Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[Li+].S(=O)(=O)(O)[OH:16]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:16]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
1.77 g (10 mol) of 2,3,4-trifluoronitrobenzene are added to 2.5 l of water, and the mixture is warmed to 40° C. and vigorously stirred. 1320 g (22 mol) of 40% strength lithium hydroxide solution are then added dropwise in such a way that the temperature rises from 40° to 55° C. within 2.5 h. After this time, GC checking no longer shows any starting compound. The reaction mixture is brought to pH 2 with 70% strength sulfuric acid. It is then worked up, as described in Examples 1 and 2. 1.48 kg of 2,3-difluoro-6-nitrophenol having a purity >99.9% (GC) are obtained after drying (melting point 63.5° C.), which corresponds to a yield of 85% of theory.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[N:32]=[C:31]5[C:26]([CH2:27][CH2:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[N:32]=[C:31]5[C:26]([CH2:27][CH2:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:16][CH2:17]3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5c(n4)NC(=O)CC5)CC3)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4CC(O)CC5)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 7-{4-[4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.24 g, 0.54 mmol) in methanol (5 mL) was added portionwise NaBH4 (0.081 g, 2.14 mmol). The reaction mixture was stirred at room temperature for 30 min and quenched with saturated NH4Cl solution and the compound was extracted with CH2Cl2 (2×20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (10% methanol in ethyl acetate) to afford compound the title compound (0.16 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.36 (d, 1H), 7.12 (t, 1H), 6.93–6.85 (m, 2H), 6.35 (d, 1H), 4.23 (t, 2H), 4.14–4.09 (m, 1H), 3.20–3.19 (m, 1H), 3.02–2.83 (m, 8H), 2.66–2.47 (m 10H), 1.83–1.67 (m, 6H). ES MS: 451.27 (M+H)+ (Exact mass: 450.26).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])=[CH:8][N:7]1C(=O)C)=[O:5])C.Br>>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[C:9]([CH2:10][C@@H:6]([C:4]([OH:3])=[O:5])[NH2:7])=[CH:8][NH:18]2
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2N)=CN1C(C)=O
Agent: Br
Product: N[C@@H](Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Yield: 91.1 %

Procedure:
A mixture of 60 g (0.16 mol) of the compound of Example 11, and 450 ml. of 2 N aqueous HBr was heated under N2 at 95° for 30 hours. The solution was concentrated in vacuo and the residual salt was taken up in 300 ml of water. The solution was brought to pH 5.5 with 4 N NaOH and the mixture was chilled in an icebath for 1 hour. The precipitate was collected, washed with cold water and dried to give 34.8 g of product. Crystallization from glacial acetic acid (360 ml.) afforded, after drying at 100°/0.2 mmHg, 30.8 g (82%) of white crystals, m.p. 280° (dec.) (lit. m.p. 285°-286°), which was identical with an authentic sample.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23]([OH:25])=O)=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[O:37]1[CH2:38][CH2:39][CH:34]([NH:33][C:23]([C:21]2[S:22][C:18]3[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=4)(=[O:12])=[O:13])=[CH:32][C:19]=3[C:20]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:35][CH2:36]1
Reactant: NC1CCOCC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)NC4CCOCC4)c(-c4ccccc4)c3c2)cc1
Yield: 50 %

