Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][NH2:15]>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3]([NH:15][CH2:14][CH2:13][CH2:12][NH:11][CH3:10])=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCCN
Solvent: C1CCOC1
Product: CNCCCNC(=O)C(F)(F)F
Reaction time: 17 h
Yield: 106.4 %

Procedure:
Ethyl trifluoroacetate [383-63-1] (7.5 mL, 62.9 mmol) was slowly added to an ambient temperature solution of N1-methylpropane-1,3-diamine [6291-84-5] (6.5 mL, 62.8 mmol) in anhydrous THF (100 mL) then allowed to stir, under N2 blanket for 17 h. The reaction solution was then evaporated to provide 12.3 g of clear colorless liquid. LRMS (ESI) m/z 185.1 [(M+H)]+, calc'd for C6H11F3N2O: 184.16.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1C(O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>Cl.O1CCOCC1.CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
(2S)-1-(tert-Butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)-pyrrolidine (1.93 g) was dissolved in 31 ml of 4N hydrochloric acid/1,4-dioxane, and the mixture was,stirred at room temperature for 0.5 hour. The reaction mixture was concentrated to dryness, and the residue obtained was dissolved in DMF (15 ml), after which N-(tert-butoxycarbonyl)-L-proline (1.36 g), N-methylmorpholine (0.69 ml), and HOBt (1.02g) were added thereto. After the reaction mixture was cooled to -25° C., DCC (1.30 g) was added thereto, and the mixture was stirred at -25° C. to 0° C. for 3 hours, and then at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, and saturated brine successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 2.10 g of the title compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I.Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Cu]I.C(NCC)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6]
Reactant: Brc1ccccc1I
Reactant: C#CCCC(=O)O
Agent: [Cu]I
Agent: [Pd]
Agent: Cl
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1Br
Reaction time: 2 h

Procedure:
To 10 ml of diethylamine was added with stirring 0.5 g (5.1 mmol) of 4-pentynoic acid, 1.4g (5 mmol) of 1-bromo-2-iodobenzene, and 60mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(O) The slurry was degassed with argon and 0.19g (1.0 mmol) of CuI was added. The reaction mixture was stirred for 2 hr. at room temperature and then poured into approximately 100ml of a 10% HCl solution. The resulting precipitate was filtered, washed with water and dried. The solid was taken up in hot CHCl3 and filtered to remove insoluble salts. After evaporation of the solvent, the resulting orange solid was recrystallized from a chloroform-hexane mixture to produce a tan solid, m.p. 87-91°C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[BH4-].[Na+].Cl>CO>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1Cc2ccc([N+](=O)[O-])cc2CN1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-ethyl-7-nitro-3,4-dihydroisoquinoline (5.0 g) in methanol (100 ml) was added sodium borohydride (3×0.4 g), and the reaction was stirred for 2 h. Enough 4N HCl was added to the reaction mixture to make it acidic whereupon a solid crystallized out and was collected by filtration (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>C1COCC1>[OH:19][C:9]1([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the ketal of step D (11.5 g, 43.3 mmol) in THF (100 mL) was added 3N HCl (75 mL) and the solution stirred overnight at rt. The pH of the solution was adjusted to ˜11 by the addition of 3N NaOH solution. After removal of most of the THF by rotary evaporation, the aqueous was extracted with CH2Cl2 (3×). The combined extracts were dried (MgSO4), filtered, and concentrated to give the title compound as a yellow solid; yield 8.2 g, 37.1 mmol, 86%; 1H NMR (CDCl3) δ 8.26 (s, 1H), 7.75 (d, 1H), 6.73 (d, 1H), 3.91 (s, 3H), 2.91 (m, 2H), 2.78 (s, 1H), 2.32 (m, 2H), 2.21 (m, 4H); MS m/z=222.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:10])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1F

