Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:14][C:13](=[O:15])[C:12]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][C:13](=[O:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CC(CCOCc2ccccc2)C1
Temperature: 60 °C

Procedure:
Zinc dust was added to a solution of 3-(benzyloxyethyl)-2,2-dichlorocyclobutanone in glacial acetic acid at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane:EtOAc=6:1). 1H NMR (CDCl3, 400 MHz): δ 1.85-1.90 (q, J=6.0, 2H), 2.45-2.56 (m, 1H), 2.66-2.74 (m, 2H), 3.07-3.15 (m, 2H), 3.48-3.51 (t, J=6.0, 2H), 4.48 (s, 2H), 7.24-7.35 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 21.29, 36.02, 52.56, 68.85, 72.99, 127.56, 127.62, 128.40, 138.33, 208.25. Rf=0.45 (Hexane:EtOAc=3:1). IR (neat) νmax 3054, 2927, 2856, 1779, 1266, 737, 704.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[C:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].O>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7]1[C:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:9]([C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Concentrated nitric acid (0.62 ml) was added dropwise to an ice cooled solution of methyl 3,4-dimethoxy-2-methanesulfonyloxybenzoate (1.94 g, 0.0067 mol) in acetic anhydride (3 ml) and the reaction stirred for 1 hour. Water (20 ml) was carefully added, and the resulting precipitate filtered and washed with further water. Drying under suction filtration gave the subtitle compound as a white solid (1.94 g, 86%). 1H-NMR (CDCl3): Γ=3.34 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 4.18 (3H, s), 7.68 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+].Cl.[NH:33]1[CH2:36][CH:35]([C:37]([O:39]C)=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:33]4[CH2:34][CH:35]([C:37]([OH:39])=[O:38])[CH2:36]4)[CH:22]=[CH:23][CH:24]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylbenzaldehyde (D53) (100 mg) in dichloromethane (DCM) (8 mL) and methanol (8.00 mL) was added sodium acetate (31.8 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (58.8 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (110 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.58 mL) was added, the reaction solution was heated to 80° C. for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=2-3. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (E25) (40 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.28 (6H, d), 2.87 (2H, q), 3.19 (3H, m), 3.34 (2H, m), 3.60 (2H, s), 4.78 (1H, m), 7.23 (1H, t), 7.31 (1H, d), 7.38 (1H, d), 7.64 (1H, d), 7.94 (1H, dd), 8.07 (1H, d). δF (DMSO-d6, 376 MHz): −73.4. MS (ES): C24H26ClN3O3S requires 471. found 472.2 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: COc1ccc(C=O)cn1
Product: COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-methoxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-methoxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)=[CH:13][C:12]=1[F:18]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1cc(C)nc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)nc(Oc2ccc(Br)c(F)c2)c1
Temperature: 150 °C
Yield: 68.8 %

Procedure:
A mixture of 2-bromo-4,6-dimethylpyridine (1 g, 5.4 mmol), 4-bromo-3-fluoro-phenol (1.03 g, 5.4 mmol), and potassium carbonate (0.89 g, 6.4 mmol) was heated at 150° C. (oil bath temperature) in a sealed tube for 7 days. After cooling to room temperature the mixture was diluted with DCM and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 7 (1.1 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1.O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][CH:40]([SH:42])[CH3:41]>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([S:42][CH:40]([CH3:41])[CH3:39])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)S
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)SC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 6 h
Yield: 41.2 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid was dissolved in 30 ml of dichloromethane, and the resulting solution was cooled to below 10° C. on the water bath. Then, 2.1 g of N,N'-dicyclohexylcarbodiimide (DCC) was added, followed by addition of 0.8 g of 2-propanethiol. The reaction was allowed to proceed at room temperature for about 6 hours. After completion of the reaction, the formed solid substance was filtered off, and the filtrate was subjected to evaporation-removal of the solvent under reduced pressure to obtain a crude product. The thus obtained crude product was subjected to purification by the silica gel column chromatography (elution was performed by using a mixed solvent of toluene and n-hexane). As a result, there was obtained 1.6 g of S-1-methylethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-phenylthioacetate.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:21][N:22]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[N:21][N:22]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCOCC3)o2)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1N(O)[C@@H]2CC[C@@H](c3nnc(N4CCOCC4)o3)N1C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-2-(5-morpholino-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.12 g) and 10% Pd/C (70 mg) in THF (5 mL) was stirred at rt under H2 atmosphere for 1-2 hrs. The reaction mixture was then filtered and concentrated to afford (2S,5R)-6-hydroxy-2-(5-morpholino-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (83 mg, 90%), which was used directly in the next step. ESI-MS (EI+, m/z): 296 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccnc3ccccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Sc2ccnc3ccccc23)cc1
Yield: 58.3 %

