Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[Cl:16])=[C:4]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[N:3]=1.[Cl:24]C1C=C(Cl)C=CC=1CC#N>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[N:3]=1
Reactant: CCOC(OCC)c1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: N#CCc1ccc(Cl)cc1Cl
Product: CCOC(OCC)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared in a manner analogous to 2,4-diamino-5-(2,3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine (Example 18.1) from 2,4-dichlorophenylacetonitrile, mp. 225° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:30]4[C:25]([O:24][CH3:23])=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: COc1ncccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 21.3 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (338.7 mg, 0.9 mmol) and 2-methoxy-3-pyridineboronic acid [163105-90-6] (169.4 mg, 1.1 mmol) to afford 76.0 mg of yellow powder as a free base, mp. 131-132° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.06 Hz, 6 H) 3.47-3.56 (m, 4 H) 3.71-3.80 (m, 4 H) 4.00 (s, 3 H) 4.82 (spt, J=6.23 Hz, 1 H) 6.81 (d, J=8.08 Hz, 1 H) 7.08 (dd, J=7.45, 4.93 Hz, 1 H) 7.98 (dd, J=4.93, 1.89 Hz, 1 H) 8.51 (s, 1 H) 8.76 (d, J=7.83 Hz, 1 H) 8.82 (dd, J=7.58, 2.02 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 42.85, 44.06, 53.10, 68.16, 97.21, 98.90, 116.40, 117.17, 134.55, 136.43, 141.99, 144.65, 144.71, 154.26, 155.46, 158.89. LRMS (ESI) m/z 397.1 [(M+H)]+, calc'd for C20H24N6O3: 396.45.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[OH:9])=[CH:17][CH:16]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: COc1ccc(CCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cc2c(C)cc(C)cc2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3,5-dimethylphenol (12 g) were added lithium hydroxide monohydrate (4.2 g) and 4-methoxybenzyl chloride (14 mL) at 85° C., and the mixture was stirred 1.5 hours. The reaction mixture was cooled to ambient temperature and purified by column chromatography on silica gel (eluent: dichloromethane) to give 2-(4-methoxybenzyl)-3,5-dimethylphenol (5.1 g).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:9])C1C=CC=CC=1.Cl.[NH2:18][N:19]1[CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([NH:18][N:19]2[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]2)=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)NN1CC=CCC1
Yield: 45.9 %

Procedure:
A solution of 4-(phenoxycarbonylamino)pyridine (4.284 g), N-amino-1,2,3,6-tetrahydropyridine hydrochloride (4.038 g) and triethylamine (3.036 g) in chloroform (70 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (52 g) using chloroform to give N-[(4-pyridylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (2.005 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[N:20]=[C:19]([CH:21]2[CH2:26][CH2:25][NH2+:24][CH2:23][CH2:22]2)[O:18][N:17]=1>N1C=CC=CC=1>[C:1]1([NH:7][C:8]([N:24]2[CH2:25][CH2:26][CH:21]([C:19]3[O:18][N:17]=[C:16]([C:12]4[S:11][CH:15]=[CH:14][CH:13]=4)[N:20]=3)[CH2:22][CH2:23]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
40 μl (1 eq.) of phenyl isocyanate were added to a solution of 100 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride in 0.6 ml of pyridine. The reaction medium was stirred at room temperature overnight and then evaporated under reduced pressure. The residue obtained was chromatograph on a thick layer of silica (eluent: CH2Cl2/MeOH (95/5; v/v)). After evaporating off the solvent, 48 mg (37%) of the expected compound were obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])=[C:5]([CH2:20][CH3:21])[CH:4]=1.CCN(CC)CC.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C(Cl)Cl>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:32])[CH:30]=[CH2:31])[CH2:16][CH2:15]2)=[O:13])=[C:5]([CH2:20][CH3:21])[CH:4]=1
