Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:19][C@H:18]([F:20])[C@@H:17]([O:21][CH3:22])[C@H:16]1[C:23](=[O:34])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Cl:32][C:28]1[C:27]([F:33])=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:23]([C@@H:16]1[C@H:17]([O:21][CH3:22])[C@@H:18]([F:20])[CH2:19][NH:15]1)=[O:34]
Reactant: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)NC[C@@H]1F
Reaction time: 8 h

Procedure:
TFA (0.86 mL, 11.12 mmol) was added to a solution of (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (450 mg, 1.12 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred overnight then was concentrated. The residue was triturated with Et2O (10 mL) to give a precipitate which was filtered off, washed with Et2O (10 mL) then dried under high vacuum. The absolute stereochemistry was confirmed by X-ray. tR (HPLC conditions f): 0.40 min; MS (UPLC): 349 [M+HCOO]−, 305 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:9]=2)=[CH:4][CH:3]=1>[Pt].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C:15]([F:18])([F:16])[F:17])[C:11](=[O:19])[N:10]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: [Pt]
Solvent: CO
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O

Procedure:
Of the compound from Example 76A, 1.2 g (3.32 mmol), 150 mg of platinum on carbon (5%) and 150 ml of methanol were hydrogenated under standard hydrogen pressure. For work-up, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. The crude product was purified by preparative HPLC (Method 20). The product fractions were combined and freed from the solvent on a rotary evaporator. Drying in an HV gave 890 mg (73% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[N:25]([CH3:28])C=O>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:28]#[N:25])=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOCC1
Reactant: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(-c2cn(C3CCOCC3)c3ncnc(N)c23)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A warm solution of 4-[4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol (0.082 g) in dimethylformamide (3.4 ml) was added to a The vial was flushed with nitrogen then sealed. The mixture was shaken at 120° C. for 6 hours and then left to cool to ambient temperature over 16 hours. The mixture was diluted with water (11 ml) and then extracted with ethyl acetate to give 2-[4-(4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzonitrile, m.p. 125° C. (softens).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.CCO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:11]([O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH3:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
After 2-chloropyrimidin-4-carboxylic acid (0.223 g, 1.4 mmol) was dissolved in DCM (7 mL), dicyclohexylcarbodiimide (0.29 g, 1.4 mmol), DMAP (0.017 g, 0.14 mmol) and EtOH (0.1 mL, 1.4 mmol) were added thereto, and the mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was filtered and separated by column chromatography to obtain the title compound (0.13 g, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](Cl)=[O:16])[CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:30][CH:31]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCOC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21
Product: C=CCOC(=O)c1ccc(NC(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example l(d), by reaction of 4.5 g (16.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylacetyl chloride with 3 g (16.8 mmol) of allyl 4-aminobenzoate, 5.1 g (75%) of the expected ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [ClH:1].Cl.[OH:3][C:4]1[C:5]([CH2:19]O)=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([NH:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7]2>[H][H].[Pd]>[ClH:1].[OH:14][CH:10]1[C:11]2[C:6](=[C:5]([CH3:19])[C:4]([OH:3])=[CH:13][CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:15][CH:16]([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)NC1CCc2c(ccc(O)c2CO)C1=O
Agent: [Pd]
Agent: Cl
Product: Cc1c(O)ccc2c1CCC(NC(C)C)C2O

