Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:30]([C:32]1[N:33]=[C:34]([C:45]([O-])=[O:46])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=1)#[N:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45]([C:34]3[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=[C:32]([C:30]#[N:31])[N:33]=3)=[O:46])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 89.0 mg (0.231 mmol) 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 77.8 mg (0.255 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), 162 mg (0.347 mmol) PyBrOP, and 121 μL (0.694 mmol) DIEA and stirred at RT for 2 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 124 mg (84%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C31H44N5O4Si, 578.3 (M−C4H9+2H), found 578.0.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:15][N:14]([CH3:16])[CH2:13]2)[N:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH3:43])[C:21]2[O:25][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:28]=3)=[N:23][C:22]=2[CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:15][N:14]([CH3:16])[CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24]4[O:25][C:21]5[C:20]([CH3:43])=[CH:19][C:18]([CH3:17])=[CH:42][C:22]=5[N:23]=4)=[CH:32][CH:31]=3)[C:10]=12
Reactant: CN1CC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CN(C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A mixture of 3-iodo-1-(1-methyl-3-azetanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.17 g, 0.00052 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.23 g, 0.000624 mol), tetrakis(triphenylphosphine)-palladium (0.030 g, 0.000026 mol) and sodium carbonate (0.14 g, 0.0013 mol) in ethylene glycol dimethyl ether (20 mL) and water (15 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-50% methanol/dichloromethane as a mobile phase to give N2-{4-[4-amino-1-(1-methyl-3-azetanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine (0.13 g, 0.0003 mol).
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl[CH:30]([S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:31](=O)[CH3:32]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:32]=[C:31]([CH2:30][S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CC(=O)C(Cl)S(=O)(=O)C(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(CS(=O)(=O)C(C)C)cs3)nc21

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-chloro-1-(isopropylsulfonyl)propan-2-one (example 5a) using same procedure as reported for 2.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: COc1ccc2nc(NN)sc2c1
Product: COc1ccc2nc(NNC(=O)c3ccc([N+](=O)[O-])o3)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4c was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and 2-hydrazino-6-methoxybenzothiazole (260 mg, 1 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 283 mg, 85%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 46) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow oil. MS: 531.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[N:27]1[O:31][N:30]=[C:29]2[C:32]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:34]=[CH:35][C:28]=12.N1C=CC=CC=1>>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:36]([C:32]2[C:29]3=[N:30][O:31][N:27]=[C:28]3[CH:35]=[CH:34][CH:33]=2)(=[O:38])=[O:37])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH3:26]
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Solvent: c1ccncc1
Product: CCOc1ccc(NS(=O)(=O)c2cccc3nonc23)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
120 ml (0.34 mmol) of the compound from example 42A are reacted with 111 mg (0.509 mmol) of benzofurazane-4-sulfonyl chloride and 0.17 ml (2.10 mmol) of pyridine. Yield: 109 mg (60.1% of theory).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH2:19][CH2:20][CH3:21].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:25][CH:24]=2)=[C:7]([CH2:19][CH2:20][CH3:21])[CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-bromopropoxy)-4-phenoxy-2-propylbenzene (1.01 g, 2.9 mmol) and 4-hydroxybenzenesulfonamide (0.5 g, 2.9 mmol) in dry DMF (29 mL) was added cesium carbonate (1.04 g, 3.2 mmol). The resulting suspension was stirred in a 50° C. oil bath for 5 h. After cooling to room temperature, the reaction suspension was concentrated under vacuum to a residue, which was then partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was chromatographed over silica gel with hexanes/ethyl acetate (2:1) to isolate the title compound.,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:26]6[C:31]([C:32]=5[CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:34]1([N:25]2[C:24]3[CH:23]=[CH:22][C:21]([C:17]4[CH:18]=[CH:19][C:20]5[N:8]([C:5]6[CH:6]=[CH:7][C:2]([C:12]7[CH:11]=[CH:10][C:9]8[N:8]([C:5]9[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=9)[C:45]9[C:40]([C:46]=8[CH:13]=7)=[CH:41][CH:42]=[CH:43][CH:44]=9)=[CH:3][CH:4]=6)[C:9]6[C:14]([C:15]=5[CH:16]=4)=[CH:13][CH:12]=[CH:11][CH:10]=6)=[CH:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Brc1ccc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)ccc32)cc1
Reactant: Cc1ccccc1
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: [K+]
Solvent: CCO
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc(-n5c6ccccc6c6cc(-c7ccc8c(c7)c7ccccc7n8-c7ccccc7)ccc65)cc4)ccc32)cc1
Temperature: 72 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