Procedure:
4-(4-nitrophenylthio)quinoline (17.0 mmoles, 4.9 g) was dissolved in 200 ml ethanol and hydrogenated over 5 g of 5% Pd/C at 40 psi for 1 hr at room temperature. The solution was filtered through celite and the solvent removed to yield 4-(4-aminophenylthio)quinoline 2.5 g, 58%. Mass spec (FD) 253. Calculated for C15H12N2S: C, 71.40; H, 4.79, N, 11.10. Found: C, 1.12; H, 4.93 N, 10.88.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([CH2:27][C:28]([OH:30])=[O:29])=[C:19]2[CH3:31])(=[O:17])=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#N.[F:32]C1C=C(S(N2C3=NC=CC=C3C(CC(O)=O)=C2C)(=O)=O)C=CC=1F>>[F:32][C:3]1[CH:4]=[C:5]([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([CH2:27][C:28]([OH:30])=[O:29])=[C:19]2[CH3:31])(=[O:16])=[O:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(F)c(F)c1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(C#N)c1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(F)c1

Procedure:
The titled compound is prepared analogously to [1-(3-cyano-4-morpholin-4-yl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Intermediate 151b) by replacing [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester with [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (Example 59) and by heating using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 60-80° C. for 4 hours. (MH+ 434)
Reaction SMILES: [OH:1][CH:2]([CH:23]=[CH2:24])[CH:3]([NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])[C:4](OCC)=[O:5].[CH3:25][NH2:26]>CO>[OH:1][CH:2]([CH:23]=[CH2:24])[CH:3]([NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])[C:4](=[O:5])[NH:26][CH3:25]
Reactant: C=CC(O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)OCC
Reactant: CN
Solvent: CO
Product: C=CC(O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)NC

Procedure:
4.5 g (12.9 mmol) of ethyl 3-hydroxy-2-(4-fluoro-2-trifluoromethylbenzoylamino)pent-4-enoate were dissolved in methanol. With ice cooling methylamine gas was introduced for 2 h. The reaction solution was then concentrated and washed. This gave 3.1 g (80% of theory) of the title compound as a colorless solid (diastereomer ratio 2:1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1B(O)O>>[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1F
Reactant: Cc1ccc(F)c(Br)n1
Product: COc1ccc(F)c(-c2nc(C)ccc2F)c1F
Yield: 60 %

