Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](Cl)=[O:12].C([O:16][C:17]([C@@:19]12[CH2:37][C@H:36]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:27](=[O:46])[N:26]1[C@@H:22]([CH2:23][C@@H:24]([NH2:47])[CH2:25]1)[C:21](=[O:48])[NH:20]2)=[O:18])C.CCN(C(C)C)C(C)C.[OH-].[Li+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.O>[C:42]([O:41][C:39]([NH:38][C@@H:28]1[C:27](=[O:46])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([NH:47][C:11]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)=[O:12])[CH2:25]2)[C:21](=[O:48])[NH:20][C@@:19]2([C:17]([OH:18])=[O:16])[C@@H:36]([CH2:37]2)[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(Cl)N1CCc2ccccc2C1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](N)C[C@H]1C(=O)N2
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](NC(=O)N3CCc4ccccc4C3)CN2C1=O
Reaction time: 5 h

Procedure:
A solution of 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride (0.030 g, 0.152 mmol), (1S,4R,6S,14S,18R)-18-amino-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (0.025 g, 0.050 mmol), DIEA (0.027 ml, 0.153 mmol) and a catalytic amount of DMAP were stirred together in methylene chloride (0.3 ml) for 18 h. The reaction was placed onto silica gel and the product eluted with 40% acetone/hexanes and isolated as a white solid. The solid was dissolved in methanol and treated with lithium hydroxide (0.011 g, 0.254 mmol) and 1 drop of water. After stirring for 5 h, the reaction was diluted with methylene chloride (30 ml), washed with 1N aqueous HCl (30 ml), brine (30 ml), dried over magnesium sulfate and concentrated to give the title compound as a white solid. LCMS=624 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N:15]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21]
Reactant: O=C1COCCN1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
1.00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen atmosphere and 36.6 mg (40 μmol) tris-(dibenzylideneacetone)-dipalladium(0), 67.1 mg (116 μmol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95° C. for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1.31 g (quantitative)
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:4]=1[O:5][CH:6]([OH:8])[CH3:7].[N-:14]=[C:15]=[O:16].[K+]>O>[OH:2][C:3]1[CH:12]=[C:11]([NH:13][C:15]([NH2:14])=[O:16])[CH:10]=[CH:9][C:4]=1[O:5][CH:6]([OH:8])[CH3:7]
Reactant: CC(O)Oc1ccc(N)cc1O
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(O)Oc1ccc(NC(N)=O)cc1O

Procedure:
0.03 mol (6.16 g) of 2-hydroxy-4-aminophenoxyethanol hydrochloride is dissolved in 34 ml of water at 15° C. 0.03 mol (2.43 g) of potassium isocyanate dissolved in 7.5 ml of water is added to this solution, with stirring. The temperature of the reaction medium rises to 25° C. After stirring for 30 minutes, the expected product which has precipitated is filtered off. It is washed with a normal solution of hydrochloric acid and then with water. After recrystallization from acetic acid and drying in vacuo, the product melts at 191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:15][C@@:14]2([CH2:16][O:17][CH3:18])[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:19](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:15][C@@:14]2([CH2:16][O:17][CH3:18])[CH2:13][N:12]([CH3:19])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)O
Reactant: COC[C@]12CNCC[C@@]1(c1ccc(Cl)c(Cl)c1)C2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC[C@]12CN(C)CC[C@@]1(c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane (E2a, 25 mg) was dissolved in methanol (1 mL); acetic acid (0.015 mL) was added followed by sodium triacetoxyborohydride (27.8 mg) and formaldehyde 37% in water (0.06 mL). The reaction mixture was stirred at room temperature overnight. Volatiles were then evaporated and the residue partitioned between DCM (20 mL) and aqueous sat NaHCO3 (20 mL) solution, dried and concentrated. Purification by chromatography (NH column) eluting with a gradient 0-100% ethyl acetate-cyclohexane afforded the title compound (16 mg).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O>>[S:3]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:4][CH2:1][CH2:2]1
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: SCCS
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Yield: 22.3 %

