Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]([F:30])([F:29])[F:28])=[C:6]([CH:26]=1)/[CH:7]=[C:8]1/[C:9](=[O:25])[C:10]2[C:15]([CH2:16]/1)=[CH:14][C:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[C:12]([O:23][CH3:24])[CH:11]=2>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]([F:29])([F:28])[F:30])=[C:6]([CH:26]=1)[CH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=2)[C:9]1=[O:25]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)ccc1C(F)(F)F)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(Cl)ccc1C(F)(F)F)C2=O
Reaction time: 6 h

Procedure:
Compound 52 (50 mg, 0.114 mmol) was dissolved in methanol 30 mL, Pd/C 17 mg added and the reaction stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude, which was purified by flash chromatography using 100-200 mesh silica gel. The compound 53 was eluted at 24% ethyl acetate in hexane as half white coloured solid compound 2-(5-chloro-2-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 53. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 3H), 7.18 (s, 1H), 6.82 (s, 1H), 3.90 (m, 3H), 3.87 (m, 4H), 3.48 (d, 1H), 3.38 (m, 1H), 3.17 (m, 4H), 3.09 (m, 1H), 2.95 (m, 1H), 2.67 (m, 2H); MS (ESI) m/z 440.0 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][C:27](=[CH2:29])[CH3:28].[OH-].[Na+]>O1CCOCC1>[CH2:6]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:23]([O:25][C:27]([CH3:29])([CH3:28])[CH3:26])=[O:24])[NH2:22])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=C(C)C
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
Into two separate 500 ml hydrogenation vessels each containing 100 ml of dioxane and 9.0 ml (160 mmol) of concentrated sulfuric acid was placed 11.0 gm (39.2 mmol) and 10.6 gm (37.8 mmol) of Nε-benzyloxycarbonyl-L-lysine. The two solutions were cooled to -78° C. and 140 ml of condensed (-78° C.) isobutylene was added to each vessel. The mixtures were then mechanically shaken (Parr shaker) at room temperature for 4 hours (26 psi). The reaction mixtures were combined and poured into 1000 ml (1.0 mol) of an ice cold solution of 1.0N aqueous sodium hydroxide and subsequently extracted three times with ether. The organic portions were combined (ca. 3000 ml), washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 16.7 gm (64%) of t-butyl Nε-benzyloxycarbonyl-L-lysinate (IV-A) as an oil.
Reaction SMILES: C[Al](C)C.Cl.[CH2:6]([O:8][NH2:9])[CH3:7].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31](OC)=[O:32])(=[O:24])=[O:23])=[O:20])[N:12]=1.Cl>C(Cl)Cl>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([NH:9][O:8][CH2:6][CH3:7])=[O:32])(=[O:24])=[O:23])=[O:20])[N:12]=1
Reactant: CCON
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CCONC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C

Procedure:
To 2.9 g of trimethylaluminum in 100 ml of methylene chloride is added 2.0 g of ethoxyamine hydrochloride with stirring at ambient temperature. To this mixture is added 3.0 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide and the solution is refluxed for 18 hours. The reaction mixture is treated with aqueous hydrochloric acid and the resulting precipitated product is purified by chromatography.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[N:21]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]3=[N:19][N:18]=1)[CH:13]=[CH:12]2)(=O)=O.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:24]1[CH:23]=[CH:22][N:21]2[C:17]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[C:7]([N:36]5[CH2:35][CH2:34][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37]5)[CH:8]=[CH:9][CH:10]=4)[N:15]=3)=[N:18][N:19]=[C:20]2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OS(=O)(=O)C(F)(F)F)c4n3)nnc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCCOc1ccn2c(-c3ccc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl trifluoromethane sulfonate (0.027 g, 0.0576 mmol), tert-butyl piperazine-1-carboxylate (0.0215 g, 0.115 mmol), Cs2CO3 (0.0282 g, 0.0865 mmol), Pd2dba3 (0.00528 g, 0.00576 mmol) and Binap-rac (0.00718 g, 0.0115 mmol) were combined in toluene (0.5 mL) in a sealed vial. The reaction mixture was stirred at 100° C. for 16 hours then concentrated under reduced pressure. The resulting residue was diluted with EtOAc, washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to an orange solid. Purification via flash column chromatography (40:1 DCM/MeOH followed by 20:1 DCM/MeOH) provided 22 mg (76%) of desired product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:10][CH:11]=1)=[CH2:19]
Reactant: C1CCOC1
Reactant: Cc1cccc(Oc2ccc(C=O)cc2)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a stirred suspension of 4-[(6-methyl-2-pyridinyl)oxy]benzaldehyde (2.43 g, 11.40 mmol) and methyl(triphenyl)phosphonium bromide (4.07 g, 11.40 mmol) in dry THF (30 mL) was added NaH (1.595 g, 39.9 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 2 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (1.23 g, 5.82 mmol, 51.1% yield) as a light green oil. LCMS: rt=3.27 min, [M+H+]=212
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:20]=[O:21]>>[Br:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]=[O:21])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCc1cn2cncc(Br)c2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2c(Br)cncn2c1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-Bromo-2-ethylimidazo[1,2-c]pyrimidine (1.0 g) was added to a mixture of phosphorus oxychloride (1.2 mL) and N,N-dimethylformamide (4.4 mL) at room temperature. The mixture was heated under stirring as it was at 80° C. for 1 day. After cooled to room temperature, it was poured slowly on ice. The material was extracted with ethyl acetate and washed with water, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (0.5 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:21][OH:22])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])(=[O:11])=[O:10])[CH:7]=1.O.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:21][O:22][CH2:24][N:8]([S:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][CH3:20])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(Br)ccc1CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCOCC
Solvent: CCCCCCC
Product: COc1ccc(Cl)cc1S(=O)(=O)N1COCc2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 871 %

