Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][CH:12]([F:30])[C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][C:23]2([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[N:14][C:13]([CH:12]([F:30])[F:11])=[N:18][CH:17]=1)[CH2:22][C:23]1([C:26]([F:29])([F:27])[F:28])[CH2:25][CH2:24]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=434.0, tR (minutes, Method F)=2.42. [α]D20=+25.30 (c=3.75 mg/mL,CHCl3)
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[Cl:34][C:35]1[C:40]([C:41]2[NH:22][C:20]3[CH:21]=[C:16]([N:14]4[CH2:13][CH2:12][CH2:11][C:10]5([CH2:27][CH2:28][CH2:29][NH:8][CH2:9]5)[CH2:15]4)[CH:17]=[C:18]([CH3:26])[C:19]=3[N:25]=2)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (100:9:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (288 mg, 55%). 1H NMR (CDCl3) δ 1.28-1.72 (8H), 2.57 (s, 3H), 2.57-3.12 (8H), 6.82 (s, 1H), 6.92 (s, 1H), 6.73 (d, J=6 Hz, 1H), 7.98 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[CH:18]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[N:22]=1)([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:18]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH:1][CH2:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=3)=[CH:32][CH:33]=2)[N:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1nc(-c2ccc(C=O)cc2)no1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(-c3noc(C(C)C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate (1 g; 4.22 mmol) in dichloromethane (30 ml) was treated under nitrogen with 4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde (0.96 g; 4.43 mmol), sodium triacetoxyborohydride (0.94 g; 4.43 mmol) and acetic acid (0.24 ml; 4.23 mmol). After stirring at rt overnight, the mixture was concentrated and partitioned between ethyl acetate and 1N NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using an ethyl acetate-hexane gradient (20–70%) followed by a methanol-dichloromethane gradient (1–10%) afforded the title compound (1.5 g; 81% yield).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:33])([CH3:3])[CH3:2].Cl.C(OCC)C>ClCCl>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5](=[O:33])[N:4]([CH:1]([CH3:2])[CH3:3])[C:13]=2[CH:14]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C(C)C)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of ((S)-tert-butyl (1-((6-isopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (160 mg, 0.353 mmol) in anhydrous dichloromethane (4 mL) was added a 2 M solution of HCl in diethyl ether (0.88 mL, 1.76 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude product which was purified by preparative HPLC (10 mM ammonium acetate in water; acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-isopropylbenzo[c][2,7]naphthyridin-5(6H)-one (45 mg, 0.127 mmol, 36% yield) as an off-white solid. LC/MS (ESI) m/e 354.2 [(M+H)+, calcd for C21H28N3O2 354.2]; LC/MS retention time (method C): tR=1.81 min; HPLC retention time (method A): tR=8.85 min; HPLC retention time (method B): tR=9.50 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.43 (d, J=0.75 Hz, 1H), 8.75 (d, J=5.77 Hz, 1H), 8.42 (d, J=9.04 Hz, 1H), 8.22 (d, J=5.52 Hz, 1H), 7.30 (d, J=2.26 Hz, 1H), 7.10 (dd, J=8.78, 2.26 Hz, 1H), 5.26-5.43 (m, 1H), 4.16 (dd, J=9.16, 3.89 Hz, 1H), 3.98 (dd, J=9.29, 7.03 Hz, 1H), 3.27-3.31 (m, 1H), 1.81-1.92 (m, 1H), 1.73 (d, J=7.03 Hz, 6H), 1.41-1.51 (m, 2H), 1.02 (dd, J=9.54, 6.53 Hz, 6H).
