Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[CH:30][CH:29]=1.BrC1C=CC(CN(C2(CO)CCCCC2)S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)=[CH:32][CH:33]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1(CO)CCCCC1)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncco2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(Br)cc1)C1(CO)CCCCC1
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)C1(CO)CCCCC1
Yield: 82.8 %

Procedure:
The title compound was synthesized from 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (114 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (98 mg, 0.41 mmol) according to the procedure described for N-(4-bromobenzyl)-4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 39) to give 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (145 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (2H, d, J=8.06 Hz), 7.77 (2H, d, J=8.56 Hz), 7.69 (1H, s), 7.45 (4H, dd, J=15.36, 8.56 Hz), 7.21 (1H, s), 4.78 (2H, s), 3.86 (2H, br. s.), 2.92 (1H, hr. s.), 1.81-1.90 (2H, m), 1.42-1.54 (5H, m), 1.20-1.31 (2H, m), 0.95-1.07 (1H, m). LC/MS R.T.=2.18 min; [M+H]+=461.08. HRMS [M+H]+ calc'd 461.1302, found 461.1321.
Reaction SMILES: [OH:1][C@@H:2]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([O:1][C@@H:2]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Solvent: c1ccncc1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@H](COc3ccccc3)OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1

Procedure:
Analogously to Example 1(a), 5 g of (1S,5R,6R,7R)-6-[(E)-(3R)-3-hydroxy-4-phenoxy-1-butenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one, 22 ml of pyridine, and 2.84 g of benzoyl chloride yield 6.1 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2.[F:25][C@@H:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27]O>>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH2:27][C@@H:26]([F:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=2
Reactant: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(O)ccc12
Reactant: CCCCCC[C@H](F)CO
Product: CCCCCCCCc1ccc2c(c1)c(F)cc1cc(OC[C@@H](F)CCCCCC)ccc12

Procedure:
From 9-fluoro-7-octylphenanthren-2-ol by reaction with 2-(S)-fluorooctan-1-ol by Mitsunobu reaction.
Reaction SMILES: [CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14]N(CC)CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N#C[Br:31].O.Cl>C(OCC)C>[CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14][Br:31])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CBr
Reactant: CCN(CC)CC#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C#CCBr)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 9.5 g 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclohexyl-α-phenylglycolate in diethyl ether, was added dropwise an etheral solution of 3.2 g cyanogen bromide, and the mixture was stirred for one hour under ice cooling and then for 18 hours under cooling with water. 2N-HCl (14 ml) was added to the reaction mixture under ice cooling, and the separated etheral layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue left was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 6.0 g of the objective compound as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10](=[O:23])[CH:11]([N:13]2[CH:16]([S:17][C:18](=[O:20])[CH3:19])[CH:15]([CH3:21])[C:14]2=[O:22])Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26]1([P:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10](=[O:23])[C:11]([N:13]2[CH:16]([S:17][C:18](=[O:20])[CH3:19])[CH:15]([CH3:21])[C:14]2=[O:22])=[P:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)SC1C(C)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: CC(=O)SC1C(C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
The crude 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 12 ml of absolute dioxan, 1 g of poly-Hunig base is added and the mixture is stirred for 30 minutes, then 312 mg of triphenylphosphine are added and the mixture is stirred under nitrogen for 15 hours at 50°. The poly-Hunig base is filtered off, washed with dioxan and the filtrate and washing liquid are together concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate and yields a cis-trans mixture of the title compound having the following physico-chemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:36]([C:35]4[O:31][N:32]=[CH:33][CH:34]=4)=[O:37])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: O=C(O)c1ccno1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3ccno3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 522.1 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:5][CH:4]=1)#N.C(O)(=[O:28])C.N1C=CC=CC=1>[Ni].O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:5][CH:4]=1)=[O:28]
Reactant: CC(=O)O
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc(NS(C)(=O)=O)cc21
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)n1cc(-c2ccc(C=O)cc2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Method Z-1 Place N-[3-(4-Cyano-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (500 mg, 1.41 mmol), sodium hyposulfite hydrate (311 mg, 3.53 mmol) and Raney nickel (50% soln in water, 700 μL, 2.96 mmol) in a round bottom flask then add water (6 mL), glacial acetic acid (12 mL) and pyridine (12 mL). Warm to 50° C., and stir for 1.5 hours. Cool to ambient temperature; dilute with water (10 mL); and extract with ethyl acetate (10 mL×3). Combine organic layers, and wash with saturated sodium bicarbonate, water (×3) and brine. Dry over sodium sulfate, and concentrate in vacuo. Purify residue by flash chromatography on silica (2-50% ethyl acetate in hexanes) to give N-[3-(4-formyl-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (413.1 mg, 82%). LRMS (API ES−)=355.0 (M−H).
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.C[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=c1c(Br)coc2ccccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c(-c2ccc(O)cc2)coc2ccccc12
Temperature: 110 °C
Yield: 19.8 %

