Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]#[N:35])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:37].[K+].[K+].OO>CS(C)=O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34](=[O:37])[NH2:35])=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCCCC#N)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCCCC(N)=O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
The nitrile from Example 105 (0.32 g, 0.68 mmol) and potassium carbonate (0.23 g, 1.67 mmol) were slurried in DMSO (5 mL) and cooled to 0° C. in an ice bath. Aqueous hydrogen peroxide (1.5 mL) was added slowly, and the reaction stirred at room temperature for 48 hours. The reaction was quenched by pouring into water, and extracting the aqueous layer with ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to a light tan oil. The material was purified by flash chromatography over silica gel eluting with EtOAc/hexanes/10% NH4OH in MeOH (5:4:1) to provide 0.30 g (89%) of a light tan oil. MS (FD+) 489.62. NMR.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: ON=Cc1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(F)cc1F
Yield: 68.4 %

Procedure:
In a fashion similar to that for preparation 14, 2,4-difluorobenzaldehyde oxime (2.52 g, 16.1 mmol), N-chlorosuccinimide (2.21 g, 16.5 mmol), and dimethyl formamide (25 ml) gave 2,4-difluorobenzoyl chloride oxime (2.11 g, 68%) after chromatography (silica gel, hexanes/ether).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:4]=2[N:3]=1.[Cl-].Cl[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][NH+:21]=1.O>C(O)C.[OH-].[Na+]>[CH3:27][O:26][C:24]1[C:23]([O:28][CH3:29])=[CH:22][N:21]=[C:20]([CH2:19][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:10][C:4]=3[N:3]=2)[CH:25]=1
Reactant: COc1c[nH+]c(CCl)cc1OC
Reactant: FC(F)(F)COc1ccc2[nH]c(S)nc2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc(CSc2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1OC
Reaction time: 20 h

Procedure:
1.0 g of 2-mercapto-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole is dissolved in 15 ml of ethanol and 8.5 ml of 1N sodium hydroxide solution, 0.90 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride are added and the mixture is stirred for 20 hours. After addition of 30 ml of water, the mixture is extracted three times with 30 ml of methylene chloride each time, the methylene chloride phase is washed once with 5 ml of 0.1N sodium hydroxide solution, the combined organic phases are dried over magnesium sulfate and, after the drying agent has been filtered off, the filtrate is completely concentrated. 1.51 g (94% of theory) of the title compound are obtained as an amorphous solid residue of m.p. 55°-57° C.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][SiH:15]([Cl:17])[Cl:16]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:7]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][Si:15]([Cl:17])([Cl:16])[Cl:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOCCOc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: Cl[Si](Cl)(Cl)CCCOCCOc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
Under a nitrogen atmosphere, 8 mg of hexachloroplatinic acid are added to 178 g (1.0 mol) of 2-allyloxyethyl phenyl ether, the preparation of which is described above under a), and the mixture is heated to 70° C. 169 g (1.25 mol) of trichlorosilane are added dropwise to the mixture over a period of 2 hours and the mixture is stirred for a further 2 hours at 70° C. The crude product is purified by distillation in vacuo, giving 250 g of 3-(2-phenoxyethoxy)propyltrichlorosilane having an acid number of 531.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([O-])=O>C(O)C.O.[Fe]>[N:16]1[CH:15]=[CH:14][C:13]([S:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH2:3])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1Sc1ccncc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Sc1ccncc1
Yield: 81.4 %

Procedure:
To a refluxing mixture of iron powder (3.15 g, 56.82 mmol) and ammonium chloride (380 mg, 7.1 mmol) in ethanol (45 mL) and water (8 mL) was added 4-(2-nitrophenylsulfanyl)-pyridine (AMR01105, 2.4 g, 10.33 mmol) and the resulting mixture was stirred at reflux for 2 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated to give 2-(pyridin-4-ylsulfanyl)-phenylamine (1.7 g, 81%) as a yellow solid, mp 103-107° C., which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Fc1cccc(Cl)c1CN1CCNCC1