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([OH:12])=O)=[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[NH:2][N:1]=[C:5]4[CH2:6][CH2:7][O:8][CH2:9][C:4]=34)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1[nH]nc2c1COCC2
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1COCC2
Yield: 32.5 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid (0.078 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by recrystallization from acetonitrile. Yield 32.5%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 2.79 (t, 2H), 3.89-3.94 (m, 2H), 4.27 (dd, 1H), 4.39 (dd, 1H), 4.48-4.58 (m, 1H), 4.84-4.94 (m, 2H), 6.61 (d, 1H), 7.52 (d, 1H), 7.65 (dd, 1H), 7.69 (d, 1H), 7.80-7.82 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([CH2:21][CH2:22][Cl:23])[C:7]1=[O:17])=[O:5])[CH3:2]
Reactant: ClCCBr
Reactant: CCOC(=O)n1c(=O)[nH]c2cc(OC)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(=O)n(CCCl)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-methoxy-2-oxo-2,3-dihydrobenzimidazole-1-carboxylic acid ethyl ester and 80% NaH (0.38 g; 0.013 mol) in anhydrous DMF was stirred 20 minutes at room temperature. Then 1-bromo-2-chloroethane (1.1 ml; 0.013 moles) was added and the solution was stirred overnight. After cooling, the reaction mixture was poured into water and the separated oil was extracted into ethyl acetate. The organic layer was dried over MgSO4 and evaporated under vacuum to give the crude title compound which was crystallized with diisopropyl ether. White solid. 1.35 g; m.p. 116-118° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][C:15]([NH2:19])([CH3:18])[CH2:16][NH2:17]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][CH2:16][C:15]([CH3:18])([NH2:19])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: CC(C)(N)CN
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2nc(Cl)nc(NCC(C)(C)N)c2c1
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.35 mmol) and 2-methylpropane-1,2-diamine (365 μL, 3.52 mmol) in methanol (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and stirred for 30 minutes. The formed solid was collected by filtration and dried in vacuo to afford 500 mg of the desired product as a white solid (yield was 80.6%).
Reaction SMILES: [K].[CH3:2][S:3]([NH:6][C:7](=O)[CH3:8])(=[O:5])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19]C(CBr)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>CN(C=O)C.O>[N+:10]([C:13]1[CH:20]=[CH:19][C:8]([CH2:7][NH:6][S:3]([CH3:2])(=[O:5])=[O:4])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CC(=O)NS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of N-(methylsulphonyl)acetamide potassium salt (23 g) and 4-nitrobenzyl bromide (24 g) in dry DMF (160 ml) was stirred in an oil bath at 130° for 2 h. After standing overnight at room temperature, a solution of sodium hydroxide (8 g) in water (50 ml) was added and the mixture stirred under nitrogen for 0.75 h. The mixture was diluted with water (900 ml) and the product extracted into ethyl acetate (2×400 ml). The combined extract was washed with brine (3×200 ml), dried (Na2SO4) and evaporated in vacuo to leave an orange solid (22 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:12]2[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CCCCCC2)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCCCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cycloheptyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6](=[O:33])[CH:7]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:16]2=[O:32])C(OCC)=O)C>CO>[CH3:3][O:5][C:6](=[O:33])[CH2:7][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:16]2=[O:32]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2ncn(Cc3ccc(OC)cc3)c(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cc1ccc2ncn(Cc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Sodium hydroxide [2N] (0.59 mL) was added to a solution of 2-[3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-malonic acid diethyl ester (0.250 g, 0.590 mmol) in methanol (5 mL) and stirred at room temperature for several hours. The crude reaction was then evaporated in vacuo, 1N HCl was added and the product was extracted with ethyl acetate to give 0.141 g of [3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid methyl ester. This was dissolved in a mixture of toluene/methanol [8/1] (3 mL) and trimethylsilyldiazomethane [2.0M] (0.22 mL) was added at room temperature and stirred until bubbling has stopped. The reaction was then evaporated in vacuo and purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.119 g (60%) of [3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid methyl ester. Mass spectrum (LCMS, ESI pos.): Calcd for C19H18N2O4; found: 339.1, 340.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:7]2.C(=O)([O-])[O-].[K+].[K+].O.[C:34](Cl)(=[O:36])[CH3:35]>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:34](=[O:36])[CH3:35])[CH2:5]2
Reactant: CC(=O)Cl
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCNC(C)=O)C2
Reaction time: 0.25 h

Procedure:
To a mixture of 8-(4,5,6,7-tetramethoxyindan-2-yl)octylamine (878 mg), potassiumcarbonate (2.54 g),water (16 ml), and ethyl acetate (16 ml) was dropwise added acetyl chloride (0.341 ml) with cooling with ice. After being stirred for 15 min, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization (hexane-ethyl acetate) to give the entitled compound (0.830 g) as crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>Cl.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2nc(CSc3ccc(C)cc3)c(C)o2)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(SCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A mixture of methyl 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate (3.1 g, 8.78 mmol, 1.00 equiv) in 6N hydrochloric acid (90 mL) was stirred overnight at 90° C. The reaction mixture was diluted with 150 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.2 g (74%) of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z): 381 [M+CH3CN+H]+, 340 [M+H]+, 257, 216, 189, 146, 105. H-NMR: 1HNMR (400 MHz, CDCl3, ppm) δ 8.18-8.09 (dd, 4H), 7.30-7.28 (d, 2H), 7.10-7.08 (d, 2H), 3.95 (s, 2H), 2.32 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[S:6][C:5]=2[CH:7]=1
Reactant: N#Cc1c(N)sc2cc(F)ccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(F)ccc12
Yield: 92.4 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile (4.9 g) and 2,4-difluoro-nitrobenzene (4.1 g), 6-fluoro-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (7.8 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=1>C(O)C.[Pd]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=1
Reactant: CCCCCC(O)c1cccc(OCC2C=Cc3ccccc3N2C)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCC2CCc3ccccc3N2C)c1
Reaction time: 2 h

Procedure:
A mixture of 0.88 g (0.0025 mol) N-methyl-1,2,-dihydro-2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline and 0.05 g Pd/C (10%) in 100 ml ethanol was hydrogenated at 50 psi for a period of 2 hours. After filtration and evaporation of the solvent under reduced pressure, the residue was passed through a silica gel column and the desired product was isolated.
