Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH2:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+].C(OC(=O)C)(=O)C.C(Cl)Cl>O>[C:22]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:10]=2[O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:15]1)(=[O:24])[CH3:23]
Reactant: COc1ccc2c(c1OCc1ccccc1)CCNC2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1OCc1ccccc1)CCN(C(C)=O)C2
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of 122.3 g of 5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline-hydrochloride, 36.1 g of sodium acetate, 81.7 g of acetic anhydride, and 500 ml of methylene chloride is stirred for 1 hour at the boiling point. After cooling, the mixture is combined with 500 ml of water and the organic phase is separated and evaporated to dryness under reduced pressure. 99.5 g of 2-acetyl-5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline are obtained. m.p. = 94° - 95° C. (ethyl acetate - diisopropyl ether).
Reaction SMILES: C(O)(=O)C.O.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[C:8]=1[NH:20][CH3:21]>[Fe].C1COCC1>[Br:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([NH2:17])[C:8]=1[NH:20][CH3:21]
Reactant: CNc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CNc1c(N)cc(C(F)(F)F)cc1Br
Temperature: 70 °C
Yield: 122.3 %

Procedure:
To a mixture of an iron powder (11 g), acetic acid (12 ml), THF (40 ml), and water (10 ml) was added dropwise a mixture of (2-bromo-6-nitro-4-trifluoromethyl-phenyl)-methyl-amine (10 g) and THF (50 ml) while stirring and heating at 70° C. After that, the mixture was stirred at 70° C. for 3 hours. The resulting reaction mixture was filtered through celite (registered trademark), and washed with THF. The resulting filtrate was concentrated under reduced pressure. To the resulting residue was poured 10% sodium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 3-bromo-N2-methyl-5-trifluoromethyl-benzene-1,2-diamine (11 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]#[C:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C1C=C2N=NN(O)C2=CC=1.O.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]#[C:15][CH3:16])[C:10]([N:19]([O:20][CH3:21])[CH3:18])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC#CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CCC(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reaction time: 3 h
Yield: 88.1 %

Procedure:
The product from Step I (10.58 g, 46.6 mmol), N,O-dimethylhydroxylamine hydrochloride (9.09 g, 93.2 mmol), HOBT hydrate (9.44 g, 69.9 mmol) and triethylamine (13.0 mL, 93.2 mmol) were stirred in dry DMF (150 mL) at 0° C. under nitrogen. EDC hydrochloride (11.5 g, 60.6 mmol) was added, and the reaction was stirred for 3 hours. The solution was partitioned between 2:1 ethyl acetate:hexane and water, washed with water, 10% aq. HCl, sat. NaHCO3 soln and brine, then dried with sodium sulfate. The solvent was removed in vacuo to give the title compound (11.10 g, 88 % yield) as an orange oil
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][O:18][CH:19]([CH3:22])[CH2:20][Cl:21])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].C1COCC1>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][O:18][CH:19]([CH3:22])[CH2:20][Cl:21])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](COC(C)CCl)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCl)OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
To a solution of (R)-methyl 2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg, 1.77 mmol) in THF—H2O (8 mL-4 mL) was added lithium hydroxide monohydrate (223 mg, 5.30 mmol). The mixture was stirred at room temperature for 25 minutes THF was removed in vacuo and the mixture extracted with EtOAc and dried over Na2SO4. Solvent was removed to give crude (R)-2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoic acid as an oil. MS [M+H] found 316.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[NH:8])=[O:7])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[N:8][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:7])[CH3:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CCS(=N)(=O)c1nsnc1-n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CC)CCS(=O)(=NC(=O)OCc1ccccc1)c1nsnc1-n1ccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of S-[2-(diethylamino)ethyl]-S-[4-(1H-imidazol-1-yl)-1,2,5-thiadiazol-3-yl]sulfoximine (10 mmol), benzyl chloroformate (12 mmol) and potassium carbonate(32 mmol) in methylene chloride is stirred at ambient temperature for 5 hr.The mixture is filtered and the filtrate concentrated to obtain the productwhich is purified using standard laboratory procedures.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][O:4][C:5](=[O:20])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15]S[CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1.O[O:23][S:24]([O-:26])=O.[K+].O.CC(C)=O>CO>[CH3:21][CH:2]([CH3:1])[CH2:3][O:4][C:5](=[O:20])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][S:24](=[O:26])(=[O:23])[CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1
Reactant: O=S([O-])OO
Reactant: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)COC(=O)Nc1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reaction time: 3 h