Procedure:
According to Step 1, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with 4-aminotetrahydropyrane (22 mg, 0.35 mmol), the desired compound is obtained at 50% yield (92 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]2[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:17])[CH3:18]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M120) (0.67 g, 1.29 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (210 mg, 41%).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3Cl)OCO4)[nH]c12
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2Cl)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-chloro-benzo[1,3]dioxol-5-ylmethyl)adenine (11 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol) and pent-4-ynyl tosylate (10.5 mg, 0.044 mmol) in anhydrous DMF (85 L) was stirred at 50° C. for 1 h. Following solvent removal, the product (4.2 mg, 31.9%) was collected through silica gel column purification (EtOAc:hexanes:CHCl3:i-PrOH at 10:20:20:1). 1H NMR (400 MHz, CDCl3) 6.89 (s, 1H), 6.61 (s, 1H), 5.98 (bs, 2H), 5.96 (s, 2H), 4.27 (s, 2H), 4.13 (t, J=7.5 Hz, 2H), 2.24-2.10 (m, 2H), 2.00-1.91 (m, 3H); 13C NMR (100 MHz, CDCl3) 1597, 158.0, 156.3, 150.6, 147.7, 147.2, 126.2, 125.3, 110.0, 102.0, 82.3, 69.9, 42.2, 31.4, 28.1, 15.8; MS m/z 388.1 (M+H)+. HPLC: (a) 98.1% (65% water—35% acetonitrile); (b) 97.0% (35% to 45% acetonitrile).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6][C:5]=2[N:19]=1
Reactant: CC(=O)C1C(=O)CC(c2ccc(C)cc2)CC1=O
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Product: Cc1ccc(C2CC(=O)c3c(C)nc(N)nc3C2)cc1

Procedure:
The title compound was prepared from 2-acetyl-5-p-tolyl-cyclohexane-1,3-dione (850 mg, 3.50 mmol), stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3).
Reaction SMILES: B.[Na].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]=[O:15])=[N:11]2)=[CH:6][C:5]=1[F:16]>CO>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][OH:15])=[N:11]2)=[CH:6][C:5]=1[F:16]
Reactant: O=Cc1ccc2cc(F)c(Cl)cc2n1
Agent: B
Agent: [Na]
Solvent: CO
Product: OCc1ccc2cc(F)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3 g of sodium boron hydride was added to 11.19 g of 7-chloro-6-fluoro-2-formylquinoline obtained in Reference example 2 suspended in 250 ml of methanol and the mixture was stirred at room temperature for 1 hour. After the solvent was removed, the residue was extracted with ice water-methylene chloride and the organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was removed, the residue was applied to silica gel column chromatography to obtain 7.84 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2N2CC(Oc3cccc(F)c3)C2)cc1
Yield: 76 %

Procedure:
The title compound (D157) (55 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (50 mg, 0.154 mmol) and Methyl 4-(aminomethyl)benzoate hydrochloride (31.24 mg, 0.154 mmol, available at Aldrich#328383).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22](Br)[C:23]#[CH:24]>CN(C)C=O>[C:1]1([N:7]([C:22]#[C:23][CH3:24])[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCBr
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Solvent: CN(C)C=O
Product: CC#CN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1

Procedure:
1-Phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine 5 g (0.015 mol) was dissolved in dimethylformamide (20 ml). To this was added propargyl bromide 3.6 g (0.03 mol) and the mixture heated at 95°-100° C. for about 2 hours. The reaction mixture was concentrated under reduced pressure at about 40°-45° C. on a rotary evaporator. The concentrate was then diluted with approximately 2 volumes of isopropanol and added slowly to about 600 ml of vigorously stirred water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to provide 1-phenyl-1-propynyl-2-(3-sulphamoyl-4-chlorobenzoyl)-hydrazine (m.p. 168°-170° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([C@H:29]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[C:33](=[O:35])[CH2:32][CH2:31][CH2:30][C@H:29]1[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Reactant: O=C1CCC[C@@H](C2CCCCC2)N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)CCC[C@H]1C1CCCCC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 39.8 %

Procedure:
To a 10 mL vial was added trans-cyclohexane diamine (283 mg, 2.5 mmol, 0.5 equiv), 3-Bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.24 g, 7.4 mmol, 1.5 equiv), K2CO3 (1.37 g, 9.9 mmol, 2.0 equiv), CuI (473 mg, 2.5 mmol, 0.5 equiv), (S)-6-Cyclohexyl-piperidin-2-one (900 mg, 5.0 mmol, 1.0 equiv) and 1,4-dioxane (5.0 mL). The mixture was flushed with N2 and stirred at 110° C. for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, EtOAc/heptane 30% to give product 800 mg (yield 40%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[CH:11][C:12]1[C:13](=[O:21])[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1>CO.C(O)C.C1COCC1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:21])[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(C=Cc2nc3ccccc3o2)c(=O)[nH]c1C
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1C

