Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=3)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:21])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[O:21]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])[NH:1]1
Reactant: CCO
Reactant: O=C(O)c1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1Cc2c(cccc2-c2cccc(C(=O)O)c2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To the suspension of 3-(1H-indol-4-yl)-benzoic acid (7.58 g, 33 mmol) in t-BuOH: ethanol: acetic acid (150 mL: 100 mL: 50 mL) was added pyridinium tribromide (31.66 g, 99 mmol) portionwise. The mixture was stirred at room temperature for 2 hours, and then to the mixture was added with acetic acid (150 mL). Water (4 mL) and Zinc dust (13.07 g, 200 mmol) was added to the reaction mixture portionwise and stirring was continued at room temperature for 2 hours. The solvent was removed under reduced pressure. The oily residue was suspended in 1N HCl (400 mL) and stirred at room temperature overnight. The precipitate solid was collected by filtration, purified by recrystallization from ethyl acetate to give (6.4 g, 77%) of 3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzoic acid as a pinkish white solid.
Reaction SMILES: [C:1]([CH:9]1[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1C=CC=CC=1.O>[O:15]=[C:14]1[NH:13][CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]1[CH:1]1[O:8][CH2:23][CH2:24][O:25][C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1C(=O)c1ccccc1
Reactant: OCCO
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1C1OCCOc2ccccc21

Procedure:
A mixture of 2.0 g (6.5 mmole) of 27d, 1.25 g (20.0 mmole) of ethyleneglycol, and 1.0 g of p-toluenesulfonic acid monohydrate is refluxed in 50 ml of benzene in a Dean-Stark apparatus until the collection of water ceases. The reaction mixture is cooled, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and filtered. The filtrate is stirred with 2.2 g (10 mmole) of di-t-butyldicarbonate at reflux temperature and then concentrated to a solid residue and recrystallized from benzene/hexane to yield the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)[CH3:4].C(N(CC)C(C)C)(C)C.[N:23]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[C:24]=[O:25]>ClCCCl>[CH:26]1([NH:23][C:24](=[O:25])[NH:2][CH:3]([C:5]2[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=2)[CH3:4])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(C(C)N)s1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(C)NC(=O)NC2CCCC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride (33.2 mg, 0.150 mmol) and N,N-diisopropylethylamine (104 μL, 0.60 mmol) dissolved in 1,2-dichloroethane (1 mL) was added isocyanatocyclopentane (24 mg, 0.22 mmol). The reaction solution was shaken at room temperature overnight. The solution was further diluted with DCE (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The layers were separated and the organic layer concentrated to afford methyl 5-(1-(3-cyclopentylureido)ethyl)thiophene-2-carboxylate as an oil residue. LC-MS: (FA) ES+ 297.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCC.C[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:19]=2)=[CH:14][CH:13]=1>ClCCl>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nn(-c3ccc(C)cc3)c3ncccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCS
Solvent: ClCCl
Product: Cc1ccc(-n2nc(-c3ccc(O)cc3)c3cccnc32)cc1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
In 250 ml of dichloromethane was suspended 22.4 g of anhydrous aluminium chloride. While stirring, 22.4 ml of butylmercaptan was added. After the mixture was stirred at room temperature for 1 hour, 17.7 g of 3-(4-methoxyphenyl)-1(4-methylphenyl)-1H-pyrazolo[3,4-b]pyridine was added thereto under ice-cooling. After the mixture was stirred at room temperature for 4 hours, the reaction mixture was poured into about 1 l of ice-water. The resulting crystals were collected by filtration, washed with water and recrystallized from methanol to give 13.8 g of 3-(4-hydroxyphenyl)-1-(4-methyl- phenyl)-1H-pyrazolo[3,4-b]pyridine, m.p. 201°-203° C.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH:3]=[O:4]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1=CCC(CCC(C)C=O)C1(C)C