Procedure:
Synthesized according to General Procedure A: 2-chloro-6-fluorobenzyl chloride (4{7}, 5 mL, 39.1 mmol, 1 equiv.), piperazine (20.2 g, 234.8 mmol, 6 equiv.), THF (85.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{7} (6.92 g, 77%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.14-7.08 (m, 2H), 6.94-6.86 (m, 1H), 3.62 (d, 2H, J=2.0 Hz), 2.78 (t, 4H, J=4.8 Hz), 2.44 (br s, 4H), 1.40 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 161.8 (d, JC-F=247.5 Hz), 136.4 (d, JC-F=6.0 Hz), 128.8 (d, JC-F=9.6 Hz), 125.2, 123.6 (d, JC-F=18.0 Hz), 113.7 (d, JC-F=23.3 Hz), 54.0, 52.8, 45.9.
Reaction SMILES: ClC1C(OCC(F)F)=C(C2C=C(F)C([C@H](NC(=O)C)C)=NC=2)C=C(Cl)C=1.BrC1C=C(Cl)C=C(Cl)C=1OCC(F)F.ClC1C(OCC(F)F)=C(C2C=C(F)C([C@H](N)C)=NC=2)C=C(Cl)C=1.C1C2C(COC(=O)[NH:80][C:81]3([C:85](=[O:109])[NH:86][C@@H:87]([C:89]4[C:94]([F:95])=[CH:93][C:92]([C:96]5[CH:101]=[C:100]([Cl:102])[CH:99]=[C:98]([Cl:103])[C:97]=5[O:104][CH2:105][CH:106]([F:108])[F:107])=[CH:91][N:90]=4)[CH3:88])[CH2:84][O:83][CH2:82]3)C3C(=CC=CC=3)C=2C=CC=1>>[Cl:103][C:98]1[C:97]([O:104][CH2:105][CH:106]([F:107])[F:108])=[C:96]([C:92]2[CH:93]=[C:94]([F:95])[C:89]([C@H:87]([NH:86][C:85]([C:81]3([NH2:80])[CH2:84][O:83][CH2:82]3)=[O:109])[CH3:88])=[N:90][CH:91]=2)[CH:101]=[C:100]([Cl:102])[CH:99]=1
Reactant: C[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)COC1)c1ncc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F
Agent: CC(=O)N[C@H](C)c1ncc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F
Agent: C[C@@H](N)c1ncc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F
Agent: FC(F)COc1c(Cl)cc(Cl)cc1Br
Product: C[C@@H](NC(=O)C1(N)COC1)c1ncc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F

Procedure:
The title compound was prepared in analogy to intermediate 1 synthesizing N—((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-acetamide in step A (using 1-bromo-3,5-dichloro-2-(2,2-difluoro-ethoxy)-benzene (intermediate 9) instead of 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole), (R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylamine in step B and [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester in step C. White foam. MS: 464.1 [M+H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.[NH2:20][C:21]1[O:22][CH2:23][C@:24]2([N:47]=1)[C:37]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:32]=1[O:31][C:30]1[C:25]2=[CH:26][C:27]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[C:43]#[N:44])=[CH:28][C:29]=1[F:39]>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.CN(C=O)C>[NH2:20][C:21]1[O:22][CH2:23][C@:24]2([N:47]=1)[C:37]1[CH:36]=[C:35]([C:6]3[CH:11]=[N:10][CH:9]=[CH:8][N:7]=3)[CH:34]=[CH:33][C:32]=1[O:31][C:30]1[C:25]2=[CH:26][C:27]([O:40][CH2:41][C:42]([CH3:45])([CH3:46])[C:43]#[N:44])=[CH:28][C:29]=1[F:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cnccn3)ccc1O2
Temperature: 100 °C

Procedure:
To a flask charged with Pd(PPh3)4 (8.82 mg, 0.034 mmol), 2-(tributylstannyl)pyrazine (248 mg, 0.672 mmol), and (S)-3-(2-amino-2′-bromo-5′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile (150 mg, 0.336 mmol) was added 3 ml of DMF. The resulting mixture was heated in the microwave at 100° C. for one hour. The solution was concentrated in vacuo and the derived residue was purified by HPLC (gradient elution 10-90% MeCN/H2O, 0.1% TFA) to afford (S)-3-(2-amino-5′-fluoro-2′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile as a white solid. MS m/z=446.0 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1cccc2ccncc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=[N+]([O-])c1ccc(F)c2cnccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of 8-fluoroisoquinoline (Description 41; 1.24 g, 8.4 mmol) in concentrated sulfuric acid (10 ml) cooled to between −5° C. and 0° C. was added slowly, over 10 minutes, a solution of potassium nitrate (0.93 g, 9.24 mmol) in concentrated sulfuric acid (5 ml). The mixture was stirred at 0° C. for 30 minutes after which time TLC indicated that reaction was complete. The mixture was poured onto ice (100 g) and basified by the careful addition of 33% aqueous ammonium hydroxide. The mixture was extracted with dichloromethane (3×150 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered through a 1 inch plug of silica gel. The silica gel plug was further washed with 150 ml of a 1:1 mix of ethyl acetate and iso-hexanes. The combined organics were evaporated to give the title compound (1.33 g, 82%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:27][CH:26]=2)[C:21](O)=[O:22])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:37][NH2:38].C1COCC1.O>ClCCl>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:20]([NH:19][C:17]([C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:10])=[O:9])=[O:18])[C:21](=[O:22])[NH:38][CH3:37])=[CH:30][CH:29]=1
Reactant: CN
Reactant: COCCCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OCCCOC)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1