Procedure:
A mixture of N-(5-bromo-2-hydroxymethyl-phenyl)-5-chloro-2-methoxy-benzenesulfonamide (2.51 g, 6.17 mmol), toluene-4-sulfonic acid monohydrate (117 mg, 0.617 mmol), and formaldehyde diethyl acetal (15.5 mL) was heated under reflux at 100° C. for 16 h. After cooling, heptane was added to the suspension, which was stirred for 15 min. The precipitate was collected by filtration and dried to afford 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (2.25 g, 87%). Off-white solid, MS (ISP)=418.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[N:10][C:9]([NH2:12])=[N:8][CH:7]=1.CO.[Br:15]Br>O>[Br:15][C:5]1[S:1][C:2]([C:6]2[N:11]=[N:10][C:9]([NH2:12])=[N:8][CH:7]=2)=[N:3][CH:4]=1
Reactant: Nc1ncc(-c2nccs2)nn1
Reactant: BrBr
Solvent: O
Solvent: CO
Product: Nc1ncc(-c2ncc(Br)s2)nn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 36.5 %

Procedure:
To a vial was added 6-(thiazol-2-yl)-1,2,4-triazin-3-amine (600 mg, 3.4 mmol), methanol (1.2 mL), water (0.6 mL). The mixture was cooled to 0° C. and bromine (816 mg, 5.1 mmol) was added. The reaction was stirred for 45 min and then quenched with saturated sodium bicarbonate solution (20 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were dried over Na2SO4, concentrated, and purified using silica gel chromatography to afford 320 mg of 6-(5-bromothiazol-2-yl)-1,2,4-triazin-3-amine as an off-white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)O1.Br[C:25]1[CH:26]=[C:27]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][N:39]=3)[C:34](=[O:41])[C:33]([C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])=[CH:32]2)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:44]1([C:42]([C:33]2[C:34](=[O:41])[C:35]3[C:40](=[N:39][CH:38]=[CH:37][CH:36]=3)[N:31]([C:27]3[CH:26]=[C:25]([C:9]4[CH:10]=[CH:11][C:12]([C@@H:15]5[CH2:17][C@H:16]5[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=4)[CH:30]=[CH:29][CH:28]=3)[CH:32]=2)=[O:43])[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: O=C(c1cn(-c2cccc(Br)c2)c2ncccc2c1=O)N1CCOCC1
Reactant: CCOC(=O)C1CC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2cccc(-n3cc(C(=O)N4CCOCC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of acid from step 2 (1 eq), amide from step 1 (1 eq), Na2CO3 (3.5 eq.; 2M in H2O), Pd(PPh3)4 (0.15 eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CHCl3:THF; 50:50), triturated in ether/acetone and then isolated by filtration to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=2[CH3:8])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Br
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 20.2 %

