Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[CH3:20][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CNCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1ccccn1)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 55.9 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 2-(2-methylaminoethyl)pyridine (0.078 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided N2-methyl-N2-(2-pyridin-2-ylethyl)-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (0.095 g) as its trifluroacetic acid salt after reverse-phase HPLC purification.MS (ESI) m/z 378 ([M+H]+).
Reaction SMILES: O[C@:2]12[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][C@:15]1([CH2:21][OH:22])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[CH3:24]>CO>[OH:22][CH2:21][C@@:15]12[C@@H:14]3[C@H:5]([C@H:6]4[C@@:10]([CH2:12][CH2:13]3)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]4)[CH2:4][C@H:3]([CH3:24])[C:2]1=[CH:19][C:18](=[O:20])[CH2:17][CH2:16]2
Reactant: C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C[C@]12O
Solvent: CO
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12

Procedure:
A solution of 5α,19-dihydroxy-6β-methylandrostane-3,17-dione bis ethylenektal in methanol containing aqueous sulfuric acid is heated to its reflux temperature. The solvent is subsequently removed. Crystallization of the residue from an acetone-hexane solution yields 19-hydroxy-6α-methyl-4-androstene-3,17-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[N:9][N:8]=1.Cl.[CH3:32][O:33][NH2:34].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:20][CH2:21][C:22](=[N:34][O:33][CH3:32])[CH2:23][CH2:24]2)=[N:9][N:8]=1
Reactant: COc1ccc(CNc2nnc(N3CCC(=O)CC3)c3ccc(C#N)cc23)cc1Cl
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCN(c2nnc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc23)CC1
Yield: 48.7 %

Procedure:
A mixture of 1.19 g 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-oxopiperidino]-6-phthalazine carbonitrile, 354 mg methoxyamine hydrochloride, 1.2 g sodium carbonate, and 10 ml ethanol was heated under reflux for 2 hr. After cooling, saline was added to the reaction solution which was then extracted with ethyl acetate. It was dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated, and the resulting residue was purified by silica gel column chromatography to give 620 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidino]-6-phthalazine carbonitrile. This product was dissolved in a mixed solvent of methanol and ethanol, and recrystallized by adding 0.35 ml of 4 N hydrochloric acid/ethyl acetate to give 388 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidino]-6-phthalazinecarbonitrile hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[NH:5][C:4]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[S:21][CH2:22][C:3]1=2>CS(C)=O>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[N:5]=[C:4]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[S:21][CH:22]=[C:3]12
Reactant: N#Cc1ccc(-n2[nH]c3c(c2=O)CSc2ccccc2-3)cc1
Solvent: CS(C)=O
Product: N#Cc1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Yield: 36 %

Procedure:
A solution of 4-(3-oxo-1,4-dihydro-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzonitrile (0.100 g, 0.33 mmol) in DMSO (2 ml) was stirred vigorously at room temperature and air was flushed over the solution. After 48 h the precipitation was filtered, washed with toluen and dried. The crude product recrystallized from toluene to yield 4-(3-oxo-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzonitrile (0.036 g): 1H NMR (400 MHz, CDCl3) δ 8.65 (1H, s), 8.53 (1H, d), 8.38 (2H, d), 7.72 (2H, d), 7.66 (2H, t), 7.58-7.62 (1H, m); ESI MS m/z 304 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH3:19])([O:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C>C(O)C>[CH2:18]([C:11]1([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:19]
Reactant: [H][H]
Reactant: CCC1(OCCO)CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: CCC1(OCCO)CCNCC1
Yield: 78.9 %

Procedure:
A solution of 37 g of 2-(1-benzyl-4-ethyl-4-piperidyloxy)-ethanol in 300 ml of absolute ethanol was reacted with hydrogen at 50° C in the presence of 4 g of 10% palladized charcoal until the theoretical amount of hydrogen was absorbed (about 3 hours) and the catalyst was filtered off. The ethanol was evaporated off and the residue was distilled to obtain 19.2 g of 2-(4-ethyl-4-piperidyloxy)-ethanol as a colorless oil boiling at 102°-106° C at 0.5 mm Hg.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:14]=[CH:13][N:12]=1)=[O:9])[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:10][C:8](=[O:9])[NH:7][CH:5]([CH3:6])[C:4]([OH:25])=[O:3])[CH:16]=1
Reactant: CCOC(=O)C(C)NC(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)NC(C)C(=O)O)ncn1
Reaction time: 2 h