The resulting 9-(4-bromophenyl)-9′-phenyl-9H,9′H-[3,3′]bicarbazolyl (17.00 g), 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)-9H-carbazole (12.25 g), toluene (160 ml), ethanol (40 ml), and a 2 M potassium carbonate aqueous solution (23 ml) were added to a nitrogen-substituted reaction vessel, and aerated with nitrogen gas for 30 minutes under ultrasonic waves. After adding tetrakis(triphenylphosphine)palladium (1.74 g), the mixture was heated, and stirred at 72° C. for 12.5 hours. The mixture was allowed to cool to room temperature, and extraction was performed by adding toluene (100 ml) and water (150 ml) thereto. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain a black crude product. The crude product was purified by column chromatography (carrier: silica gel; eluent: hexane/toluene) to obtain a pale yellowish white powder of 9′-phenyl-9-[4-(9-phenyl-9H-carbazol-3-yl)-phenyl]-9H,9′H-[3,3′]bicarbazolyl (10.44 g; yield 48%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:17]1[CH:22]=CC=C[CH:18]=1.CNC>ClCCl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:15])[N:17]([CH3:22])[CH3:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: c1ccncc1
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
A solution of 1-Boc-4-(chlorocarbonyl)piperazine (300 mg, 1.22 mmol), pyridine (288.4 mg, 3 equiv) (Preparation B-12-A), and dimethylamine (1.83 mmol, 1.5 equiv) in dichloromethane was refluxed overnight. The solution was quenched by the dropwise addition of water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜70% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[C:7]([CH:22]=[O:23])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)CCOc2c(I)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCOc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
14.40 g (50.0 mmol) of 4,4-dimethyl-8-iodochroman and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 22 ml (55.0 mmol) of n-butyllithium (2.5M in hexane) are added dropwise at -78° C., the reaction mixture is stirred for 30 minutes, then 4.2 ml (55.0 mmol) of DMF are added and the mixture is allowed to return to room temperature. The reaction mixture is poured onto an aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 10.40 g (100%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4](CC2C=CC=CC=2)[CH2:5][C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)[CH3:2].Cl>>[C:10]1([CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH2:5][NH:4][C:3](=[NH:9])[CH2:1][CH3:2])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCC1=NC(c2ccccc2)c2ccccc2CN1Cc1ccccc1
Agent: Cl
Product: CCC(=N)NCc1ccccc1Cc1ccccc1

Procedure:
By a process substantially similar to that of Example 2, 2.82 g (7.5 mmol) of 4,5-dihydro-3-ethyl-1-phenyl-4-(phenylmethyl)-1H-2,4-benzodiazepine was converted to 1.1 g of product as the hydrochloride after recrystallization from isopropyl alcohol/ether, mp 172-174.
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].N(S([O-])(=O)=O)(S([O-])(=O)=[O:23])[O].[K+].[K+].Cl>[OH-].[Na+].O>[CH3:17][C:16]1[C:2](=[O:1])[C:3]([C:4](=[O:5])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:13]([CH3:19])[C:14](=[O:23])[C:15]=1[CH3:18]
Reactant: Cc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1C
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1=C(C)C(=O)C(C(=O)CCCCC(=O)O)=C(C)C1=O
Temperature: 20 °C

Procedure:
5-(2'-Hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.048 part) was dissolved in 0.5% NaOH (3.3 volume parts) and, while the solution was stirred at 20° C., potassium nitrosodisulfonate (0.4 part) was added. The mixture was stirred for 10 minutes. Then, under cooling with ice, the reaction mixture was diluted with water (100 volume parts) and rendered acidic with dilute hydrochloric acid. It was then extracted with diethyl ether and the extract was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was then recrystallized from hexane-ethyl acetate (2:1). The procedure provided 2,3,5-trimethyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone (formula I-1 wherein R=H3C, n=4, in the free form) (0.042 part) as yellow needles melting at 96.5°-98.5° C.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Br-].[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:19][CH2:20]2)=[CH:16][CH:15]=1.[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O>CCCCCC>[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:18]1[C:17]2[C:21](=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH2:20][CH:19]=1