Procedure:
A mixture of 3-bromo-2,4-dimethyl-6-nitropyridine (1.00 g, 4.33 mmol), 2-chloropyridin-4-ol (1.12 g, 8.66 mmol) and K2CO3 (1.79 g, 12.98 mmol) in DMA (5 mL) was sparged with Ar, heated at 105° C. overnight, then cooled to RT. The mixture was diluted with EtOAc, washed successively with 10% K2CO3, 5% LiCl, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (245 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, J=5.2 Hz, 2H), 7.15 (d, J=2.3 Hz, 1H), 7.01 (dd, J=5.8, 2.3 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:20])[C:15]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:13]1[CH:12]=[C:11]2[C:16](=[C:15]([C:17]([OH:19])=[O:18])[C:14]=1[F:20])[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)c(C(=O)O)c21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)c(F)c(C(=O)O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a stirred solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (6.9 g, 0.025 mol) in DCM (140 mL) was added NBS (4.8 g, 0.027 mol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was washed with water (3×75 mL) and brine (1×75 mL), dried (Na2SO4) and concentrated under reduced pressure, giving 8.3 g (92%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.C[Si](C)(C)[O-:15].[K+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:15])=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanenitrile (3.29 g) in toluene (33 mL) was added potassium trimethylsilanolate (8.37 g) portionwise. After being stirred at reflux temperature for 5 h, the reaction mixture was cooled to room temperature. Water(17 mL) was added to the mixture dropwise. Filtration gave the product (3.28 g, 92%). 1HNMR (CDCl3) 400 MHz δ: 7.49 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 5.52-4.93 (m, 2H), 1.57 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=12)([O-])=O.C(O)(=O)C.O.[S:18](=[O:22])(=[O:21])([OH:20])[OH:19]>[Pd]>[S:18](=[O:20])(=[O:19])([OH:22])[OH:21].[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=12
Reactant: O=[N+]([O-])c1cnn2c1NCCC2
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1cnn2c1NCCC2

Procedure:
A solution of 3-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.68 g) in a mixture of sulfuric acid (0.6 ml), acetic acid (100 ml) and water (10 ml) was treated with 10% palladium on carbon (0.5 g) under a hydrogen atmosphere at room temperature for 6 days. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with ethanol and dried in vacuo to give 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (2.3 g) as a solid.
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=O.[C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:21]3[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[CH2:19][CH2:18][C@H:17]([NH:32][C:33](=[O:35])[CH3:34])[C:16]=2[CH:36]=1)(=O)[NH2:10].P(OC)(OC)(OC)=O>>[C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:21]3[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[CH2:19][CH2:18][C@H:17]([NH:32][C:33](=[O:35])[CH3:34])[C:16]=2[CH:36]=1)#[N:10]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(C(N)=O)cc1[C@@H](NC(C)=O)CC2
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: COP(=O)(OC)OC
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C#N)cc1[C@@H](NC(C)=O)CC2
Temperature: 60 °C
Yield: 61 %

Procedure:
Trichloromethyl chloroformate (0.094 ml; 0.77 mmol) was added in portions at 0° C. to a solution of N-[(5S)-3-carbamoyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (0.2 g; 0.484 mmol), (prepared as described for Example 29) and trimethyl phosphate (0.306 ml; 2.6 mmol). The mixture was allowed to warm up and then heated at 60° C. for 5 minutes. The reaction mixture was poured onto ice and stirred. The resulting precipitate was filtered, dried and purified by flash chromatography, eluting with dichloromethane/ethyl acetate (1/1) to give N-[(5S)-3-cyano-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]Br)=[CH:26][C:25]=1[CH3:34])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:15][CH:14]=3)[CH2:13][CH2:12]2)=[CH:26][C:25]=1[CH3:34]
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(OCCN2CCC(Cc3ccc(F)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine hydrochloride (344 mg, 1.5 mmol), 2-(4-benzoxy-3-methylphenoxy)ethyl bromide (482 mg, 1.5 mmol) and potassium carbonate (518 mg, 3.8 mmol) in two steps as white-off solid (240 mg): mp 118-120° C. 1H NMR (CD3OD) 1.40 (m, 2 H), 1.699 (m, 3 H), 1.975 (s, 3 H), 2.441 (t, 2 H), 2.82 (m, 2 H), 3.310 (m, 2 H), 3.45 (m, 2 H), 4.054 (s, 2 H), 6.481 (s, 2 H), 6.753 (s, 1 H), 6.83 (m, 2 H), 7.021 (m, 2 H). Anal. Calcd for C21H27ClFNO2.0.7H2O: C, 64.25; H, 7.29; N, 3.57. Found: C, 64.24; H, 7.02; N, 3.91.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.CC(C)=[O:20].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[O:9]=[C:7]1[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][O:4][C:3]([C:2]([OH:20])=[O:1])=[CH:8]1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reaction time: 2 h
Yield: 5 %