Procedure:
Ethane-1,2-dithiol (20.6 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (41.4 g.) in a similar manner to that of Example A--(i) to give ethyl 2-(2,3-dihydro-1,4-dithiin-6-yl)-2-methoxyiminoacetate (syn isomer, 11 g.), white crystals, mp. 65° to 67° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([CH:13]=[O:14])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>ClCCl>[CH3:24][O:25][CH2:26][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(C=O)ccc(O)c12
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(C=O)c2cccc(C)c12
Yield: 75.5 %

Procedure:
18 g of 4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 15 g of N,N-diisopropylethylamine were dissolved in 200 ml of dichloromethane, in which 9.3 g of chloromethyl methyl ether was gradually dropped under ice-cooling conditions. After agitation at room temperature overnight, the reaction solution was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 16.8 g of the captioned compound as light brown crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.[NH4+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[Cl:14])[OH:27])=[CH:24][CH:23]=1
Reactant: Clc1ccncc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccc(Cl)cc1)c1cnccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Diisopropylamine (11.7 mL, 83.3 mmol) was dissolved in THF (200 mL) under a nitrogen atmosphere at 0° C. and n-butyllithium (52.5 mL, 1.6 M in hexanes, 84.0 mmol) was added. The solution was stirred for 1 h, cooled to −78° C. and 4-chloropyridine hydrochloride (5.00 g, 33.3 mmol) was added portionwise. The reaction mixture was stirred 2 h and 4-chlorobenzaldehyde (4.68 g, 33.3 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 3 d. Sat aq NH4Cl solution (20 mL) was iii added and the reaction mixture was poured into 1 M aq Na2CO3 solution (500 mL). The layers were separated and the aq layer was extracted with DCM (2×500 mL). The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo to give (4-chlorophenyl)-(4-chloro-pyridin-3-yl)-methanol (7.57 g, 89.4%) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[O:6][CH:5]1[CH2:31][O:32][CH3:33])[N:14]=[CH:13][N:12]=[C:11]3[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][Si](C)(C)C)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][CH2:3][CH:4]1[O:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[O:6][CH:5]1[CH2:31][O:32][CH3:33])[N:14]=[CH:13][N:12]=[C:11]3[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1
Reactant: COCC1Oc2cc3ncnc(Nc4cccc(C#C[Si](C)(C)C)c4)c3cc2OC1COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc4c(cc23)OC(COC)C(COC)O4)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound of Example 47 (34 mg, 0.073 mmol) was dissolved in 5 ml of methanol, and then added potassium carbonate (26 mg), followed by stirring for 24 hours at a room temperature. Water was added to the reaction mixture, which was then extracted with methylene chloride, dried over MgSO4 and concentrated. The resulting residue was purified by a column chromatography(mobile phase: hexane:ethylacetate:methanol=20:30:1 (v:v:v)) to prepare the titled compound (6 mg, 21%).
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].[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[O:20]1[C:24]2([CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]3[CH:19]=[CH:18][C:9]4[O:10][C:11]5[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:8]=4[CH:7]=3)=[O:4])[CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCC2(CC1)OCCO2)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 46.2 %

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), 1,4-dioxa-8-azaspiro(4.5)decane (0.072 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided 2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.080 g) as its trifluroacetic acid salt after reverse-phase HPLC purification.MS (ESI) m/z 385 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6]CCCC#N)=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.ClC1C=CC(O)=CC=1C=O.N1CCCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([OH:6])=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CCCCOc1ccc(Cl)c(CN2CCCCC2)c1
Agent: O=Cc1cc(O)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: Oc1ccc(Cl)c(CN2CCCCC2)c1

