Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C.[Pt]>[NH2:7][C:5]1[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]([CH3:1])[CH:6]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)c1cc(N)cn1C
Reaction time: 16 h

Procedure:
Ethyl 1-methyl-4-nitro-2-pyrrolecarboxylate (16.0 g, 0.081 mol) (M. J. Weiss, J. S. Webb and J. M. Smith, J. Amer. Chem. Soc., 79, 1266 (1957)) is dissolved in (200 mL) ethanol and (1.60 g) of 10% platinum on carbon is then added. The mixture is shaken for 16 hours in a PARR hydrogenator. The catalyst is removed by filtration through a pad of celite and the filtrate is concentrated in vacuo to a yellow oil. The oil is carried on directly without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([OH:22])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(O)c3c2c1COC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(=O)CCC3
Reaction time: 6 h
Yield: 15.3 %

Procedure:
0.7 g of 5-hydroxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is hydrogenated in 50 ml of ethanol with 0.5 g of Raney nickel at a hydrogen pressure of 80 bars and a temperature of 100° C. for 6 hours. After filtering off of the catalyst, the solvent is evaporated in a vacuum. The residue is chromatographed on silica gel with dichloromethane and ethanol=10+1. 0.108 g of 4-methoxymethyl-5-oxo-5,6,7,8-tetrahydro-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 249°-250° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=O)=O)=[CH:15][CH:14]=1>C(O)(=O)C.CO>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:21]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cccc([N+](=O)[O-])c3nc2-c2ccc(C)cc2)cc1

Procedure:
1.84 g (12 mmol) of 2,3-diaminonitrobenzene and 2.38 g (10 mmol) of 4,4′-dimethylbenzil were dissolved in 40 g of a mixed solvent of acetic acid and methanol (1:1) and reacted at a reaction temperature of 80° C. for 4 hours. After completion of the reaction, the solvent was removed and the resulting reaction product was extracted by means of a silica gel column.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([NH:33][CH2:34][CH:35]5[CH2:37][CH2:36]5)[S:31][CH:32]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([NH:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)[S:31][CH:32]=2)=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cn3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1CSc1ccc(-c3csc(NCC4CC4)n3)cn1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-pyridin-2-ylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.386 g, 0.693 mmol) in anhydrous DCM (16 mL) at room temperature add trifluoroacetic acid (15.9 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to a RediSep° column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-{5-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-pyridin-2-ylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.315 g, 99%). MS (ES+) m/z: 457.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:4]1.[ClH:16]>C(O)C>[ClH:16].[NH2:8][C@H:6]1[CH2:7][C@@H:3]([CH2:2][OH:1])[CH:4]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Agent: Cl
Solvent: CCO
Product: N[C@@H]1C=C[C@H](CO)C1

Procedure:
(+)-(1S,4R)-tert-Butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate (part b of this example, 10.66 g, 50.0 mmol) was refluxed in absolute ethanol (25 mL) with concentrated hydrochloric acid (5.0 mL, 60 mequiv) for 2.5 hours. Evaporation of volatiles left title compound as white solid; mass spectrum (ES): 114 (M+1); 1H-NMR (DMSO-d6) δ: 7.9 (m, 3H), 6.03 and 5.75 (two m, 2H), 4.11 (m, 1H), 3.41 (d, J=5.4 Hz, 2H), 2.8 (m, 1H), 2.36 (m, 1H), 1.4 (m, 1H). This solid was used immediately in the following example.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)=O.Cl.[NH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=1)[NH2:21]>C(O)C>[CH3:15][C:9]1[CH:8]=[C:7]([C:5]2[N:20]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=3)[N:21]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)cc1C
Temperature: 25 °C
Yield: 43.3 %

Procedure:
4,4,4-Trifluoro-1-(3-methyl-4-methoxylphenyl)-1,3-butanedione (0.78 g, 3 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride (0.671 g, 3 mmol) were mixed in ethanol (60 ml), and the resulting reaction mixture was heated at reflux temperature for 72 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc (250 ml), and the organic layer was washed with saturated NaHCO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified first by flash chromatography using 40% hexane in methylene chloride to and then by recrystallization from 3:1 of isooctane:methylene chloride to give the title compound (535 mg, 43%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16](=[O:18])[CH3:17])[C:12]([CH3:14])=[CH2:13])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:3])[CH3:2]>CCO.O=[Pt]=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16](=[O:18])[CH3:17])[CH:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: C=C(C)C(OC(C)=O)c1ccc(OC(C)=O)c(OC)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc(C(OC(C)=O)C(C)C)ccc1OC(C)=O

