Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH:24]([OH:27])[CH2:25][CH3:26].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml). A sulfur trioxide trimethylamine complex (70 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (25 mg, yield 14%).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=[O:5])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:37]([O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])([CH3:40])([CH3:39])[CH3:38]>C1COCC1.CN(C=O)C>[CH2:20]([O:19][P:4]([O:3][CH2:1][CH3:2])([CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:49])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:9])=[O:5])[CH3:21]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOP(=O)(OCC)C(Cc1ccc(OC)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cc1ccc(OC)cc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
The product of stage (b) was dissolved in THF (20 ml), cooled to -25° C. and with stirring NMM (1.28 g) and then isobutylchloroformate (1.65 g) successively added. After two minutes, a precooled solution of leucine tert-butyl ester (2.15 g) in DMF (5 ml) was added and the mixture stirred at -15° C. for 2 hr. The temperature was raised to 0° C. and stirring continued for 0.5 hr after the addition of 2 M KHCO3 (14 ml). The product was evaporated in vacuo, the residue suspended in ethyl acetate and succesively washed with 5% citric acid, 10% NaHCO3 and brine, dried (MgSO4) and concentrated to a white solid, m.p. 80°-87° (dec). The structure was confirmed by NMR and the product was used in the next stage without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]1)[N:20]=[C:19]([CH3:32])[N:18]=2>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:33][CH2:34][NH2:35])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH2:29]1)[N:20]=[C:19]([CH3:32])[N:18]=2
Reactant: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3CCNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3CCN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
Add trifluoroacetic acid (3 mL) to a solution of tert-butyl N-[2-[8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-purin-9-yl]ethyl]carbamate (0.6 g, 1.2 mmol) in dichloromethane (3 mL) at 0° C. and stir for 2 h at room temperature. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution, and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane-methanol (96:4) as eluent to give 2-[8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-purin-9-yl]ethanamine (0.3 g). ES/MS m/z 400 (M+1).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:16][O:17][NH:18][CH3:19].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:16][O:17][N:18]([CH3:19])[C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N(C)OC)cc1NC
Temperature: 180 °C
Yield: 73.8 %

Procedure:
A mixture of ethyl 6-chloro-4-(methylamino)nicotinate (8 g, 37.4 mmol) and O,N-dimethylhydroxylamine hydrochloride (91 g, 0.94 mol) in dioxane (10 mL) was heated to 180° C. for 6 h. The reaction mixture was cooled to RT, and saturated aq Na2CO3 solution was added until pH 7. The aqueous solution was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 6-(methoxy(methyl)amino)-4-(methylamino)nicotinate (6.6 g, 74% yield), which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 8.44 (s, 1 H), 7.82 (m, 1H), 6.05 (s, 1 H), 4.20 (q, J=7.2 Hz, 2 H), 3.67 (s, 3 H), 3.17 (s, 3 H), 2.82 (d, J=5.2 Hz, 3 H), 1.25 (t, J=7.2 Hz, 3 H), MS (ESI) m/z: 240.1 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:35]3[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]3)[CH:30]=[CH:29][CH:28]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: OC1CCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(O)CC2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 150 mg (0.313 mmol) of the compound from Example 1A, 63 mg (0.626 mmol) of 4-hydroxypiperidine, 19 mg (0.021 mmol) of tris(dibenzylideneacetone)dipalladium(0), 30 mg (0.063 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) and 254 mg (0.782 mmol) of caesium carbonate in 3 ml of anhydrous DMF was stirred at 80° C. under argon for 12 h. After cooling to RT, the reaction mixture was filtered through a little Celite and the filtrate was then separated into its components by means of preparative HPLC (method 11). After concentration of the product fractions and drying under high vacuum, 36 mg (23% of theory) of the title compound were obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:8]1[C:7]([N:24]2[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: N#CC1CCNC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(C#N)C1
Temperature: 65 °C
Yield: 15.7 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), pyrrolidine-3-carbonitrile hydrochloride (0.054 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The resulting residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (16 mg, 16%). LCMS calculated for C16H15ClN3O (M+H)+: m/z=300.1; Found: 300.0.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].O1C2C=CC=CC=2CC1CO.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH2:49]>>[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH:49][CH2:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10]1
Reactant: CN(C)CCCN
Reactant: C=CCc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: OCC1Cc2ccccc2O1
Product: CN(C)CCCNCC1Cc2ccccc2O1

