Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:15]([O:14][C:12]([C:4]1[CH:3]=[C:2]([C:25]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:13])[CH3:16]
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)c1cc(Br)c2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccccn2)c2ccccc2n1
Temperature: 77.5 °C
Yield: 50.3 %

Procedure:
A mixture of ethyl 4-bromoquinoline-2-carboxylate (2.80 g, 10.0 mmol, J. Org. Chem. 1947, 12, 456), triethylamine (1.7 mL, 12 mmol), bis(triphenylphosphine)-palladium(II)chloride (0.561 g, 0.80 mmol), CuI (0.114 g, 0.60 mmol), and 2-ethynylpyridine (1.11 g, 10.8 mmol) in CH3CN (80 mL) is heated at 75-80° C. for 18 h in a sealed tube. Additional triethylamine (0.85 ml, 6.1 mmol), bis(triphenylphosphine)palladium (II) chloride (0.23 g, 0.40 mmol), and CuI (0.055 g, 0.29 mmol) is added and the mixture heated for an additional 18 h. The mixture is concentrated in vacuo and partitioned between water and chloroform. The chloroform extracts are washed with brine and evaporated. The residue is chromatographed on SiO2 (50% ethyl acetate/hexanes) to yield 1.52 g (50%) of a yellow solid. Precipitation from ethyl acetate gave the title compound as yellow crystals: mp 129-131° C.; MS ES+ m/e 303 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C(O)(=O)C.[O-:18][C:19]#[N:20].[K+]>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([NH:10][C:19]([NH2:20])=[O:18])[CH:11]=[CH:12][CH:13]=1
Reactant: COCCCOc1cccc(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COCCCOc1cccc(NC(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a flask containing 3-(3-methoxypropoxy)aniline (11A) (2.00 g, 11.04 mmol) was charged a 100 mL solution of 80% glacial acetic acid and 20% water. This mixture was chilled to 0° C. A solution of potassium cyanate (1.34 g, 16.56 mmol) in 5 mL of water was slowly added portion-wise to the reaction mixture. The reaction was then stirred for about 1 hour at RT. The glacial acetic acid was then removed under reduced pressure. The resulting white solid residue was then rinsed with copious amounts of water then dried under vacuum to give title compound 11B (1.70 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86-1.95 (m, 2H) 3.24 (s, 3H) 3.46 (t, J=6.32 Hz, 2H) 3.94 (t, J=6.32 Hz, 2H) 5.82 (br. s., 2H) 6.45 (dd, J=8.08, 2.27 Hz, 1H) 6.81 (d, J=7.33 Hz, 1H) 7.00-7.17 (m, 2H) 8.49 (s, 1H). ESI-MS: m/z 225.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=3[O:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)[CH:32]=3)[N:23]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccc(C(F)(F)F)cc1Nc1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
A mixture of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.23 g, 0.99 mmol), 2-methoxy-5-trifluoromethyl-phenylamine (0.226 g, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.185 g, 0.2 mmol), dicyclohexyl-(2′-4′-6′-triisopropyl-biphenyl-2-yl)-phosphane (0.19 g, 0.4 mmol), and sodium tert-butoxide (0.29 g, 3.0 mmol) in toluene (10 mL) was degassed with nitrogen for 3 minutes, then heated at 100° C. for 2 hours under argon. The reaction was cooled to room temperature, diluted with dichloromethane, filtered through diatomaceous earth, and concentrated. The residue was diluted with dichloromethane, washed with 10% sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated. The crude product was triturated with ether and dichloromethane to give (2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine (0.23 g, 68%). MP=144-146° C. MS=343 (MH)+. 290b) N(8)-(2-Methoxy-5-trifluoromethyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine, 3-(4-methylpiperazin-1-yl)aniline with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.005 g, 20%). MP=198-200° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.44 (s, 1H), 8.37 (d, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.30 (m, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.93 (m, 1H), 6.48 (m, 1H), 3.97 (s, 3H), 3.10 (m, 4H), 2.45 (m, 4H), 2.21 (s, 3H). MS=498 (MH)+.
Reaction SMILES: [Cl:1][C:2]1C(C(F)(F)F)=CN=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20]C)=[CH:15][CH:14]=2)[N:3]=1.O=P1(CC2C=CC(N)=CC=2)OCCCO1.ClC1N=C(Cl)[C:47]([C:51]([F:54])([F:53])[F:52])=[CH:46][N:45]=1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][P:18]3(=[O:25])[O:19][CH2:20][CH2:24][CH2:23][O:22]3)=[CH:26][CH:27]=2)[C:47]([C:51]([F:54])([F:53])[F:52])=[CH:46][N:45]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: Nc1ccc(CP2(=O)OCCCO2)cc1
Product: O=P1(Cc2ccc(Nc3nc(Cl)ncc3C(F)(F)F)cc2)OCCCO1

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 4-[(2-oxido-1,3,2-dioxaphosphinan-2-yl)methyl]aniline (Compound 230C) and 2,4-dichloro-5-trifluoromethylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH:5][CH3:6].N1C=CC=CC=1.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[N:5]([CH3:6])[C:20](=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: CNc1ccc(Cl)c(Cl)c1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)CC(=O)N(C)c1ccc(Cl)c(Cl)c1

