Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:43][C:44](=[O:54])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:46])[CH3:42].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:43][C:44](=[O:54])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH:46][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[CH3:42]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and L-phenylalanine ethylester hydrochloride (690 mg, 3 m mole) were suspended in DMF (10 ml) and WSC (0.5 ml) were added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution, ethyl acetate (100 ml) was added, and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-phenylalanine ethylester (1.3 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: C(N(CC)CC)C.[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:14][C:15]1[NH:16][C:17](=[O:33])[C:18]2[C:23](I)=[CH:22][N:21]([C@@H:25]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[CH2:26]3)[C:19]=2[N:20]=1>[Cu](I)I>[NH2:14][C:15]1[NH:16][C:17](=[O:33])[C:18]2[C:23]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][N:21]([C@@H:25]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[CH2:26]3)[C:19]=2[N:20]=1
Reactant: Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: C#CCCCC
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2nc(N)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Copper iodide (38.1 mg, 0.2 mmol), triethylamine (2.8 ml, 2 mmol), tetrakis(triphenylphsophine)palladium(0) (40.5 mg, 0.1 mmol) and 1-hexyne (492 mg, 6 mmol) are added to an argon-flushed solution of compound (58) (390 mg, 1 mmol in 5 ml of dried DMF), and the solution is stirred at room temperature for 24 h. It is then evaporated and the residue is loaded onto a silica gel column (5×25 cm). Title compound (65) is obtained following stepwise elution with 5%, 10% and 20% MeOH in CH2Cl2. Recrystallization from MeCN affords a colorless solid (120 mg, 35%). 1H-NMR ([D6 ] DMSO): δ=0.94 (m, CH3), 1.49, 2.38 (m, CH2), 2.0 (M, Hα --C(2')), 2.35 (m, Hβ --C(2')), 3.50 (m, H2 --C(5')), 3.76 (m, H--C(4')), 4. (m, H--C(3')), 4.88 (t, 5'-OH), 5.18 (d, J=3.5, 3'-OH), 6.27 (m, H--C(1')+NH2), 7.13 (s, H--C(6)), 10.34 (br., NH). MS: m/e 346 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](Cl)=[O:9])[S:4][N:3]=1.[NH2:11][CH:12]([CH:15]([CH3:17])[CH3:16])[C:13]#[N:14].C(N(CC)CC)C>ClCCl>[C:13]([CH:12]([NH:11][C:8]([C:5]1[S:4][N:3]=[C:2]([Cl:1])[C:6]=1[Cl:7])=[O:9])[CH:15]([CH3:17])[CH3:16])#[N:14]
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Reactant: CC(C)C(N)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C#N)NC(=O)c1snc(Cl)c1Cl
Reaction time: 4 h
Yield: 55.6 %

Procedure:
A solution of 3,4-dichloro-5-isothiazolecarboxylic acid chloride (2.1 g) in dichloro-methane (5 ml) was added drop by drop to a solution of 2-amino-3-methyl-butyronitrile (1.2 g) and triethylamine (1.5 g) in dichloromethane (10 ml) under ice cooling. After the addition was completed, the temperature was brought to room temperature, and the mixture was stirred for further 4 hours. The reaction mixture was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluent: chloroformn) to obtain N-(1-cyano-2-methyl-propyl)-3,4-dichloro-5-isothiazolecarboxamide (1.5 g) (mp 120-121° C.).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[C:8]=1[O:23][CH3:24])[CH:2]=[CH2:3].C1C(=O)N(Br)C(=O)C1.[N:34]1([C:40](=[S:42])[NH2:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl.CS(C)=O>[CH2:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:41]=[C:40]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[S:42][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[C:8]=1[O:23][CH3:24])[CH:2]=[CH2:3]
Reactant: NC(=S)N1CCOCC1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Agent: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 2-propen-1-yl[3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (30 g, 82.9 mmol) in DCM (300 mL), NBS (14.8 g, 82.9 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated on the rotovap and the resulting oil was diluted with DMSO (240 mL) and 4-morpholinecarbothioamide (14.8 g 101 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the product of Step A (40 g, 98.8% yield) which was used directly in the next step.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:10]=2)[N:3]=1
Reactant: Cc1cccc(-c2cccc(-c3nc(C)cc(O)n3)n2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2cccc(-c3nc(C)cc(Cl)n3)n2)c1
Yield: 91.9 %

