Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]1(O)[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[NH:17][C:16]1=[O:28].[F:30][C@H:31]1[CH2:35][NH:34][C@H:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]1([N:34]2[CH2:35][C@H:31]([F:30])[CH2:32][C@H:33]2[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[NH:17][C:16]1=[O:28]
Reactant: COc1ccc(C2(O)C(=O)Nc3cc(OC)c(OC)cc32)c(OC)c1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(N3C[C@H](F)C[C@H]3C(=O)N(C)C)C(=O)Nc3cc(OC)c(OC)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
362 mL of thionyl chloride was added at −78° C. and under a nitrogen gas flow to a 14 mL chloroform solution of 700 mg of the compound obtained in step 9-1 and 240 mg of pyridine, and the reaction mixture was stirred for 30 minutes at the same temperature. After this, a 5 mL chloroform solution of 485 mg of the compound obtained in step 9-2 and 2.05 g of triethylamine was added over a period of 2 minutes, after which the temperature was raised to room temperature and the reaction mixture was stirred for 15 hours at that temperature. 50 mL of ethyl acetate and 30 mL of a 5% potassium carbonate aqueous solution were added to the reaction solution, and the reaction mixture was stirred for 5 minutes. After liquid separation, the aqueous layer was extracted with ethyl acetate (30 mL×2), the combined organic layer was washed with saturated brine and dried with magnesium sulfate, the drying agent was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel 60N, mobile phase: ethyl acetate/acetone=1/1; v/v) to obtain 697 mg of mixture of diastereoisomers of the titled compound (reddish-brown, amorphous).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:15]([O:18][CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:29])[CH:24]2[NH2:28])[C:21]=1[C:30]([OH:32])=[O:31])(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:18][CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:29])[CH:24]2[NH:28][C:12](=[O:13])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][CH:7]=2)[C:21]=1[C:30]([OH:32])=[O:31])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A mixture of p-azidomethylphenylacetyl chloride (1.38 g) and 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.38 g) in 250 ml of ethyl acetate was refluxed for 45 minutes. The solvent was removed under vacuum at 35° C. yielding a solid residue which was purified by chromotography using 200 g of silica gel eluting with benzene-acetone to give 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid. M.P. 135°-136° C.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].[CH:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](OC2C=CC=CC=2)=[N:14][C:15]#[N:16])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>CC#N>[F:2][CH2:3][CH2:4][NH:5][C:13](=[N:14][C:15]#[N:16])[O:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: NCCF
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CN=C(NCCF)Oc1ccccc1
Reaction time: 14 h

Procedure:
Fluoroethyl amine hydrochloride (5.50 g, 90% purity, 49.75 mmol) was added to a solution of diphenyl cyanocarbonimidate (11.84 g, 49.70 mmol) in CH3CN, followed by addition of diisopropylethyl amine (17.30 mL, 99.32 mmol). After stirring for 14 hours, the reaction mixture was concentrated and the residue was taken up in EtOAc. The organic layer was washed sequentially with H2O (3×75 mL) and aq 2N KOH (3×100 mL), then concentrated to give a viscous oil, which was solidified upon standing at room temperature. Recrystallization from ether gave the desired 1-(2-fluoro-ethyl)-2-phenyl-3-cyanoisourea intermediate. A portion of this intermediate was mixed with an appropriate amine in CH3CN. The resulting reaction mixture was refluxed for 14 hours. After cooling to room temperature, the mixture was diluted with EtOAc and the resulting organic phase was washed with H2O (3×75 mL) and then concentrated. The residue was purified by column chromatography using hex:EtOAc (2:3) as eluant to give a semi-pure product. Recrystallization from EtOAc afforded the final pure cyanoguanidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH:12]=[C:13]([N+:15]([O-])=O)[CH3:14])[C:4]=1[CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)(=O)C>[CH3:11][O:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:18])[C:5]=1[CH2:12][CH:13]([NH2:15])[CH3:14]
Reactant: COc1cc(C)c(OC)c(C=C(C)[N+](=O)[O-])c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(OC)c(CC(C)N)c1C
Yield: 94.5 %

