Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C>[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C(N)=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C(N)=O)c1ccccc1
Yield: 65.3 %

Procedure:
2.2 g (5.3 mmoles) of H-Leu-Asp-L-Phg-NH2.HCl, prepared as described in Example 6, Step 3, are reacted with 2.32 g (5.8 mmoles) of BOC-Trp-OSu in 50 ml of DMF in the presence of 1.48 ml (10.6 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo and the residue is triturated with water. The obtained crude product, weighing 3.30 g, is crystallized from 70 ml of 80% ethanol under decolourizing. 2.30 g (65%) of BOC-Trp-Leu-Asp-L-Phg-NH2 are obtained; m.p.: 205°-207° C. (decomposition), Rf5 : 0.40, [α]D : -7.3° (c: 1.0, in dimethyl formamide).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.[CH3:19][O:20][CH:21]([O:26][CH3:27])[C:22](OC)=O.C(O)(=O)C.[CH3:32][NH:33][NH2:34]>C1COCC1>[CH3:19][O:20][CH:21]([O:26][CH3:27])[C:22]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:33]([CH3:32])[N:34]=1
Reactant: CNN
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COC(=O)C(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(OC)c1cc(-c2ccc(F)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of lithium diisopropylamide (1.8M in THF, 160 mL, 0.29 mol) at −78° C. was added 4-fluoroacetophenone (17.6 mL, 0.145 mol) in THF (150 mL), dropwise. The reaction was stirred at −78° C. for 1 h before the addition of methyl dimethoxyacetate (17.7 mL, 0.145 mol) in THF (150 mL). The reaction was warmed to 25° C. and stirred for 16 h. The solvent was removed in vacuo and the residue taken up in EtOH (250 mL), acetic acid (17 mL, 0.3 mol) added, followed by methyl hydrazine (8 mL) and the reaction heated to reflux for 2 h. The ethanol was removed in vacuo and the residue extracted with dichloromethane (×3), the organic layer washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on silica eluting with 50% ethyl acetate/hexanes to give the title compound (more polar isomer) along with its isomer (less polar). 9 g 1H NMR (360, CDCl3) δ 7.38 (m, 2H), 7.14 (m, 2H), 6.34 (s, 1H), 5.48 (s, 1H), 3.85 (s, 3H), 3.43 (s, 6H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=2)=[CH:20][CH:21]=1)=[O:36]
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1ccc(F)cc1F

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.105 g 0.30 mmoles) and 2,4-difluorophenyl isocyanate (71 mg, 0.45 mmoles) the title compound was isolated as a white solid. Yield; 40 mg (27%); (M+H)=498.6
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH:13]([OH:17])[C:14](O)=[O:15])[CH:8]=[CH:9][CH:10]=1>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH:13]([OH:17])[C:14](=[O:15])[NH:2][N:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CC(O)C(=O)O)c1cccc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2cccc(Br)c2)CC1O
Temperature: 65 °C
Yield: 58.2 %

Procedure:
0.25 g of hydrazine hydrate was added, at room temperature, to a mixture of 10 ml of ethanol and 1.36 g of 4-(3-bromophenyl)-2-hydroxy-4-oxobutyric acid (prepared following the procedure described in Preparation 3), and then the mixture was heated at 65° C. for 1.5 hours. The crystals which precipitated were collected by filtration at the same temperature and then washed with ethanol, giving 0.78 g (yield 58%) of the pure title compound melting at 158°-161° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=O>CO>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Borane-pyridine complex (445 μL, 4.18 mmol) was added to a methanol solution (10 mL) of an amine (3) (363 mg, 1.39 mmol) and 3,5-dimethoxybenzaldehyde (301 mg, 1.81 mmol), and the mixture was stirred for two hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (4) as a pale yellow solid (329 mg, yield: 