Procedure:
232 g (1 mol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one was put into a 10 l stirring flask containing 6.6 l of acetone and 400 ml of water. The clear solution was cooled to +5° C. by means of an ice bath. While maintaining the temperature at +5° C. to 10° C., 640 ml of Jones reagent (202 g CrO3, 600 ml water, 174 ml H2SO4) was added dropwise over a period of 1 hour. Stirring was continued for 2 hours without cooling. The reaction mixture was filtered through a glass frit and the dark green residue washed with 500 ml of acetone. The filtrate was then evaporated until all of the acetone was removed. To the aqueous, partly crystalline product was added 1.2 l of methanol, and this mixture was then heated to its boiling point. The resulting clear dark green solution was placed in an ice bath and the product allowed to crystallize. The crystalline product was filtered and washed with 500 ml of a cold solvent mixture consisting of 250 ml of methanol +250 ml of water and finally dried. Yield: 195 g. From the mother liquor, a further 5% of the product could be isolated.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([CH3:18])=[CH:10][C:9]=12)[CH3:2].C([O-])(=O)C.[K+].CC(O)=O.C1OCCOCCOCCOCCOCCOC1.C(OC(=O)C)(=O)C.[N:61](OCCC(C)C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[CH2:1]([C@:3]12[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:18]=[N:61][N:14]([C:15](=[O:17])[CH3:16])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CC[C@]12CCC3(C[C@H]1CCCc1cc(NC(C)=O)c(C)cc12)OCCO3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC[C@]12CCC3(C[C@H]1CCCc1cc4c(cnn4C(C)=O)cc12)OCCO3
Temperature: 70 °C
Yield: 64.4 %

Procedure:
rac-N-((4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-yl)acetamide (25, R2=Ethyl) (0.125 g, 0.350 mmol) in CHCl3 (8 mL) was treated with potassium acetate (0.069 g, 0.699 mmol), AcOH (0.042 g, 0.699 mmol), 18-Crown-6 (15 mg, 0.057 mmol), acetic anhydride (0.071 g, 0.699 mmol) and isopentyl nitrite (0.123 g, 1.049 mmol). The mixture was warmed to about 70° C. for about 3 h then a second portion of isopentyl nitrite (0.200 g, 1.707 mmol) and acetic anhydride (0.110 g, 1.077 mmol) were added. After about 11 h the mixture was cooled to rt and treated with sat. aq. NaHCO3 (3 mL) and water (10 mL). The mixture was extracted with DCM (30 mL) then the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-1-((4aR,12bS)-12b-ethyl-4a,5,6,7-tetrahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-[1,3]dioxolan]-9(2H,4H,12bH)-yl)ethanone (26, R2=Ethyl) (0.083 g, 64%); LC/MS, method 3, Rt=2.87 min, MS m/z 369 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=0.6 Hz, 1H), 8.06 (s, 1H), 7.75 (s, 1H), 3.95-3.68 (m, 4H), 3.11-3.04 (m, 1H), 2.98-2.92 (m, 1H), 2.69 (s, 3H), 2.57-2.48 (m, 1H), 2.32-1.13 (m, 12H), 0.59 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:6].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][N:34]=[C:35]=[O:36].CCN(C(C)C)C(C)C.C(O)C(N)(CO)CO>C(Cl)Cl>[CH:11]([N:7]([CH:8]([CH3:9])[CH3:10])[C:5]([CH:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:2][NH:1][C:35]([NH:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[F:26])=[O:36])=[O:6])([CH3:13])[CH3:12]
Reactant: CC(C)N(C(=O)C(c1cccnc1)C(CN)c1ccccc1)C(C)C
Reactant: O=C=NCc1ccccc1F
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)C(c1cccnc1)C(CNC(=O)NCc1ccccc1F)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-amino-N,N-diisopropyl-3-phenyl-2-(pyridin-3-yl)butanamide (0.030 g, 0.09 mmol) in dry DCM (2 mL) was added 1-fluoro-2-(isocyanatomethyl)benzene (0.028 g, 0.18 mmol), and DIPEA (0.023 mL, 0.135 mmol). The reaction mixture was agitated for 15 h at room temperature before adding PS-trisamine (0.022 g, 0.09 mmol) and agitating for 1 h at room temperature. The crude product was then filtered to remove the solid phase and concentrated. Purification of enantiomers by ChiralPak AD (n-hexanes/EtOH, 85:15) yielded (−)-1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea as a foamy, off-white solid. Analytical LCMS: single peak (214 nm), 2.523 min. 1H NMR (CDCl3, 300 MHz) δ 8.26 (d, J=4.5 Hz, 1H), 8.03 (s, 1H), 7.38-7.42 (m, 2H), 7.19-7.25 (m, 1H), 6.99-7.13 (m, 6H), 6.91-6.93 (m, 2H), 4.54-4.59 (m, 1.37 (d, J=6.9 Hz, 3H), 1.26 (d, J=6.9 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 0.60 (d, J=6.3 Hz, 3H); HRMS m/z 491.2841 (C29H35FN4O2+H requires 491.2817).