Procedure:
To a solution of 1,4-dimethoxy-2,5-dimethyl-3-(2-nitro-1-propenyl)benzene (5.0 g, 19.9 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (4.0 g, 105.4 mmol) with cooling on ice, and the reaction mixture was heated under reflux for 6 hours. To the reaction mixture was added HIFLO-SUPERCEL (trade name) (5 g), and then water was added dropwise (1.5 ml) with cooling on ice. The resultant mixture was suspended in ethyl acetate, filtered and concentrated under reduced pressure to obtain 4.2 g of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Br)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (i) using 4-bromo-3-fluorobenzenesulfonyl chloride and benzene.
Reaction SMILES: [OH:1]O.[O:3]1[CH2:14][CH:4]1[CH2:5][S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Na+].[Cl-]>O.CO>[O:3]1[CH2:14][CH:4]1[CH2:5][S:6]([C:7]1[N:8]=[CH:9][C:10]([Cl:13])=[CH:11][N:12]=1)=[O:1]
Reactant: OO
Reactant: Clc1cnc(SCC2CO2)nc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(CC1CO1)c1ncc(Cl)cn1
Yield: 24 %

Procedure:
A mixture of 35% H2O2 (1.9 mmol) and SeO2 (1.9 mmol) in water (1.5 ml H2O) was added to a solution of 2-(2,3-epoxypropyl)thio-5-chloropyrimidine (1.9 mmol) in methanol (7 ml). The mixture was stirred at room temperature for 4 h before saturated NaCl aq. (30 ml) was added and the mixture extracted with chloroform (3×15 ml). The dried (MgSO4) chloroform solution was evaporated and the residue purified by preparative TLC on silica gel using CHCl3 : EtOH (95:5); yield 24%, m.p. 92° C. 1H NMR (CDCl3): δ2.4-3.6 (5H, m), 8.84 (H-4, H-6). IR (KBr): 1050 cm-1 (SO).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]/[C:6](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7]\[C:8]([O:10]C)=O.CC(C)([O-])C.[K+]>C1COCC1>[OH:10][C:8]1[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:5][C:4]=1[C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[CH3:1]
Reactant: COC(=O)/C=C(\SCc1ccccc1C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1sc(-c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl Z-3-(2'-methylbenzylthio)-3-phenyl-2-propenoate (900 mg, 3.02 mmol) in THF (8 mL) was added dropwise through a double-ended needle to a solution of potassium tert-butoxide (1.02 g, 9.09 mmol) in THF (12 mL). An additional 2 mL of THF was used to rinse the ester into the reaction. The reaction was stirred 30 minutes at 25° C., then cooled in an ice bath and quenched by the addition of 7.0 mL of 2.0 N aqueous hydrochloric acid. The reaction was poured into 50 mL of saturated aqueous sodium chloride solution and extracted with 2×50 mL of ethyl acetate. The ethyl acetate layers were washed in succession with 50 mL of saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and evaporated. Flash column chromatography on 45 g of silica gel, eluting with 500 mL of 4% ethyl acetate in hexane followed by 500 mL of 6% ethyl acetate in hexane, gave 3-hydroxy-2-(2'-methyl phenyl) 5-phenylthiophene as an oil weighing 421 mg. The product could be distilled bulb-to-bulb, bp (0.4 mm) 140°-150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][CH:14]([CH2:15]2)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11]3=[O:21])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]([CH2:16]2)[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11]3=[O:21])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
0.35 g of 5% palladium-on-carbon catalyst is added to a solution of 3.5 g of 1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 70 ml of ethyl acetate and the whole is hydrogenated under normal pressure and at 30°-35° in a hydrogen atmosphere. When the absorption of hydrogen is complete, the reaction mixture is diluted with 30 ml of methylene chloride and freed of catalyst by filtration over HYFLO Super-Cel ®. The solvent is evaporated off in vacuo, and the residue is recrystallised from a mixture of ethyl acetate/n-hexane, yielding the title compound in the form of white crystals having a melting point of 166-167°.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:10]([F:11])[C:2]=3[F:1])=[CH:39][CH:40]=2)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(O)cc2)CC1
Reactant: CCCCCCCOc1ccc(C(=O)O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
1.9 g of 2,3-difluoro-4-heptyloxybenzoic acid, 2 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenol and 0.1 g of 4-(dimethylamino)pyridine were dissolved in 250 ml of dichloromethane and the solution was treated portionwise within 10 minutes while stirring with 1.6 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulfate, filtered and then concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) and recrystallization from ethanol gave 2 g of 2,3-difluoro-4-heptyloxybenzoic acid 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenyl ester with m.p. (C-SC) 67° C., SC -N 70° C. and cl.p. (N-I) 128° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.CN>CCOC(C)=O.C1COCC1>[CH3:29][NH:31][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:28])([CH3:27])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:18]
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 14 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and methylamine (2 M solution in THF, 0.2 mL, 0.4 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (14 mg, 0.035 mmol, 14% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.27 (s, 12H), 1.30-1.46 (m, 4H), 2.03-2.17 (m, 1H), 2.22 (s, 1H), 2.79 (d, J=4.7 Hz, 3H), 3.22 (dt, J=11.4, 3.1 Hz, 2H), 3.80-3.88 (m, 2H), 4.17 (d, J=7.5 Hz, 2H), 7.63-7.77 (m, 2H), 8.32-8.37 (m, 1H), 8.38 (s, 1H), 8.74 (d, J=1.4 Hz, 1H); MS (DCI/NH3) m/z 397 (M+H)+; Anal. Calculated for C24H32N2O2.0.3H2O: C, 71.72; H, 8.18; N, 6.97. Found: C, 71.96; H, 8.19; N, 6.69.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>CO>[CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(N)CC1
Yield: 79.3 %