Procedure:
To a mixture of 3-bromochromone (1.5 g, 6.66 mmol), 4-methoxy phenyl boronic acid (1.01 g, 6.66 mmol), sodium carbonate (2.12 g, 20.0 mmol), toluene (40 mL) and water (10 mL) was added tetrakis-triphenyl phosphine palladium (385 mg, 0.33 mmol) under N2. The reaction mixture was heated to 110° C. for 5 h and then cooled to rt. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography, using 20% EtOAc in hexane to give, 885 mg of 4′-methoxychromone product in 52% yield. A mixture of the above mentioned 4′-methoxychromone (400 mg, 1.58 mmol) and pyridinium hydrochloride (5 g) was heated at 190° C. for 4 h. The reaction mixture was cooled to rt, diluted with water, neutralized with NaHCO3 and filtered to give 314 mg of 3-(4-hydroxyphenyl)-4H-chromen-4-one (83%). MS (ES) m/z: 239.95 (M+1), 238.99 (M); Mp. 237-238° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:24]3[N:23]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: CCOc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 47.8 %

Procedure:
Reaction of 1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (108 mg, 48%). MS (ISP) 453.1 [(M+H)+]; mp 251° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[O:32]=[C:25]1[C:26]2([CH2:27][CH2:28][N:29]([C:2]3[CH2:7][CH2:6][C:5]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)([C:8]#[N:9])[CH2:4][CH:3]=3)[CH2:30][CH2:31]2)[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][NH:24]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccccc2)CC=C(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CC1

Procedure:
A mixture of 5 parts of 4-oxo-1-phenyl-1-cyclohexanecarbonitrile, 5.8 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 0.1 parts of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and evaporated, yielding 10.35 parts of 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)-1-phenyl-3-cyclohexene-1-carbonitrile as a residue.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](O)=[O:29])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C[O:33][C:34](=[O:37])[CH2:35][NH2:36].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](=[O:29])[NH:36][CH2:35][C:34]([OH:33])=[O:37])=[CH:23][C:22]=3[F:31])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Reactant: COC(=O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)NCC(=O)O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-1 (32 mg, 0.073 mmol), amino-acetic acid methyl ester (0.11 mmol) and HOBT (15 mg, 0.11 mmol) were combined in DCM (1 mL) and stirred at room temperature for 10 minutes. EDC(19 mg, 0.1 mmol) was added and the mixture was stirred for 18 h. The solution was washed with 2 mL of aqueous NaHCO3, concentrated and taken up with 0.5 mL of dioxane. 0.5 mL of 1N NaOH was added and the mixture was stirred at 60° C. for 1 h. It was then cooled to room temperature, acidified with 0.5 mL of 2N HCl and extracted with ethyl acetate (1.5 mL). The organic layer was concentrated under a stream of nitrogen and purified on preparative HPLC to give 30-1: LC-MS 497.4 (MH).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CN(CCN(C)C)C.[Cl-].[NH4+]>>[CH:14]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCCC1
Reactant: Br[Mg]c1ccc2ccccc2c1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: c1ccc2cc(C3CCCCC3)ccc2c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
2-Naphthyl magnesium bromide (1.46 mL of 0.82 M-THF solution, 1.2 mmol) was added to a mixture of bromocyclohexane (163.1 mg, 1.0 mmol), FeCl3 (0.5 mL of 0.1 M-THF solution, 5 mol %) and TMEDA (181.1 μL, 1.2 mmol) at 25° C. over 20 minutes through an injection pump. After the addition of Grignard reagent mixture was completed, the reaction mixture was stirred for 10 minutes at this temperature. After treating with saturated aqueous ammonium chloride solution in a conventional manner, the reaction mixture was filtered through a pad of Florisil® and concentrated in vacuum. Using the internal standard (tetrachloroethane, 79 mg, 0.47 mmol), the crude product was analyzed by 1H NMR to give 2-cyclohexylnaphthalene in a yield of 96%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH3:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 90.0 mg (0.28 mmol) (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate) in 1.0 mL N,N-dimethylformamide was added 14.8 mg (0.34 mmol) sodium hydride (55–65% dispersion in oil) and the reaction was stirred for 30 min. Then, 35 μl (80.0 mg, 0.56 mmol) methyl iodide was added. After 2 h the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:23][CH2:22][CH2:21][C:16]=3[N:17]=[C:18](Cl)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[S:23][CH2:22][CH2:21][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2SCC3)CC1
Yield: 38.2 %