Procedure:
A mixture of 111 g (0.58 mole) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal, 2.7 g of 5% palladium on carbon and 80 ml of ethanol was hydrogenated at 30°-40° C and 40-55 psi until hydrogen uptake ceases. The mixture was filtered to remove the catalyst and the solvent removed by distillation. The residual oil was fractionally distilled to yield 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butanal. Yield 110.7 g (98.4% theory); bp 60°-61° (1.4 mm); mol wt. 194 (ms); ir, 3040, 2700, 1728 (s), 800 cm-1 ; nmr, 0.5δ, 0.8, 0.9 and 1.0 (6H, 4 s, geminal dimethyl groups of various diastereomers in the mixture), 1.1 (3H, d, J~7 Hz), 1.3-2.6 (7H, broad complex), 1.6 (3H broad s, olefinic methyl), 5.2 (1 H, broad multiplet, olefinic H), 9.7 (1H, d, J~1.5 Hz, aldehyde H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]=[C:10]([C:13](=[O:34])[NH:14][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[C:19]=2[F:33])[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:15]([NH:14][C:13]([C:10]2[CH2:9][NH:8][CH2:12][CH:11]=2)=[O:34])[CH2:16][CH3:17])=[C:19]([F:33])[C:20]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]
Reactant: CC[C@H](NC(=O)C1=CCN(C(=O)OC(C)(C)C)C1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)C1=CCNC1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 1 h
Yield: 61.5 %

Procedure:
3-{(S)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylcarbamoyl}-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (0.125 g, 0.26 mmol) treated with saturated HCl/EtOAc stirred at ambient for 1 hour, solid filtered off then purified by Prep HPLC to give N-[(1S)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]-2,5-dihydro-1H-pyrrole-3-carboxamide (0.062 g), MS: [M+H] 388
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([C:18]1[S:22][C:21]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)=[CH:20][CH:19]=1)=[O:17])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([C:18]1[S:22][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3[N+](=O)[O-])s2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)s2)CC1
Reaction time: 72 h
Yield: 9.4 %

Procedure:
To a stirred solution of 354 (270 mg, 0.53 mmol) in methanol (25 mL) was added 10% palladium on charcoal (150 mg). The resulting mixture was purged with H2 gas and stirred under a hydrogen atmosphere for 3 days, filtered through a celite pad, evaporated and purified by flash chromatography, eluent 1:1 hexanes-ethyl acetate, to afford the title compound 355 as a white solid (24 mg, 10% yield). 1H NMR: (CD3OD) δ 7.73 (d, J=3.3 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.2, 2.2 Hz, 1H), 7.23-7.19 (m, 2H), 7.01 (dd, J=4.7, 3.7 Hz, 1H), 6.96 (d, J=3.9 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.17 (d, J=13.1 Hz, 2H), 3.00-2.90 (m, 2H), 2.04 (d, J=12.1 Hz, 2H), 1.60-1.54 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[O:7])=[CH:4][N:3]=1.[CH3:20][NH2:21]>CO>[OH:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([NH:21][CH3:20])=[N:3][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Reactant: CN
Solvent: CO
Product: CNc1ccc(C(=O)Nc2ccc(OC)cc2O)cn1
Temperature: 250 °C

Procedure:
6-Chloro-N-(2-hydroxy-4-methoxyphenyl)nicotinamide (0.40 g, 1.44 mol) was mixed with a solution of 8M methylamine in methanol (4 mL) and heated in a microwave reactor at 250° C. for 10 minutes. The solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted five timed with ethyl acetate The pooled organics were dried (MgSO4), filtered and evaporated. The solid was titurated with CH2Cl2, filtered and dried, giving the title compound (0.25 g) as a solid. 1H NMR δ ppm 9.73 (s, 1H) 9.38 (s, 1H) 8.65 (d, 1H) 7.92 (dd, 1H) 7.33 (d, 1H) 7.16 (d, 1H) 6.24-6.58 (m, 3H) 3.70 (s, 3H) 2.83 (d, 3H); MS m/z (M+H) 274; (M−H) 272.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11](=[O:35])[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:40]=[N+:41]=[N-:42])(C)C.[N-]=[N+]=[N-].Cl>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11](=[O:35])[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:42][N:41]=[N:40][N:34]=3)=[CH:25][CH:26]=2)[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 96 h