Procedure:
To solution of 4-hydroxy-6-methyl-2-(6-m-tolyl-2-pyridinyl)pyrimidine (5 g) in toluene (100 ml), was added phosphoryl chloride (5 g). The mixture was heated under refluxing for one hourand left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chloro-6-methyl-2-(6-m-tolyl-2-pyridinyl)pyrimidine (4.9 g, yield 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][N:18]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound X) (100 mg, 0.33 mmol) in CH2Cl2 (5 mL) was added DIPEA (0.23 mL, 1.32 mmol) and methanesulfonyl chloride (57 mg, 0.49 mol). The reaction mixture was stirred at room temperature for 1 hour, and then quenched with sat. NH4Cl, then diluted with EtOAc (60 mL). The mixture was washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give 7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound Y) (105 mg, 95%) as yellowish oil. MS: calc'd (MH+) 341, measured (MH+) 341.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2H); 4.07-3.92 (m, 2H); 3.91-3.78 (m, 2H); 3.72-3.52 (m, 3H) and 2.36-2.21 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]([NH:39][NH2:40])=[O:38])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[O:38][C:41](=[O:42])[NH:40][N:39]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(-c4n[nH]c(=O)o4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide (4.5 g, 8.03 mmol) and 1,1′-carbonyldiimidazole (1.43 g, 8.84 mmol) dissolved in acetonitrile (53.6 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one. MS ESI calc'd. for O31H32ClN7O3 [M+H]+ 586. found 586. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.79 (d, J=8.3, 2H), 8.27 (s, 1H), 7.87 (s, 1H), 7.42 (t, J=10.0, 2H), 7.25 (t, J=7.2, 2H), 7.22-7.17 (m, 1H), 4.76 (s, 1H), 4.05-3.81 (m, 4H), 3.80-3.69 (m, 1H), 3.67-3.47 (m, 2H), 3.27 (s, 1H), 1.37 (t, J=13.0, 2H), 1.03 (broad, 1H), 0.83 (broad, 1H), 0.68 (d, J=6.2, 4H), 0.64-0.52 (m, 2H), 0.51-0.27 (m, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:17]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a suspension of 1-(4-chlorophenyl)piperazine dihydrochloride (539 mg) and 3-(chlorosulfonyl)benzoic acid (441 mg) in dichloromethane (50 ml) was added diisopropylethylamine (0.8 ml). After stirring overnight at room temperature the reaction mixture was washed with 2N HCl (3×25 ml) and brine (25 ml), dried over MgSO4, filtered and evaporated to give the title compound as white solid (290 mg, 38%).
Reaction SMILES: [C:1]([CH:5]1[CH2:25][CH2:24][C:8]2([O:12][CH2:11][CH:10](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C-:26]#[N:27].[Na+]>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][CH2:11][CH:10]([C:26]#[N:27])[CH2:9]2)[CH2:24][CH2:25]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC2COC3(CCC(C(C)(C)C)CC3)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC2(CC1)CC(C#N)CO2
Temperature: 100 °C
Yield: 99.4 %

Procedure:
A mixture of 8-t-butyl-3-(p-toluenesulfonyloxy)-1-oxaspiro-(4,5)decane (18.3 g, 50 mmol) and sodium cyanide (4.9 g, 100 mmol) in dry DMF (75 ml) was heated to 100° C. for 6 hours. Light petroleum/ethylacetate 4:1 (50 ml) was added and the mixture was filtrated from insoluble material. The filtrate was then evaporated in vacuo and the resulting residue was taken up in toluene (100 ml). It was washed with water, dried (MgSO4) and evaporated in vacuo to yield a brownish oil (11.0 g) which was Kugelrohr distilled (120°-125° C., 0.015 mbar) to furnish the product as colourless crystals (8.94 g, m.p. 35°-40° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:17]1[N:22]=[C:21]2[N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:34][CH2:33][CH2:32][C:31]=4[CH:35]=3)[N:24]=[N:25][C:20]2=[N:19][CH:18]=1.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:17]2[N:22]=[C:21]3[N:23]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]5[O:34][CH2:33][CH2:32][C:31]=5[CH:35]=4)[N:24]=[N:25][C:20]3=[N:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (37 mg, 0.165 mmoL) in anhydrous DMF (2 mL) was added NaH (60% in oil, 7 mg, 0.18 mmol). The solution was stirred at 23° C. for 15 minutes. 6-Bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (50 mg, 0.15 mmol) was added and the reaction solution was microwaved at 100° C. for 30 min. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (3×10 mL). The combined extracts were dried with Na2SO4, and concentrated to provide {(R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (67 mg, 99% yield).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(C(=O)O)c3ccccc3n2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL pear-shaped flask was added 2-(N-Boc-3-indolyl)-4-quinolinecarboxylic acid or ester (1 mmol) and 3 mL of a 50% mixture of TFA and DCM. The reaction mixture was stirred for 30 min at 20° C. The solvent was removed under reduced pressure and the residual solid lyophilized to give 2-(3-indolyl)-4-quinolinecarboxylic acid or ester (95-100% yield).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1.[CH3:17][N:18](C)C=O.CN.N>ClC(Cl)Cl.CO>[ClH:2].[ClH:1].[CH3:17][NH:18][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: CC(c1ccccc1)n1cncc1CCl
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCc1cncn1C(C)c1ccccc1
Yield: 44.5 %

