Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccccc1C=Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCc1ccccn1

Procedure:
A solution of 2-(o-nitrostyryl)pyridine (94.3 g., 0.42 mole) in 400 ml. of ethanol is reduced on a Parr hydrogenation apparatus employing 2 g. of 10% palladium on carbon catalyst to provide 2-(o-aminophenethyl)pyridine, m.p. 59°-61°C. The isolation of the pyridine product is carried out in the usual manner by collecting the catalyst and evaporating the ethanolic solvent.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:16][NH:15][S:14]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:26][C:27]([NH:29][C:30]1[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=1[CH:39]([CH3:41])[CH3:40])=[O:28].O>CN(C)C=O>[CH:39]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([CH:36]([CH3:37])[CH3:38])[C:30]=1[NH:29][C:27](=[O:28])[CH2:26][N:15]1[CH2:16][C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:14]1(=[O:23])=[O:24])([CH3:40])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: O=S1(=O)NCC2(CCCCC2)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CC2(CCCCC2)N(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
75 mg (0.54 mmol) of potassium carbonate are added to a solution of 130 mg (0.49 mmol) of 1-phenyl-2-thia-1,3-diazaspiro[4.5]decane-2,2-dioxide and 136 mg (0.54 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)-acetamide in 30 ml of dimethylformamide. The reaction medium is stirred at room temperature for one night and then it is heated to reflux for 6 hours and at room temperature for 48 h. The medium is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 90/10). 125 mg of N-(2,6-diisopropylphenyl)-2-(2,2-dioxo-1-phenyl-2-thia-1,3-diazaspiro[4.5]dec-3-yl]acetamide are obtained in the form of a yellow oil. The product is triturated in dichloromethane and plenty of heptane. A solid is obtained. M.p. 140-2° C., yield=53%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[Cl:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23])=[O:30]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: O=C(Cl)CCCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NC(=O)CCCl)c1SC(F)(F)F

Procedure:
To a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (10.0 g, 19.0 mmol) in toluene was added 3-chloropropionyl chloride (3.92 g, 30.9 mmol), then zinc chloride (0.97 g, 7.1 mmol). The mixture was heated at reflux for 4 hours. After extractive workup and recrystallisation with heptane-ethyl acetate (1:1) the title product was obtained (9.05 g), 19F-NMR: −43.3; −63.7 ppm.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CNCC2
Reaction time: 0.5 h
Yield: 199.6 %

Procedure:
At 0° C. a mixture of 16.93 g 2-tert-butyl 7-methyl 3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate, 160 ml dichloromethane and 80 ml trifluoroacetic acid is stirred for 30 min. Then, the mixture is stirred for 5 h at ambient temperature. The reaction mixture is evaporated and the residue is treated with a 10% KOH solution and dichloromethane. The organic layer is dried and evaporated. 22.18 g of the title compound are obtained.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Mg]Br>O1CCCC1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:12]([C:13]#[N:14])[C:15]#[N:16]
Reactant: COc1ccccc1[Mg]Br
Reactant: N#CC(C#N)=Cc1cccc2ccccc12
Solvent: C1CCOC1
Product: COc1ccccc1C(c1cccc2ccccc12)C(C#N)C#N
Reaction time: 1.5 h

Procedure:
A flask was charged with (1-naphthalenylmethylene)-propanedinitrile (408 mg, 2 mmol) and 10 mL anhydrous tetrahydrofuran. To this stirred solution was added, at room temperature, 2-methoxy phenyl magnesium bromide (2.4 mL, 2.4 mmol, 1 M in tetrahydrofuran). The reaction was stirred 1.5 hours, after which it was quenched with 1 N hydrochloric acid and taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to dryness. Following purification on silica (20% ethyl acetate/hexanes) 551 mg product was isolated as an off white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([NH:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CCc1csc(Nc2ncccc2OCc2ccccc2)n1)NCCN1CCCC1
Temperature: 0 °C