Procedure:
The starting diamine of formula II can be prepared according to known processes; for example starting from 2-allylphenol, which is then converted to 2,3-dihydrobenzofuran-2-yl-methanol by the action of a peracid and subsequently to the tosylate by the action of para-toluene-sulphonyl chloride, the said tosylate then being reacted with 3-(dimethylamino)-propylamine to give N,N-dimethyl-N'-(2,3-dihydro-benzofuran-2-ylmethyl)-1,3-propanediamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[C:24]([C:28]#[N:29])=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:20][C:21]1[N:26]=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:24]([C:28]#[N:29])=[CH:23][N:22]=1
Reactant: N#Cc1cnc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine.2HCl (164 mg, 0.50 mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (77 mg, 0.50 mmol) and DIPEA (427 μL, 2.49 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) followed by trituration from Et2O to afford 367 as a white solid (72 mg, 39%). LCMS (Method K): RT 3.06 min [M+H]+ 375.00. 1H NMR (DMSO-d6, 400 MHz): δ 8.59 (1H, m), 8.06 (2H, m), 7.77 (2H, m), 7.68 (1H, d, J=7.41 Hz), 7.48 (1H, m), 7.19-6.80 (4H, m), 5.85 (1H, m), 1.52 (3H, d, J=6.81 Hz
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[CH2:7]1
Reactant: Cc1cccc(CN=C=O)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1cccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1

Procedure:
Example 4 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-3-methylbenzene (19.1 μl) to give the title compound (0.0382 g). LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12].ClCCl>C(Cl)CCC>[C:8]([C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:7]=1)#[CH:9]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: C=Cc1cc(C)nc(N)n1
Solvent: CCCCCl
Solvent: ClCCl
Product: C#Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
In a dry flask under a nitrogen atmosphere was mixed 0.24 g of 2-amino-4-ethenyl-6-methylpyrimidine, 0.61 g of 2-carbomethoxybenzenesulfonylisocyanate and 25 ml of dry dichloromethane. The solution was heated to reflux for five minutes and allowed to stir at room temperature overnight. A precipitate formed. The reaction mixture was stripped, titurated with butyl chloride to give 0.56 g of the title compound as a solid, m.p. 185°-190° (dec); IR(nujol) 2111 (C≡C), 3250 (NH), 3321 (NH), 1716 (CO) and 1725 (CO) cm-1.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([N+:23]([O-])=O)[CH:3]=1.CCCCCC>C(#N)C.[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[C:11]([CH3:12])=[C:10]2[C:5]=1[C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[C@@H:13]1[CH2:15][C@@H:14]1[F:16]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc([N+](=O)[O-])c2c1=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc(N)c2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 38 %

Procedure:
Ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate (2.50 g, 7.10 mmol) was dissolved in acetonitrile (20 ml), and after adding a 5% palladium carbon catalyst (water content: 50%, 1.0 g) thereto, it was stirred at room temperature for 20 hours under a hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtering (methanol washing), the filtrate was concentrated under a reduced pressure, and the residue obtained was dissolved in ethyl acetate (10 ml) and heated under reflux for 30 minutes. n-hexane (10 ml) was then added, and after performing heated refluxing for 30 minutes, there action solution was allowed to stand under room temperature. The precipitated crystals were then filtered out, washed with a 1:1 mixed solution of n-hexane:ethyl acetate and dried under a reduced pressure at 60° C. for 16 hours. 869 mg (38%) of the title compound was thereby obtained as a yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[N:5]=1)(=[O:3])C.[BH4-].[Na+].[CH:15](O)(C)C>>[CH3:15][C:10]([CH3:11])([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][OH:3])[N:5]=1)[OH:12]
Reactant: CC(C)O
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(O)c1cccc(CO)n1