Procedure:
In a similar manner to that described in Example 17 4-(4-chloro-3-piperidinomethylphenoxy)butyronitrile was prepared by the reaction of 2-chloro-5-hydroxybenzaldehyde (1.379 g), piperidine (1.8 ml) and sodium borohydride (0.33 g) in absolute ethanol (10 ml) to produce N-(2-chloro-5-hydroxybenzyl)piperidine which was then reacted with 4-bromobutyronitrile to yield the above-mentioned product.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C([O-])O
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnn[nH]3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnnn3C)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (44 mg, 0.172 mmol) in acetone (5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (12 mg) and the other regioisomer (26 mg).
Reaction SMILES: [BH4-].[Na+].[BH4-].CO[C:6](=[O:31])[CH2:7][CH:8]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9]1>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[O:31]=[C:6]1[O:30][CH:29]2[C:28]3[C:23]([C:10]4([CH2:9][CH:8]2[CH2:7]1)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]4)=[CH:24][CH:25]=[CH:26][CH:27]=3
Reactant: COC(=O)CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1CC(=O)OC1c1ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
Zn(BH4)2 was prepared following a known procedure (Beatrix Merla, Hans-Joachim Grumbach, Nikolaus Risch, Synthesis, 1998 1609-1614). At 0° C., zinc chloride (anhydrous, 5 g, 36.6 mmol) was added to a solution of sodium borohydride (2.72 g, 72 mmol) in diethyl ether (100 ml). The reaction mixture was stirred at 0° C. for 2 h. After filtration under N2, the borohydride solution (9 ml) was added to a suspension of the tert-butyl 3-(2-methoxy-2-oxoethyl)-4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (589 mg, 1.52 mmol). After 1 h, additional borohydride solution (9 ml) was added and the mixture stirred for 15 h. The mixture was quenched with 1N HCl, neutralized with saturated sodium bicarbonate, extracted with EtOAc. The extract was concentrated and the residue purified by flash chromatography to give the title compound (140 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br.[OH-].[Na+]>O>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nc(-c3ccccc3)[nH]c2-c2ccc(OC)cc2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(-c2nc(-c3ccccc3)[nH]c2-c2ccc(O)cc2)cc1
Yield: 79.6 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-phenylimidazole (15.8 g, 0.044 mol) was placed in a 250 ml three neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, thermometer, reflux condenser and hydrogen bromide gas trap along with acetic acid (75 ml) and 47-49% aqueous hydrogen bromide solution (130 ml). The mixture was heated to reflux for 16 hours, cooled, poured into water to give a white solid, which was neutralized with sodium hydroxide, collected, washed with water and dried at 100° C. Yield was 13.7 g of white solid. Recrystallization from ethanol/water (3:1) gave 11.5 g (79%) of white crystals, m.p. 327°-330° C. Anal. Calcd. for C21H16N2O2 : C, 76.80%; H, 4.91%; N, 8.53%. Found: C, 76.50%; H, 5.00%; N, 8.44%.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:25])[C:8](=[O:26])[C@H:7]2[CH2:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1>CN(C(OC)OC)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13](/[C:16](/[C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:1]/[N:6]([CH3:15])[CH3:7])[N:12]=[CH:11][C:10]=3[N:9]([CH3:25])[C:8](=[O:26])[C@H:7]2[CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(CC(=O)c3ccccc3)nc2N1C1CCCC1
Agent: COC(OC)N(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(/C(=C/N(C)C)C(=O)c3ccccc3)nc2N1C1CCCC1
Temperature: 110 °C

Procedure:
A suspension of (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(2-oxo-2-phenylethyl)-7,8-dihydropteridin-6(5H)-one (Intermediate B-1, 700 mg) in 10 mL of DMF-DMA was heated at 110° C. for 3 hours. The resulting mixture was concentrated to give the desired (R,Z)-8-cyclopentyl-2-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (compound I-132).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:1].[ClH:1].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH2:22][N:15]1[CH2:16][CH2:17][N:12]([CH2:3][C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:13][CH2:14]1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1CN1CCN(CC(=O)c2ccccc2)CC1
Yield: 133.4 %