Reactant: CCc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNCC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(Cl)c(Cl)cc2CC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a mixture of above crude 2-(4,5-dichloro-2-ethylphenylamino)-1-(piperazin-1-yl)ethanone hydrochloride (82 mg) and Et3N (69 mg, 0.686 mmol) in DCM (3 mL) 0° C., a solution of acryloyl chloride (23 mg, 0.251 mmol) in DCM (1 mL) was added. The resulting mixture was stirred at room temperature for 1 h and then was quenched withed saturated NaHCO3 solution. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (20 mg, 18.76% yield, 2 steps) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.11 (s, 1H), 6.58 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.36 (dd, J=1.6, 16.4 Hz, 1H), 5.79 (dd, J=1.6, 10.4 Hz, 1H), 5.08 (bs., 1H), 3.89-3.52 (m, 10H), 2.52 (q, J=7.2 Hz, 2H), 1.29-1.26 (t, J=7.6 Hz, 3H). ESI-MS m/z: 370.2[M+H]+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][NH2:13]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([S:3](=[N:13][CH3:12])([NH:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: CN
Reactant: CNS(=O)c1ccc(Br)cc1
Product: CN=S(=O)(NC)c1ccc(Br)cc1

Procedure:
The title compound is prepared from 4-bromo-benzenesulfinic acid methylamide and methylamine following a procedure analogous to that described for Intermediate 17 (Step 2). LC (method 1): tR=0.70 min; Mass spectrum (ESI+): m/z=263, 265 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH3:11])[CH:4]=1.C(N(CC)CC)C.CS([Cl:23])(=O)=O>C1(C)C=CC=CC=1>[Cl:23][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CCl)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-methoxy-2-methylphenyl)methanol (8.2 g, 54.0 mmol) and triethylamine (9.1 mL, 65.0 mmol) in toluene (100 mL) at 0° C., methanesulfonyl chloride (5.1 mL, 65.0 mmol) was added via syringe over 20 min. The ice water bath was removed, and the reaction was allowed to stir at room temperature for 30 min, heated at 80° C. for 3 days, and then concentrated. The reaction was diluted with DCM, washed with H2O (3×100 mL) and brine, dried over Na2SO4, and concentrated under reduced pressure to 1-(chloromethyl)-4-methoxy-2-methylbenzene (8.1 g) as a dark brown oil. 1H NMR (300 MHz, CDCl3): δ 7.25 (d, 1H), 6.75 (m, 2H), 4.62 (s, 2H), 3.82 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [BH4-].[Na+].O1C2C=CC(CN(CC3C=CC4OCOC=4C=3)[CH2:14][C:15]3[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][C:19]=3Br)=CC=2OC1.C[OH:42]>>[CH2:27]([N:16]1[C:15]([CH2:14][OH:42])=[CH:19][N:18]=[C:17]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCn1c(-c2ccccc2)nc(Br)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCCCn1c(CO)cnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.135 g, 30 mmol) is added to a solution of aldehyde 138 (6.849 g, 30 mmol) in 100 ml of methanol cooled to 0° C. The resulting solution is stirred at 0° C. for 30 min, evaporated and the residue dissolved in 150 ml of ethyl acetate, washed with water and brine, dried over Na2SO4, concentrated and taken to dryness under high vacuum to give the product 139 as an oil. MS (+VE) m/z 231 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:25][C:26](OC(C)=O)=[O:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:26](=[O:27])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (46.6 mg, 0.20 mmol), Et3N (26.0 mg, 0.26 mmol) and DMAP (2.5 mg, 0.02 mmol) in CH2Cl2 (4 mL) was added dropwise Ac2O (24.5 mg, 0.24 mmol), and the reaction mixture was then heated to reflux under argon for 1 hr. Cooled to r.t., the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (54.0 mg, 98.2%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:22][CH3:23])[C:18]=1[CH2:19][CH2:20]C)[C:12]([O:14]C)=O.[CH3:24]COCC>>[CH3:23][O:22][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[C:18]=1[CH:19]([CH3:20])[CH3:24])[CH2:12][OH:14]
Reactant: CCCc1c(OC)cc(C(=O)OC)cc1OC