Procedure:
To (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-methoxy-propoxy)-phenyl]-propionic acid (98 mg, 0.19 mmol) in dichloromethane (3 mL) was added, a 2.0M methyl amine solution in THF (97 μL, 1.9 mmol), PyBoP (87 mg, 0.19 mmol) at room temperature. Upon reaction completion water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane/ethyl acetate, 80/20 as eluant) to produce 35 (34%) mg of (S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid {(S)-2-[4-(3-methoxy-propoxy)-phenyl]-1-methylcarbamoyl-ethyl}-amide. LC/MS rt=3.95, 536 m/e (M+H). 1H NMR (300 MHz, dmso-d6) 7.93 (d, J=8.2 Hz, 1H), 7.85 (m, 1H), 7.48-7.37 (m, 4H), 7.11 (d, J=8.3 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.51 (d, J=4.5 Hz, 1H), 4.25 (m, 1H), 3.95 (t, J=6.5 Hz, 2H), 3.61 (m, 1H), 3.42 (t, J=6.2 Hz, 2H), 3.30-3.21 (m, 5H), 3.15 (m, 1H), 2.90-2.83 (m, 1H), 2.73-2.66 (m, 1H), 2.54 (d, J=4.8 Hz, 3H), 1.95-1.97 (m, 2H), 1.50-1.25 (m, 2H), 1.50-1.05 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:22])(=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.[H-].[Na+].[Br:32][C:33]1[CH:34]=[N:35][C:36](Cl)=[N:37][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:32][C:33]1[CH:34]=[N:35][C:36]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:21])(=[O:22])[NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:6]=2[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[N:37][CH:38]=1
Reactant: Cc1ccc(NS(=O)(=O)Nc2ncnc(OCCO)c2-c2ccc(C)cc2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NS(=O)(=O)Nc2ncnc(OCCOc3ncc(Br)cn3)c2-c2ccc(C)cc2)cc1
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To 4-methyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(p-tolyl)-4-pyrimidinyl]-amide (47 mg, Example 11) dissolved in THF (8 ml) was added sodium hydride (14.6 mg, 60% dispersion in mineral oil) and stirring was continued for 15 min followed by the addition of 5-bromo-2-chloro-pyrimidine (39 mg). Stirring was continued for 2 h at 50° C. and 80 h at r.t. The mixture was evaoprated and a 10% citric acid solution was added. The precipitate was filtered off, washed with water and purified by chromatography over silicagel with EtOAc/Hex=1/1 to give 4-methyl-phenyl sulfamic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(p-tolyl)-4-pyrimidinyl]-amide (34 mg). tR=5.34 (LC); [M+H]+=573.02 (ES+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:11][CH2:10][CH:9]([NH:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][CH:5]=1)[CH3:19]
Reactant: CC(CNC(=O)OC(C)(C)C)Nc1ccc([N+](=O)[O-])c(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CN)Nc1ccc([N+](=O)[O-])c(N)n1

