Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1>CO.Cl.O1CCOCC1>[CH3:30][C:17]1([N:14]2[CH2:15][CH2:16][CH:11]([N:3]3[C@@H:4]4[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]4)[CH2:10][C:2]3=[O:1])[CH2:12][CH2:13]2)[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCNCC1

Procedure:
A solution of tert-butyl 4-[4-[(3aR,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-indol-1-yl]-1-piperidyl]-4-methyl-piperidine-1-carboxylate in MeOH (14 mL) and 4M HCl in dioxane (5 mL) was stirred at room temperature overnight. Concentrated in vacuo and the residue was purified by preparative LC/MS (high pH) to provide the title compound as a colorless oil (0.41 g). MS (M+1): 320.30.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](O)=[O:18])[N:16]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17]([Cl:3])=[O:18])[N:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1

Procedure:
Thionyl chloride (0.66 mL, 9 mmol) was added to a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (1 g, 3 mmol) in toluene (10 mL). The mixture was refluxed under argon for 1.5 h and concentrated to provide 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride, which was used in the next step without purification. 1H NMR (300 MHz, CD2Cl2) δ 8.40 (s, 1H), 7.69-7.09 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:17]>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][CH3:17])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(trans-3-hydroxycyclobutyl)carbamate (1.18 g, 6.3 mmol) was dissolved in dry THF (25 mL) under a nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution was added, sodium hydride (60% dispersion in oil, 0.25 g, 6.3 mmol) portion wise (evolution of H2 observed). The reaction mixture was stirred at RT for 30 min. then iodomethane (0.40 mL, 1.5 mmol) added dropwise and the resulting yellow suspension stirred at RT for 16 h. The reaction mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and partitioned between saturated aqueous solution of NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-70% EtOAc in cyclohexane) to afford the title compound as a yellow oil (1.05 g, 82%). 1H NMR (CDCl3, 300 MHz): δ 4.65 (1H, br s), 4.22-4.10 (1H, m), 4.00-3.92 (1H, m), 2.40-2.28 (2H, m), 2.18-2.12 (2H, m), 1.43 (9H, s).
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[F:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]=[N:23][C:17]=2[CH:16]=1>O1CCCC1>[F:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]([CH:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)[NH:23][C:17]=2[CH:16]=1
Reactant: Fc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CN1CCC(C2Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
In a dried 1 L three-necked flask, 1,2-dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (6.3 gm) in tetrahydrofuran (50 ml) to initiate a Grignard reaction. The mixture became cloudy and a vigorous reaction ensued. A solution of N-methyl-4-chloropiperidine (37 ml) in tetrahydrofuran (40 ml) was added in portions to maintain a fast reflux over a period of 10 minutes. The resultant slurry was refluxed for 1.5 hours and thereafter cooled to about 5° C. with an ice-water bath. A solution of 9-fluoro-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (15.7 gm) in tetrahydrofuran (70 ml) was added in 5 minutes. The mixture was stirred for 40 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Trans-4-tert-butoxycarbonylamino-aminocyclohexane (1 g) and potassium carbonate (1.3 g) were suspended in ethanol (20 mL), and then 1,5-dibromopentane (1.07 g) was added thereto. The reaction solution was stirred at 80° C. for 48 hours. After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure. The residue was dissolved in water (50 mL). The aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: 10%-saturated aqueous ammonia-methanol=1:0→10:1) to obtain the title compound (492 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([Br:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[NH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].[CH:27](I)([CH3:29])[CH3:28]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]([Br:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13]([O:20][CH:27]([CH3:29])[CH3:28])=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2[nH]1
Reactant: CC(C)I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2n1
Reaction time: 28 h
Yield: 100.4 %

Procedure:
To a suspension of 5-benzyloxy-6-bromo-4-(trifluoromethyl)-1H-quinolin-2-one (11.7 g, 29.4 mmol) and CsF (17.8 g, 117 mmol) in 150 mL DMF was added isopropyl iodide (19.9 g, 117 mmol). After 28 h, the mixture was partitioned between EtOAc (500 mL) and water (250 mL) and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (200 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to afford 13 g (100%) of 5-benzyloxy-6-bromo-2-isopropoxy-4-(trifluoromethyl)quinoline. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 1H, J=9.0), 7.55–7.65 (m, 3H), 7.38–7.48 (m, 2H), 7.32–7.38 (m, 1H), 7.31 (s, 1H), 5.54 (sept, 1H, J=6.2), 5.06 (s, 2H), 1.42 (d, 6H, J=6.2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CCC2)cc1
Temperature: 100 °C