Procedure:
In 20 ml. of 2N hydrochloric acid is dissolved 200 mg. of 6-hydroxy-5-hydroxymethyl-2-isopropylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride and with the addition of 100 mg. of 5 % palladium-on-carbon, the solution is agitated in hydrogen streams for 4 hours. After the hydrogen has ceased to be absorbed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure and at a temperature not exceeding 40° C. The residue is then recrystallized from ethanol-ether. The procedure yields 1,6-dihydroxy-2-isopropylamino-5-methyl-1,2,3,4-tetrahydronaphthalene hydrochloride as colorless powders. Yield 152 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][N:10]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Product: CN(C)CCn1cc(-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound is prepared as described in Example 55, starting from {4-[3-(4-chloro-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 2-dimethylamino-ethanol (Fluka).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([C:21]#[N:22])=[C:11]([N:14]3[CH2:20][C:16]4([CH2:19][O:18][CH2:17]4)[CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1.[BH4-].[Na+].O>C1COCC1>[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH:21]([NH2:22])[CH3:1])=[C:11]([N:14]3[CH2:20][C:16]4([CH2:19][O:18][CH2:17]4)[CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1
Reactant: Cn1ccc2nc(C#N)c(N3CC4(COC4)C3)cc21
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
Methylmagnesium bromide (1.56 mL, 2.18 mmol) was added slowly to a stirred solution of 1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (222 mg, 0.873 mmol) in THF (20 mL). The reaction was stirred at 40° C. for 1.5 hours, then cooled to 0° C. and quenched with MeOH (10 mL). After 10 minutes, sodium tetrahydroborate (83 mg, 2.18 mmol) was added. The reaction mixture was stirred for 20 minutes. Water (1 mL) was added and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was dried over MgSO4, filtered through Celite, and concentrated. The crude product was purified by basic silica column chromatography (3-5% MeOH in DCM) to give the title compound as a clear oil (111 mg, 47%). 1H NMR (500 MHz, CD3OD) δ ppm 7.28 (d, 1H, J=3.5 Hz), 7.14 (s, 1H), 6.47 (d, 1H, J=3.5 Hz), 4.89 (s, 4H), 4.33 (q, 1H, J=7.0 Hz), 4.10 (qAB, 4H, J=35.5, 7.5 Hz), 3.36 (s, 3H), 1.43 (d, 3H, J=7.0 Hz). ESI-MS m/z [M+H]+ calc'd for C15H20F4O, 273; found 273.
Reaction SMILES: O.[NH2:2][NH2:3].[NH:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O>CO>[NH:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([NH:2][NH2:3])=[O:11]
Reactant: NN
Reactant: COC(=O)c1ccc[nH]1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc[nH]1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
Hydrazine monohydrate (31.0 g, 620 mmol) was added to a mixture of methyl 1H-pyrrole-2-carboxylate (10 g, 77.5 mmol) and methanol (100 ml) followed by stirring at 65° C. for 15 h. The mixture was evaporated and the product was isolated as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:28][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCOc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.6 %

Procedure:
A mixture of 0.61 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene, 0.19 g of 4-chlorophenol, 0.22 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at room temperature. After 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.54 g of 3,5-dichloro-4-(4-(4-chlorophenoxy) butyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (59% yield), m.p. 54.5° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:21]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:20][C:19]3[C:18]([CH3:29])([CH3:28])[CH2:17][CH2:16][C:15]([CH3:31])([CH3:30])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:28][C:18]1([CH3:29])[CH2:17][CH2:16][C:15]([CH3:30])([CH3:31])[C:14]2[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[C:21]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:20][C:19]1=2
Reactant: COC(=O)c1ccc(C=Cc2cc3c(cc2Cn2cccn2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 27.6 g (64.4 mmol) of methyl-4-[2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 97 mL (193 mmol) of 2 N sodium hydroxide in 300 mL of ethyl alcohol was heated at reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with 900 mL of water. The reaction mixture was acidified with 2 N HCl and the product was isolated by filtration, washed with water and pentane and dried to give 25.9 g (97%) of 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid (m.p.=246.5-248° C.) 6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[NH:10][NH2:11].[C:12](#[N:15])[CH:13]=[CH2:14]>C1COCC1.[OH-].[Na+]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:10]([CH2:14][CH2:13][C:12]#[N:15])[NH2:11]
Reactant: C=CC#N
Reactant: NNc1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CCCN(N)c1cc2ccccc2[nH]1

