. overnight. The crude product was used without purification. (+/−)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (8.8 g, 26.6 mmol, 95% yield) was obtained as a white solid.
Reaction SMILES: [CH:1]1([NH:8][C:9](=[O:30])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18]([O:20]CC2C=CC=CC=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)CC)(=O)[CH2:32]C>Br.C(O)(=O)C.CCOCC>[CH:1]1([NH:8][C:9](=[O:30])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18](=[O:20])[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCC(=O)OC(=O)CC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2.6 g (0.0063 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cycloheptylamide were dissolved in 15 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated from the solution. The ether phase was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.6 g (0.0126 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated. The solid residue was taken up in 100 ml of chloroform and the solution was washed with sodium chloride solution and dried over magnesium sulphate. The chloroform was removed by evaporation to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crystallised out of the solution. There was obtained 1.85 g (88.1%) of N-propionyl-L-alanyl-L-proline cycloheptylamide of melting point 155°-156° C. [α]D20 =-119.4° (c=0.91% in methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(I)cc4)cc3c2C1

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 17.9 mg (0.051 mMol) 4-iodobenzoyl chloride, the title compound was recovered as a light beige solid.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](\[CH2:11][CH2:12][CH2:13][CH3:14])/[C:6]([O:8]CC)=[O:7].Cl[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:19][CH:18]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:24][C:23]=1[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:3]/[N:4]=[C:5](\[CH2:11][CH2:12][CH2:13][CH3:14])/[C:6]([OH:8])=[O:7])=[CH:36][CH:35]=1
Reactant: CCCC/C(=N\O)C(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of ethyl E-2-hydroxyiminohexanoate (553 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at room temperature for 30 minutes. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]hexanoic acid (922 mg, yield 68%) as colorless crystals. m.p. 112-114° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-])=O)[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>FC(F)(F)CO.[OH-].[OH-].[Pd+2]>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][C@H:13]1[O:12][CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](/C=C/c2ccccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2ccccc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To tert-butyl (2R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[(E)-2-(2-nitrophenyl)ethenyl]morpholine-4-carboxylate (1 eq.) in 2,2,2,-trifluoroethanol (0.4 M) at rt was added 20% Pd(OH)2 (0.2 eq.). The reaction was degassed and then shaken under 1 atm of H2 for 24 hrs. The reaction mixture was filtered on celite and concentrated to afford the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>CN(C=O)C>[NH2:17][C:9]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:5]2[N:4]=[CH:3][C:2]([C:22]3[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nn2cc(-c3ccc(O)cc3)cnc2c1-c1ccccn1
Temperature: 120 °C
Yield: 67.9 %

Procedure:
6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine (50 mg, 0.17 mmol) and 4-hydroxyphenylboronic acid (48 mg, 0.35 mmol) were suspended in dry DMF (1.4 ml). Aqueous 2M Na2CO3 (0.346 mL, 0.69 mmol) was added and the reaction mixture was degassed. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex in dichloromethane (1:1 ratio, 8 mg, 0.010 mmol) was added and the mixture was heated in a microwave at 120° C. for 20 minutes. After allowing the reaction to cool down to room temperature, the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc to afford the title compound as a yellow solid (35 mg, 67% yield). MS (ES+) 304. δH (DMSO-d6) 6.8 (1H, d), 7.1 (3H, m), 7.2 (1H, d), 7.3 (1H, t), 7.9 (1H, t), 8.6 (2H, m), 8.8 (1H, s), 9.2 (1H, s), 9.7 (1H, s).
Reaction SMILES: FC(F)(F)S(OC1CCCC2C=C(OC)C=CC=2C=1)(=O)=O.C([Sn](CCCC)(CCCC)C1C=CC=CC=1[N+]([O-])=O)CCC.[CH3:44][O:45][C:46]1[CH:65]=[CH:64][C:49]2[CH:50]=[C:51]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[N+:61]([O-])=O)[CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=1>>[CH3:44][O:45][C:46]1[CH:65]=[CH:64][C:49]2[CH:50]=[C:51]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[NH2:61])[CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=1
Reactant: COc1ccc2c(c1)CCCC(c1ccccc1[N+](=O)[O-])=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccc1[N+](=O)[O-]
Agent: COc1ccc2c(c1)CCCC(OS(=O)(=O)C(F)(F)F)=C2
Product: COc1ccc2c(c1)CCCC(c1ccccc1N)=C2
Yield: 59.3 %