Procedure:
To a solution of 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-propionic acid ethyl ester (LIV) (470 mg, 1.4 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (0.11 g, 2.7 mmol) in water at ice bath temperature over 30 min and then allowed to stir for 2 hours. THF was evaporated and the aq. solution was acidified with 2N HCl. This aq. phase was then extracted with ethyl acetate (2×100 ml), the separated and combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-propionic acid (compound #32A) as a white solid. Yield: 223 mg, 50.4%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2Cl)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-2-chlorobenzene (0.44 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 45%).
Reaction SMILES: [C:1]([N:5]([C:19]([C:21]1[CH:48]=[CH:47][C:24]2[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:23]=2[CH:22]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].O>CO.[Pd]>[C:1]([N:5]([C:19]([C:21]1[CH:48]=[CH:47][C:24]2[N:25]=[CH:26][NH:27][C:23]=2[CH:22]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1c(OC)cccc1C(=O)NN(C(=O)c1ccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1)C(C)(C)C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCc1c(OC)cccc1C(=O)NN(C(=O)c1ccc2nc[nH]c2c1)C(C)(C)C
Reaction time: 6 h

Procedure:
About 120 mg of 3-trityl-3H-benzoimidazole-5-carboxylic acid N-tert-butyl-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide were dissolved in 35 mL of CH3OH and added into a hydrogenation bottle, together with 2 drops of glacial acid and 0.20 g Pd/C. Hydrogenation was conducted by shaking the bottle for 6 hours and then remaining under H2 pressure for 16 hours. The Pd/C was removed by filtration and the methanol removed by an evaporator. The residue was stirred with CH2Cl2 and the CH2Cl2 was decanted. Evaporation of the CH2Cl2 yielded a solid product identified by NMR, as triphenylmethane. The residue was stirred with dilute KOH/H2O and extracted with ethyl acetate. The ethyl acetate was dried and concentrated on a rotary evaporator to yield the product 3H-benzoimidazole-5-carboxylic acid N-tert-butyl-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide. NMR analysis of the product indicated the absorbances for the methoxy and t-Butyl groups occurred at 3.69 and 1.61 vs. 3.77 and 1.59 for the starting material.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]([CH:14]2[CH2:16][CH2:15]2)[C:10](=[O:17])[CH:9]=1.[OH:18][C:19]([CH3:53])([CH3:52])[CH2:20][C@@:21]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:26][C:25](=[O:27])[N:24]([C@H:28]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:31]=2[CH3:45])[CH3:29])[CH2:23][CH2:22]1>CN(C)C=O>[CH:14]1([N:11]2[CH:12]=[CH:13][C:8]([C:33]3[CH:34]=[CH:35][C:30]([C@@H:28]([N:24]4[CH2:23][CH2:22][C@:21]([CH2:20][C:19]([OH:18])([CH3:53])[CH3:52])([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:26][C:25]4=[O:27])[CH3:29])=[C:31]([CH3:45])[CH:32]=3)=[CH:9][C:10]2=[O:17])[CH2:16][CH2:15]1
Reactant: O=c1cc(Br)ccn1C1CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1[C@H](C)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccn(C3CC3)c(=O)c2)ccc1[C@H](C)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (0.41 mL) was added to a mixture of 4-bromo-1-cyclopropyl-1H-pyridin-2-one (0.11 g) and (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (0.20 g) in N,N-dimethylformamide (2 mL). The resulting mixture was sparged with argon for 10 min prior to the addition of [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (33 mg). The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling the mixture to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 0.13 g (64% of theory); LC-MS (Method 5): tR=3.43 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:27]([O:29]C(C1C2C=CC(O)=CC=2OC=1)=O)[CH3:28].C(OCCBr)C>>[CH2:27]([O:29][CH2:2][CH2:1][O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:28]
Reactant: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Agent: CCOCCBr
Product: CCOCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1