Procedure:
3-(2-(3-(Benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoic acid (40 mg, 0.113 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.0171 mL, 0.135 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (22.4 mg, 0.146 mmol) and 4-methylmorpholine (0.0173 ml, 0.158 mmol) were placed in an 8.5 mL screw-cap vial. The reaction mixture was cooled to 0° C. in an ice bath, and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (33.0 mg, 0.172 mmol) was added as a solid. The mixture was stirred at 0° C. and then allowed to warm to room temp overnight. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was partitioned between dichloromethane and saturated aqueous NaHCO3 diluted with an equal part of water. The organic phase was washed with once with water, then with brine, and dried by passing through a plug of anhydrous sodium sulfate. The solution was concentrated in vacuo and dried under high vacuum to provide the title compound as a colorless oil. 1H NMR (CDCl3) δ 1.76 (s, 4H), 2.56 (m, 4H), 2.59 (dd, J=5.6, 12.9 Hz, 4H), 3.01-2.94 (m, 4H), 3.37 (dd, J=11.3, 5.5 Hz, 2H), 5.13 (s, 2H), 6.75 (bs, 1H), 6.47 (s, 1H), 6.82 (dd, J=8.2, 5.1 Hz, 2H), 7.10 (dd, J=1.2, 7.9, Hz, 1H), 7.42 (br s, 4H), 7.94 (dd, J=1.2, 5 Hz, 1H), 8.59 (bs, 1H); Mass spectrum (apci) m/z=452.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:26][OH:27]>>[OH:27][NH:26][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:5])=[O:4]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)cc1
Product: CN(C/C=C/c1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-({methyl[3-(1,1'-biphenyl-4-yl)-trans-prop-2-enyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1>C(O)(=O)C>[OH:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1
Reactant: O=C1COc2ccc(O)cc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1COc2cc([N+](=O)[O-])c(O)cc2N1

Procedure:
Fumic nitric acid (δ 1.52, 2.6 ml, 0.062 mole) in acetic acid (5 ml) was added dropwise under stirring to 6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (Coupler (1), 10.3 g, 0.062 mole) in acetic acid (100 ml) at room temperature. The 6-hydroxy-7-nitro-1,4-benzoxazin-3-one (6.7 g, 51%) separated as yellow prisms.
Reaction SMILES: [BrH:1].[CH2:2]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>COCCOC>[Br:1][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1
Reactant: C=CCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: O=C(O)c1ccc(NCCCCCCCCCCCBr)cc1

Procedure:
Anhydrous hydrogen bromide is passed rapidly into a solution of 5 g. of 4-(10-undecenylamino)benzoic acid and 1 g. of dibenzoyl peroxide in 300 ml. of 1,2-dimethoxyethane for 1 hour. Partial evaporation of the solvent affords a crystalline solid which is separated by filtration and recrystallized from etherpetroleum ether to yield the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[N:7]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)[C:6]=2[CH:24]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:23][C:19]1[N:18]=[C:17]([N:7]2[C:6]3[CH:24]=[C:2]([C:34]#[C:33][C:31]([C:28]4[CH:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:22]=[CH:21][N:20]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(C(=O)N3CCCC3)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(C(=O)N4CCCC4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 4-[6-bromo-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (200 mg, 0.49 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (350 mg, 0.50 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred under nitrogen at 70° C. for 2 hr. The reaction mixture was cooled to room temperature and purified on a C18 column (acetonitrile/water, 5:95-80:20) to afford 88 mg (38%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a light yellow solid. 1H NMR (300 MHz, DMSO) delta 8.42 (d, J=5.1 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.03 (s, 2H), 6.74 (d, J=5.1 Hz, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 3.61 (d, J=6.6 Hz, 2H), 3.48 (d, J=6.6 Hz, 2H), 2.40 (s, 3H), 1.92 (s, 4H), 1.80 (s, 3H); LC-MS: m/z=+458 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.[CH:15]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:22]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:23])[CH2:12][CH2:11]2
Reactant: COc1cccc2c1OC(CN)CC2
Reactant: O=C(Cl)C1CCCCCC1
Product: COc1cccc2c1OC(CNC(=O)C1CCCCCC1)CC2