Procedure:
To a solution of 2-indolyl hydrazine (1.47 g.) in THF (100 ml.) was added acrylonitrile (0.75 g.) and five drops of 2N sodium hydroxide solution. The reaction mixture was heated under reflux for eight hours and then concentrated in vacuo. The residue was dissolved in ethanol, treated with activated charcoal, filtered and cncentrated again to give 3-[1-(2-indolyl)hydrazino]propanenitrile, crystallized from ether-ethanol, m.p. 120°-122° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:26])[CH2:21][C@H:20]3[CH3:33])=[N:11][N:10]=2)=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:36]([N:38]=C=O)=[O:37]>C(Cl)(Cl)Cl>[C:36](=[O:37])([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][C@H:20]3[CH3:33])=[N:11][N:10]=2)=[CH:5][CH:4]=1)[NH2:38]
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(CO)cc2)c2ccccc12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(COC(N)=O)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Compound 81 was prepared as described in general Method K. (R)-(4-(4-(4-(hydroxymethyl)phenyl)phthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (JK-28) (125 mg, 0.285 mmol), was dissolved in chloroform (2.50 mL). 2,2,2-trichloroacetyl isocyanate (40.5 μl, 0.342 mmol) was added and the reaction stirred at rt for 80 minutes. The reaction was adsorbed onto alumina (Brockmann II, 3 g), and after 2 hours was eluted with 10% methanol in dichloromethane. The resulting solution was evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-45% ethyl acetate gave a pale yellow solid, compound 81. MS (M+H)+=482.2
Reaction SMILES: [NH2:1][CH:2]1[NH:7][CH2:6][CH:5]=[CH:4][NH:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18]>CN(C=O)C.O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1)=[O:18]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: NC1NC=CCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NCCCN1)Nc1c(Cl)cccc1Cl

Procedure:
A solution of 4.20 g (0.0424 mol) of 2-aminotetrahydropyrimidine in 30 ml of dry DMF was warmed to 70° C. and with stirring was added 7.16 g (0.0381 mol) of 2,6-dichlorophenyl isocyanate in 25 ml of dry DMF over a period of 0.5 hours. After stirring for 2 hours at 70° C., the reaction mixture was cooled, diluted with H2O and filtered. The filter cake was washed well with H2O and air dried. The crude product, 5.1 g (47%) was dissolved in CH2Cl2, dried over K2CO3, filtered through a prewashed pad of filter aid and hexane was added to the cloud point. The resulting crystals were filtered, washed with hexane and dried in vacuo for 3 hours (50° C.; 5 mm Hg) to give pure N-(2,6-dichlorophenyl)-N'-(1,4,5,6-tetrahydropyrimidin-2-yl)urea, 4.71 g (43%); m.p. 179°-180.5° C. TLC: 5×20 cm silica gel; toluene-ether-MeOH (8:4:1) or CHCl3 -MeOH-NH4OH (90:10:1) indicated homogeneity; IR (KBr) 3421,1628 cm-1 ; UV max. (MeOH) 222 nm (ε=28300) and 239 nm (inflection) (ε=18,000).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21]1([C@H:27]([N:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]2([OH:35])[CH2:33][CH2:34][N:29]([C@@H:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])[CH2:30][CH2:31]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccccc1)N1CCC(=O)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 121.8 %

Procedure:
175.2 g (666 mmol) 4-benzyloxybromobenzene was dissolved in 1.4 L dry THF (MS 4 A) under argon. The solution was cooled to −75° C. and a solution of 416 mL 1.6 M butyllithium (666 mmol) in hexane was added during 40 minutes. After stirring for 1 hour a solution of 113 g (555 mmol) (R)-1-(1-phenyl-ethyl)-piperidin-4-one in 400 mL THF was added during 1hour at −75° C. The mixture was stirred for another 1 hour and, after heating to room temperature, poured into 1.5 L of ice-water. The mixture was extracted with 1 L ethyl acetate. The organic phase was washed with 1 L of a half-saturated NaCl solution, dried over Na2SO4 and concentrated to yield 262 g of (R)-4-(4-benzyloxy-phenyl)-1-(1-phenyl-ethyl)-piperidin-4-ol.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>O1CCCC1.CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([OH:23])=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 88.5 %