Procedure:
2-Methylpropyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate in methanol (250 ml) is added to a slurry of oxone (140.8 g, 229.1 mmol, 1.5 equiv.) in a slurry of water (250 ml). Acetone (375 ml) is added to the reaction mixture and an exotherm of 30° to give 53° is noticed. The reaction mixture is stirred for 3 hr, during which time the reaction gradually cooled to 25°. The slurry is quenched with aqueous sodium bisulfite (10%, 250 ml) and stirred 1 hr. The slurry is filtered to remove salts and the cake washed with methylene chloride (250 ml) followed by water (250 ml). The filtrate is separated into two phases and the lower organic phase is collected. The aqueous phase is washed with methylene chloride (2×250 ml). The combined organic phases are washed with saline (250 ml) and then concentrated. The concentrate is dried under reduced pressure overnight to give the title compound, TLC Rf=0.73 (methanol/methylene chloride, 5/95); mp=147-149°; NMR (CDCl3) d 7.36, 7.13, 7.03, 6.92, 5.75, 3.96, 3.80, 3.22, 3.10, 2.02-1.93 and 0.96; CMR (CDCl3) d 159.5, 153.4, 139.5, 134.1, 129.5, 123.0, 119.1, 113.9, 106.2, 71.6, 50.7, 47.8, 29.2, 27.9 and 18.9; MS (CI, NH3) m/z (relative intensity) 359 (100), 341 (5), 295 (18), 285 (20), 277 (23) and 178 (18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C(C)C)=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reaction time: 3 h
Yield: 97.1 %

Procedure:
1-Methylethyl 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylate (D30) (1.6 g, 6.21 mmol) in isopropanol (70 ml) and water (35.0 ml) was treated with 2N sodium hydroxide (6.21 ml, 12.42 mmol) and stirred for 3 hours to give a single product. Evaporated off the IPA, acidified with glacial acetic acid and extracted product into EtOAc (100 ml). Dried over MgSO4 and evaporated off the solvent to yield 1.30 g of the title compound as a white solid. MS (ES) C9H1035ClNO3 requires 215; found 214 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[C:15]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:3]1[C:2]([Cl:1])=[C:7]([C:8]#[N:9])[C:6](=[C:5]([Cl:12])[C:4]=1[Cl:13])[C:10]#[N:11]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2-c2ccccc2)c(Cl)c1C#N

Procedure:
To a 250 mL flask, 4.8 g of tetrachlorophthalonitrile, 4.3 g of biphenyl-2-ol, 5 g of potassium carbonate (K2CO3) and 55 mL of acetonitrile are added, followed by heating for 12 hours while refluxing. After completion of the reaction, 30 mL of ethyl acetate is added and filtered to remove the solvent. To the obtained solid, a suitable amount of dichloromethane is added to dissolve the solid, followed by adding hexane for crystallization. The obtained solid is filtered and dried under vacuum to obtain a compound, 4-[(biphenyl-2-yl)oxy]-3,5,6-trichlorophthalonitrile. The second step reaction may be represented by Reaction Scheme 2:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[F:25][C:26]([F:53])([F:52])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:37]2[CH2:41][C:40]([CH:43]=O)([CH3:42])[C:39]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)=[N:38]2)=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl.[Zn]>[F:53][C:26]([F:25])([F:52])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:37]2[CH2:41][C:40]([CH:42]=[C:20]([Br:24])[Br:21])([CH3:43])[C:39]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)=[N:38]2)=[O:36])=[CH:30][CH:29]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C=O)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C=C(Br)Br)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
To 1.5 g of zinc dust (23.8 mmole) and 5.2 g of triphenylphosphine (20 mmole) in 20 ml of methylene chloride was added 6.8 g of carbon tetrabromide (20 mmole) after stiring for 90 minutes a solution of 3 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-formyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide in 10 ml of MeCl2 is added and the mixture is stirred an additional 60 minutes. The reaction is partitioned between ether and aqueous sodium thiosulfate, dried, rotovaped and chromatographed (ether/hexane) to yield 2.0 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-(2,2-dibromovinyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide an oil. NMR data was consistent with the structure.
Reaction SMILES: P(OC)(OC)OC.C(N(CC)CC)C.[CH2:15]1[CH2:42][O:41][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C:28](=[O:40])[C@@H:29]([CH3:39])[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:16]1>C(O)(C)C.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[CH2:42]1[CH2:15][O:16][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C@H:28]([OH:40])[C@H:29]([CH3:39])[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:41]1
Reactant: C[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)CC1=O
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: COP(OC)OC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Yield: 63.3 %