Procedure:
t-Butyl-1-isopropylpiperidin-4-ylcarbamate (2.64 g, 10.9 mmol) obtained in Preparation Example (2-iii-1) was dissolved in methanol (20 ml) in a 250 ml vessel at 0° C., and trifluoroacetic acid (TFA; 4.06 ml, 54.5 mmol, 5 eq.) was slowly added thereto while stirring. The resulting mixture was reacted for 18 hrs. After the completion of reaction, the reaction product was concentrated under reduced pressure, subjected to azeotropic distillation with CHCl3 3 times, basified with 2N aqueous KOH solution (20 ml) and extracted with CHCl3 3 times. The organic layer was separated, washed with brine, dried, filtered and distilled under reduced pressure to obtain 1.23 g of the title compound as yellow oil (yield 79.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:21][OH:22].CC(C)([O-])C.[K+].C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=C(CO)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCc1ccccc1
Reaction time: 5 h
Yield: 30.2 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (173 mg, contaminated with 10% sulfone, 0.62 mmol) in THF (6 mL) was added benzyl glycolate (128 μL, 0.90 mmol) followed by potassium tert-butoxide (1 M in THF, 0.3 mL, 0.3 mmol) and DBU (139 μL, 0.93 mmol). The solution was stirred for 5 h, diluted with 50% ethyl acetate/hexane, and passed through a plug of SiO2 followed by washing with 40% ethyl acetate/hexane. The filtrate was concentrated in vacuo, and the residue flash-chromatographed on SiO2 with 35% ethyl acetate/hexane to afford 71.5 mg (30% yield) of the titled product as a white solid. ESI-MS m/z 382 (MH+), 380 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>CO.[Pt](=O)=O>[N:12]1([CH2:11][CH2:10][O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][CH:17]=2)[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: O=[N+]([O-])c1ccc(COCCn2ccnn2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(COCCn2ccnn2)cc1
Yield: 95 %