57%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:29]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH:30]1[OH:38].C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:35]2[CH2:36][CH2:37][C:32]3([CH2:31][CH:30]([OH:38])[CH2:29]3)[CH2:33][CH2:34]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: OC1CC2(CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)CC(O)C4)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (134 mg, 0.35 mmol) in DCE (5 mL) was added 7-azaspiro[3.5]nonan-2-ol (60 mg, 0.43 mmol), trimethyl orthoformate (0.19 mL, 1.77 mmol) and acetic acid (0.02 mL, 0.35 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (113 mg, 0.53 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give 343 as a white solid (80 mg, 45%). LCMS (Method G): RT=5.23 min, [M+H]+ 503.2. 1H NMR (400 MHz, CHCl3-d): δ 8.11-8.06 (m, 1 H), 7.73-7.68 (m, 1 H), 7.30-7.24 (m, 2 H), 4.37-4.24 (m, 4 H), 3.90-3.83 (m, 7 H), 3.72 (s, 2 H), 2.94 (s, 3 H), 2.58-2.31 (m, 4 H), 2.30-2.23 (m, 2 H), 1.75-1.55 (m, 8 H)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C.O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
In 185 ml of ethanol and 185 ml of water, 68.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 22.4 g of sodium hydroxide were added. To this mixture, 84.6 g of 1-bromoheptane was added, and the resulting mixture was warmed to 60° C. and stirred for 2 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/hexane mixture. Thus 90.2 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10](B(O)O)=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38].Br[C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[C:43]#[N:44].[OH-].[Ba+2].[OH-].O>C(OC(C)=O)CCC.C(Cl)Cl>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]([C:40]3[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=3)[C:43]#[N:44])=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38]
Reactant: N#Cc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(B(O)O)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A suspension comprising 1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Intermediate F) (300 mg, 0.571 mmol), 3-bromobenzonitrile (104 mg, 0.571 mmol) and barium hydroxide (196 mg, 1.142 mmol) in n-BuOAc (5710 μL) was treated with Pd-118 (18.61 mg, 0.029 mmol) and the mixture was heated to 80° C. Water (247 μL, 13.70 mmol) was added at 80° C. and the suspension was stirred rapidly for 90 minutes. After cooling to RT, the mixture was allowed to stand at RT overnight. The mixture was diluted with DCM (50 ml) and washed with water (50 ml). The layers were separated and the aqueous portion was extracted with DCM (3×30 ml). The organics were combined and dried over MgSO4, filtered and concentrated. Purification of the crude product by trituration with EtOAc/iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:8])=[CH:16][C:15]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 18.2 g (0.1 mole) of 2-chlorobenzoylisocyanate in 50 ml of toluene was added dropwise at 40° C to 19.5 g (0.1 mole) of 4-chloro-3-trifluoromethylaniline in 200 ml of toluene. The batch was stirred for 1 hour at 40° C. After cooling, the product which had precipitated was filtered off and washed first with toluene and then with petroleum ether. After drying, 21.0 g (55% of theory) of analytically pure N-(4-chloro-3-trifluoromethylphenyl)-N'-(2-chlorobenzoyl)-urea of melting point 164° C were obtained.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C)C=O.O>[CH:47]1([CH2:46][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=34)=[O:20])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=3)=[CH:33][CH:34]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCC2CCCCC2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and (bromomethyl)cyclohexane (401 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (129 mg, 27%).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([F:4])[F:3].[C:13]([O-])([O-])=O.[Cs+].[Cs+].C(O[CH2:23][CH3:24])(=O)C>CN(C=O)C>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:23]=[CH2:24])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: CCOC(C)=O