Procedure:
The title compound is prepared analogously to the instructions of Example XII from 2-aminomethyl-8-methoxy-chroman and cycloheptanecarbonyl chloride, and is further reacted directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: COCCN1CCN(c2ccc(N)cc2C#N)CC1
Product: COCCN1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 47.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.8 g) and 5-amino-2-[4-(2-methoxyethyl)piperazin-1-yl]benzonitrile (0.8 g), the title compound (0.7 g) was obtained, melting point: 207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[NH2:12].[I:13]I>C(O)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:13][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH2:12])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: II
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: COc1cc(I)cc([N+](=O)[O-])c1N
Temperature: 60 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
A mixture of 6.2 g (36.9 mmol) 2-methoxy-6-nitro-phenylamine, 9.4 g (37 mmol) iodine and 5.8 g (18.5 mmol) silver sulfate in 90 ml glacial acetic acid is stirred at 60° C. for 12 h. The reaction mixture is cooled to room temperature, poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 8.57 g of the title compound as bright red crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Cc1nc2ccc(O)cc2o1
Product: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1

Procedure:
37.3 g (0.1 mol) of 2-methyl-6-hexadecyloxybenzoxazole obtained by the reaction of 2-methyl-6-hydroxybenzoxazole with hexadecyl bromide was added to a mixture composed of 30 ml of hydrochloric acid and 300 ml of ethanol and the mixture was stirred at a temperature range between 40° C. and 50° C. for 1 hour. After cooling, the crystals deposited were collected by filtration and washed with ethanol to obtain 35.8 g of 2-acetylamino-5-hexadecyloxyphenol.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1)=[O:23])[CH3:26]
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCn1nc(C2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a stirred suspension, under nitrogen, of 1.7 g of a 50% oil dispersion of sodium hydride in 75 ml of dimethylformamide was added, dropwise, 6.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 30 ml of hot dimethylformamide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for 1 hr and a solution of 6.5 g of ethyl 3-bromopropionate was added dropwise. The reaction mixture was stirred at ambient temperature for 3 hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate and the extracts were washed with water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate under vacuum gave 6.5 g (70.8%) of product, as an oil.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](Cl)(Cl)=[O:16]>O.C1(C)C=CC=CC=1>[CH2:7]([CH:6]1[O:14][C:15](=[O:16])[NH:4][CH2:5]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCC(O)Cc1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NCC(Cc2ccccc2)O1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of KOH (9.4 g) in water (85 ml) was added to a stirred solution of the product from step (b) (5.1 g) in toluene (150 ml) at 0° C. A solution of phosgene (9.8 g) in toluene (78.4 ml =12.5% w/v) was added dropwise over 15 minutes and the mixture brought to room temperature, then stirred overnight. The aqueous-phase was separated and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give the desired product as a white solid (2.2 g), mp 106°-108° C. Elemental analysis was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[NH:23][N:22]=1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:8][CH:9]=2)[N:22]=1)=[O:20])[CH3:17]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CCCc1cc(C(=O)OCC)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the recovered intermediate (19a) (1.4 g, 5 mmol, 1.0 eq) dissolved into 15 mL DMF, was added 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (910 mg, 5.0 mmol, 1.0 eq) and potassium carbonate (0.8 g, 5.5 mmol, 1.1 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was