Procedure:
A mixture of 472 mg of 3-tert.-butoxycarbonylaminomethyl-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine, 206 mg of trimethyltin azide and 12 ml of xylene is boiled for 96 hours; a further 0.2 g of azide is added after 48 hours. The mixture is cooled, treated with ethereal hydrochloric acid and evaporated. Chromatography of the residue (silica gel; methylene chloride/methanol 95:5) yields 3-tert.-butoxycarbonylaminomethyl-6-butyl-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]pyridine; m.p. 105°. The corresponding K salt is prepared therefrom in conventional manner.
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.P(=O)(O)(O)O.[NH2:20][C@:21]1([CH2:42]O)[CH2:25][CH2:24][C@H:23]([C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:29][C:28]=3[CH:27]=2)[CH2:22]1>O>[P:2]([OH:13])([OH:9])([O:3][CH2:42][C@@:21]1([NH2:20])[CH2:25][CH2:24][C@H:23]([C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:29][C:28]=3[CH:27]=2)[CH2:22]1)=[O:1]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@](N)(CO)C3)ccc2C1
Agent: O=P(O)(O)O
Solvent: O
Product: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@](N)(COP(=O)(O)O)C3)ccc2C1
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A mixture of phosphorus pentoxide (150 mg, 0.528 mmol) and 85% phosphoric acid (0.15 mL, 10.01 μmol) was stirred at 100° C. under nitrogen for 1 h before ((1R,3S)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (Example 1, 6 mg, 0.018 mmol) was added. The solution was stirred at the same temperature for 3 h. Water (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 h. Purification using reverse phase HPLC (PHENOMENEX® Luna Axia 5μ c18 30×100 mm, 10 minute run, Solvent A: 10% MeOH: 90% H2O: 0.1% TFA, Solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, and lyophilization gave ((1R,3S)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methyl dihydrogen phosphate (4 mg, 9.38 μmol) as a white solid. LC/MS M+1=410. HPLC retention time=3.96 min (Condition C). 1H NMR (400 MHz, methanol-d4+CDCl3) δ 7.10-6.83 (m, 3H), 4.06-3.77 (m, 2H), 3.20-3.06 (m, 1H), 2.85-2.74 (m, 2H), 2.48 (dd, J=12.9, 6.9 Hz, 1H), 2.40-2.28 (m, 1H), 2.19-2.08 (m, 1H), 2.05-1.90 (m, 4H), 1.80-1.62 (m, 2H), 1.48-1.22 (m, 12H), 0.95-0.86 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:17][CH:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[N:15]=[C:16]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:17][CH:18]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2coc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2coc(-c3cccnc3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)oxazole (1.185 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish suspension was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then carefully poured into ice-water (100 mL) and stirred for 1 hour. The resulting yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallized from ethanol to give 3-nitro-5-(2-(2-(trifluoromethyl)pyridin-3-yl)oxazol-4-yl)benzene-1,2-diol as a yellow solid, 0.627 g, (57%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(OCC(F)(F)F)c2nc(Cl)ccc2n1
Reactant: OB(O)c1ccc(F)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(OCC(F)(F)F)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
To a degassed suspension of 2-amino-4-(trifluoroethoxy)-6-chloro-pyrido[3,2-d]pyrimidine (24 mg, 0.1 mmol), 4-fluorophenyl boronic acid (21 mg, 0.15 mmol), and potassium carbonate (280 mg, 2.03 mmol) in a mixture of dioxane (15 ml) and water (5 ml) was added a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The mixture was refluxed for 45 minutes. The solvents were evaporated in vacuo, and the crude residue was purified by preparative TLC, using a mixture of methanol and dichloromethane (in a ratio of 10:90) as mobile phase, yielding the pure title compound, which was characterised by its mass spectrum as follows: MS (m/z): 339 ([M+H]+, 100).
Reaction SMILES: [N:1](=[C:3]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)O.[H][H].[ClH:19]>O1CCCC1.[Pd]>[ClH:19].[NH2:1][CH:3]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: ON=C1c2ccccc2CC2CCCCC12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: NC1c2ccccc2CC2CCCCC21
Reaction time: 0.5 h