Procedure:
Through a stirred mixture of 3 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride and 45 parts of N,N-dimethylformamide were bubbled 3 equivalents of gaseous methanamine at room temperature during a 1 hour-period: exothermic reaction, the temperature rose to 50° C. The reaction mixture was taken up in trichloromethane and methanol, previously saturated with ammonia, was added. The formed precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol, dried and crystallized from 2-propanol, yielding 1.6 parts (44.5%) of (±)-N-methyl-1-(1-phenylethyl)-1H-imidazole-5-methanamine dihydrochloride.monohydrate; mp. 109° C. (compound 8.38).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[CH3:18][C:19]([CH3:22])([CH3:21])[CH2:20][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: CC(C)(C)CBr
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)(C)C

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 1-bromo-2,2-dimethylpropane: 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.94 (s, 2H), 2.49 (s, 3H), 1.01 (s, 9H); MS (ES) m/z 295 (M+1).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH:11][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:14]=2[C:13]([F:12])([F:27])[F:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, yellow solid, MS: m/e=395.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,4-bis(trifluoromethyl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]=3[F:38])=[C:7](C3CC3)[N:8]2[C:12]2[CH:13]=N[N:15]([CH2:17][CH2:18]CC(O)=O)[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl.O>[Br:46][C:7]1[N:8]([C:12]2[CH:16]=[N:15][CH:17]=[CH:18][CH:13]=2)[C:9]2[C:5]([C:6]=1[S:26][C:27]1[C:28]([F:38])=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Sc2c(Br)n(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 16 h
Yield: 51.4 %

Procedure:
To a stirred solution of indole 1 (Example 22, Step 2; 60 mg, 0.13 mmol) in CH2Cl2 (5 mL) under inert atmosphere was added NBS (60 mg, 0.33 mmol) at RT and stirred for 16 h. The mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel; 10% EtOAc/hexanes) to afford compound 2 (35 mg, 50%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.81-8.80 (m, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.40-7.37 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 7.16-7.13 (m, 1H), 4.33 (q, 2H), 1.32 (t, J=7.5 Hz, 3H); MS: m/z 525.3 (M++2).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=O>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C(=O)/C=C/N(C)C)c1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: COc1cccc(-c2ccnn2-c2cc(C#N)ccn2)c1
Yield: 98 %

Procedure:
The title compound was prepared in 98% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.78 (3H, s), 6.53 (1H, s), 6.81-6.85 (2H, m), 6.90-6.93 (1H, m), 7.24-7.28 (1H, m), 7.38 (1H, dd, J=5.6, 1.2 Hz), 7.77 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.44 (1H, dd, J=5.2, 0.8 Hz).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α-Bromo-p-chloroacetophenone (4.64 g) in acetonitrile (50 ml) was treated with 1,2,4-triazole (1.4 g) followed by triethylamine (2 g). The mixture was stirred at room temperature for two hours and refluxed for one hour. The solvent was removed under reduced pressure and the residue was treated with water to give a yellow solid which was filtered, washed with water and dried. Crystallisation from ethanol-petroleum ether (60°-80°) gave α-1,2,4-triazol-1-yl-p-chloroacetophenone as cream coloured plates.