Procedure:
1.0 g (3.6 mmol) diacetate 13 is dissolved in 17 ml EtOH and hydrogenated over PtO2. The catalyst is removed by filtration over Celite and the solvent is evaporated. Flash chromatography of the crude product gave 0.83 g (82% by weight) of compound 14 in the form of a yellowish oil having the following 1H NMR (CDCl3) values: 0.81 (d, J=7.0, CH3); 0.98 (d, J=7.0, CH3); 1.98-2.15 (m, 1H, CH); 2.08 (s, CH3); 2.30 (s, CH3); 3.82 (s, OCH3); 5.46 (d, J=7.0, CH); 6.84-7.02 (m, 3 aromatic H). MS: 280 (8, [M+]), 238 (38), 195 (56), 153 (100), 43 (68).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH:14]=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[S:7][CH:8]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(CCl)cs2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The HCl salt of 4-(chloromethyl)thiazol-2-amine (10 mmol) was suspended in DCM (50 ml), and 2,4-dimethoxybenzaldehyde (1.0 eq. of) and DIEA (1.0 eq.) were added. To the mixture, acetic acid (1 ml) was added followed by addition of sodium triacetoxyborohydride (2.5 eq.) and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was concentrated and purified by column chromatography using 0-10% gradient of 7 N ammonia/MeOH and DCM to give 4-(chloromethyl)-N-(2,4-dimethoxybenzyl)thiazol-2-amine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 84.9 %

Procedure:
A mixture of 4-nitrophenyl 2-iodobenzenesulphonate (0.405 g), 4-isobutylphenylboronic acid (obtained as described in European Patent Application, publication No. 0569193) (0.179 g), tetrakis(triphenylphosphine)palladium(0) (0.058 g), toluene (15 ml), ethanol (10 ml) and 2M sodium carbonate solution (5.5 ml) was stirred vigorously and heated under reflux for 5 hours. Water (20 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column to give 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.349 g); 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 7.1-7.25 (m,4H), 7.35 (d,2H), 7.55 (d,1H), 7.7 (t,1H), 7.9 (t,1H), 8.05 (d,1H), 8.2 (d,2H); mass spectrum (+ve FAB, DMSO/methanol/NBA): 412 (H+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:15]=[O:16])=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][CH2:18][O:14][C:11]1[CH:10]=[C:9]([CH:15]=[O:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cc(O)ccc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(-c2ccc(Cl)cc2)c(C=O)c1
Temperature: 70 °C

Procedure:
A mixture of EXAMPLE 125A (0.5 g), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.771 g) and cesium carbonate (1.4 g) was suspended in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column purification with 0-5% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>CCOC(C)=O>[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: OB(O)c1ccccc1O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccccc3O)nc12

Procedure:
1-[2-(2-Hydroxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 2-hydroxybenzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 5-70% EtOAc in hexanes as eluant gave 53 mg (28%) of a yellow solid. MP 282-283° C., M+H=296.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[S:32]1C=C[CH:34]=[C:33]1CC(O)=O.[CH3:41][O:42][C:43](=[O:66])[C@H:44]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:45][C:46](=[O:61])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][C:48]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:41][O:42][C:43](=[O:66])[C@H:44]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:45][C:46](=[O:61])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][O:54][C:33](=[S:32])[CH3:34])=[CH:49][C:48]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(COC(C)=S)cc1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To triphenylphosphine (1.2 equivalents) in THF at −78° C. is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added followed by the resultant compound from Example 115A (1. equivalent) in THF. The reaction is stirred at −78° C. for 1 h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2CO3 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on silica gel to afford the title product.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[F:22].CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][OH:11]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
DIBAL (115.7 mL, 1.0 M in toluene) was added at −78° C. to a solution of 2-fluoro-3-nitrobenzoic acid methyl ester (compound 2b-1) (9.22 g, 46.3 mmol) in toluene (92 mL), and the reaction mixture was stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. The resultant reaction solution was cooled again to −78° C., and methanol, aqueous saturated Rochelle salt solution and ethyl acetate were added thereto. The reaction mixture was then stirred at room temperature for 1 hour, and extracted three times with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The title compound (7.52 g, 95%) was then obtained by vacuum concentration as a brown oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:15][CH3:16])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)([O:15][CH3:16])[O:7][CH3:6])=[CH:20][CH:19]=1
Reactant: COC(OC)c1ccncc1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(Cc1ccc(F)cc1)(OC)c1ccncc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
315 mL of n-butyllithium 1.6 M solution in hexane is added dropwise to a solution of 70.3 g (0.46 mole) of 4-dimethoxymethyl-pyridine in 1.4 L of tetrahydrofuran under nitrogen at −70° C. After 30 min. at −70° C., 73 g (0.505 mole) of 4-fluorobenzyl chloride in 280 mL of tetrahydrofuran is added dropwise. After 10 more min. at −70° C., the reaction mixture is allowed to reach room temperature and then stirred for 30 further min. The reaction mixture is poured into 2 L ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the residue is purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 114 g of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14].[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:22]([NH:26][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: COc1ccc(C(=O)O)cc1NC(=O)Nc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCCNC(=O)c1ccc(OC)c(NC(=O)Nc2cnccn2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a stirred solution of 4-Methoxy-3-(3-pyrazin-2-yl-ureido)-benzoic acid (32 mg; 0.11 mmol) in N-methyl pyrrolidinone (1 mL) was added O-benzotrazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU; 45 mg; 0.12 mmol), butyl amine (12 μL; 0.12 mmol), and diisopropylethylamine (35 μL; 0.20 mmol). The reaction was stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (20 mL) and 10% aqueous sodium carbonate (20 mL) and stirred for 5 minutes. A precipitate formed which was filtered and dried under reduced pressure to yield an off white solid (49% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=1)[CH:7]=[CH:6]2.[O:36]1CCCC1.CO.S(O)([O-])(=O)=O.S(O)(OO)(=O)=O.[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][C:31]([S:34]([CH3:35])=[O:36])=[CH:32][CH:33]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(SC)s3)ccc2c1
Reactant: C1CCOC1
Agent: O=S(=O)(O)OO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)=O)s3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add 1-(2-(4-(6-methoxy-2-(5-(methylthio)thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine (84 mg, 0.17 mmol), tetrahydrofuran (3.3 mL) and methanol (3.3 mL) to a round bottom flask under nitrogen. Cool the resulting solution to 0° C. and add solution of potassium peroxymonosulfate sulfate (102 mg; 0.17 mmol) in water (1.7 mL). Stir the resulting mixture at 0° C. for 30 min. Load the mixture onto an SCX acidic ion exchange column. Flush the column with 1:1 methanol/dichloromethane and elute with 1:1 2M ammonia in methanol/dichloromethane. Concentrate the ammonia containing eluent in vacuo to give the title compound (87 mg, 0.17 mmol): mass spectrum (m/z): 522 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11](/[CH:14]=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=3[CH3:25])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CO.[H][H]>C1COCC1>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([S:11]([CH2:14][CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=3[CH3:25])(=[O:13])=[O:12])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Cc1cc(C(=O)O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)OCCO2
Reactant: [H][H]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC2(CC1)OCCO2
Yield: 90.7 %