Reaction SMILES: C(OC(N1CCN([C:14]([Cl:16])=[O:15])CC1)=O)(C)(C)C.[C:17]([O:21][C:22]([N:24]1[C@H:29]([CH3:30])[CH2:28][NH:27][CH2:26][C@@H:25]1[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C@H:29]([CH3:30])[CH2:28][N:27]([C:14]([Cl:16])=[O:15])[CH2:26][C@@H:25]1[CH3:31])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(C(=O)Cl)C[C@H](C)N1C(=O)OC(C)(C)C

Procedure:
cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared in analogy to 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester from cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by a modified procedure of Rhone-Poulenc DE 25 50 111 (Rhone-Poulenc).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](F)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].Cl.CN.C[CH2:31][N:32](C(C)C)C(C)C>CS(C)=O.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([NH:32][CH3:31])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CNc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Yield: 27.4 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (343) (16 mg, 0.04 mmol), methanamine hydrochloride (15 mg, 0.22 mmol, Sigma-Aldrich), and DIEA (47.4 μL, 0.27 mmol) in DMSO (0.45 mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 2-(3-(tert-butylamino)-2-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (344) (4 mg, 24% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 9H) 2.85 (t, J=6.85 Hz, 2H) 2.95 (d, J=4.30 Hz, 3H) 3.42 (td, J=6.80, 2.45 Hz, 2H) 6.32 (s, 1H) 6.89 (d, J=2.15 Hz, 1H) 6.90 (br. s., 1H) 7.17 (t, J=7.63 Hz, 1H) 7.28 (dd, J=8.02, 1.37 Hz, 1H) 7.30-7.33 (m, 1H) 7.51 (dd, J=7.63, 1.37 Hz, 1H) 12.10 (br. s., 1H). MS (ESI, pos. ion) m/z: 365.3 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 105.7 %

Procedure:
To 3-[2-(4-Amino-1-piperidyl)ethyl]indole (1.307 g.) suspended in a solution of triethylamine (2 mls.) in dichloromethane (10 mls.) at room temperature with stirring was added methane sulphonyl chloride (0.570 g.) in dichloromethane (5 mls.). After stirring for 18 hours the solution was washed with water and the organic phase separated, dried and evaporated to yield the title compound (1.690 g.) as an oil. This was recrystallized from ethanolic hydrogen chloride as the hydrochloride salt (0.560 g., m.p. 241°-242° C.).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:16][NH:15][CH:14]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[C:27]#[N:28])[CH2:21][CH2:20]4)=[O:18])[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:33]([N:15]1[CH2:16][CH:12]([N:10]2[N:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11]2)[CH2:13][CH:14]1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]#[N:28])[CH2:21][CH2:20]1)=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
2-(4-{4-[5-(Phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (2), benzaldehyde and acetic acid (cat) is dissolved in DCM and the solution is stirred for 20 min. Then NaBH(OAc)3 is added. The resulting mixture is warmed to r.t and stirred overnight. The solution is then washed with sat NaHCO3, brine, dried and concentrated to afford 2-(4-{1-Benzyl-4-[5-(phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (I).