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(CO)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of LiAlH4 (95%) (5.00 g, 125 mmol) in dry ether (100 mL) at 0° C. was added a solution of methyl 3,5-dimethoxy-4-1-propylbenzoate (15.7 g, 90.1 mmol), in ether (300 mL) under N2. The suspension was stirred at 0° C. for one hour then for an additional hour at room temperature. The reaction was quenched by slow addition of a saturated Na2SO4 aqueous solution (10 mL) at 0° C. The mixture was stirred overnight. The solid was filtered off and the filtrate was evaporated to dryness to give the desired alcohol (13.8 g, 88% yield) as white crystals. 1HNMR (CDCl3. ppm): δ 1.34 (d, J=7.2 Hz, 6H), 3.65 (hept., J=7.2 Hz, 1H), 3.88 (s, 6H), 4.70 (s, 2H), 6.62 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)(=[O:10])=[O:9]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Yield: 94.9 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (0.500 g, 1.96 mmol), 4-acetamidopiperidine (0.335 g, 2.45 mmol), and diisopropylethyl amine (1.0 mL, 5.8 mmol) in CH2Cl2 (5 mL) was stirred for 15 min at rt. The reaction mixture was then washed with 1 N HCl (2×5 mL) followed by brine (10 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (0.672 g, 95%). The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.09-8.05 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.38 (m, 2H), 6.08 (d, J=8.0, 1H), 3.87-3.79 (m, 2H), 2.93-2.85 (m, 2H), 2.00-1.93 (m, 5H), 1.59-1.51 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: COc1ccnc(C)c1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccnc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 2-methyl-4-methoxypyridine (2.03 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 12.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.99 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(4-methoxypyridin-2-yl)propan-2-one (2.35 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].O1CCCC1>O>[C:26]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:28])[CH3:27]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3ccccc32)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3ccccc32)cc1C(=O)O
Reaction time: 48 h

Procedure:
A mixture of 8.25 g. (0.025 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenylindole and 76.5 g. (0.75 mole) of acetic anhydride was heated under reflux for 1 hour, diluted with 75 ml. of tetrahydrofuran and poured into 1 l. of water. An oil separated, and during 2 days solidified. The solid was collected and recrystallized from acetonitrile to provide 4.8 g. (52%) of colorless crystals, m.p. 178°-180°.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:23]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21][NH:22][CH2:2][CH2:1][C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: C=Cc1ncccn1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(C(CCNCCc2ncccn2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of 2-vinylpyrimidine (0.373 g, 3.51 mmol) in EtOH (6 mL) at room temperature was added AcOH (1 mL) and 3,3-diphenylpropan-1-amine (2.21 g, 10.5 mmol). The reaction mixture was heated to reflux for 1 d, cooled to 0° C., and the solids were removed by filtration. The filtrate was concentrated and diluted with 5 M NaOH, brine, and EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% MeOH in DCM) gave 3,3-diphenyl-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:18])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2cn[nH]c2c1
Solvent: CC#N
Product: Clc1ccc2c(I)n[nH]c2c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
An acetonitrile solution (250 mL) containing the intermediate from Step A (6.14 g, 40.2 mmol) and NIS (9.33 g, 41.4 mmol) was heated at 60° C. for 3 hours. The reaction solution was cooled to room temperature and concentrated to approximately 70 mL volume. The reaction was then diluted with water (ca 400 mL). The suspension was stirred for 10 minutes and then filtered. The solid was air dried on the filter to give the indicated product. The material was used in Step C without further purification. 1H NMR (400 MHz, CH 3 CN-d3): δ 1.52 (broad s, 1H); 7.62 (d, J=1.7 Hz, 1H); 7.44 (d, J=8.6 Hz, 1H); 7.21 (dd, J=8.6, 1.7 Hz, 1H). m/z=279.0 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:35][C:36]1([C:39]#[N:40])[CH2:38][CH2:37]1.[CH2:41]1[C:45]2([CH2:50][CH2:49][N:48]([C:51]([NH:53][C@@H:54]([CH2:58][C:59]([F:68])([F:67])[CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55](O)=[O:56])=[O:52])[CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[C:39]([C:36]1([NH:35][C:55]([C@@H:54]([NH:53][C:51]([N:48]2[CH2:47][CH2:46][C:45]3([CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:50][CH2:49]2)=[O:52])[CH2:58][C:59]([F:67])([F:68])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:56])[CH2:38][CH2:37]1)#[N:40]
