Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:13]=[C:12]([S:14][CH2:15][S:16]([NH:19][CH:20]2[CH2:22][CH2:21]2)(=[O:18])=[O:17])[C:11]([CH:23]=O)=[C:10]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])[N:9]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N>ClCCl>[CH:20]1([NH:19][S:16]([C:15]2[S:14][C:12]3[N:13]=[C:8]([NH2:7])[N:9]=[C:10]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[C:11]=3[CH:23]=2)(=[O:18])=[O:17])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2nc(N)nc(SCS(=O)(=O)NC3CC3)c2C=O)c(C)c1
Agent: N
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(-c2nc(N)nc3sc(S(=O)(=O)NC4CC4)cc23)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyridine was added to a suspension of C-[2-Amino-6-(2,4-dimethylphenyl)-5-formyl-pyrimidin-4-ylsulphanyl]-N-cyclopropyl-methane sulphonamide in dichloromethane and the mixture cooled, ice/water. Trifluoroacetic anhydride was added and the mixture stirred for ˜2 hrs and heated under reflux for ˜24 hrs. The resulting dark red solution was allowed to cool and aqueous ammonia (0.880) added and the mixture stirred for ˜30 mins. Dichloromethane was added and the mixture washed with dilute hydrochloric acid, water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a red/orange solid. The crude solid was purified by preparative HPLC.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:6]([S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:27].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>C1C=CC=CC=1>[C:34]1(=[O:43])[N:1]([CH2:2][C@H:3]2[C@H:6]([S:7][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:5][C:4]2=[O:27])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: NC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: O=C1N[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Yield: 92.7 %

Procedure:
A solution of trans 3-aminomethyl-4-tritylthio-2-azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 ml) was heated under reflux for 15 h. The solvent was evaporated in vacuo and the residue crystallized from ether to give (17.4 g (93%) of the title compound; mp 172°-3° C.; Anal. calcd for C31H24N2O3S: C 73.78, H 4.79, N 5.55, found: C 73.92, H 4.87, N 5.49; ir (CHCl3) νmax : 1770 and 1715 cm-1 ; 1Hmr (CDCl3) δ: 7.8 (4H, m), 7.3 (15H, m), 4.45 (1H, d, J=2 Hz), 3.3-4.1 (3H, m) and 3.3-4.6 ppm (1H, m).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18].[C-:31]#[N:32].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[C:1]1([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]([O:13][C:21](=[O:22])[CH:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:17]([CH3:19])[CH3:18])[C:31]#[N:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(C=Cc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(C=Cc2ccccc2)c1)c1ccc(Cl)cc1
Yield: 69.8 %

Procedure:
4.16 g (0.02 mol) of 3-(2-phenyl-vinyl)-benzaldehyde and 4.62 g (0.02 mol) of α-isoproyl-4-chlorophenyl-acetic acid chloride were added dropwise, together, to a mixture of 1.5 g of sodium cyanide, 2 ml of water, 40 ml of n-hexane and 0.5 g of tetrabutylammonium bromide at 20°-25° C., whilst stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 300 ml of toluene were then added to the reaction mixture, and the mixture was extracted by shaking twice with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by subjecting the product to brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 6 g (69.9% of theory) of α-isopropyl-4-chlorophenylacetic acid 3-(2-phenylvinyl)-α-cyanobenzyl ester were obtained as a yellow oil with the refractive index nD22 : 1.5879 (isomer mixture with a cis-stilbene proportion of about 90%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O:21][C:22]1[C:23]([C:35](=[O:44])[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[C:24]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>O1CCCC1.C(O)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:21][C:22]1[C:23]([C:35](=[O:44])[C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[C:24]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1C(=O)c1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC)cc(O)c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Triphenylphosphine (0.22 g, 0.84 mmol) and palladium (II) acetate (47 mg, 0.21 mmol) were dissolved in tetrahydrofuran (2.0 mL) in an atmosphere of argon, followed by stirring at room temperature for 10 minutes. To the reaction mixture was added a solution of methyl 3,5-dimethoxy-2-(4-methoxybenzoyl)phenylacetate (0.78 g, 2.1 mmol) obtained in Example 26, Step 1 in formic acid (20 mL), followed by stirring at 80° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain Compound 27 (0.39 g, 56%).
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8]C=1C#N.[CH2:16]([OH:19])[CH2:17]O>O>[CH3:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:17]=1[C:16]([OH:19])=[O:1]
Reactant: Cc1cc(C(F)(F)F)ccc1C#N
Reactant: OCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 125 °C