Procedure:
To a solution of 116 (0.40 g; 1.1 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added aqueous sodium hydroxide (20 mL; 2N) and then heated at 80° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as an off-white solid (0.34 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.N12CCN(CC1)CC2.[C:20](#[N:23])[CH:21]=[CH2:22]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:22][C:21]([C:20]#[N:23])=[CH:4]2
Reactant: C=CC#N
Reactant: COc1ccc(O)c(C=O)c1
Agent: C1CN2CCN1CC2
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C=C(C#N)CO2

Procedure:
A solution of 0.61 g (4 mmol) of 2-hydroxy-5-methoxybenzaldehyde and 0.112 g (1 mmol) of 1,4-diazabicyclo[2.2.2]octane in 18 ml of acrylonitrile is heated at reflux for 24 hours under argon. After cooling, the medium is diluted with chloroform and then washed with a saturated solution of sodium hydrogen carbonate. The organic phase is then acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with chloroform. The organic phases, dried over magnesium sulphate and then filtered, are concentrated under reduced pressure. The title nitrile is obtained pure in the form of a yellow solid after passage over a silica column (eluant: AcOEt/PE: 25/75).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:20])=[O:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A mixture of 16.2 g (64.5 mmol) of 4-(tert-butoxycarbonylaminomethyl)benzoic acid, 13.6 g (70.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.00 g of 4-dimethylaminopyridine and 200 ml of methanol was stirred at room temperature for 4 hours. Methanol was distilled off under reduced pressure and ice water was poured to the residue thus obtained. The mixture was extracted twice with ethyl acetate and the extract was washed with 10% citric acid aqueous solution and then with saturated sodium hydrogencarbonate aqueous solution and finally with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 14.3 g (83.6%) of methyl 4-(tert-butoxycarbonylaminomethyl)-benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 81.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,6-trifluorobenzoic acid ethyl ester (Example 2b, 5.4 g, 13.9 mmol), cyclopropylamine (40 mL, 577 mmol), and dimethyl sulfoxide (28 mL) in a sealed glass tube is heated at 100° C. for 27 hours. The excess amine is removed by blowing in compressed air before the solution is concentrated under high vacuum. The residue is then purified by column chromatography (1:1:8 ethyl acetate/chloroform/hexanes) to afford the title compound (4.80 g). 1H NMR (CDCl3): δ 7.42 (bs, 1H), 5.69 (ddd, 1H), 4.76-4.61 (m, 1H), 4.37-4.19 (m, 3H), 3.81-3.66 (m, 1H), 3.65-3.43 (m, 2H), 3.39-3.28 (m, 1H), 2.98-2.82 (m, 1H), 2.30-2.09 (m, 1H), 1.98-1.82 (m, 1H), 1.45 (s, 9H), 1.34 (t, 3H), 0.72-0.68 (m, 2H), 0.67-0.44 (m, 2H).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1.C([Sn](CCCC)(CCCC)[C:19]([O:21][CH2:22][CH3:23])=[CH2:20])CCC.[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:22]([O:21][C:19]([C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)=[CH2:20])[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc(C)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a N,N-dimethylformamide (10 mL) solution of 5-bromo-2-methylpyrimidine (0.50 g), tributyl(1-ethoxyethenyl)stannane (1.5 g) and bis(triphenylphosphine)palladium(II) dichloride (0.14 g) were added, and the resultant was stirred at 100° C. for 1 hour. After standing to cool to room temperature, an aqueous potassium fluoride solution (20 mL) and diethyl ether (20 mL) were added to the reaction solution, and the resultant was stirred. Insoluble material was filtered off through Celite, and the filtrate was subjected to extraction with diethyl ether. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→75/25) to obtain the title compound (0.48 g) as a pale yellow solid.