Procedure:
A solution of 80% pure 3-[2-(benzoxazol-2-yl)ethenyl]-5-ethyl-6-methyl-2-(1H)-pyridinone (200 mg) in methanol/ethanol/THF (25 mL, 1:1:1) was hydrogenated at atmospheric pressure over 5% palladium/charcoal for four hours. After filtering off the catalyst, the solvents were evaporated and the residue flash chromatographed over silica gel. Elution with 2% methanol-98% chloroform gave 75 mg of analytically pure product, mp 155°-156.5° C.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[CH3:23][C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1>>[CH3:21][C:20]1[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([C:4]3[CH:3]=[C:2]([N:25]4[C@H:24]([CH3:23])[CH2:28][O:27][C:26]4=[O:29])[S:6][CH:5]=3)=[O:8])[CH2:10][CH2:11]2)=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3csc(Br)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3csc(N4C(=O)OC[C@H]4C)c3)CC2)c(C)c1
Yield: 57.7 %

Procedure:
Using (5-bromothiophen-3-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 244 and (R)-4-methyloxazolidin-2-one (34 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (65 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(N(C)C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1ncc(O)cn1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of 2-amino-5-hydroxypyrimidine (1.00 g, 9.00 mmol) in DMA (25 mL) was treated with potassium tert-butoxide (1.24 g, 11.05 mmol). The thick mixture was stirred at RT for 1 h. To this was added a solution of 2,4-dichloropyridine (1.21 g, 8.18 mmol) in DMA (10 mL) and the reaction was stirred at RT overnight under Ar. The mixture was partitioned into EtOAc (100 mL) and water (100 mL). The organic phase was separated and the aqueous was extracted with EtOAc (100 mL). The combined EtOAc layers were washed with 5% LiCl (100 mL) and brine (100 mL) and then dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine as a pale yellow solid (592 mg, 32%). MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[CH2:26][C:27]([CH2:29][CH3:30])=[CH2:28]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:28][C:27]([CH2:29][CH3:30])=[CH2:26])[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC)CCl
Reactant: C1=C(c2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(CC)CC1(c2ccccc2)C=CN(Cc2ccccc2)CC1

Procedure:
A solution of 1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine in tetrahydrofuran containing n-butyl lithium is added to a solution of 3-chloro-2-ethylpropene in tetrahydrofuran. The reaction is carried out according to the procedure of Example 1 to give 1-benzyl-4-phenyl-4-(2-ethylallyl)-1,4,5,6-tetrahydropyridine. The later compound is reacted with phosphoric acid and formic acid to give, after treatment with sodium hydroxide, 2-benzyl-3,4-dehydro-5-phenyl-7-ethylmorphan. Catalytic hydrogenation of the latter compound provides 2-benzyl-5-phenyl-7-ethylmorphan.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:16]=1[O:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:19][CH2:18][O:17][C:16]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:15]=2[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: Cc1cccc(C)c1OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCCSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
In 30 mm of N,N-dimethylformamide was dissolved 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.3 g of 2-(2',6'-dimethylphenoxy)ethyl bromide, and thereto were added 1.1 g of anhydrous sodium carbonate. The resulting solution was stirred at room temperature for fifteen hours. This solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and freed of solvent under reduced pressure to give crystals. The crystals thus obtained were washed with n-hexane to give 3.5 g of the intended compound. m.p. 104.3°~105.2° C.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17]>[OH-].[Na+]>[NH:1]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)Cl
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.7 g (30 mmol) of H-Phe(4-CN)—OH were dissolved in 100 ml of 1M NaOH with addition of 2M NaOH to pH=10 with ice cooling. With vigorous stirring, allyl chloroformate (7.5 ml) was slowly added (pH kept at 10 by 2M NaOH). The reaction mixture was stirred at 0° C. for 15 min and at RT for 30 min, acidified with HCI to pH=2, extracted with ethyl acetate (3 times), dried with MgSO4, and evaporated. The residue was recrystallized from ethyl acetate/hexane to give a white solid. Yield: 7.0 g (85%).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cu]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:17])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: Ic1ccccc1
Agent: [Cu]
Product: COC(=O)c1cc([N+](=O)[O-])c(-c2ccccc2)c([N+](=O)[O-])c1
Reaction time: 4.5 h