Procedure:
Pd(OH)2—C (20.0 g) was added to a solution of 4-[(E)-2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-vinyl]-3-methyl-benzoic acid (20.0 g, 54.43 mmol) in THF (600 ml)-methanol (200 ml), and the mixture was stirred at room temperature overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was then concentrated under reduced pressure to give 4-[2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-ethyl]-3-methyl-benzoic acid as a white solid (18.23 g, 90.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>CC(C)=O.[Cl-].[Na+].O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[CH:14][CH:13]=3)[N:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(-n2nccc2-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2nc(COc3ccc(-n4nccc4-c4ccncc4)cc3)ccc2c1
Temperature: 60 °C
Yield: 69.6 %

Procedure:
To a solution of 4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenol (82 mg) in acetone was added potassium carbonate (153 mg) and 2-Chloromethyl-quinoline (95 mg) and the reaction mixture heated at 60° C. for 18 h. The reaction mixture was poured into brine and extracted with ethyl acetate, dried magnesium sulfate, filtered and concentrated. Purification via combiflash MPLC provided the title compound (91 mg). 1H NMR (400 MHz, CDCl3) δ 8.51 (m, 2 H), 8.20 (d, J=8.7 Hz, 1 H), 8.06 (d, J=8.7 Hz, 1 H), 7.83 (d, J=7.1 Hz, 1H), 7.74 (m, 2H), 7.65 (d, J=8.7 Hz, 1 H), 7.57 (m, 1H), 7.20 (d, J=8.7 Hz, 2 H), 7.09 (d, J=5.8 Hz, 2H), 7.02 (d, J=9.1 Hz, 2H), 6.60 (d, J=1.7 Hz, 1H), 5.39 (s, 2H); MS: (M+H m/z=379.0).
Reaction SMILES: ClP(C(C)(C)C)C(C)(C)C.Br[C:12]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:16]=[CH:15][C:14]=2[CH:13]=1.[C:30]1([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:37]1([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:12]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH:16]=[CH:15][C:14]=3[CH:13]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1cc2ccc3ccccc3c2c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(N(c2ccccc2)c2cc3ccc4ccccc4c3c3ccccc23)cc1
Temperature: 60 °C

Procedure:
190 μl (1 mmol) of chlorodi-tert-butylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a suspension of 15.3 g (50 mmol) of 5-bromobenzo[c]phenanthrene, 10.2 g (60 mmol) of diphenylamine and 7.7 g (80 mmol) of sodium tert-butoxide in 500 ml of toluene, and the mixture is subsequently heated under reflux for 5 h. After the mixture has been cooled to 60° C., 500 ml of water are added, the organic phase is separated off, filtered through silica gel, evaporated virtually to dryness at 80° C. in vacuo, and 300 ml of ethanol are then added. After cooling, the solid is filtered off with suction. The product is purified by recrystallisation from dioxane five times (about 8 ml/g). Yield: 12.6 g (32 mmol), 64.1%, purity 99.9% (HPLC).