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(SC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(trifluoromethylsulfanyl)phenol (1.9 g, 10 mmol), allyl brimide (1.8 g, 15 mmol) and Cs2CO3 (6.5 g, 20 mmol) in DMF, 80 mL) was stirred for 2 hrs at 50° C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to give essentially pure allyl 4-(trifluoromethylsulfanyl)phenyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12]([C:15]#[CH:16])=[CH:11][N:10]=1.I[C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][C:12]([C:15]#[C:16][C:18]2[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=1
Reactant: CC1(O)CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1cnc(-c2ccc(Cl)cc2Cl)cn1
Product: CC1(O)CCN(CCOc2ccc(C#Cc3cnc(-c4ccc(Cl)cc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product was prepared analogously to Example 48.1c from 180 mg (0.72 mmol) of 2-(2,4-dichlorophenyl)-5-ethynylpyrazine and 260 mg (0.72 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidin-4-ol (IP 15) (stirring the reaction mixture overnight at RT). Yield: 16 mg (5% of theoretical); C26H25Cl2N3O2 (M=482.401); calc.: molpeak (M+H)+482/484/486 (2 Cl); found: molpeak (M+H)+:482/484/486 (2 Cl); HPLC-MS: 7.5 minutes (method G).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[ClH:29].[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:20]([CH2:19][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:18]=[CH:17][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(OCCCN2CCOCC2)c(CNCCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCCCN2CCOCC2)c(CN(CCc2ccccc2)C(=O)c2ccc(Cl)cc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 16.0 g. of 4-[3-[4-methoxy-2-[[(2-phenylethyl)amino]methyl]phenoxy]propyl]-morpholine in 50 ml. of chloroform is added dropwise (at 10°-15° C.) to a stirred solution of 7.7 g of p-chlorobenzoyl chloride in 150 ml. of chloroform. After the addition is completed, the solution is stirred at room temperature for 2 hours, heated at reflux for 1 hour, cooled and concentrated to give a glass-like residue. The residue is rubbed under ether, the evaporation repeated and the partly solid residue taken up in 100 ml. of acetonitrile. On diluting to 650 ml with ether, seeding and rubbing, the crystalline hydrogen chloride salt separates. After cooling overnight, the product weighs 21.7 g, melting point 137°-139° C. Recrystallization from 50 ml. of warm acetonitrile-50 ml. of ether, yields 20.3 g of the title compound, melting point 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)cc(OC)c1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To a solution of 3,5-Dimethoxy-benzaldehyde (9.5 g, 57.17 mmol) in pyridine (60 ml), malonic acid (9 g, 85.725 mmol) was added, and followed by piperidine (2 ml), the mixture was heated to 100° C. and stirred at this temperature for 6 hs under N2. Then most of pridine was removed, and the residue was poured into water (250 ml), acidified to PH=3 by aq.HCl, the precipitate was collected and dried to give product (10.9 g, 91.8%). LC-MS: m/e 207 (M−1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>ClCCl>[C:1]([O:5][C:6]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:20](=[O:23])[CH:21]=[CH2:22])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 100.3 %

Procedure:
To a stirred solution of 5.0 g (29.2 mmol) D-Proline tert-butyl ester and 4.5 ml (32.1 mmol) triethylamine in 180 ml dichloromethane at 0° C. was added dropwise 3.6 ml (43.8 mmol) acryloyl chloride and stirring continued for 48 h at room temperature. The reaction mixture was then washed sequentially with water, saturated ammonium chloride solution, once more with water and then with saturated brine, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 6.6 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[C@@H:19]12[CH2:20][C@H:21]([CH:17]=[CH:18]1)[C@H:3]1[C@@H:2]2[C:1](=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1=CCC=C1