Reactant: COc1ccc2c(c1)CCC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCC=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)CCCCCCC1=CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 9.625 g. of potassium t-butoxide in 60 ml. of dimethylsulfoxide is added dropwise a solution of 40 g. of the phosphonium salt of Example 1 in 300 ml. of dimethylsulfoxide. After six minutes an equimolar amount (12.93 g.) of methyl-6-formylhexanoate is added dropwise just discharging the red color of the reaction mixture. The mixture is stirred for 1 hour at room temperature, and then poured into 1 liter of ice-water and 350 ml. of hexane. It is shaken, the white triphenylphosphine oxide is filtered off and the aqueous layer is extracted with ten 75 ml. portions of hexane. The combined hexane extracts are succcessively washed with four 250 ml. portions of (1:1) dimethylsulfoxide-water, four portions of water and one 300 ml. portion of saturated salt solution. After drying over magnesium sulfate the hexane mixture is concentrated to a yellow oil containing 6-methoxy-Δ3,ω-indanheptanoic acid methyl ester (Compound 3). The yellow oil is dissolved in chloroform (200 ml.) and to this is added 5 drops of trifluoroacetic acid. The mixture is allowed to stand at room temperature for 4.5 hours and then concentrated to dryness in vacuo. Upon trituration with hexane (15 ml.) 6-methoxy-3-indeneheptanoic acid methyl ester (Compound 4) separates in cystalline form, m.p. 30°-31.5°C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Cl>C(O)C>[Cl:3][C:4]1[C:5]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[OH:22])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 23 °C
Reaction time: 20 h

Procedure:
With ice-cooling, 0.36 g of sodium borohydride were added a little at a time to a solution of 6.0 g of 3-chloro-2-(4-chlorobenzoyl)-5-trifluoromethylpyridine in 10 ml of anhydrous ethanol. The reaction mixture was stirred at 23° C. for 20 hours, after which 50 ml of 10% strength hydrochloric acid were carefully added dropwise. The ethanol was evaporated and the product was subsequently extracted with tert-butyl methyl ether (three times 30 ml). The combined organic phases were dried over sodium sulfate and then concentrated. The crude product was purified by silica gel chromatography (eluent: cyclohexane/tert-butyl methyl ether=9:1). Yield: 3.6 g (60%) of a colorless oil; 1H NMR (270 MHz; in CDCl3): δ[ppm]=5.02 (d,1H), 6.02 (d,1H), 7.33-7.41 (m,4H), 7.91 (s,1H), 8.81 (s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH2:9].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[C:10]([NH:18][C:19]([NH:9][C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[Br:1])=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)ccc1Br
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)ccc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 2,5-dibromo-phenylamine I (2.44 g, 9.72 mmol) in acetone (60 mL) was added benzoylisothiocyanate (1.74 g, 26.0 mL, 10.6 mmol) at room temperature. After 15 min, solid precipitated out. The reaction mixture was continued to stir for 30 min at room temperature. After completion of reaction (TLC monitoring) acetone was distilled off and crude solid filtered with hexane (100 mL) and again washed with hexane (100 mL) to obtain the desired compound as pale-yellow solid (3.9 g, 97%). 1H NMR (DMSO-d6, 400 MHz): δ 7.47 (dd, J=6.4, 6.0 Hz, 1H), 7.53 (m, 2H), 7.66 (s, 1H), 7.70 (m, 1H), 7.99 (m, 1H), 8.01 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 11.91 (br s, 1H) and 12.63 (br s, 1H).
Reaction SMILES: [F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].[Li+].[OH-]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(cis-4-(1,1-Difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (32 mg, 0.083 mmol) was dissolved in EtOH (5 mL). Then LiOH (60 mg, 2.5 mmol, 30.0 eq.) in 1 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. LCMS showed starting material was gone. Solvent was removed. DCM was added and filtered. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give product (12 mg, 40%) as a slight yellow solid. EDI-MS (M−NH2): 347.0. HPLC: 98.82%. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.72-7.66 (m, 2H), 7.49 (d, 1H), 7.10 (d, 2H), 4.30-4.27 (m, 1H), 3.78-3.68 (AB, 2H), 3.18 (b, 3H), 2.32-2.30 (m, 2H), 2.04-1.99 (m, 2H), 1.63-1.19 (m, 11H).
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:13]([O:14]COC)=[C:12]([O:18][CH3:19])[CH:11]=[CH:10][C:9]=2[NH:20][CH2:21][C@@H:22]([OH:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])OC1.Cl.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[NH2:46])[C:42](=[O:47])[N:41]([CH:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1)[CH2:40]2.CC(O)=O>C1COCC1.CCO>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[O:24][CH2:23][C@H:22]([OH:33])[CH2:21][NH:20][C:9]1[C:8]([C:5]2[NH:46][C:45]3[C:37](=[CH:38][C:39]4[CH2:40][N:41]([CH:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]5)[C:42](=[O:47])[C:43]=4[CH:44]=3)[N:36]=2)=[C:13]([OH:14])[C:12]([O:18][CH3:19])=[CH:11][CH:10]=1
Reactant: CN1CCC(N2Cc3cc(N)c(N)cc3C2=O)CC1
Reactant: COCOc1c(OC)ccc(NC[C@@H](O)COc2ccc(C)cc2C)c1C1OCC(C)(C)CO1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(NC[C@@H](O)COc2ccc(C)cc2C)c(-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4)c1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
To a solution of (R)-1-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-4-methoxy-3-methoxymethoxy-phenylamino]-3-(2,4-dimethyl-phenoxy)-propan-2-ol (102 mg, 0.21 mmol) in THF (5.0 mL) was added 36% aqueous HCl (1.0 mL). After it was heated at 50° C. for 1.5 h, the reaction mixture was evaporated and the residue was mixed with 5,6-diamino-2-(1-methyl-piperidin-4-yl)-2,3-dihydro-isoindol-1-one (76 mg, 0.21 mmol) and AcOH (0.4 mL) in EtOH (8 mL). The mixture was stirred at the room temperature for 30 min, heated at 80° C. for 1.5 h, and evaporated to dryness. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (40:10:1) afforded the title compound (13 mg, 10%). ESI-MS m/z 586.5 (MH+).