Procedure:
Synthesized from 2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl trifluoromethanesulfonate and tributyl(2-nitrophenyl)tin according to an analogous synthetic method to Preparation Example 77, 3-methoxy-8-(2-nitrophenyl)-6,7-dihydro-5H-benzocycloheptene (830 mg) was used according to an analogous synthetic method to Example 57 to provide the title compound (442 mg).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:10])([CH3:9])[CH3:8])=O.[OH-].[K+]>CO>[NH2:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:9])([OH:10])[CH3:8]
Reactant: CC(C)(O)[C@H](NC(=O)C(F)(F)F)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)[C@H](N)c1ccccc1
Reaction time: 8 h

Procedure:
The product from step B (1.07 g, 4.10 mmol) was dissolved in MeOH (5 mL) and KOH (0.460 g, 8.19 mmol, 1 mL MeOH) was added at rt. The reaction was stirred overnight, concentrated, diluted in EtOAc and washed with DI water. The organic layer was dried with Na2SO4, filtered and concentrated. The product was used as is. HPLC/MS: 166.2 (M+1); Rt=0.68 min.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=2)=[N:3]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1>>[C:23]([O:22][C:21](=[O:27])[NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[N:2]([NH:1][C:36](=[O:37])[CH2:35][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:3]=2)=[CH:15][CH:16]=1)([CH3:24])([CH3:26])[CH3:25]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2nn(N)c(=O)c3ccccc23)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 103B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.83-10.76 (m, 1H), 8.30-8.25 (m, 1H), 8.06-7.99 (m, 1H), 7.99-7.93 (m, 1H), 7.93-7.86 (m, 1H), 7.44 (d, J=8.8, 2H), 7.41-7.37 (m, 2H), 7.35-7.31 (m, 4H), 3.53 (s, 2H), 1.32 (s, 9H); MS (APCI+) M/Z 537 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.O.[OH-].[Li+].O>CS(C)=O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[C:4]#[N:5])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccc(F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Nc2ccc(Cl)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 38.3 %

Procedure:
Heat a solution of 2-fluoro-5-methyl-benzonitrile (2.0 g, 14.80 mmol) with 4-chloro-2-nitro-phenylamine (2.5 g, 14.80 mmol) and lithium hydroxide monohydrate (1.24 g, 29.60 mmol) in DMSO (30 ml) to 55° C. for 14 hours. Add an additional 0.61 g (14.80 mmol) of lithium hydroxide monohydrate, and increase heating to 70° C., continue for another 14 hours. Cool the reaction to ambient temperature and pour into a mixture of 100 ml water and 200 ml ethyl acetate. Extract with three 200 ml portions of ethyl acetate. Combine organic layers, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a step gradient starting with 90% hexanes: 10% ethyl acetate and going to 40% hexanes: 60% ethyl acetate to obtain 1.63 g (5.67 mmol, 38% yield) of the title compound as a red-orange amorphous solid: Mass Spectrum (m/e): 288 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]=[C:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2cccnc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2cccnc2)CC1
Yield: 78.3 %

Procedure:
Similarly to Example 11, 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(3-pyridyl)-4-piperidinylideneamino]-2-piperazinone (420 mg) was reduced by sodium cyanoborohydride (53 mg) to obtain the title compound (330 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2[O:24][C:25]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:26]=3[C:27](=[O:30])[C:28]=2[OH:29])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](#[N:38])[CH3:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2[O:24][C:25]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[NH:38])[CH3:37])=[CH:31][C:26]=3[C:27](=[O:30])[C:28]=2[OH:29])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: Nc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(O)c(=O)c2c1
Product: CC(=N)Nc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(O)c(=O)c2c1
Temperature: 0 °C
Reaction time: 120 h
Yield: 92 %