Procedure:
Potassium hydroxide (15.7 g, 0.28 mole) and 15 mL of water were added as a solution to a stirred, heterogeneous mixture of 2-methyl-4-(trifluoromethyl)benzonitrile (13 g, 70 mmol) and 135 mL of ethylene glycol. The reaction mixture was heated at 120-130° C. for 20 hours and allowed to cool to room temperature. The dark solution was poured into 800 mL of water and filtered through celite. The filtrate was washed with ether and then the aqueous was acidified with concentrated hydrochloric acid. This aqueous phase was extracted three times with ethyl acetate, the organic extracts were combined, dried over magnesium sulfate and evaporated under reduced pressure to afford the title compound as a tan solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[N:15]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(F)c(-c2cccs2)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCCC2)c(-c2cccs2)c1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Ex-20B: A solution of 4-fluoro-3-(thiophen-2-yl)-benzaldehyde (1.11 g, 5.38 mmol) from Ex-20A and pyrrolidine (13.0 g, 183.0 mmol) in dimethylformamide (30 mL) was treated with solid K2CO3 (1.7 g, 12.3 mmol), and the resulting mixture was stirred at reflux for 1 week. Upon cooling to room temperature, the reaction was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 2:1) gave 400 mg (29%) of the desired 4-pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde product as a yellow oil. 1H-NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.71–7.74 (m, 2H), 7.30 (dd, 1H, J=5.1 and 1.6 Hz), 7.02 (dd, 1H, J=5.1 and 3.7 Hz), 6.96 (m, 1H), 6.81 (d, 1H, J=10.1 Hz), 3.15 (m, 4H), 1.84 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:15]=[N:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]12
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)[nH]c2ccccc2c1=O
Product: CCOC(=O)c1ncn2c3ccccc3c(=O)n(C)c12

Procedure:
M.p. 211.4°-211.8° C. by reaction between 3-methyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[C:9]([S:11][CH:12](C)C)[C:8]([S:15][CH:16](C)C)=[CH:7][C:6]=1[S:19][CH:20](C)C)(C)C.[Na].CI>N1C=CC=CC=1>[CH3:20][S:19][C:6]1[CH:7]=[C:8]([S:15][CH3:16])[C:9]([S:11][CH3:12])=[CH:10][C:5]=1[S:4][CH3:1]
Reactant: CC(C)Sc1cc(SC(C)C)c(SC(C)C)cc1SC(C)C
Agent: [Na]
Solvent: CI
Solvent: c1ccncc1
Product: CSc1cc(SC)c(SC)cc1SC
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
Into a 3-neck 1 liter flask equipped with a thermometer, magnetic stirring bar, and gas inlet and outlet tubes was placed a solution of 25 g (66.72 millimoles) of the product of Example 1 in 300 ml of dry pyridine. The mixture was heated rapidly to 105°-110° C. and 8.29 g of Na pellets (360 millimoles) were added rapidly against a nitrogen flow. The reaction mixture was maintained below reflux but above 100° C. for 1 hour until all of the sodium had reacted. The mixture was then cooled to 10° C. and methyl iodide (24 ml) was added slowly by means of a syringe. The resulting mixture was stirred for 40 minutes and quenched with 350 ml of saturated aqueous NaCl. Water was then added to form a dilute suspension which was filtered under suction and washed copiously with water to yield a yellow, crystalline solid. The solid was washed with 150 ml of -10° C. methanol to yield 11.5 g (66%) of white product; mp:127°-129° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([S-:11])[CH3:10].[Na+]>CN(C=O)C.O>[CH2:9]([S:11][CH:3]([CH3:4])[CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CC[S-]
Reactant: C/C=C/C(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)SCC
Temperature: 25 °C
Yield: 14 %