Procedure:
Method 4 was followed using 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) and 2,6-difluoro-3-methoxyphenylboronic acid (2.0 equiv.) to give 2-(2,6-difluoro-3-methoxyphenyl)-3-fluoro-6-methylpyridine in 60% yield. LC/MS=254.1 (M+H), Rt=0.85 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:46])[C:37](=[O:45])[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][C:37]([N:36]([CH3:46])[CH3:35])=[O:45])[CH2:44][CH2:43]3)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC)n1
Product: CCOc1ncc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N(C)C)CC2)c(OCC)n1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 8) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C32H37N7O4Cl2 [(M+H)+] 654.2357, observed 654.2355.
Reaction SMILES: BrC1N=C(C(N2CCN(C(C3N=CN(C4C=CC=C(Cl)C=4)N=3)=O)C(C)(C)C2)=O)C=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH:43]=[N:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([C:52]([C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([C:60]5[CH2:61][CH2:62]O[CH2:64][CH:65]=5)[N:55]=4)=[O:53])[CH2:48][C:47]3([CH3:67])[CH3:66])=[O:45])=[N:40]2)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH:43]=[N:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([C:52]([C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([C:60]5[CH2:61][CH2:62][CH2:64][CH:65]=5)[N:55]=4)=[O:53])[CH2:48][C:47]3([CH3:67])[CH3:66])=[O:45])=[N:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: CC1(C)CN(C(=O)c2cccc(C3=CCOCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Agent: CC1(C)CN(C(=O)c2cccc(Br)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Product: CC1(C)CN(C(=O)c2cccc(C3=CCCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
This intermediate was prepared from [4-(6-bromo-pyridine-2-carbonyl)-2,2-dimethyl-piperazin-1-yl]-[1-(3-chloro-phenyl)-1H-[1,2,4]triazol-3-yl]-methanone and cyclopenten-1-ylboronic acid ester according to the preparation of [1-(3-chloro-phenyl)-1H-[1,2,4]triazol-3-yl]-[4-[6-(3,6-dihydro-2H-pyran-4-yl)-pyridine-2-carbonyl]-2,2-dimethyl-piperazin-1-yl]-methanone.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][C@@H:9]([O:42][C:43](=[O:45])[CH3:44])[C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([OH:24])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:25]([CH3:41])[CH2:26][CH:27]=[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6]1)(=[O:3])[CH3:2].N1(C2C=CN=CC=2)CCCC1.[CH3:57][C:58]([CH3:64])([CH2:62][CH3:63])[C:59](Cl)=[O:60]>N1C=CC=CC=1.CCOCC.CCCCCC>[C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][C@@H:9]([O:42][C:43](=[O:45])[CH3:44])[C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([O:24][C:59](=[O:60])[C:58]([CH3:64])([CH3:57])[CH2:62][CH3:63])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:25]([CH3:41])[CH2:26][CH:27]=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](OC(C)=O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H](C(C)CC=C(c3ccccc3)c3ccccc3)CC[C@@H]12
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2[C@@H]([C@H](OC(C)=O)C[C@@H]3C[C@H](OC(C)=O)CC[C@@]32C)[C@@H]2CC[C@H](C(C)CC=C(c3ccccc3)c3ccccc3)[C@@]12C
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 3α,7α-diacetoxy-12α-hydroxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (7.6 g), 4-pyrrolidinopyridine (0.184 g) and 2,2-dimethylbutyryl chloride (2.0 g) in pyridine (40 ml) is heated at 110° C. for about 1 hour, additional 2,2-dimethylbutyryl chloride (2.0 g) is added and heating is continued for about 16 hours. The mixture is cooled, diluted with 20% ether in hexane and the organic solution washed with 1.0M hydrochloric acid, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 30% ether in hexane to give the desired product.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][NH:9][CH:10](C)[CH2:11][CH2:12][NH2:13].Cl.[OH-].[Na+]>O>[N:9]12[CH2:2][CH2:6][CH2:7][CH:8]1[NH:13][CH2:12][CH2:11][CH2:10]2
Reactant: CC(CCN)NCCCC1OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C1CNC2CCCN2C1
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In a 500 ml three-necked flask, 41.08 g (0.2 mol) of 3-{3-([1,3]dioxolan-2-yl)propylamino}-1-aminobutane are added to 65 g of 33% strength hydrochloric acid and 100 ml of water and the mixture is stirred vigorously for three hours. It is then neutralized by dropwise addition of 100 ml of 30% strength sodium hydroxide solution, and the neutralized solution is subjected to extraction with CH2Cl2. The organic extracts are dried over sodium carbonate and concentrated. This gives 27.54 g of a reddish liquid. Distillation under a high vacuum (overhead temperature=34° C., p=0.006 mbar) gives 15.87 g of 1,5-diazabicyclo[4.3.0]nonane as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([F:57])[C:51]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][C:51]4[C:52]([F:57])=[CH:53][CH:54]=[C:55]([F:56])[C:50]=4[Cl:49])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reactant: Oc1c(F)ccc(F)c1Cl
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4c(F)ccc(F)c4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E9 and 2-chloro-3,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.22 min, ES+: 831.36.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[Cl:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[Cl:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=1[CH:16]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=BOB=O
Solvent: CCCCN
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)C=Cc1ccc(O)cc1Cl
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
Ethyl acetate (0.8 mL), 2,4-pentanedione (1.03 mL, 10.0 mmol) and boron trioxide (0.63 g, 9.1 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 2-chloro-4-hydroxybenzaldehyde (238 mg, 1.52 mmol) and trimethyl orthoformate (0.17 mL, 1.5 mmol) in 3.0 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (0.80 mL, 7.6 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (3.5 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a yellow crystal (56 mg, 12%).
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:4]#[N:5].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[OH:1][CH2:2][CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:4]#[N:5]
Reactant: Cc1cccc(C)c1C(C#N)=CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(C)c1C(C#N)CO
Reaction time: 2 h

Procedure:
58 g (0.33 mol) of hydroxymethylene-2,6-dimethylphenylacetonitrile are dissolved in 250 ml methanol and combined with 37 g (0.59 mol) of sodium cyanoborohydride. After 2 h, 250 ml of acetic acid are added dropwise, during which time the mixture heats up to 50° C. After the exothermic reaction has died down, the mixture is refluxed for a further 3 h. It is left to cool and the mixture is evaporated down in vacuo. The residue is mixed with 500 g of ice, neutralised with ammonia and extracted twice with 500 ml of ethyl acetate. The combined organic extracts are washed with 100 ml of water. After drying, the solvent is eliminated in vacuo. The residue is further processed from the crude state. 54.1 g (92% of theory) of the title compounds are obtained in the form of an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:29][NH:30][CH3:31]>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:14]([N:30]([CH3:31])[CH3:29])=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Agent: Cl
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N(C)C)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and dimethylamine hydrochloride as starting materials and isolated (31 mg, 57%); MS (ESI, m/z): 416.6 (M+H+).