Procedure:
A solution of chloroiridic acid (10 mg.) and trimethyl phosphite (1.5 ml.) in aqueous 90% isopropanol (20 ml.) was heated under reflux for 17 hours. The solution was then neutralised with triethylamine, 20,20-ethylenedioxy-2β-methyl-5α-pregnane-3,11-dione (0.66 g.) was added, and the mixture was heated under reflux for 48 hr. The reaction mixture was cooled and partitioned between methylene chloride and water. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue (0.69 g.) was purified by preparative layer chromatography and crystallised from methyl acetate/petroleum ether (b.p. 60°-80°) to give 20,20-ethylenedioxy-3α-hydroxy-2α-methyl-5α-pregnan-11-one (0.42 g.), m.p. 167°-168°, [α]D + 68°.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].[CH2:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32](=[O:54])[CH:33]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:34](OC3C(Cl)=C(Cl)C(Cl)=C(Cl)C=3Cl)=[O:35])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>ClCCl>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]([CH:33]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:34]([NH:17][CH:14]3[C:15](=[O:16])[N:11]4[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]34)=[O:35])=[O:54])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: O=C(Oc1ccc2c(c1)CCC2)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc4c(c3)CCC4)c3ccccc3)C(=O)N2C1C(=O)[O-]
Product: CC[NH+](CC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.88 ml. (0.092 moles) of triethylamine are added to a suspension of 9.66 g (0.046 moles) of 6-APA in 150 ml. of dichloromethane, and the mixture is stirred at room temperature until a solution is obtained. The solution is cooled to 0° C., and 25 g. (0.046 moles) of phenyl-malonic acid pentachlorophenylester 5-indanylester are added to it at such a rate that the temperature of the mixture always remains below "5° C. The mixture is stirred at 0° C. for one hour, and thereafter the solvent is evaporated in vacuo. The residue is admixed with 100 ml. of ethyl acetate, whereupon 26 g. (98%) of 6-(α-[5-indanyloxy-carbonyl]-phenylacetamido)-2,2-dimethyl-penam-3-carboxylic acid triethylammonium salt separate in the form of a crystalline substance. M.p.: 153°-155° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH2:17][CH2:18][CH2:19][NH:20][C:21](=O)[C:11]=3[C:10]=2[CH:9]=1.O1CCOC[CH2:24]1>>[CH3:24][N:20]1[CH2:19][CH2:18][CH2:17][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=3[C:11]=2[CH2:21]1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)NCCC3
Reactant: C1COCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc2[nH]c3c(c2c1)CN(C)CCC3

Procedure:
Lithium aluminum hydride (3 g, 78.95 mmol) was placed in 1,4-dioxane (100 mL) under inert atmosphere and 9-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (3 g, 14.018 mmol) was added, and the mixture heated to reflux for 15 h. The reaction was monitored by TLC. The reaction was quenched with saturated aqueous sodium sulfate at 0° C., and the reaction mixture filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford solid, which was washed with water followed by EtOAc, and dried to afford 1.25 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CS(C)=O.CO>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Yield: 6.3 %

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol), 4-methylstyrene (239 mg, 2.3 mmol) and NaH (120 mg, 60% dispersion in oil, 3 mmol) were heated in DMSO (4 mL) at 120° C. overnight (16 h) after which methanol was added and the contents were concentrated to dryness. The resulting crude product was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol: 5 mL) and/or silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient to obtain 20 mg (6.2% yield) of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 13.3 (bs, 1H), 7.4-7.0 (m, 5H), 6.80-6.70 (d, 2H), 4.7-4.6 (d, 1H), 4.40-4.22 (m, 1H), 4.20-4.10 (m, 1H), 4.10-4.0 (d, 1H), 3.5-3.4 (t, 1H), 3.20-3.17 (t, 1H), 3.0 (t, 2H), 2.80 (s, 3H), 2.7-2.61 (m, 1H), 2.40 (s, 3H), 2.23 (s, 3H), 2.2-2.1 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:24]1[C:25]2[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1>CC(O)C.C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[N:33][C:25]2[C:24]([NH:1][C:2]3[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]4([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]4)[CH:7]=3)=[N:29][CH:28]=[N:27][C:26]=2[CH:30]=1
Reactant: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Reactant: Clc1cnc2c(Cl)ncnc2c1
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3cc(Cl)cnc23)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Temperature: 100 °C
Yield: 50 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.044 g, 0.136 mmol) and 4,7-dichloropyrido[3,2-d]pyrimidine (0.030 g, 0.150 mmol) in iPrOH (2 mL) was added a catalytic amount of concentrated H2 SO4 and the resulting mixture was heated in microwave at 100° C. for 45 min. The mixture was diluted with DCM, washed with 1 N NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM to afford a light brown solid as (4S,6S)-4-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.033 g, 0.068 mmol, 49.8% yield). MS m/z=486.9 [M+H]+. Calculated for C20H16ClF5N6O: 486.10.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:28]2[CH2:30][CH2:29]2)[C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:28]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[N:19][CH:18]=2)=[O:16])[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-n3ccnc3)nc2)C2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc(-n2ccnc2)nc1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 4-[cyclopropyl-(2-imidazol-1-yl-pyrimidine-5-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester by treatment with trifluoroacetic acid in dichloromethane. LC (method 10): tR=0.68 min; Mass spectrum (ESI+): m/z=313 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Br:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(-c3ccc(Br)cc3)nccc12
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2c(-c3ccc(Br)cc3)nccc12
Reaction time: 0.5 h