Procedure:
A mixture of methyl 4-chloro-3,5-dinitrobenzoate (60 g), iodobenzene (36 ml) and copper powder (60 g) is stirred at 145°-155° C for 4-5 hours. After cooling, the resulting solids are extracted with three portions of boiling chloroform (each portion 150 ml), and the combined extracts are, after filtration, evaporated in vacuo. After trituration of the residue with methanol (150 ml) followed by recrystallization from 2-methoxyethanol, methyl 3,5-dinitro-4-phenylbenzoate is obtained with a melting point of 147.5°-148° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13]Cl>>[O:11]1[C:9]([CH3:13])([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10]1
Reactant: CC(=O)CCc1ccccc1
Reactant: ClCCl
Product: CC1(CCc2ccccc2)CO1
Yield: 72 %

Procedure:
Using the same conditions described in Example 5, but using dichloromethane as the extraction solvent, 4-phenyl-2-butanone (22.2 g, 0.15 mole) yielded an orange oil; 1,2-epoxy-2-methyl-4-phenylbutane (19.8g, 72% yield of theory). 1H NMR (CDCl3 /TMS): δ 1.3(s,3H, CH3); 1.6-2.1(m, 2H), 2.-2.8(m, 4H); 6.8-7.4(m, 5H, aromatic H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:26]1([NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[O:31])[CH2:28][CH2:27]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:5]2[N:6]([C:8]([C:35]3[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH:26]4[CH2:27][CH2:28]4)=[O:31])=[CH:33][CH:34]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)CNc1nc(Br)cn2c(I)cnc12
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 40 °C
Reaction time: 72 h
Yield: 56.1 %

Procedure:
To a stirred solution of (6-bromo-3-iodo-imidazo[1,2-a]pyrazin-8-yl)-isobutyl-amine (74.20 g, 188 mmol) in dioxane (1300 mL) was subsequently added 130 mL water, 119 g tripotassium phosphate (563 mmol, 3 eq), 50.06 g [4-[(cyclopropylamino)carbonyl]phenyl]-boronic acid (244 mmol, 1.3 eq) and 7.42 g Pd(dppf)Cl2 (9 mmol, 0.05 eq) in one portion at rt under argon atmosphere. After stirring for 72 h at 40° C., the mixture was poured on 5 L water and the precipitate was filtered off and washed with water. The precipitate was taken up in DCM, washed with sat. sodium chloride solution, dried over sodium sulphate and after filtration the solvent was evaporated. Purification by flash chromatography (DCM/acetone 95:5) yielded 45.2 g (56.20%) 4-(6-bromo-8-isobutylamino-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropyl-benzamide: 1H-NMR (300 MHz, CDCl3): δ=7.90 (2H, d), 7.65 (1H, s), 7.58 (2H, d), 7.56 (1H, s), 6.32 (1H, s), 6.20 (1H, tr), 3.46 (2H, dd), 2.95 (1H, m), 2.01 (1H, m), 1.04 (6H, d), 0.92 (2H, m), 0.66 (2H, m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:29][CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Reactant: OCc1ccncc1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
3′-Chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.88 g, 6.0 mmol), pyridin-4-yl-methanol (1.35 g, 12.4 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (14 mL, 14 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with H2O and washed with EtOAc (3×). The combined EtOAc extractions were washed with 6% NaHCO3 (2×), sat's NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 1.89 g (81%) of 2-methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.06 (d, 2H), 7.75 (d, 1H), 7.51 (d, 1H), 7.30 (d, 2H), 5.42 (s, 2H), 4.52 (m, 1H), 4.11-3.81 (complex m, 3H), 3.36-3.11 (complex m, 3H), 1.48 (s, 9H), 1.17 (d, 3H) ppm. LC-MS (MH+)=386.