Procedure:
Ethyl crotonate (commercially available, for example, from Aldrich) (2.37 g, 20.8 mmol) was dissolved in DMF (60 ml) and stirred at room temperature. Sodium ethanethiolate (commercially available, for example, from Aldrich) (1.66 g, 19.7 mmol) was added portionwise. On completion of the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic solutions were dried (MgSO4), and concentrated in vacuo, for an extensive period of time to remove excess DMF. The residue was applied to a silica cartridge (50 g), eluting with a gradient of EtOAc-cyclohexane (2%-6%) to give the title compound as a colourless oil (527 mg, 14%): 1H NMR δ (CDCl3) 4.16 (2H, q, J=9 Hz), 3.28-3.18 (1H, m), 2.66-2.55 (3H, m), 2.44 (1H, dd, J=15, 8 Hz), 1.33 (3H, d, J=7 Hz), 1.31-1.23 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][CH:28]([F:30])[F:29])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][CH:28]([F:30])[F:29])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4-difluoro-butyramide (180 mg, 0.35 mmol), methanol (5 mL) and p-toluenesulfonic acid hydrate (20 mg). The mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire, 40 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4,4-difluoro-butyramide (109 mg, 66%) as a white foam: HR-ES-MS m/z calculated for C20H21N4O5ClF2 [M+Na]+ 493.1061, observed 493.1057; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.43 (m, 2H), 3.19-3.31 (m, 2H), 3.76 (br. s., 1H), 3.85 (dd, J=13.3, 7.8 Hz, 1H), 4.08 (dd, J=13.3, 3.8 Hz, 1H), 4.35 (d, J=18.4 Hz, 1H), 4.45 (d, J=18.4 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.81 (s, 1H), 4.93 (d, J=5.1 Hz, 1H), 4.94-5.02 (m, 1H), 6.10 (tt, J=56.1, 4.2 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.31-7.39 (m, 1H), 7.41-7.52 (m, 2H), 7.53 (d, J=2.1 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:1].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[C:14]([CH3:20])[CH:15]=1
Reactant: CNc1ccccc1
Reactant: Cc1cc(Cl)ccc1Nc1nc(Cl)c2ccccc2n1
Product: Cc1cc(Cl)ccc1Nc1nc(N(C)c2ccccc2)c2ccccc2n1
Product: Cl
Yield: 12.6 %

Procedure:
Substituting 4-chloro-2-[(4-chloro-2-methylphenyl)amino]quinazoline (1.0 g) and N-methylaniline (1.0 g) for the reagents in Example 33C and using analogous conditions and work-up gave the title compound (0.17 g), m.p. 263°-265°, after two recrystallisations from ethanol/diethyl ether.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O1CCOCC1>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)C[C@@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@H](CC(N)=O)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
D-asparagine (13.2 g, 100.0 mmol) is dissolved in dioxane 1,75.0 mL) and water (125.0 mL), triethylamine (21.0 mL, 150.0 mmol) is added, and the solution is cooled to 0° C. To this solution is added 4-methoxybenzenesulfonyl chloride (22.7 g, 110.0 mmol) over 10 minutes. The reaction is warmed to room temperature and stirred for 3 days. The precipitate is then filtered off, the filtrate is acidified to pH=~4, and extracted well with ethyl acetate. A first crop of pure product precipitates from the ethyl acetate and is collected by filtration. A second crop is obtained by evaporating off the ethyl acetate, and rinsing the solid obtained with water to remove inorganic salts. The two crops are combined to give N-[4-methoxybenzenesulfonyl]-(D)-asparagine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]2[O:6][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
2-Chloro-4-fluoro-5-nitrobenzoic acid (4.00 g, 18.2 mmol), 2-aminophenol (2.09 g, 20.1 mmol), CHCl3 (80 mL), and WSC (3.84 g, 20.0 mmol) were added together and stirred at room temperature for 2 hours. Water was added, and this was extracted with chloroform/acetone (3:1). After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a toluene (80 mL) solution of the solid obtained was added p-toluenesulfonic acid monohydrate (0.18 g, 1.8 mmol), and this was heated to reflux for 40 hours. After the reaction solution was concentrated, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (1.40 g, 26% yield) as yellowish-brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1cccc(CCCCc2ccccc2OCc2ccccc2)c1
Yield: 86.4 %

