Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[CH:6]([CH2:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][C:5]2([CH3:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CC=C2C(C1)C(C)(C)CCC2(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Temperature: 84 °C
Yield: 386.3 %

Procedure:
A solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene 1 (2.00 g, 9.88 mmol), N-bromosuccinimide (1.85 mmol, 10.37 mmol), benzoyl peroxide (91 mg, 0.28 mmol) in 35 mL of CCl4 was heated at reflux (84° C., oil bath) for 2.5 h. After cooling top room temperature, the solution was concentrated in vacuo. Diethyl ether (100 mL) was added and the solution was filtered (to remove the succinimide formed) and concentrated to give a crude oil. The crude oil was purified by silica gel column chromatography using as eluent petroleum ether. 6-(Bromomethyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 8 (2.01 g, 72.5% yield) was obtained as a colourless oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[C:23](Br)=[CH:22][CH:21]=[C:20]2[C:15]=1[CH2:16][CH2:17][C@H:18]([CH3:25])[NH:19]2)[CH:2]=[CH2:3].[CH:26]1([N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:26]1([N:29]2[CH:33]=[C:32]([C:23]3[C:14]([O:13][C:5]4[N:4]([CH:1]=[CH:2][CH3:3])[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=5[N:6]=4)=[C:15]4[C:20](=[CH:21][CH:22]=3)[NH:19][C@@H:18]([CH3:25])[CH2:17][CH2:16]4)[CH:31]=[N:30]2)[CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: C=CCn1c(Oc2c(Br)ccc3c2CC[C@H](C)N3)nc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC=Cn1c(Oc2c(-c3cnn(C4CC4)c3)ccc3c2CC[C@H](C)N3)nc2ccccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of (S)-5-(1-allyl-1H-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoline (0.115 g, 0.29 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.269 g, 1.15 mmol), potassium carbonate (0.118 g, 0.85 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.023 g, 0.03 mmol) in 1,4-dioxane (10 mL) and water (3 mL) stirred for 3 h at 100° C. The reaction mixture was cooled to room temperature, filtered through a short pad of Celite and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:2, ethyl acetate/petroleum ether) to afford (S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-((1-(prop-1-en-1-yl)-1H-benzo[d]imidazol-2-yl)oxy)-1,2,3,4-tetrahydroquinoline (0.106 g, 86%) as a red oil which is mixture of E and Z isomers. MS (ESI, pos. ion) m/z 426 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>C(O)(=O)C.[Zn]>[NH2:2][C:1]1[NH:19][C:10]2[C:9]([C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:18][CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2
Reactant: CCOC(=O)C(C#N)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)[nH]c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Reaction time: 0.58 h

Procedure:
In a 500 mL round-bottom flask were added methyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-3-nitrobenzoate (14.9 g, 51.0 mmol) and zinc dust (16.7 g, 255 mmol) in acetic acid (255 mL) to give a gray suspension. The addition of zinc was done over 35 minutes at room temperature over an atmosphere of nitrogen and was fairly exothermic. The mixture was heated at 100° C. for 15 hours. The mixture was allowed to cool down, filtered through Celite and rinsed with ethyl acetate. Evaporation afforded a residue which was triturated in dichloromethane-hexanes and afforded, after filtration 6.3 g of the title compound. LCMS m/z 263.2 (M+H)+, retention time (on analytical HPLC)=1.90 minutes.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([O:9][C:7]2[CH:6]=[CH:5][C:4]([CH:10]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]3=[O:21])=[C:3]([CH2:1][CH3:2])[CH:8]=2)=[N:24][CH:25]=1
Reactant: CCc1cc(O)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc(C(F)(F)F)cn2)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
4-(2-Ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.100 g, 0.34 mmol) is added to a mixture of 2-fluoro-5-trifluoromethylpyridine (0.061 g, 0.41 mmol) and potassium carbonate (0.110 g, 0.69 mmol) in N,N-dimethylformamide (2 ml), and the mixture is heated at 140° C. under microwave irradiation for 1 hour. The mixture is cooled to room temperature, then acidified by addition of 2M aqueous hydrochloric acid. The mixture is diluted with dichloromethane and passed through a phase separation cartridge. The organic phase is concentrated to around 2 ml, and purified by preparative reverse phase HPLC to give 4-[4-(5-trifluoromethylpyridin-2-yloxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]1([C:44]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[N:48]([CH2:55][CH2:56][O:57][CH:58]3[CH2:63][CH2:62][CH2:61][CH2:60][O:59]3)[C:47](=[O:64])[CH:46]([NH2:65])[N:45]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:65][CH:46]1[N:45]=[C:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[N:48]([CH2:55][CH2:56][O:57][CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)[C:47]1=[O:64])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O)c1cc2ccccc2[nH]1
Yield: 76 %

Procedure:
To a mixture of indole-2-carboxylic acid (0.19 g), N-hydroxybenzotriazole (0.16 g) and N,N'-dicyclohexylcarbodiimide (0.24 g) in chloroform (10 ml) was added a mixture (0.43 g) of (3RS)-1,3-dihydro-5-phenyl-3-amino-1-{2-((RS)-2-tetrahydropyranyloxy) ethyl }-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-amino-1-{2-((SR)-2-tetrahydropyranyloxy) ethyl }-2H-1,4-benzodiazepine-2-one at ambient temperature under stirring. The mixture was stirred for 2 hours under the same conditions. The resultant precipitate was filtered off. The combined filtrate and washings were evaporated under reduced pressure and the residual oil (1.20 g) was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10:1) to give a mixture (white powder, 0.45 g) of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-3-(2 -indolylcarbonylamino )-5-phenyl-1-{2-((SR)-2-tetrahydropyranyloxy) ethyl}-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:2].Br[CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[P:1]([O:23][CH3:24])([O:21][CH3:22])([O:3][C:4](=[C:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:6]=1)=[O:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)n[nH]c2c1
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)nn(CC(=O)C(C)(C)C)c2c1

Procedure:
The title compound was prepared from cyclopentylidene(6-methoxy-1H-indazol-3-yl)methyl dimethyl phosphate and 1-bromo-3,3-dimethylbutan-2-one using the procedure described in Method I Step C of Example 1 followed by RP-HPLC purification using 30-100% MeCN gradient without TFA. It was obtained as a solid following lyophilization. LC-MS: 3.56 min. (m/Z=325.2, 451.2, 473.1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[OH-].[Na+]>C1COCC1.CCO.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1nc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)cc(N2CCC3(CC2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C3)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (190 mg, 0.27 mmol) was added NaOH (100 mg, 0.26 mmol) in 15 mL THF/EtOH/H2O (2/1/2.5), and the reaction was stirred for 12 h at RT. Then, the reaction mixture was concentrated in vacuo to remove most of the organic solvents, and the pH was adjusted to 6 with 1 N HCl. EtOAc was added, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC[C@H](C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 88.1 %

Procedure:
0.29 mol (40.0 g) of p-hydroxybenzoic acid and 0.35 mol (30.9 g) of (S)-(-)-2-methylbutanol were refluxed for 20 hours in 150 ml of toluene in the presence of 1 ml of concentrated sulfuric acid. The reaction solution was concentrated and then purified by column chromatography to obtain 53.2 g of 2-methylbutyl p-hydroxybenzoate [[α]D23 =+4.95° (CHCl3)]. (Yield: 88%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[O:8]C.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(Nc2ncccc2C(=O)Nc2ccc(F)cc2)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1cccnc1Nc1ccc(O)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-(3-fluoro-4-methoxyphenylamino)-N-(4-fluorophenyl)nicotinamide (8.00 g, 22.5 mmol) and DCM (75 mL). The reaction mixture was cooled to 0° C. and BBr3 (10.9 ml, 115 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours, then slowly quenched by pipetting the reaction into a flask (500 mL) containing saturated NaHCO3 (20 mL), water (150 mL). This solution was extracted with EtOAc. The organic layer was dried and concentrated to provide the product 6.25 g (73%). LRMS M−1 (339.9) observed.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(O)CO.[OH-].[K+].Cl>[Cu]I.C(O)(C)C>[C:44]1([S:50][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][CH:3]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: CC(C)O
Product: Oc1cccc(-c2cnc3[nH]cc(Sc4ccccc4)c3c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 17.5 %

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol), copper(I) iodide (1.5 mg, 0.004 mmol), and potassium carbonate (16 mg, 0.155 mmol) under nitrogen atmosphere was added isopropanol (0.2 mL), benzenethiol (8 μL, 0.077 mmol), and ethylene glycol (9 uL, 0.155 mmol). The reaction mixture was stirred at 80° C. for 24 h. A (1:1) mixture of 2 M aqueous KOH and MeOh (1 mL) was added, and the reaction mixture was further stirred at 50° C. for 3 h. The mixture was acidified to pH5 with 1N aqueous HCl and extracted with EtOAc twice. Extracts were combined and concentrated under vacuum. Purification by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier) afforded 3-(3-phenylsulfanyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol as a white solid (4.3 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.74 (dd, J=2.5, 9.0 Hz, 1H), 6.98 (t, J=2.0 Hz, 1H), 7.08 (m, 4H), 7.23 (m, 3H), 7.85 (d, J=2.5 Hz, 1H), 7.98 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 9.55 (broad s, 1H), 12.4 (broad s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])([CH3:5])[CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH2:29]Br>CN(C=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]2[C:23]=1[CH2:29][N:11]([C:9]([C:8]1[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=1[O:6][CH:3]([CH3:5])[CH3:4])=[O:10])[CH2:21]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(N)=O
Reactant: Fc1cccc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cccc(F)c2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50° C., the reaction mixture was cooled to 0° C., and treated by a solution of 0.29 mmol 1,2-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0° C., quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H+], 100%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:18])[CH2:17][CH2:16][C:11]2([O:15]CCO2)[CH2:10][CH2:9]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:18])[CH2:9][CH2:10][C:11](=[O:15])[CH2:16][CH2:17]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Oc1ccccc1C1(O)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCC(O)(c2ccccc2OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 162.9 %

Procedure:
To a solution of of 8-(2-Hydroxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (2.76 g, 8.12 mmol) in 70 mL 1,4-dioxane was added aqueous hydrogen chloride (40.6 mL 1M, 40.6 mmol). The solution was stirred for 30 min., poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo to give the product (1.96 g, 82%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([NH:29][N:30]([C:32]1[CH:37]=[C:36]([C:38]#[N:39])[CH:35]=[CH:34][C:33]=1[F:40])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[F:40][C:33]1[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:32]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CN(NC(=O)OC(C)(C)C)c1cc(C#N)ccc1F
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1cc(C#N)ccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 9.9 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 1.00 g, 4.7 mmol) of in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(5-cyano-2-fluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (700 mg, 2.6 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to give a yellow foam. This was triturated with ether and then petroleum ether and the solvent was removed. The residue was co-evaporated with methanol and the petroleum ether and then further purified on an ISCO system, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol, diethyl ether, and petroleum ether, and then dried under high vacuum at room temperature to give 4-fluoro-3-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzonitrile (84 mg, 10%) as a white foam. APCI(+)-MS (M+H) 326.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[N:18]1([CH2:17][CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: [H][H]
Reactant: c1ccc(COc2cccc(CCCn3ccnn3)c2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1cccc(CCCn2ccnn2)c1
Yield: 91.4 %

Procedure:
To a solution of 1-[3-(3-benzyloxyphenyl)propyl]-1H-1,2,3-triazole (0.937 g) in methanol (32 ml), 10% palladium carbon (0.1 g) was added, followed by vigorous stirring in a hydrogen atmosphere at room temperature for 8 hours. The catalyst was filtered off; the filtrate was concentrated to dryness under reduced pressure to yield the titled compound (0.593 g) as colorless crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=2)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]([C:25]4[C:24]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[CH:41][CH:40]=3)=[O:38])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 0.65 g of 10,11-dihydro-5H-pyrrolo[2, 1-c][1,4]benzodiazepine and 0.52 g of N, N-diisopropylethylamine in 25 ml of methylene chloride is added 1.34 g of 4-[([1, 1'-biphenyl]-2-carbonyl)amino]-benzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.02 g of the desired product as a residue. M+ =482.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.O>[OH-].[Na+]>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2nnn(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)On2nnc3ccc([N+](=O)[O-])cc32)cc1
Yield: 56.1 %

Procedure:
In 1 N aqueous sodium hydroxide (45 ml) is dissolved 1-hydroxy-6-nitro-1,2,3-benzotriazole (7.2 g). To the solution is gradually added p-toluenesulfonyl chloride (7.7 g) with stirring under ice-cooling and further are added thereto ethyl acetate (100 ml) and water (50 ml) and the mixture is stirred for 1 hour. The ethyl acetate layer is separated, dried over magnesium sulfate-charcoal, and concentrated until it becomes about 30 ml. n-Hexane (about 50 ml) is added thereto and the mixture is allowed to stand. The precipitated crystals are separated and dried to give faint yellow needles of 1-(p-toluenesulfonyl-oxy)-6-nitro-1,2,3-benzotriazole (7.5 g), melting point: 142°-144° C. The product is recrystallized from ethyl acetate-n-hexane to give a pure product, melting point: 144° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:7]=1[F:21])[CH3:2].Cl.[NH2:33][OH:34].C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:7]=1[F:21])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[NH:30])[NH:33][OH:34])=[CH:25][CH:24]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a mixture of 8.85 g (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester described in example 3.6 in 515 ml EtOH were added 20.21 g hydroxylamine hydrochloride and 81.1 ml triethylamine. The solution was stirred over night at 50° C., then evaporated. The crude product was isolated by extraction with EtOAc, then purified by chromatography on silica gel (CH2Cl2/MeOH) to yield 7.64 g (RS)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester as a light brown amorphous solid.