Procedure:
4.3 Parts of a syn-anti-mixture of 9-oximino-1,2,3,4,4a,9,9a,10-octahydroanthracene were dissolved in 40 ml of tetrahydrofuran and 8.7 ml of methanolic hydrochloric acid. 1.3 Parts of a 10% palladium-on-carbon catalyst were added and the mixture was hydrogenated with 896 ml gaseous hydrogen at 30-35° C. and normal pressure within 30 minutes. The catalyst was filtered off, and the filtrate concentrated. 4 Parts of 9-amino-1,2,3,4,4a,9,9a,10-octahydroanthracene hydrochloride, mp. 240-245° C., were obtained. The hydrochloride was dissolved in water, and sodium hydroxide was added to adjust the pH-value to pH 8. The alkaline solution was extracted with ether. The combined etheral phases were dried with Na2SO4, filtered and concentrated. 2.8 Parts (70% of theory) of 9-amino-1,2,3,4,4a,9,9a,10-octahydroanthracene (int. 13), mp. 37-39° C., were obtained. The amine-product consists of a mixture of at least 3 stereochemical isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30]O)[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:33][N:34](CC)[CH2:35]C.CS(Cl)(=O)=O.N(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][N:34]([CH3:35])[CH3:33])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)Cc1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12
Reaction time: 0.08 h

Procedure:
To a solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 50 mg, 116 μmol) in THF was added NEt3 (50 mL, 361 μmol), followed by MsCl (15 μL, 194 μmol). After 5 min, of Me2NH (0.3 mL of a 2M solution in THF, 600 μmol) was added and stirring continued for a further 2 h. The mixture was adsorbed onto SiO2 and purified via column chromatography to give the title compound: RT=1.82 min; m/z (ES+)=458.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.S1(CCCC1)(=O)=O.S(N)([NH2:29])(=O)=O.[OH-].[Na+]>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]#[N:29])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: NS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: N#C/C=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A suspension of 3-(4-fluorophenyl)acrylic acid (2.5 g, 15 mmol) in dry dichloromethane (50 ml) was treated with DMF (2 drops), oxalyl chloride (2.6 ml, 30 mmol) and the reaction was stirred at room temperature under argon for 3 h. The reaction mixture was evaporated to dryness and azeotroped with dichloromethane (25 ml×2) and evaporated to dryness giving a yellow oil. The acid chloride was mixed with sulfolane (15 ml) and treated with sulfamide (1.73 g, 0.018 moles) (A. Hulkenberg and J. J. Troost, Tetrahedron Letters Vol.23, No. 14, 1505-1508, 1982) and the reaction mixture was heated to 120° C. for 3 h. The reaction mixture was cooled, poured into 1N NaOH (100 ml) and extracted with 1:1 diethyl ether:hexane (3×75 ml). The organic extracts were combined, washed with water (3×50 ml), dried (MgSO4) and evaporated to dryness. Purification by flash column chromatography eluted with 2:1 hexane:ethyl acetate gave E-3-(4-fluorophenyl)acrylonitrile as a cream solid (2.12 g, 96%); 1H-NMR (CDCl3) 5.77, 5.83 (1H, d), 7.16 (2H, m), 7.26, 7.40 (1H, d), 7.45 (2H, m). MS (APCI+) M+1=148, C9H6FN requires 147.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH2:26]>C(O)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:26][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1c(F)cccc1F
Solvent: CCO
Product: O[C@H](CNCc1c(F)cccc1F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 2,6-difluorobenzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=96%, [M+H]+=429.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CCO>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH:11]([OH:12])[CH2:13][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@@H:23]2[CH2:27][OH:28])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
6-Fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile (prepared as described above for I-17A and I-17B, Method 1, Steps A-C) (4.80 g, 27.1 mmol) and (R)-4-N-BOC-2-hydroxymethyl-piperazine (commercially available, e.g. from Acesys Pharmatech, catalog #A1612R; and also described in J. Org. Chem., 2007, 72(22), p. 8591-8592) (8.79 g. 40.6 mmol) were suspended in EtOH (30 mL) and heated in a microwave apparatus at 150° C. for 1 h. The reaction mixture was cooled and evaporated to dryness. The residue was purified by chromatography through a 330 g ISCO Redi-sep column eluting with ethyl acetate to 5% MeOH/ethyl acetate gradient to yield the title compound. LC-MS: M+1=394;
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>O1CCCC1>[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)=[O:18]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1F)N1CCN(Cc2ccccc2)CC1
Yield: 87.8 %

Procedure:
To a stirred and cooled mixture (10° C.) of 64 parts of 1-(phenyl-methyl)piperazine and 360 parts of tetrahydrofuran were added during 20 minutes 32.5 parts of 2,4-difluorobenzoyl chloride. Upon complete addition, stirring was continued until room temperature. The formed salt was filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 50 parts (87.8%) of 1-(2,4-difluorobenzoyl)-4-(phenylmethyl)-piperazine as a residue (int. 5).