Procedure:
4-[6-(2-Ethoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid (30c) is synthesized analogous to 30a from 6-hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) and 2-bromoethyl ethyl ether.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)([CH3:13])[CH3:12]>>[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:6]([Cl:10])(=[O:8])=[O:7])([CH3:13])[CH3:12]
Reactant: CC(C)c1cc2ccccc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-i-propylbenzo[b]thiophene-3-sulfonyl chloride compound was prepared by the method of Example 40B with DMF (5.2 mmoles, 0.40 ml), using sulfuryl chloride (4.2 mmoles, 0.34 ml) and 2-i-propylbenzo[b]thiophene (2.1 mmoles, 0.37 g). Flash chromatography (1% ethyl acetate/hexanes) provided 0.17 g (29%) of a yellow solid.
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]([S-:4])=[S:3].[Na+].[CH3:12]I>CO>[O:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]([S:4][CH3:12])=[S:3]
Reactant: S=C([S-])OC1CCCCC1
Reactant: CI
Agent: [Na+]
Solvent: CO
Product: CSC(=S)OC1CCCCC1

Procedure:
3 g (0.015 mol) of sodium cyclohexyl xanthate is dissolved in 50 ml of dried methanol and heated to reflux with 10.7 g (0.075 mol) of methyl iodide for 1 hour. After cooling, the reaction solution is evaporated by using a rotary evaporator, dissolved in ether/water (50/50), the ether phase being separated and dried with sodium sulfate, purified with active carbon/bleaching earth, and evaporated with the aid of a rotary evaporator.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][C:12]1([CH3:25])[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:11][C:12]1([CH3:25])[N:17]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(C)(C)C1
Temperature: 120 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-2-nitropyridine (5.6 g, 28.0 mmol), tert-butyl 3,3-dimethyl-piperazine-1-carboxylate (3.0 g, 14.0 mmol), cesium carbonate (9.1 g, 28 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting solution for 30 min, Binap (870 mg, 1.4 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.2 g, 1.4 mmol) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and stirred at 120° C. for 24 h. After this time the reaction was cooled to room temperature it was filtered and the filtrate was partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 125a (1.27 g, 27%). LCMS: [M+H]+ 337.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([NH2:14])=O>O>[CH3:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][NH:14][C:7]2=[O:8]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: NC=O
Solvent: O
Product: Cc1ccc2nc[nH]c(=O)c2c1

Procedure:
8 g of 5-methyl 2-aminobenzoic acid and 15 ml formamide was heated at −170° C. 1.5 hour. Water was added and the solid filtered to give 7.3 g of 6-methyl 4-quinazolinone as a light brown-white solid, mp—268° C.
Reaction SMILES: [S:1]=[C:2]1[NH:14][C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[N:3]1[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[OH-].[NH4+].I[CH3:28]>O.C(O)C>[CH3:28][S:1][C:2]1[N:3]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(=S)[nH]c2cnc3cccnc3c21
Reactant: CI
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethylcarbamate (31 g, 89.8 mmol) in water (150 mL) and ethanol (150 mL) was treated with ammonium hydroxide (30 mL) and iodomethane (25.5 g, 180 mmol) according to the general method of Part E of Example 22. After three hours, most of the ethanol was removed under reduced pressure, and water (500 mL) was added to the resulting suspension. The mixture was allowed to stand for 30 minutes. A solid was present and was isolated by filtration, washed with water and diethyl ether, and dried under vacuum for three hours to provide tert-butyl 2-[2-(methylthio)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]ethylcarbamate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9](=O)[CH3:10].[Cl:12][CH2:13][C:14]#[N:15]>O1CCOCC1.Cl>[Cl:12][CH2:13][C:14]1[N:15]=[C:9]([CH3:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[N:1]=1
Reactant: CC(=O)c1c(C)cccc1N
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc2nc(CCl)nc(C)c12

Procedure:
Prepared by reacting 1-(2-amino-6-methyl-phenyl)-ethanone with chloroacetonitrile in dioxane while piping in hydrogen chloride at 30-38° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([NH:17][CH:18]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:29]([F:32])([F:31])[F:30])[CH:9]=2)[N:4]=1>O1CCOCC1>[NH:20]1[CH2:21][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:29]([F:31])([F:30])[F:32])[CH:9]=3)[N:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:12]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cc(C(F)(F)F)nc3ccc(C(F)(F)F)cc23)C1
Solvent: C1COCCO1
Product: O=C(CNc1cc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12)NC1CNC1