Procedure:
A mixture of N-phenacyl piperazine dihydrochloride (1.7 g, 6.1 mmol), 2-methoxy-5-nitro-benzylbromide (1.5 g, 6.1 mmol) and K2CO3 (2.7 g, 19.5 mmol) in 40 ml of acetone was treated according to general preparation 2 to give 1.80 g of compound (IV-23), yield 60%. M+ 368.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[CH2:9][CH2:10][CH2:11][C:12]2=[O:13]
Reactant: Cc1ccc(C)cc1
Reactant: O=C1CCCO1
Product: Cc1ccc(C)c2c1CCCC2=O
Temperature: 25 °C
Yield: 28.7 %

Procedure:
After the completion of the first reaction in Example 1, the supernatant was removed, the remained catalyst was washed with 100 ml of hexane with stirring at room temperature. The hexane supernatant was removed, followed by drying under reduced pressure at 50° C. 100 ml of p-xylene (799 mmol) and 1 ml of γ-butyrolactone (14.8 mmol) as raw materials were charged again and then reacted at 196° C. for 3 hours. As a result, 5,8-dimethyltetralone (yield based on γ-butyrolactone: 28.7%) was obtained. The effect of regenerating the catalyst was exerted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:16][CH2:17]O>Cl>[CH2:16]([O:14][C:13]([C:10]1([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:12]1)=[O:15])[CH3:17]
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1(c2ccc(OC)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(3-chloro-4-methoxy-phenyl)-cyclopropanecarboxylic acid (250 mg, 0.96 mmol, 1 eq.) in 1.25M HCl in EtOH (2.4 mL) was stirred at r.t. for 2 hours and further at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a colorless oil. LC-MS 3: tR=0.91 min; [M+H]+=255.2
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].N1[CH:17]=[CH:16][CH:15]=[CH:14]C=1.C1(C(Cl)=O)CC1.N>CC(N(C)C)=O.O.CO>[Cl:1][C:2]1[C:3]2[NH:4][C:14]([CH:15]3[CH2:17][CH2:16]3)=[N:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccncc1
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: N
Agent: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CO
Product: Clc1cccc2nc(C3CC3)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
2-Chloro-6-nitroaniline (3.00 g, 17.4 mmol) and pyridine (7.0 mL, 86.9 mmol) were dissolved in DMA (17 mL), cyclopropanecarbonyl chloride (4.0 mL, 43.5) was added and the mixture was stirred at 50° C. for 3 hr. To the mixture were added methanol (10 mL) and aqueous ammonia (9 mL), and the mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the precipitated solid was collected by filtration. The solid was suspended in ethanol (38 mL) and water (38 mL), ferrous sulfate 7 hydrate (13.86 g, 49.9 mmol) and aqueous ammonia (19 mL) were added, and the mixture was stirred at 50° C. for 4 hr. The mixture was filtered, and the filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Acetic acid (8 mL) was added to the residue, and the mixture was stirred at 90° C. for 1 hr. The mixture was concentrated under reduced pressure, neutralized with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (5 mL) and diisopropyl ether (5 mL) were added to the residue, and the precipitated solid was collected by filtration to give the title compound (1.20 g, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:31]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:31])[N:17]=3)=[CH:14][N:13]=[C:12]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(-c3ccncc3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccncc3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(pyridin-4-yl)pyrimidin-4-amine (8 mg, 0.019 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 10% MeOH/EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-(pyridin-4-yl)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (4 mg, 10.33 μmol, 54.0% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.96 (s, 1H); 8.77 (d, J=5.12 Hz, 1H); 8.59 (s, 1H); 8.21 (dd, J=9.06, 2.34 Hz, 1H); 8.15 (d, J=5.12 Hz, 1H); 7.99 (s, 1H); 7.82 (s, 1H); 6.96 (d, J=8.77 Hz, 1H); 3.90 (s, 2H); 2.45 (s, 3H). m/z (ESI, +ve ion) 388.1 (M+H)+.