Procedure:
1-[2-(4-Nitro-benzyloxy)-ethyl]-1H-[1,2,3]triazole (3.6 g, 14.5 mmol) and platinum dioxide (0.4 g) were suspended in methanol (30 ml) and THF (30 ml) and hydrogenated for 3 h at 42 mbar. After filtration and concentration 3 g (95%) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenylamine were obtained as beige solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: c1cscn1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 99.9 %

Procedure:
The title compound (90 mg, 99%) was prepared from thiazole (0.07 g, 0.8 mmol) and (R)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.2 mmol) using the procedure of Example 146, step 1; 1HNMR (400 Hz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H); MS?
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCCC2)CC1
Yield: 23 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white solid (23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](Cl)=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:24]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and 2-chloro-isonicotinoyl chloride the title compound was obtained as a brown solid (59%), MS: m/e=407 (M{37Cl}+H+), 405 (M{35Cl}+H+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2[CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:11][C:4]1[CH:3]=[CH:2][CH:1]=[C:6]2[C:5]=1[CH2:7][CH2:8][C:9]2=[O:10]
Reactant: O=C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(O)cccc21
Temperature: 200 °C
Yield: 41.5 %

Procedure:
Dihydrocoumarin (35 g, 0.236 mol) was added to 62.9 g (0.472 mol) of aluminum chloride and the mixture was heated in an oil-bath at 200° C. for 2.5 h with stirring. The reaction mixture was cooled, poured into ice (300 g), 300 mL of methylene chloride added to the mixture, cooled, and 400 mL of methylene chloride was added. The mixture was filtered and the solid residue was dissolved in hot methanol, filtered, and the filtrate was cooled to afford 14.5 g (41%) of 4-hydroxy-indan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[C:10](=[O:26])[C:11]([C:23]([OH:25])=[O:24])=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:13]=3[O:14][C:4]=2[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+].Cl>CO.[Ti](Cl)(Cl)(Cl)Cl>[CH2:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[C:10](=[O:26])[C:11]([C:23]([OH:25])=[O:24])=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:13]=3[O:14][C:4]=2[CH:3]=1)[CH3:37]
Reactant: CC=O
Reactant: COc1ccc(-c2c(C(=O)O)c(=O)n(Cc3ccccc3OC)c3c2oc2cc(N)ccc23)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCNc1ccc2c(c1)oc1c(-c3ccc(OC)cc3)c(C(=O)O)c(=O)n(Cc3ccccc3OC)c12
Reaction time: 30 h

Procedure:
A solution of 6 g of 7-amino-1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro-[3,2-b]pyridine-3-carboxylic acid and 0.5 g of titanium tetrachloride in 100 ml of methanol is treated with 1 ml of freshly distilled acetaldehyde. 4 g of sodium cyanoborohydride are then added and the mixture is stirred for 30 hours. Half-concentrated hydrochloric acid is added, the mixture is worked up in the customary manner and 7-ethylamino-1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro-[3,2-b]pyridine-3-carboxylic acid is obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>C1COCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]([OH:21])[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]1
Reactant: Clc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
Diisopropylamine (1.82 mL, 12.9 mmol) was dissolved in THF (40 mL) and cooled to −78° C. nBuLi (4.93 mL, 2.5 M in hexanes, 12.3 mmol) was added drop-wise and the solution was warmed to room temperature, stirred for 45 min and re-cooled −78° C. A solution of 3-chloropyridine (1.40 g, 12.3 mmol) in THF (6 mL) was added and the reaction mixture was stirred at −78° C. for 4 h. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.89 g, 13.6 mmol) in THF (6 mL) was added and the reaction mixture was warmed to r.t. and stirred for 2 h. The reaction mixture was quenched with water (60 mL) and extracted with DCM (100 mL and 2×30 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (2.94 g, 73%) as a yellow gum. LCMS (ES+): 271.0 (M+H-tBu)+.