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CC(F)(F)Cc2ccccc2)NC(=O)N2CCC3(CCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIPEA (331 μl, 252 mg, 1.95 mmol, 4 eq.), HATU (185 mg, 0.49 mmol, 1 eq.) and 1-aminocyclopropanecarbonitrile hydrochloride (58 mg, 0.49 mmol, 1 eq.) were added successively to a solution of the (S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenylpentanoic acid obtained as a crude product (192 mg, 0.49 mmol) in 10 ml of DMF. The reaction mixture was stirred at RT overnight and, the next day, concentrated under reduced pressure. The residue thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The title compound was obtained in the form of a colorless crystalline material.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH2:10]([Li])CCC.[CH:15]([S:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16].CI.Cl>O1CCCC1>[CH:15]([S:18][C:19]([CH3:10])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C(C)SC(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)SC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1,1,3,3,3-hexamethyldisilazane (10.4 mL, 48 mmol) in tetrahydrofuran is cooled to 0° C., treated with a 2.04 M solution of n-butyllithium in tetrahydrofuran (22.6 mL, 46 mmol), stirred at 0° C. for 30 minutes, treated dropwise with ethyl 2-(isopropylthio)propionate (7.6 g, 42 mmol), stirred at 0° C. for 1 hour, treated with methyl iodide, stirred at room temperature for 22 hours, and poured into an ice-water mixture (100 g) containing 10 mL of 6 N hydrochloric acid. The resultant aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown liquid. Vacuum distillation of the brown liquid gives the title product as a liquid (6.8 g) which is identified by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]C(O)=O>CCOCC.C1COCC1>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: CC(=O)O
Reactant: O=C(O)c1cccnc1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of CH2N2 (4 eq.) in Et2O (1 M) was added dropwise to a solution of 2-bromonicotinic acid in THF (0.5 M) at RT. The reaction mixture was stirred at room temperature overnight, then quenched by dropwise addition of AcOH (4 eq.). The organic phase was washed with water and brine and dried (MgSO4). Evaporation of the solvent yielded (75%) the title compound which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3, 300K) δ 8.47 (1H, dd, J=4.8 Hz, 2.1 Hz), 8.07 (1H, dd, J=7.8 Hz, 2.1 Hz), 7.35 (1H, dd, J=7.5 Hz, 4.5 Hz), 3.93 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:31][CH2:30][CH2:29][CH2:28][NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: NCCCNc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1ccccc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-phenylamino-propylamine in the presence of triethylamine analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:34]=[C:35]1[NH:40][N:39]=[C:38]([C:41]2[CH:48]=[CH:47][C:44]([CH2:45]O)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1.C[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:45][C:44]2[CH:43]=[CH:42][C:41]([C:38]3[CH2:37][CH2:36][C:35](=[O:34])[NH:40][N:39]=3)=[CH:48][CH:47]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Reactant: O=C1CCC(c2ccc(CO)cc2)=NN1
Agent: C[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCc2ccc(C3=NNC(=O)CC3)cc2)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mmol of 4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxylic acid are suspended in 40 ml of absolute tetrahydrofuran and treated with 12.5 mmol of carbonyldiimidazole. The suspension is then stirred for 30 minutes at room temperature and for 30 minutes at reflux temperature. A solution of 11 mmol of 4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzyl alcohol and 10 mg of sodium methylate in 10 ml of tetrahydrofuran is then added, and the mixture is heated to reflux for 3.5 hours. It is then evaporated, and the residue is taken up in methylene chloride, washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution and water, dried with magnesium sulphate and evaporated. The residue crystallizes from a little i-propanol.