Procedure:
200 mg 4-(2-Chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester and 200 mg Raney-nickel in 20 mL methanol was stirred at 65° C. for 10 h under 4 bar hydrogen atmosphere. The reaction was filtered and the filtrate was evaporated. The residue was purified by HPLC to give 69 mg of the desired product. (M+H)+: 323/324, Rt: 1.58 min (method AD)
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH2:6][CH2:5]2)CC1.Cl>C(Cl)Cl>[NH2:11][CH2:10][CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]2[C:31]([Cl:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=2[Cl:36])=[CH:22][CH:21]=1)[C:8]([N:7]([CH:4]1[CH2:5][CH2:6]1)[CH2:40][C:41]1[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=1)=[O:39]
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(O)cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.08 M) of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 92:8 (v/v) CH2Cl2: 2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+): 615.0.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.ClCCl>C(O)C.CC(C)=O>[ClH:24].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCCN(CCOCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
The ester prepared in Example 38 (0.6 g, 1.3 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (0.5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. A concentrated hydrochloric acid solution was added with cooling on an ice-bath until pH 1 and dichloromethane (300 ml) was added. The resulting emulsion was dried (Na2SO4) ant the solvent evaporated in vacuo to give a residue which was agitated with acetone. This afforded 0.3 g (50 %) of the title compound as a solid.
Reaction SMILES: BrC1N=C(C([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.[Br:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[N:72]=[C:73]([CH:95]([C:97]2[CH:102]=[C:101]([CH2:103][CH3:104])[CH:100]=[C:99]([O:105][CH2:106][CH3:107])[C:98]=2[F:108])O)[N:74]([C:76]([C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:75]=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[N:72]=[C:73]([CH:95]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])=[N:44][CH:43]=[CH:42]3)[C:97]2[CH:102]=[C:101]([CH2:103][CH3:104])[CH:100]=[C:99]([O:105][CH2:106][CH3:107])[C:98]=2[F:108])[N:74]([C:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)[CH:75]=1
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOc1cc(CC)cc(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCOc1cc(CC)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 217.3 (424 mg, 0.641 mmol) was converted to the chloro intermediate, then displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate to afford after flash chromatography (0 to 60% EtOAc/hexanes gradient) 615 mg of intermediate 217.4 as a pale yellow solid.
Reaction SMILES: OO.[C:3]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([OH:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1)=[O:9].S([O-])([O-])=O.[Na+].[Na+].[C:41]([OH:45])([CH3:44])([CH3:43])[CH3:42]>>[C:3]([O:23][CH:24]1[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH2:42][C:41]([OH:45])([CH3:44])[CH3:43])[C:28]([CH3:31])([CH3:30])[CH2:29]1)(=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([O:19][CH2:42][C:41]([OH:45])([CH3:44])[CH3:43])[C:13]([CH3:21])([CH3:20])[CH2:12]1)=[O:9]
Reactant: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethylpieridin-4-yl) adipate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqeuous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.