Procedure:
2-(3,4-dibenzyloxyphenyl)-3-hydroxy-6-amino-4H-1-benzopyran-4-one (1.9 g; 3.78 mmol) was suspended in acetonitrile (40 mL) and cooled at 0° C. HCl was bubbled into the solution upon saturation. The reaction was then stirred for 5 days at r.t. Upon completion, H2O (20 mL) was added and the acetonitrile removed under vacuum. The precipitate was filtered off and dried to afford the titled compound as a bright yellow solid. Yield: 92%. TLC (9/1 Chloroform/Methanol) Rf: 0.2. 1H-NMR (d6-DMSO): 11.61 (br s, 1H); 9.62 (s, 1H); 8.65 (s, 1H); 8.01 (d, 1H), 7.90 (d, 2H); 7.78 (d, 1H); 7.35 (d, 2H); 7.65 (dt, 2H); 6.93 (d, 1H); 3.35 (s, 3H)
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH3:16])(=O)=O.[C-:17]#[N:18].[Na+]>C(#N)C.O>[CH3:16][C:8]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:17]#[N:18]
Reactant: Cc1c(COS(C)(=O)=O)cccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-3-nitrobenzyl methanesulfonate (207 g ) dissolved in Acetonitrile (625 ml). A solution of (41.5 g) sodium cyanide in 200 ml pure water was added to the above solution and refluxed at 80-95° C. until the completion of reaction. Acetonitrile was distilled out and 1000 ml water was added to the residue followed by addition of 1000 ml dichloromethane. The mixture was stirred for 15 minutes followed by extraction. Dichloromethane is distilled out from organic layer and Cyclohexane is to the residue and stirred for 30 minutes to get 2-Methyl-3-nitro-phenylacetonitrile. It is filtered and dried to give 2-Methyl-3-nitro phenylacetonitrile (150-160 g) as brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:25]([CH3:27])[CH3:26])[C:6]=2[N:7]=1
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cc(Br)nc2[nH]nc(CC)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1c(CC)nn2C(C)C
Yield: 77.9 %

Procedure:
Ethyl 6-bromo-3-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.45 g, 1.51 mmol) was suspended in acetonitrile (5 mL) and K2CO3 (0.312 g, 2.26 mmol) and 2-bromopropane (0.372 g, 3.02 mmol) was added to it. The reaction mixture was refluxed for overnight. On completion of reaction, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to give the desired intermediate (0.4 g, 87.7%).
Reaction SMILES: Cl.NC1NC=C(CO)N=1.Cl.Cl.NCCS.[NH2:16][C:17]1[NH:18][CH:19]=[C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])[N:21]=1.[N+:27]([CH:30]=[C:31](SC)[S:32][CH3:33])([O-:29])=[O:28]>>[N+:27]([CH:30]=[C:31]([S:32][CH3:33])[NH:26][CH2:25][CH2:24][S:23][CH2:22][C:20]1[N:21]=[C:17]([NH2:16])[NH:18][CH:19]=1)([O-:29])=[O:28]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1c[nH]c(N)n1
Agent: Cl
Agent: NCCS
Agent: Nc1nc(CO)c[nH]1
Product: CSC(=C[N+](=O)[O-])NCCSCc1c[nH]c(N)n1

Procedure:
Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which is obtained by treating the pierate salt with hydrochloric acid) with cysteamine hydrochloride and reaction of the resulting 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole with 1-nitro-2,2-bis-methylthioethylene according to the procedure of Example 8(i) gives 1-nitro-2-methylthio-2-[2-((2-amino-4-imidazolyl)methylthio)ethylamino]ethylene. Finally, reaction with methylamine by the procedure of Example 8(ii)produces the title compound.