Procedure:
A solution of tert-butyl 3-(2-((2,6-bis(trifluoromethyl)quinolin-4-yl)amino)acetamido)azetidine-1-carboxylate (291 mg, 1.04 mmol) in dry dioxane (5 mL), prepared in Step C above, was de-protected as described in example to afford the product.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>CN(C)C=O.ClCCl>[CH3:8][C:5]1[S:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]2[C:6]=1[NH:7][C:14](=[O:16])[NH:1]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sc(C)c(N)c1N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1sc(C)c2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 4777.4 %

Procedure:
Methyl 3,4-diamino-5-methylthiophene-2-carboxylate (3.0 g) was dissolved in a mixture of N,N-dimethyl formamide (5 ml) and dichloromethane (15 ml). To the solution was added triphosgene (2.4 g) in portions. The mixture was stirred for two days at room temperature, and precipitates were collected by filtration, washed with dichloromethane and dried. Resultant white powder (2.4 g) was suspended in N,N-dimethylformamide (25 ml). To the suspension was added sodium hydride (60% in oil; 0.55 g), and the mixture was stirred for three days at room temperature. The solvent was evaporated under reduced pressure. To the residue was added 2N-HCl. Resulting precipitates were collected by filtration, washed with water, ether and methanol successively, followed by drying to afford the title compound (82 g, 53%) as pale brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]#[N:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([C:18]#[N:19])[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1cc(CC#N)c2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C#N)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A stirred solution of 3-cyanomethyl-indole-1-carboxylic acid tert-butyl ester (2.15 g, 8.39 mmol) in THF (40 ml) was cooled to −78° C. under an argon atmosphere. Sodium bis(trimethylsilyl)amide (1 M in THF, 10 ml, 10 mmol) was added thereto and the cold solution was stirred for 30 minutes. Iodomethane (627 uL, 10 mmol) was added thereto and the reaction mixture was stirred 1.5 hr while gradually warming to 0° C. H2O (100 ml) was added thereto and the solution was brought to RT and diluted with EtOAc (250 ml). The aqueous layer was removed and extracted with EtOAc (250 ml). The combined organic layers were washed with aqueous HCl (1N, 3×50 ml), followed by brine, then dried over MgSO4, filtered, and concentrated to an orange oil. Purification via column chromatography (hexanes:ethyl acetate) gave 3-(cyano-methyl-methyl)-indole-1-carboxylic acid tert-butyl ester (1.8 g). 1H-NMR (300 MHz, DMSO-d6): δ 8.09 (d, 1); 7.73 (d, 1); 7.69 (s, 1); 7.74-7.29 (m, 2); 4.56 (q, 1); 1.66 (d, J=7.2, 3); 1.63 (s, 9).
Reaction SMILES: NN.C1(=O)[N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:19][C@H:18]3[C@H:13]([CH2:14][C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[CH2:17]3)[CH2:12]2)C(=O)C2=CC=CC=C12.C(OCC)C>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:19][C@H:18]2[C@H:13]([CH2:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[CH2:17]2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Agent: NN
Solvent: CCOCC
Solvent: CCO
Product: NCCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Hydrazine (9 mg, 0.28 mmol) was added to a solution of 2-(3-Phthalimido-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (50 mg, 0.14 mmol) in 1 mL of ethanol, and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, and 5 mL of diethyl ether was added with stirring. After 30 minutes, a white solid had precipitated. The solid was collected by filtration, rinsed with diethyl ether, then stirred in 10 mL of chloroform. The solids were filtered and washed with chloroform. The filtrate was concentrated to yield 20 mg of a colorless oil as product. Yield=63%. NMR (300 MHz, CD3OD) δ 7.09-7.05 (m, 4H), 3.03-2.97 (m, 2H), 2.77-2.70 (dd, 2H, J=6 Hz, 14 Hz), 2.68-2.58 (m, 4H), 2.50-2.44 (dd, 2H, J=5 Hz, 14 Hz), 2.30 (t, 2H, J=7 Hz), 1.82 (t, 2H, J=7 Hz), 1.61 (tt, 2H, J=7 Hz, 8 Hz, 7 Hz).