Procedure:
A reaction vessel was charged with 128 g (1.016 mol) of 2-fluoroanisole and 250 ml of chloroform. To this mixture was added dropwise under agitation at room temperature 177 g (1.106 mol) of bromine over the period of at least 3 hours. The reaction liquid was poured into a diluted aqueous solution of NaOH, and the chloroform layer was separated, washed with a solution of edible salt and dried over Glauber's salt. The solvent was distilled off and the residue was distilled under reduced pressure to obtain 2-fluoro-4-bromoanisole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([F:1])[CH:7]=1
Reactant: BrBr
Reactant: COc1ccccc1F
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1F
Yield: 73.3 %

Procedure:
2-Fluoroanisole (266 g) was dissolved in 700 ml of chloroform and 337 g of bromine was added dropwise to the solution. The mixture was reacted under reflux at 67° to 68° C. for 1 hour, subsequently left to cool, washed with a 5% aqueous solution of sodium hydroxide and then with water, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled (95° to 96° C./12 mmHg) to obtain 317 g of 4-bromo-2-fluoroanisole (yield 73.4%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C([O-])([O-])=O.[K+].[K+].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCOC(C)=O>[Cl:5][CH2:4][CH2:3][CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-bromo-3-chloropropane (0.79 g, 5.00 mmol) and K2CO3 (1.38 g, 10.00 mmol) in EtOAc (20 mL) was added a solution of morpholine (0.44 g, 5.05 mmol) in EtOAc (20 mL) dropwise at rt under N2. The mixture was stirred at rt overnight, then filtered and concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([C:17](=[O:18])[N:11]=2)[CH2:16][CH2:15][CH2:14]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC12CCC2

Procedure:
Synthesis was performed from N-cycloheptylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(#N)C.[OH-].[Li+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3046 g of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate, 10 l of acetonitrile and 6701 ml of 2M lithium hydroxide is stirred at room temperature overnight, and then diluted with 20 l of water. Acetic acid (1 l) is added to adjust pH to 5.5 and additional water (12 l) is added. The precipitated product is collected and resuspended in 50 l of water. The suspension is stirred, the precipitate is collected, washed with water and dried at 60°/3 mm Hg (=4.00 mbar) for 48 h. The product is recrystallized twice from ethyl acetate and once from acetonitrile to yield 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid, m.p. 116.5°-118°.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
2,5-hexanedione (46.2 g, 0.41 mol) was added to a suspension of 2-amino-5-bromopyridine (50.0 g, 0.29 mol) and the reaction heated to reflux for 24 hours under Dean and Stark conditions. para-Toluene sulfonic acid (100 mg) was added and the reaction was refluxed for a further 18 hours. 8 ml of water were removed, so the reaction was cooled to room temperature, washed with water (100 ml) and passed through a plug of silica gel, eluting with toluene. The eluent was concentrated in vacuo and the residue dissolved in pentane:dichloromethane (1:1 by volume) and passed through a plug of silica gel, eluting with pentane:dichloromethane (1:1 by volume). The eluent was concentrated in vacuo to give a red liquid, which solidified on standing. The solid was recrystallised from isopropanol to give the title compound as a pale yellow solid (54.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[N:3][CH:4]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-Amino-5-bromopyridine (6.0 Kg, 34.7 mol), 2,5-hexanedione (4.35 Kg, 38.2 mol) and p-toluenesulfonic acid (12 g) were dissolved in heptane (36 L) and refluxed under Dean Stark conditions overnight. The equipment was set for distillation and heptane (18 L) was removed by distillation. The mixture was cooled to 20° C. for 60 minutes. Seed crystals were added and the mixture granulated at 20° C. for 2 hours and then at 5° C. overnight. The product was collected by filtration, washed with heptane (2×6 L) and dried at 45° C. under vacuum overnight. Yield=80% (7.0 Kg) δH (CDCl3 300 MHz) 2.20 (6H, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1H, d), 8.70 (1H, s) ppm. MS m/z 253 (MH+, Br isotope).
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]C)[C:6]=1C#N.C[CH2:16][O:17][CH2:18][CH3:19]>C1C=CC=CC=1>[CH3:10][C:9]([C:6]1[C:5]([F:4])=[CH:12][CH:11]=[CH:19][C:18]=1[O:17][CH3:16])=[O:13]
Reactant: CCOCC
Reactant: COc1cccc(F)c1C#N
Agent: C[Mg]Br
Solvent: c1ccccc1
Product: COc1cccc(F)c1C(C)=O
Temperature: 25 °C