Procedure:
The mixture of 2.50 g (14.5 mmol) of 4-bromophenol, 2.44 ml (21.7 mmol) of bromomethylcyclobutane and 7.99 g (57.8 mmol) of K2CO3 in 3 ml DMF is stirred at 100° C. over night. The reaction mixture is extracted with water and EtOAc. The organic layer is dried, filtered and the solvent is removed in vacuo.
Reaction SMILES: [C:1]([C:3]1([O:11]C(=O)CCC)[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[OH-].[K+]>CO>[C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2]
Reactant: C#CC1(OC(=O)CCC)CN2CCC1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above oil containing (-)-3-ethynyl-3-butyryloxyquinuclidine was treated with a solution of potassium hydroxide (2.24 g) in methanol (50 ml). The mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and deionised water (2 ml) was added to the residue to give a solid. The solid was collected by filtration, washed with water (2×2 ml) and dried under vacuum over phosporus pentoxide to give (-)-3-ethynyl-3-hydroxyquinuclidine (611 mg) as a solid, m.p. 199°-202° C., [α]19D =-56.1° (C=1.02, methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:38]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.120 g, 0.212 mmol) and ammonia (7N solution in MeOH, 4.54 mL, 31.7 mmol) the title compound was obtained as a white solid (71 mg, 0.13 mmol, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.45-7.71 (m, 3H), 7.34-7.45 (m, 2H), 7.23-7.34 (m, 1H), 6.80 (s, 2H), 6.19 (d, J=5.1 Hz, 1H), 3.88-4.03 (m, 2H), 3.40-3.56 (m, 2H), 3.21-3.31 (m, 1H), 1.92-2.07 (m, 2H), 1.63-1.82 (m, 2H). MS (ESI): 548.11 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.Cl[P:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[N:13][P:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)P(Cl)C(C)C
Reactant: CN(C)CCNC(=N)c1ccccc1
Agent: [Li]CCCC
Product: CC(C)P(N=C(NCCN(C)C)c1ccccc1)C(C)C

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 0.956 g of N1-(2-(dimethylamino)ethyl)benzamidine (Amidine XII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.52 g, 99%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH2:9]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18])[CH:10]=[CH2:11].[CH3:19][O:20]C(Cl)Cl>C(Cl)Cl>[CH2:9]([N:12]1[CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=[C:13]1[C:17]#[N:18])[CH:10]=[CH2:11]
Reactant: COC(Cl)Cl
Reactant: C=CCn1cccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: C=CCn1cc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 100 mL flask charged with AlCl3 (3.3 g, 25 mmol, 2.5 equiv.) and 35 mL of dry CH2Cl2 was added 2 mL of nitromethane. The mixture was cooled to 0° C. and a solution of 1-allyl-1H-pyrrole-2-carbonitrile (1.3 g, 10 mmol, 1 equiv.) in 5 mL of CH2Cl2 was added followed by a solution of dichloromethyl methyl ether in 10 mL of CH2Cl2 dropwise. After 30 minutes, the reaction was warmed to room temperature, stirred for 1.5 hours, poured over 100 mL of ice water, and the organic layer was separated. The organic layers were washed with 30 mL of 3M HCl, 30 mL of water, 18% aqueous sodium sulfite, filtered through CELITE® filter aid and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc-hexanes (5-40% gradient) to provide 1.25 g (78%) of 1-allyl-4-formyl-1H-pyrrole-2-carbonitrile as a yellow oil.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[N:10]1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][N:9]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[N:10]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution of 6.85 g (0.0185 mol) of 1-t-butoxycarbonylmethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole in 100 ml of trifluoroacetic acid is stirred for 16 h at room temperature. The reaction mixture is poured onto 300 cm3 of an ice/water mixture. The insoluble material is recovered by filtration, washed with heptane and dried. We obtained 5.65 g of 1-carboxymethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[BH4-].[Na+].C(Br)(Br)(Br)[Br:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH2:7][Br:19])[CH:9]=1
Reactant: COc1c(C=O)cc(Br)cc1C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COc1c(CBr)cc(Br)cc1C(C)(C)C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 5-bromo-3-tert-butyl-2-methoxybenzaldehyde (0.30 g, 1.1 mmol; CASRN 417715-87-8) in EtOH (5 mL) at 0° C. was added NaBH4 (0.042 g, 1.1 mmol). The mixture was stirred for 1 h, and partitioned between 1N HCl and Et2O. The ether layer was evaporated, and the crude benzyl alcohol was dissolved in DCM and treated sequentially with CBr4 (0.55 g, 1.7 mmol) and PPh3 (0.45 g, 1.7 mmol). After stirring 2 h at RT, the reaction mixture was concentrated, and the crude product was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.34 g (90%) 5-bromo-1-bromomethyl-3-tert-butyl-2-methoxybenzene (114).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=2)[N:33]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH:26][C:28]4[CH:29]=[CH:30][C:31]5[N:32]([CH:34]=[C:35]([C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=5)[N:33]=4)[CH2:19][CH2:18]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC2c3ccccc3CCc3ccccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC4c5ccccc5CCc5ccccc54)CC3)ccc2n1
Temperature: 170 °C
Reaction time: 7 h
Yield: 24.3 %