Procedure:
1-(4-Bromophenyl)-5-methylisoquinoline (26 g) was dissolved in 200 ml of carbon tetrachloride, and 17.6 g of N-bromosuccinimide was added. Under irradiation of light, the mixture was heated with stirring for 30 minutes. After the reaction, the insoluble matter was removed by filtration. The filtrate was washed in water, dried, and concentrated to remove the solvent. Thus, 1-(4-bromophenyl)-5-bromomethylisoquinoline was obtained. The product was dissolved in 150 ml of acetic acid, and 30 g of anhydrous sodium acetate was added. The mixture was stirred at 140° to 150° C. for 3 hours. After the reaction, the acetic acid was distilled off. The residue was poured into water, and neutralized with an aqueous solution of sodium hydroxide. The resulting oily product was extracted with benzene to afford 30 g of 1-(4-bromophenyl)-5-acetoxymethylisoquinoline. The product was heated with stirring for 2 hours together with 350 ml of methanol and 60 ml of 5 N sodium hydroxide. After the reaction, the reaction mixture was concentrated to remove the solvent. Water was added, and the crystals precipitated were collected by filtration. Recrystallization from benzene-tetrahydrofuran afforded 21 g of 1-(4-bromophenyl)-5-hydroxymethylisoquinoline having a melting point of 225.5° to 226.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([C@H:30]([NH2:33])[CH2:31][NH2:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[ClH:1].[NH2:33][C@@H:30]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][NH:32][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1
Solvent: CCO
Product: Cc1cccc(-c2c(-c3ccncc3)nc(NC[C@@H](N)Cc3ccccc3)n(C)c2=O)c1
Product: Cl

Procedure:
A solution of 2-chloro-3-methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (3.34 g, 10.71 mmol) and (S)-1-benzyl-1,2-ethanediamine (2.3 g, 15.31 mmol) in ethanol (50 ml) was stirred at room temperature for 16 h. The solvent was evaporated and the crude product recrystallized from methanol. MS (m/z): 426 (M+H)+; C26H27N5O requir. 425.5 (free base).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:16]=[CH:15][C:14]3[N:13]4[CH2:17][CH2:18][NH:19][C:20](=[O:21])[C:12]4=[CH:11][C:10]=3[CH:9]=2)[CH2:3][CH2:2]1.[CH:22]1([CH:25]=O)[CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH:22]1([CH2:25][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:16]=[CH:15][C:14]4[N:13]5[CH2:17][CH2:18][NH:19][C:20](=[O:21])[C:12]5=[CH:11][C:10]=4[CH:9]=3)[CH2:5][CH2:6]2)[CH2:24][CH2:23]1
Reactant: O=CC1CC1
Reactant: O=C1NCCn2c1cc1cc(OC3CCNCC3)ccc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCn2c1cc1cc(OC3CCN(CC4CC4)CC3)ccc12
Temperature: 55 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To the solution of 0.27 g (0.95 mmol) 8-(piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 6 mL tetrahydrofuran, 20 μL water, 11 μL (99 μg, 1.42 mmol) cyclopropanecarboxaldehyde, 0.16 mL (0.17 g, 2.8 mmol) acetic acid and 1.42 mL (1.42 mmol, 1M solution in tetrahydrofuran) sodium cyanoborohydride were added and the reaction mixture was stirred for 18 hours at 55° C. The mixture was poured on 10% aqueous sodium bicarbonate and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) as eluant to give 96 μg (30%) of the desired compound as a white solid.