Procedure:
N6-(2-Amino-1-methylethyl)-3-nitropyridine-2,6-diamine trifluoracetate (Example 40A) is prepared in analogy to Example 40A from tert-butyl {2-[(6-amino-5-nitropyridin-2-yl)amino]propyl}carbamate (Example 39A) (560 mg, 1.8 mmol), trifluoroacetic acid (2.0 ml, 27 mmol) in dichloromethane (20 ml). 900 mg of the crude product are obtained thus as a solid.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc2sc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 147.4 g of dibenzothiophene in 1.6 liters of carbon tetrachloride, cooled in an ice bath, was added a filtered solution of 122.7 g of anhydrous aluminum chloride in 425 ml of dichloromethane and 65.4 ml of acetyl chloride at 10° C., over 45 minutes. The mixture was stirred for 20 minutes, then a mixture of 2.5 liters of crushed ice and 500 ml of concentrated hydrochloric acid was added in one portion. This mixture was stirred vigorously until the yellow color disappeared. The aqueous layer was separated and washed in 100 ml of carbon tetrachloride. The wash was combined with the organic layer, washed with two 2 liter portions of water, dried and evaporated. The residue was crystallized from 250 ml of toluene and 750 ml of ether, giving 85.9 g of the desired product as colorless crystals, mp 107°-110° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28](=[O:36])[NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH:30]1([NH:29][C:28]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([S:15](=[O:17])(=[O:16])[NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:20]=2)=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCCCC3)c3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Cyclohexylcarbamoyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester F-1 (320 mg, 0.62 mmol) was dissolved in 4N HCl/dioxane (10 mL). The reaction was stirred for 2 hours at room temperature and concentrated in vacuo to afford the title compound as its hydrochloride salt. Wt.: 271 mg (97%) 1H NMR (300 MHz, d6-DMSO) δ 8.68 (d, 1H), 8.59 (d, 1H), 8.40 (d, 1H), 8.15 (m, 2H), 7.72 (m, 2H), 7.60 (d, 1H), 3.75 (m, 1H), 3.67 (m, 1H), 3.08 (m, 2H), 2.80 (m, 2H), 2.54 (m, 1H), 1.92 (m, 2H), 1.74 (m, 2H), 1.62 (m, 4H), 1.48 (m, 1H), 1.32 (m, 4H), 1.25 (m, 1H); LC/MS m/z 416 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CC(C)=O>[F:10][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][OH:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(CO)c(F)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a stirred solution of (4-amino-2-fluorophenyl)methanol (100 mg, 0.709 mmol, 1 eq.) in acetone (1.0 mL) was added pyridine (0.17 mL, 2.12 mmol, 3 eq.) followed by phenyl chloroformate (0.092 mL, 0.709 mmol, 1 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated and the resulting residue was purified by CC using ethyl acetate/PE (7:13) as eluent to get phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (110 mg, 60%, off-white solid; TLC system: EtOAc/PE (1:1), Rf: 0.4).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:23]CN(CC)CC.C(OC(=O)C)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:5])[CH3:23])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of 4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 304 mg, 1.00 mmol) in a 1:1 mixture of DCM/TFA (10 mL) was stirred at room temperature for 3 h and concentrated. The residue was dried in vacuo overnight, was taken up in CH2Cl2 (10 mL) and was cooled to 0° C. To this solution, Et3N (280 μL, 2 mmol) was added drop wise, followed by acetic anhydride (102 μL, 1 mmol). The resulting mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature. The reaction mixture was washed with brine, and the organic layer was separated, dried and concentrated. The resulting product was reduced to obtain the title compound (143 mg, 65%) using a procedure similar to Example 4, step (d). 1H-NMR (CDCl3; 400 MHz): δ 6.97 (d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.4 Hz), 4.75 (m, 1H), 3.93 (m, 1H), 3.13 (m, 3H), 2.66 (m, 2H), 2.12 (s, 3H), 1.84 (m, 2H), 1.57 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15](Cl)[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.CC#N.C(O)(C(F)(F)F)=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]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[C:15]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:29])[N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1cc(-n2cnc3ccccc32)nc(NC(C)c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine and 2-methylphenylboronic acid according to the precedure described in EXAMPLE 306, Step C and using [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) as catalyst. Mass spectrum (CH3CN/TFA/NH4O2CH/ESI) 451.3 (M+1).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:25][NH:26][CH3:27]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:25][N:26]([CH3:27])[CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN(C)C)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 4-(3-tosyloxypropyl)benzoate (500 mg) in dimethylformamide (3 mL) is added 2M dimethylamine solution in tetrahydrofuran (2.2 mL) and the mixture is stirred at 50° C. for 15 hours. The reaction mixture is diluted with ethyl acetate, washed with a saturated sodium hydrogencarbonate solution and concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give methyl 4-[3-(dimethylamino)-propyl]benzoate (357 mg, yield; quantitative) as an oil. MS (APCI) m/z; 222 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: BrCCCCCBr
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 70.1 %

Procedure:
In a manner similar to that of Example 1a, by reaction of 5 g (11.6 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 5.2 ml (38.5 mmol) of 1,5-dibromopentane. 4.7 g of ethyl 4′-(5-bromopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=70%).