Procedure:
1.69 g of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-oxy)-1-piperidinepropanamine and 645 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were dissolved in 3 ml of 1-methyl-2-pyrrolidone, followed by stirring in an oil bath (170° C.) for 7 hours. After cooling, saturated aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with water and saturated saline and dried with magnesium sulfate. The solution was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, the residue was subjected to silica gel column chromatography again and eluted with dichloromethane:methanol:triethylamine (100:1:2). The desired fraction was collected and concentrated to yield 340 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[C:13]([C:19](O)=[O:20])[NH:14]3)=[CH:6][CH:5]=1)[CH3:2].Cl.Cl.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@@H:33]([N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)[CH3:34])[CH2:28][CH2:27]1>>[OH:41][CH:38]1[CH2:37][CH2:36][N:35]([C@@H:33]([CH3:34])[CH2:32][N:29]2[CH2:28][CH2:27][CH:26]([NH:25][C:19]([C:13]3[NH:14][C:15]4[C:11]([CH:12]=3)=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=3)[CH:18]=[CH:17][CH:16]=4)=[O:20])[CH2:31][CH2:30]2)[CH2:40][CH2:39]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: CCOc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Agent: Cl
Product: CCOc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C[C@H](C)N5CCC(O)CC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-ethoxy-phenyl)-1H-indole-2-carboxylic acid, (preparation analogously to 128, see example 141) and amine 50.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.0 g, 3.6 mmol) was dissolved in N,N-dimethylformamide (5 mL). α-Bromo-p-tolunitrile (0.85 g, 4.3 mmol) was added followed by K2CO3 (0.59 g, 4.3 mmol). The resulting mixture was heated to 80° C. for 16 h. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate (3×100 ml). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (0.65 g, 46%). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 2H), 7.41-7.31 (m, 7H), 7.23 (d, J=7.6 Hz, 1H), 6.11 (d, J=8.0 Hz, 1H), 5.24 (s, 2H), 5.18 (s, 2H). ES HRMS m/z 395.0404 (M+H C20H15BrN2O2 requires 395.0390).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: N#Cc1cn[nH]c1N
Reactant: CN(C)C=CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Yield: 71.3 %

Procedure:
A mixture of 0.1 g (0.93 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.26 g (0.93 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 217 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (yield 71%; m.p.=193-195° C.).
Reaction SMILES: [C:1]([O:4][C:5]([C:9](=[O:19])[CH2:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]OC)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:9](=[O:19])[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC=C(OC(C)=O)C(=O)CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1coc(-c2ccccc2)cc1=O

Procedure:
To a solution of crude 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate (3.5 mmol) in toluene (35 mL) was added pyridinium j-toluenesulfonate (130 mg, 0.5 mmol). The reaction mixture was heated at reflux under a nitrogen atmosphere for 1 h before being cooled and concentrated under reduced pressure and purified by flash chromatography (80 g Si02, 0-100% ethyl acetate/hexanes gradient elution) to provide 4-oxo-6-phenyl-4H-pyran-3-yl acetate. LC/MS (M+H)+ 231.
Reaction SMILES: [CH:1]([C:3]1([CH2:26][CH2:27][CH3:28])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.O.NN.[OH-].[K+]>C(O)COCCO>[CH3:1][C:3]1([CH2:26][CH2:27][CH3:28])[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CCCCCc1ccc(-c2ccc(C3CCC(C=O)(CCC)CC3)cc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc(-c2ccc(C3CCC(C)(CCC)CC3)cc2)cc1
Reaction time: 12 h

Procedure:
A mixture of 3.7 g (0.01 mole) of 4-(4-formyl-4-propylcyclohexyl)-4'-pentylbiphenyl (Example 2), 40 ml of diethylene glycol, 15 ml of 90% hydrazine hydrate and 5.5 g of potassium hydroxide is heated and the hydrazine and water are distilled off until the temperature has risen to about 230° C. The reaction mixture is then boiled for 12 hours and, when cold, 200 ml of water are subsequently added. After customary working up, 4-(4-methyl-4-propylcyclohexyl)-4'-pentylbiphenyl is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCC2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
2.50 g (14.5 mmol) 4-bromophenol, 2.05 mL (21.7 mmol) cyclobutylbromide and 7.99 g (57.8 mmol) K2CO3 are dissolved in 25 mL DMF and stirred at 120° C. for 12 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:16]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:17])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(=O)c1cnc(OCC(F)(F)C(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)C(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (880 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (820 mg, 3.1 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.