Procedure:
To a flask containing methyl magnesium bromide (1.18 g, 9.93 mmol) in ether is added dropwise 2-fluoro-6-methoxybenzonitrile (0.5 g, 3.31 mmol, Lancaster Synthesis Inc.) in benzene (9 ml). The reaction mixture is refluxed overnight. The reaction is cooled to room temperature and quenched slowly with saturated ammonium chloride (15 ml) and concentrated hydrochloric acid (1 ml). The mixture is extracted with diethyl ether (2×50 ml). The combined organic layers are dried over Na2SO4, filtered, and rotary evaporated to give 0.55 g of a crude yellow material. Purification is accomplished by vacuum column (eluting with 16% ethyl acetate in hexane). The compoundcontaining fractions are combined, yielding 5.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[N:13][OH:14]
Reactant: NO
Reactant: CC(C)=CCCC(C)CC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)=CCCC(C)CC=NO

Procedure:
(Compound 8). 3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alcohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for 15 minutes and then allowed to cool. Addition of an excess of water yielded 3,7-dimethyl-oct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10 percent solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60°/0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The ether solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7), bp 102°-103°/0.1 mm. The ester was epoxidized as described in the previous examples to yield VII. The crude reaction product can be readily purified by chromatography using neutral activated alumina.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:8][CH:7]=1.[S:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1>>[OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:34]3[N:33]=[CH:32][S:31][CH:35]=3)[CH2:25][CH2:24]2)=[CH:10][CH:11]=1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Reactant: O=Cc1cscn1
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1

Procedure:
An even further embodiment is directed to reacting the N-(2-hydroxy-ethyl)-N-methyl-4-(piperidin-4-ylidene-quinolin-8-yl-methyl)-benzamide with thiazole-4-carbaldehyde to form N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:19]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CN=C=O
Product: CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
The compound was prepared from 3-[3-(trifluoromethyl)phenoxy)azetidine and methylisocyanate as described in Example 4 of U.S. Pat. No. 4,226,861, m.p. 145°-147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1cnccn1
Reactant: NCCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1cnccn1

Procedure:
Reacting 2-chloropyrazine with 1,3-diaminopropane in ethanol containing sodium ethoxide by the procedure of Example 89 gives 2-(3-aminopropylamino)-pyrazine.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH3:23].C[Si](C)(C)[O-].[K+].C(OCC)(=O)C.C(OCC)C>O1CCCC1>[F:1][C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH3:23]
Reactant: COC(=O)c1cc2ncoc2c(F)c1Nc1ccc(I)cc1C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2ncoc2c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution comprised of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylate (0.024 M) in tetrahydrofuran is added solid potassium trimethylsilanolate (5.14 equiv.). The reaction mixture is stirred at ambient temperature under argon for 16 hours. An additional equivalent of potassium trimethylsilanolate is added and the mixture stirred 30 minutes. The reaction mixture is concentrated in vacuo to give a residue that is then taken up into 1:1 (v/v) ethyl acetate-diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, water, and brine, is dried (MgSO4), is concentrated in vacuo, and chased with chloroform to give a crude product. Recrystallization from an appropriate solvent like ethanol gives the purified desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[C:32][CH3:33].[Cl-].[NH4+].C(=O)=O>CN(C=O)C>[C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:30][C:31]#[C:32][CH3:33])=[CH:17][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC#CCBr
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc1
Reaction time: 21 h
Yield: 96.2 %