Procedure:
A 250 mL three-necked round bottom flask fitted with magnetic stirrer and nitrogen inlet was charged with 5.0 g (30.6 mmol) of 2,6-diacetylpyridine and 60 mL of anhydrous isopropyl alcohol. To the stirred solution was added 1.16 g (3.06 mmol) of sodium borohydride in three equal portions. The initially colorless solution became yellow and warmed then slowly returned to pale yellow.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([N:33]([CH3:35])[CH3:34])[C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([N:33]([CH3:35])[CH3:34])[C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1N(C)C
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3N(C)C)cc2)CC1

Procedure:
The product was prepared analogously to Example 7.1 e starting from 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine and [5-(4-chlorophenyl)-2-ethynylpyridin-3-yl]dimethylamine. Yield: 34 mg (5% of theoretical); C29H32ClN3O (M=474.037); calc.: molpeak (M+H)+:474/476 (Cl); found: molpeak (M+H)+:474/476 (Cl); HPLC-MS: 5.40 minutes (method D).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[S:25]1[CH:29]=[C:28]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[N:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([C:28]4[N:27]=[N:26][S:25][CH:29]=4)=[CH:31][CH:32]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1ccc(-c2csnn2)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-c4csnn4)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling the 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione to 4-[1,2,3]thiadiazol-4-yl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B(F)(F)F.CCOCC.O1CCCC1.N[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:26]1([NH:10][C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccnc1C(N)=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1cccnc1C(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 354.5 %

Procedure:
To 3-methyl-2-pyridinecarboxamide (15.0 o, 0.11 mole) are added BF3.OEt2 (14.0 mL, 0.11 mole) and tetrahydrofuran (75 mL). After about 5 minutes, aniline (10.3 g, 0.11 mole) is slowly added and the solution is heated at reflux for 5 hours. The reaction is cooled and diluted with water and the oroduct is extracted into ethyl acetate. The solvent is removed and the residue is purified by silica gel chromatography to give 8.32 g (0.39 mole, 35%) of N-phenyl-3-methyl-2-pyridinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)=O.C([NH2:21])=O.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][CH:13]([NH2:21])[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CC(N)CC1(c2ccc(Cl)cc2)CCC1
Temperature: 180 °C

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one prepared as described in Example 3 (15 g) and 98% formic acid (4 ml) was added dropwise to formamide (12 ml) at 160° C. The temperature was raised to 180° C. and maintained at this temperature for ten hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to yield a yellow oil which was hydrolysed with concentrated hydrochloric acid under reflux. The resulting aqueous solution after dilution with water was washed with ether, aqueous NaOH was added and the aqueous solution extracted with ether. The extracts were washed, dried and evaporated to yield a residue which on distillation gave 2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (b.p. 105°-107°/0.7 mm Hg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)[CH3:26])[CH3:25]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethoxyphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.O>[CH:11]1([C@@:7]([OH:17])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH3:18])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a mixture of (R)-α-cyclohexyl-α-hydroxybenzeneacetic acid (III) (12.2 g, 52.1 mmol) and K2CO3 (10.8 g, 78.2 mmol) in 100 mL of acetone was added methyl iodide (MeI) (13.0 mL, 208 mmol) dropwise at 0° C. (ice bath). After the addition (ca. 1 h) of MeI, the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite and rinsed with acetone twice. The filtrate was concentrated to give a white slurry which was diluted with water and extracted with heptane. The combined extracts were washed with water, brine, dried and concentrated to give the product (R)-IV (11.9 g, 92% yield) as a white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH2:34])[C:18]1=[O:35])=[O:15])([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH:34][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C:18]1=[O:35])=[O:15])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C2CCCCC2)c2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
Phenyl isocyanate (110 mg) was added to a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (300 mg) in anhydrous tetrahydrofuran (10 ml), the mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, etanol was added to the residue for crystallization, collected by filtration, to thereby obtain 336 mg of the title compound (Yield 83.9%).