Reactant: O=C1C=CCCCCCCCCCCCC1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: O=C1/C=C/CCCCCCCCCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: O=C1CCCCCCCCCCCC[C@@H]2[C@H]1[C@H]1C=C[C@H]2C1
Yield: 88 %

Procedure:
Prepared according to general procedure A from trans-2-cyclopentadecen-1-one (100 mg, 0.45 mmol), cyclopentadiene (56 μL, 0.67 mmol), 70% aqueous perchloric acid (7.8 μL, 0.09 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (24.3 mg, 0.09 mmol) in water (150 μL) for 72 hours at 0° C. Purification by flash chromatography (9:1 ethyl acetate:hexanes) provided the title compound as a clear, colorless crystalline solid in 88% yield (114 mg, 0.50 mmol); 5:1 endo:exo, endo 93% ee. IR (film) 3052, 2922, 2854, 1698, 1456, 1368, 1331, 1225, 1126, 1084, 1016, 905.5, 884.9, 714.4 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.21 (dd, J=5.4, 2.7 Hz, 1H, CH═CH), 5.86 (dd, J=5.4, 2.7 Hz, 1H, CH═CH), 3.09 (m, 1H, CHCH═CH), 2.61 (m, 2H, CHCO and one of CH2CO), 2.52 (m, 1H, CHCH═CH), 2.41 (m, 1H, one of CH2CO), 2.27 (m, 1H, CHCHCO), 1.81-1.24 (br m, 22H, (CH2)11); 13C NMR (75 MHz, CDCl3) δ 211.6, 138.5, 132.6, 59.6, 48.4, 47.2, 46.7, 41.5, 41.3, 36.3, 28.0, 27.9, 27.7, 27.2, 26.8, 26.8, 26, 26.7 26.0, 23.6. [α]D=+22.2 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (200° C., 23 psi); (1R, 2R, 16S, 17S) endo isomer tr=20.1 min, and (1S, 2S, 16R, 17R) endo isomer tr=19.6 min, exo isomers tr=19.0, 18.6 min. The trans relative stereochemistry of C-16 and C-17 was confirmed by the presence of an NOE between the C-16 methine proton and the two C-19 protons.
Reaction SMILES: Br[CH2:2][CH3:3].[O:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:2]([N:27]1[CH2:26][CH2:25][CH:24]([N:22]2[CH:23]=[C:19]([C:17]3[CH:18]=[C:13]([C:5]4[O:4][C:12]5[C:7]([N:6]=4)=[N:8][CH:9]=[CH:10][CH:11]=5)[C:14]([NH2:30])=[N:15][CH:16]=3)[CH:20]=[N:21]2)[CH2:29][CH2:28]1)[CH3:3]
Reactant: CCBr
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Bromoethane (0.019 ml) at 0° C. was added to a stirred mixture of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and potassium carbonate (68.8 mg) and DMF (1.5 mL) over a period of 5 minutes under argon. The resulting suspension was stirred at 25° C. for 20 hours. The solvent was evaporated. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 5-[1-(1-ethyl-4-piperidyl)pyrazol-4-yl]-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (60.0 mg) as a solid. NMR Spectrum: (DMSOd6) 1.03 (t, 3H), 1.91-2.10 (m, 6H), 2.38 (q, 2H), 2.94-3.01 (m, 2H), 4.09-4.18 (m, 1H), 7.48 (dd, 1H), 7.67 (bs, 2H), 7.92 (s, 1H), 8.23 (dd, 1H), 8.34 (s, 1H), 8.46 (d, 1H), 8.55 (dd, 1H), 8.58 (d, 1H); Mass spectrum: M+H+ 390.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)SC)=O)[CH:5]=[C:4]([CH3:23])[N:3]=1.[NH:24]([CH2:26][C@@H:27]([OH:30])[CH2:28][CH3:29])[NH2:25]>CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:24]([CH2:26][C@@H:27]([OH:30])[CH2:28][CH3:29])[N:25]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)[N:10]=2)[CH:5]=[C:4]([CH3:23])[N:3]=1
Reactant: CSC(=Nc1ccc(F)c(F)c1)NC(=O)c1cc(C)nc(Cl)c1
Reactant: CC[C@H](O)CNN
Solvent: CC(C)(C)O
Product: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(Cl)c1

Procedure:
Intermediate D2 (1 g; 2.81 mmol) was dissolved in t-BuOH (40 ml) and, then intermediate D3 (0.44 g; 4.22 mmol) was added. The reaction mixture was stirred and refluxed for 4 hours and then the solvent was evaporated. The residue was purified by silica column chromatography (gradient: CH2Cl2/10% CH3OH in CH2Cl2 from 100/0 to 0/100). Yield: 1.1 g of intermediate D4 (S-enantiomer).