Procedure:
In dehydrated DMF (5.0 mL) was dissolved 1.35 g (4.23 mmol) of Boc-L-tyrosine ethyl ester (AK Scientific, Inc catalogue No 71054), and anhydrous potassium carbonate (0.7 g, 5.08 mmol) and 1-bromo-2-butyne (0.619 g, 4.65 mmol) were added at room temperature. The mixture was stirred under argon atmosphere for 21 hours. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction solution until generation of carbon dioxide gas stopped. This reaction solution was extracted with ethyl acetate, and washed with water and a saturated brine in this order. The extracted organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The obtained oily residue was purified by silica gel chromatography (20 g cartridge was used) using 10% ethyl acetate/n-hexane as an elution solvent to obtain 1.47 g (92% yield) of the title compound as clear and colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1>[Pt](=O)=O.CO>[Cl:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2ccncc2c1Cl
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Clc1ccc2c(c1Cl)CNCC2

Procedure:
The above prepared 7,8-dichloroisoquinoline hydrochloride was reduced in two portions by hydrogenation at 50-60 psi using 0.7 g. of platinum dioxide in 100 cc. of methanol, for one hour at ambient temperature. The mixture was filtered and concentrated. The residue was converted to the base using ammonium hydroxide and was extracted into ether. The extract was dried with magnesium sulfate, filtered and concentrated to give, as the residue, 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:27](=[O:28])[N:13]3[CH2:14][CH2:15][CH2:16][N:17](CC4C=CC=CC=4)[C:18](=[O:19])[C:12]3=[C:11]([CH3:29])[CH:10]=2)[CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:27](=[O:28])[N:13]3[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:29])[CH:10]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=O)n2c1C(=O)N(Cc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(N)ncn2)c(=O)n2c1C(=O)NCCC2
Temperature: 150 °C

Procedure:
A vial was charged with 8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (8, 0.3 g, 76.9 mmol) and trifluoroacetic acid (7.0 mL) was added and the reaction mixture was heated under microwave at 150° C. for 20 min. TLC showed completion of the reaction and the mixture was cooled to ambient temperature and this was then basified with aqueous sodium bicarbonate solution and extracted with 5% methanol/dichloromethane (3×200 mL). The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to afford 8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (Cpd. No. 147) as a brown solid. Yield: 0.06 g, 26%; MS (ESI) m/z 301.15 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.44 (m, 2H), 8.15 (s, 1H), 6.52 (m, 2H), 6.13 (s 1H), 5.05 (m, 1H), 3.17 (m, 2H), 2.95 (m, 1H), 2.13 (s, 3H), 1.87 (m, 2H).
Reaction SMILES: O1CCCC1.C[O:7][C:8]([C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)[NH:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C.O>[F:22][C:20]1[CH:21]=[C:16]([C@H:12]2[NH:11][C@@H:10]([CH2:8][OH:7])[CH2:15][CH2:14][CH2:13]2)[CH:17]=[C:18]([F:24])[C:19]=1[F:23]
Reactant: COC(=O)[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Yield: 98.4 %

Procedure:
Under a nitrogen atmosphere, a tetrahydrofuran (10 mL) solution of (2R,6S)-6-(3,4,5-trifluorophenyl)piperidine-2-carboxylic acid methyl ester (3.25 g) was added dropwise at −20° C. into a tetrahydrofuran (50 mL) suspension of lithium aluminum hydride (621 mg). After confirming the disappearance of the raw materials, water (0.62 mL), 5 N sodium hydroxide solution (0.62 mL), and water (1.86 mL) were added in sequence to the reaction solution at the same temperature. After stirring for 15 minutes at the same temperature, ethyl acetate was added, and the resultant was filtered on celite. The filtrate was passed through a silica pad (carrier: Chromatrex NH, eluting solvent: ethyl acetate), and by removing the solvent under a vacuum, the title compound (2.87 g) was obtained. The physical property values are as follows.