Procedure:
3.50 g of this 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butadiene were dissolved in 125 ml of a 4:1 by volume mixture of tetrahydrofuran and ethanol. The resulting solution was stirred for 4 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal, whilst ice-cooling. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.06 g (yield 86%) of 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butane as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[N:34]=[C:33]([CH:40]=O)[CH:32]=2)=[CH:27][CH:26]=1>>[C:36]([N:35]1[C:31]([C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=2)=[CH:32][C:33]([CH2:40][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:34]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: CC(C)(C)n1nc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1-c1ccc(Cl)cc1
Yield: 57 %

Procedure:
Compound 100 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH:8]2[CH:10]([OH:11])[CH:4]([CH2:5][N:6]([CH3:12])[CH2:7]2)[CH2:3]1.[CH:13](Br)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:27]([O-:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([O-:32])=[O:31]>CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:12][N:6]1[CH2:5][CH:4]2[CH:10]([O:11][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:8]([CH2:9][N:2]([CH3:1])[CH2:3]2)[CH2:7]1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CN1CC2CN(C)CC(C1)C2O
Solvent: CO
Product: CN1CC2CN(C)CC(C1)C2OC(c1ccccc1)c1ccccc1
Product: O=C(O)/C=C/C(=O)O
Yield: 50 %

Procedure:
10 g of 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-ol are reacted with 24.7 g of benzhydryl bromide as described in Example 1. The product is converted into its fumarate, the salt is dissolved in methanol, and precipitated with methylethyl-ketone. 3,7-Dimethyl-9-benzhydryloxy-3,7-diazabicyclo[3.3.1]nonane fumarate is obtained with a yield of 50%; m.p.: 200°-201° C.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C)C=O.C(OCC)(=O)C>[O:24]1[CH2:25][CH2:26][N:2]([C:3]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:22][CH2:23]1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)C1(N)CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(N2CCOCC2)CCCCC1

Procedure:
Ethyl 1-aminocyclohexancarboxylate hydrogen chloride (5.800 g), triethylamine (13.62 mL) and 1-bromo-2-(2-bromoethoxy)ethane (4.21 mL) were stirred together in N,N-dimethylformamide (50 mL) at 95° C. overnight. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 5% to 25% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:15])[C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=O)=[O:7])=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.C(O)(=O)C.[B-]C#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)c1ccc(Cl)cc1
Reactant: OC1CCNCC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@@H](CN1CCC(O)CC1)N(C)C(=O)c1ccc(Cl)cc1
Yield: 2.5 %

Procedure:
(S)-4-Chloro-N-methyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.2) (0.12 g, 0.47 mmol) dissolved in DCM was added to piperidin-4-ol (72 mg, 0.71 mmol) and acetic acid (0.135 mL, 2.36 mmol) in MeOH (2 mL). Sodium cyanotrihydroborate (0.059 g, 0.95 mmol) was added and the resultant mixture was stirred at rt over night. The solvent was removed and the residue diluted with DCM. The organic phase was washed with LiOH (aq., 3 mL, 1M), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak IC 5 μm 20×250 mm column and Heptan/EtOH/TEA 60/40/0.1, as mobile phase to give the title compound (4 mg, 2.5%). Enantiomeric excess: 99.8%. Mixture of rotamers: (600 MHz, CD3OD) δ 0.87, 0.92, 0.96, 1.03, 1.42-1.62, 1.71-1.90, 1.92-2.03, 2.14-2.21, 2.26-2.38, 2.42-2.50, 2.55-2.79, 2.88-2.93, 3.01, 3.28-3.38, 3.52-3.64, 4.43-4.56, 7.37-7.41, 7.43-7.52.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:33][CH2:32][CH2:31][NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: Nc1nc(NCCNc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 363 (M+Na+, 20), 341 (M+H+, 100).