then added to 50 mL of 10% aq. LiCi solution and extracted with 50 mL EtOAc. The organic was dried over MgSO4, and concentrated under reduced pressure to yield intermediate (19b) and its regioisomer in a 1:1 ratio. The recovered regioisomers were dissolved into 25 mL MeOH. To this was added 10 mL of 1M NaOH and the mixture was stirred at room temperature over night. The mixture was acidified with acetic acid and concentrated under reduced pressure. The recovered oil was purified by preparatory HPLC, producing the desired regioisomer of the title compound as a white solid TFA salt after lyophilization (230 mg). 1H NMR (DMSO) 0.89 (t, 3H), 1.52 (s, 9H), 5.71 (s, 2H), 6.71 (s, 1H), 7.15 (d, 2H), 7.83 (d, 2H), 13.28 (br s, 1H).
Reaction SMILES: [C:1]1([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>O>[CH:35]([C:4]1[CH:3]=[CH:2][C:1]([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1)=[O:36]
Reactant: c1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
32.14 g (0.1 mol) of the above prepared 5-(N,N-diphenylamino)acenaphthene was dissolved in 300 ml of N,N-dimethylformamide, and 22.73 g (0.15 mol) of phosphorus oxychloride was dropwise added thereto at room temperature for 30 minutes. After raising the temperature to 50° C., the reaction mixture was stirred for 14 hours. The reaction was determined to be finished when disappearance of 5-(N,N-diphenylamino)acenaphthene was identified. The reaction product was poured into an aqueous solution having 45 g (1.05 mol) of 93% sodium hydroxide dissolved in 1000 ml of water. The resultant mixture was cooled to precipitate a crystal, and the crystal was filtrated, washed with water and dried to obtain 30.27 g (yield: 86.6%, melting point: 138.0°-141.0° C.) of 5-[N-(4-formylphenyl)-N-phenylamino]acenaphthene.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:12]=3[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1.Cl.C(OCC)C>ClCCl>[CH2:1]([N:4]1[C:13]2[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C3CC3)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCn1c(=O)c2cnccc2c2ccc(OC[C@@H](N)CC(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 10298.6 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-cyclopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.221 mmol) in anhydrous dichloromethane (2 mL) was added a 2 M solution of HCl in diethyl ether (0.176 mL, 0.353 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude product which was purified by preparative HPLC (0.1% TFA in water) to afford (S)-6-allyl-8-((2-amino-4-methylpentyl)oxy)benzo[c][2,7]naphthyridin-5(6H)-one (8 mg, 22.76 mmol, 10% yield) as a yellow solid. LC/MS (ESI) m/e 352.2 [(M+H)+, calcd for C21H26N3O2 352.2]; LC/MS retention time (method C): tR=1.80 min; HPLC retention time (method A): tR=8.06 min; HPLC retention time (method B): tR=9.21 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.56 (s, 1H), 8.85 (d, J=6.27 Hz, 1H), 8.55 (d, J=9.04 Hz, 1H), 8.48 (d, J=6.27 Hz, 1H), 7.20 (dd, J=8.91, 2.38 Hz, 1H), 7.14 (d, J=2.26 Hz, 1H), 6.08 (dd, J=17.32, 10.54 Hz, 1H), 5.28 (dd, J=10.54, 1.00 Hz, 1H), 5.18 (dd, J=17.32, 1.25 Hz, 1H), 5.09-5.13 (m, 2H), 4.44 (dd, J=10.54, 3.26 Hz, 1H), 4.27 (dd, J=10.42, 6.40 Hz, 1H), 3.77 (dd, J=6.78, 3.51 Hz, 1H), 1.64-1.88 (m, 3H), 1.07 (dd, J=6.40, 4.89 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]2[C:9]([C:10](=O)[NH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:14]2[C:9]([C:10]([Cl:18])=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(=O)[nH]cnn12
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(Cl)ncnn12
Temperature: 160 °C

Procedure:
A mixture of 4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester (300 mg) and phosphorus oxychloride (1 mL) was heated at 160° C. for 15 minutes in a microwave reactor. The resulting mixture was cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 90/10) to afford 120 mg of 4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester containing 4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile.