Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].Cl>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a mixture of 8.0 g benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate (23.5 mmol) and 11 g CoCl2 (47 mmol) in 100 mL MeOH was added 8.6 g (225 mmol) of NaBH4 portion-wise and then stirred at rt for 1 hr. To the reaction mixture was added 3N HCl until the black precipitate dissolved. The resulting mixture was concentrated to remove MeOH and the residue was extracted twice with ether. The aqueous layer was basified with 1N NaOH and then extracted twice with ethyl acetate. The combined extracts were concentrated to give an oil that was purified by MPLC chromatography (ISCO, 50% hexane/ethyl acetate, 40 g+12 g stacked column) to give 5.8 g of benzyl 4-(4-aminophenyl)piperazine-1-carboxylate. LCMS: (M+H)+=312.25.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[Cl:39][C:40]1[CH:41]=[C:42]([CH:52]=[CH:53][C:54]=1[Cl:55])[O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>>[Cl:39][C:40]1[CH:41]=[C:42]([CH:52]=[CH:53][C:54]=1[Cl:55])[O:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)c3cccc(Oc4ccc(Cl)c(Cl)c4)c3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-((3-(3,4-Dichlorophenoxy)phenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3-(3,4-dichlorophenoxy)benzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[NH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added 3-aminopentane (0.596 ml, 5.12 mmol). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 432.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.5 (2H, m), 1.6 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([NH:33][C@H:34]([C:39](O)=[O:40])[CH2:35][C:36](=[O:38])[NH2:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:39]([C@@H:34]([NH:33][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[CH2:35][C:36]([NH2:37])=[O:38])=[O:40])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC(N)=O)NC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-benzoyl-L-asparagine (70 mg, 0.3 mmol) which was prepared in step A this example. The final product was purified by preparative HPLC to yield 14 mg (9%) of the desired material.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)C>[C:3]([CH:2]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: C=CCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCC(C(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 91 %

Procedure:
Ethyl acetoacetate (6.57 g, 0.05 mol) was dissolved in ethanol (25 ml) and sodium ethoxide (3.9 g, 0.55 mol) was added. The solution was cooled to room temperature and 4-bromo-1-butene (6.96 g, 0.05 mole) was added. The mixture was refluxed for 5 hours. The resulting solution was filtered, ethyl acetate was added (75 ml), and washed with a solution of hydrochloric acid (2×200 ml, 5N) and brine (100 ml). The organic layer was dried (MgSO4), filtered, and solvent removed under reduced pressure to give ethyl 2-acetyl-5-hexenoate in the form of a light yellow liquid (9.29 g) in 91% yield.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1)#[N:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:5]=1)#[N:2]
Reactant: Clc1ccncc1
Reactant: N#CCc1cn(N)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: N#CCc1cn(Nc2ccncc2)c2ccccc12
Temperature: 90 °C
Yield: 126.4 %

Procedure:
3-Cyanomethyl-1H-indol-1-amine (12 g) and 4-chloropyridine hydrochloride (12 g) were combined in isopropanol (250 ml). After stirring at reflux (90° C.) for six hours, the mixture was poured into water (500 ml) and stirred five minutes. Thereafter the pH of the mixture was adjusted to 10 with sodium carbonate and the mixture was extracted with ethyl acetate (2x). The organic layer was washed with water (2x), brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil (22 g). This oil was eluted on a silica gel column with ethyl acetate. Fractions containing product were combined and concentrated to an oil (16 g) which solidified upon standing. A portion of this solid was recrystallized from ethanol/ether (1:20) to give the title compound as a solid (2 g), m.p. 152°-153° C.
Reaction SMILES: [CH3:1][N:2]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1)(=[O:5])=[O:4].ClCCl.C(O)C>CO.[H][H].[Pd]>[CH3:1][N:2]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: [H][H]
Reactant: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1N

Procedure:
1.5 g (4.4 mmol) of 4-methylamino-3-nitrobenzenesulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)amide were dissolved in 100 mL methanol and catalytically hydrogenated at room temperature and under 5 bar hydrogen pressure (10% palladium on charcoal). Then the catalyst was filtered off and the filtrate was evaporated down. The resulting oily product was further reacted without any purification. Yield: 1.4 g (100% of theory), C14H24N4O2S (312.4); Rf value: 0.33 (silica gel; dichloromethane/ethanol=4:1).
Reaction SMILES: [H-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:14]1[O:19][CH2:18][CH2:17][O:16][N:15]=1)=[CH:11][O:12][CH3:13].[O:20]([C:27]1[C:32]([F:33])=[C:31](F)[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[O:20]([C:27]1[C:32]([F:33])=[C:31]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([C:14]2[O:19][CH2:18][CH2:17][O:16][N:15]=2)=[CH:11][O:12][CH3:13])[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC=C(C1=NOCCO1)c1ccccc1O
Reactant: Fc1ncnc(Oc2ccccc2)c1F
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC=C(C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2)c1F
Temperature: 20 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
0.119 g of potassium hydride (60% suspension in mineral oil) is added to a solution of 0.7 g (0.00298 mol) of 3-[1-(2-hydroxyphenyl)-2-methoxyethen-1-yl]-5,6-dihydro-1,4,2-dioxazine and 0.6 g (0.00288 mol) of 4-phenoxy-5,6-difluoropyrimidine in 10 ml of dimethylformamide at 0° C., and the mixture is then stirred for 12 hours at 20° C. The reaction mixture is poured into water and extracted using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (1:1). 0.4 g (82% of theory) of 3-{1-[2-(4-phenoxy-5-fluoropyrimid-6-yloxy)-phenyl]-2-methoxyethen-1-yl}-5,6-dihydro-1,4,2-dioxazine is obtained.
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:2].[BH4-].[Na+]>O1CCCC1>[OH:2][CH2:1][CH:3]1[CH2:4][CH:5]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH:8]([CH2:7][CH2:6]2)[CH2:9]1
Reactant: O=CC1CC2CCC(C1)N2C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C2CCC1CC(CO)C2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 84B (3.4 g) in tetrahydrofuran (40 mL) was added NaBH4 (0.5 g). The mixture was stirred overnight. The solvent was evaporated and the residue was added to ethyl acetate (300 mL) and water (50 mL). The organic layer was washed with water and brine, dried over Na2SO4, and filtered. Evaporation of the solvent gave the crude title compound.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([O:18][C:19]2[CH:41]=[CH:40][C:22]3[C:23]4[N:27]([CH2:28][CH2:29][O:30][C:21]=3[CH:20]=2)[CH:26]=[C:25]([C:31]2[N:32]([CH:37]([CH3:39])[CH3:38])[N:33]=[C:34]([CH3:36])[N:35]=2)[N:24]=4)([CH2:12]OS(C)(=O)=O)[CH2:6]OS(C)(=O)=O)[CH2:3][CH2:2]1>C(N)C1C=CC=CC=1>[CH2:23]([N:24]1[CH2:6][C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)([O:18][C:19]2[CH:41]=[CH:40][C:22]3[C:23]4[N:27]([CH2:28][CH2:29][O:30][C:21]=3[CH:20]=2)[CH:26]=[C:25]([C:31]2[N:32]([CH:37]([CH3:39])[CH3:38])[N:33]=[C:34]([CH3:36])[N:35]=2)[N:24]=4)[CH2:12]1)[C:22]1[CH:40]=[CH:41][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC4CC4)cc2OCC3)n(C(C)C)n1
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(CC5CC5)CN(Cc5ccccc5)C4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C

Procedure:
A solution of methanesulfonic acid 2-cyclopropylmethyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-3-methanesulfonyloxypropyl ester from Example 283 (90 mg, 0.1476 mmol) in benzylamine (1 mL) was heated at 180° C. for 2.5 h using microwave irradiation. After cooling to RT, the crude reaction mixture was purified by column chromatography (C18, gradient 30-65% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording the title compound as a colourless gum (65 mg, 84%). LCMS (Method B): RT 2.66 min [M+H]+ 525
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[CH:23])=[N:18][CH:19]=2)=[CH:10][CH:9]=1.I[C:25]1[CH:36]=[CH:35][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1>C1COCC1.[Cu]I>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:35][CH:36]=3)=[N:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C#CCOc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(CN2CCCC2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(OCC#Cc3ccc(CN4CCCC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Under an N2 atmosphere 221 mg (0.68 mmol) Cs2CO3, 4 mg (0.02 mmol) CuI and 23 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 110 mg (0.45 mmol) 5-(4-chloro-phenyl)-2-prop-2-ynyloxy-pyridine and 129 mg (0.45 mmol) 1-(4-iodo-benzyl)-pyrrolidine in 9 mL THF and the reaction mixture is stirred for 4.5 h at RT. The mixture is evaporated down i. vac., the residue is combined with 20 mL 3% NH3 solution and 40 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by HPLC and then by chromatography (silica gel, DCM/MeOH/NH3 19:1:0.1).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([C:34]([OH:36])=O)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)CCl.Cl.[CH3:42][O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH2:46]>ClCCl>[CH3:42][O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH:46][C:34](=[O:36])[C@@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
HOBt (4 equivalents, 2038 mg, 15.08 mmol), N-methylmorpholine (3 equivalents, 11.3 mmol), N-benzyloxycarbonyl-D-leucine (1.0 equivalent, 1000 mg, 3.8 mmol), EDC (2 equivalents, 1441 mg, 7.5 mmol) and again N-methylmorpholine (2 equivalents, 7.5 mmol) are added successively at −10° C. to a solution of L-leucine methyl ester hydrochloride (1.1 equivalents, 753.2 mg, 4.15 mmol) in dichloromethane p.a. (20 ml). The reaction mixture warms slowly (about 12 h) to RT, whereby complete conversion of the amine component is observed by means of HPLC. The reaction mixture is concentrated, taken up in ethyl acetate (about 200 ml) and then washed with a saturated aqueous sodium hydrogen carbonate solution (once), 5% aqueous citric acid (twice), a saturated aqueous sodium hydrogen carbonate solution (once) and a saturated sodium chloride solution. The mixture is dried over sodium sulfate and filtered. The mixture is evaporated to dryness in vacuo and then dried further under high vacuum. 1483 mg (93% of theory) of the title compound are obtained, which is reacted without further purification.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].C(O[SiH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[C:19]([F:35])[CH:18]=2)[CH2:13][CH2:12]1)C>C1COCC1>[CH2:1]([Si@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[C:19]([F:35])[CH:18]=2)[CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: CCO[SiH]1CCC(c2cc(F)c(-c3ccc(OC(F)(F)F)cc3)cc2F)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2cc(F)c(-c3ccc(OC(F)(F)F)cc3)cc2F)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 8.8 g (20 mmol) of 4'-(4-ethoxy-4-silacyclohexyl)-2',5'-difluoro-4-trifluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-2',5'-difluoro-4-trifluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 7.5 g of the trans isomer (yield 85%).
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:11][O:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.CS(OCC1COC(=O)N1[C:31]1[CH:36]=[CH:35][C:34](Cl)=[CH:33][CH:32]=1)(=O)=O>>[C:13]1([N:8]2[CH:7]([CH2:6][O:5][C:31]3[CH:32]=[CH:33][C:34]([C:9]([O:10][CH3:11])=[O:12])=[CH:35][CH:36]=3)[CH2:11][O:10][C:9]2=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)OCC1COC(=O)N1c1ccccc1
Product: COC(=O)c1ccc(OCC2COC(=O)N2c2ccccc2)cc1
Yield: 60 %

Procedure:
The same procedure of Example 22 was repeated except that 3-phenyl-2-oxooxazolidin-4-ylmethyl methanesulfonate obtained in Reference Example 20 was used in lieu of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl methanesulfonate to give the title compound (compound 177) in a yield of 60%.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: C=C(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
One hundred milligrams (0.2744 m mol) of 4-[(1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid in 5 ml of absolute ethanol were hydrogenated in the presence of 50 mg of palladium/charcoal (10%) at 20° C. and at a hydrogen pressure of 1 bar under shaking. After 1.5 hours the catalyst was filtered off, and the filtrate was evaporated in vacuo.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH:43]1[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([OH:42])[CH2:44]1
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)c3c(N4CCCC(O)C4)cc(-c4ccc[nH]4)c1c23
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (230 mg, 0.40 mmol) and 3-hydroxy-piperidine (Aldrich, 1.23 g, 12.13 mmol) in DMF (15 ml) was heated to 120° C. for 1.5 hours. The mixture was cooled and NaH (Aldrich, 140 mg, 5.83 mmol) was added in small portions with stirring. After 30 minutes at room temperature and then 20 hours at 120° C. the mixture was cooled and poured into a mixture of ethyl acetate and water. The aqueous layer was extracted few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 60% ethyl acetate in hexanes) and further purified by HPLC (silica gel, 35% ethyl acetate in hexanes) and a precipitation out of THF with excess of pentane to give 6-fluoro-5-(3-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 45 mg, 31%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:10][C:9]=2[F:27])=[CH:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>ClCCl>[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40]([N:2]2[CH2:7][CH2:6][C:5]([C:8]3[C:9]([F:27])=[CH:10][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][N:21]5[CH:25]=[CH:24][N:23]=[N:22]5)[O:17][C:16]4=[O:26])=[CH:12][C:13]=3[F:14])=[CH:4][CH2:3]2)=[O:41])[CH2:37][O:36]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCNCC2)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (650 mg, 1.64 mM) in dry dichloromethane (20 ml) at 0–4°, was treated with pyridine (648 mg, 8.2 mM) followed by dropwise addition of (4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl chloride (430 mg, 2.64 mM). The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water and brine, dried (sodium sulfate) and evaporated to a gum which crystallised readily on trituration with diethyl ether to give the title compound (788 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:10]2[C:11]3[C@@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 150 mg, 0.49 mmol), tetrabutylammonium iodide (181 mg, 0.49 mmol) and 4-chlorobenzyl bromide (400 mg, 1.95 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 60-70% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give an off-white solid. This was dissolved in ethanol and the solution was treated with charcoal, then filtered through Celite and evaporated. 1H NMR indicated that there was some tetrabutylammonium iodide present. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed with saturated aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and chromatographed, eluting with 75% ethyl acetate/petroleum ether, to give (4S,7R)-1-(4-chloro-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (100 mg, 48%). APCI(+)-MS (M+H) 429.