Procedure:
Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried and concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.
Reaction SMILES: BrCS[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: BrCSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
51.3 g (300 mmol) of m-bromomethylthiobenzene was added dropwise to a dichloromethane (350 ml) solution containing 47.9 g (359.6 mmol) of aluminum chloride and 42.4 g (300 mmol) of benzoyl chloride which was cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (35) as 58.1 g (189 mmol, yield of 63%) of a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:4]1[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[C:11](=[O:12])[CH:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][C@H:4]1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 233.6 %

Procedure:
Methyl 1-ethyl-5-oxo-4-(phenylmethyl)-prolinate (0.024 g, 0.09 mmol) was dissolved in methanol (0.5 ml) and cooled to 0° C. in an ice-bath. 2M aqueous sodium hydroxide (0.137 ml, 0.27 mmol) was added to the mixture and stirring continued at 0° C. for 3 hrs. The solvent was evaporated and the residue was acidified by treatment with 2M aqueous hydrogen chloride (˜0.2 ml) to give a cloudy solution. Evaporation then gave crude 1-ethyl-5-oxo-4-(phenylmethyl)-proline (0.052 g) as a mixture of white solids and yellow oily residues. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([N+:24]([O-])=O)[CH:11]=2.C1COCC1.O.CN(C=O)C>C(O)(=O)C.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:24][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH2:5][C:4]1[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[CH:3]=1)[C:18]1[CH:17]=[N:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]2=1
Reactant: CCOC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(Cc3cccc(Cl)c3)c2cn1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2c3cc(N)ccc3n(Cc3cccc(Cl)c3)c2cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
A solution of ethyl 9-(3-chlorobenzyl)-6-nitro-9H-β-carboline-3-carboxylate (2.7 g, 6.59 mmol) and titanium(III) chloride (36 mL, 20% solution, 46.75 mmol) in a mixture of acetic acid (54 mL), THF (180 mL), water (54 mL) and DMF (10 mL) was stirred for 5 hours at ambient temperature. The reaction mixture was quenched with water (200 mL), and extracted with ethyl acetate (100 mL). The pH of the water layer was adjusted to 7 with saturated Na2CO3 aqueous solution. Then, the resulting precipitate was filtered and dried in vacuo. The product was extracted from the precipitate with CHCl3 in a Soxhlet extractor and purified by chromatography with ethyl acetate to provide the title compound (0.70 g, yield 27.8%). 1H NMR (DMSO-d6): δ 9.06 (s, 1H), 8.70 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 7.45 (s, 1H), 7.27–7.31 (m, 3H), 7.09 (s, 1H), 7.01 (d, 1H, J=8.0 Hz), 5.75 (s, 2H), 5.05 (s, 2H), 4.36 (q, 2H, J=7.0 Hz), 1.35 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 380.1/382.1=3/1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:23][C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)[O:26][N:25]=1>CC#N>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:23][C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)[O:26][N:25]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cc(F)cc(F)c3)n2)c1Cl
Temperature: 95 °C
Yield: 76.1 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile (0.23 g, 1.0 mmol) in anhydrous MeCN (5 mL) was added Cs2CO3 (0.38 g, 1.15 mmol) and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (0.27 g, 1.15 mmol). The mixture was heated in a sealed tube at 95° C., under N2, for 1 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (2-30% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.32 g, 77% yield): 1H NMR (400 MHz, acetone-d6) δ 7.91 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.70 (m, 2H), 7.45 (t, J=53.4 Hz, 1H), 7.42 (tt, J=9.0, 2.4 Hz, 1H), 7.20 (s, 1H), 5.95 (s, 2H); MS (ES) m/z 421 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(F)cc2)cc1
Yield: 63.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>ClCCl>[OH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:3]2([CH2:2][NH:1][S:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:10][CH:11]=1
Reactant: NCC1(Cc2ccc(CCO)cc2)CCCC1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1(Cc2ccc(CCO)cc2)CCCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 300 mg (1.086 mmol) of 2-(4-{[1-(aminomethyl)-cyclo-pentyl]methyl}phenyl)ethanol (EP 472 449), 30 ml of dichloromethane and 537.6 μl (3.857 mmol) of triethylamine is added dropwise, at −20° C., a solution of 310.1 mg (1.222 mmol) of 3-pyridinesulfonyl chloride in 10 ml of dichloromethane. The mixture is allowed to warm to room temperature slowly (over 3 hours) and is stirred for a further 2 hours. The reaction medium is then washed with water and dried over Na2SO4. After concentrating the organic phase under vacuum, the oil obtained is purified by flash chromatography on silica gel with a dichloromethane/methanol mixture (99/1). 266 mg of an amorphous white solid are obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl.O1CCOCC1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
tert-Butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (29 mg, 0.078 mmol) from Step A was treated with 4 N hydrogen chloride in 1,4-dioxane (0.5 mL, 2 mmol) for 3 hours at room temperature. The solvent was removed under a stream of nitrogen and the residue basified with aqueous sodium bicarbonate and extracted with 2×2 mL of dichloromethane. The extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.35 (t, J=7.9, 1H), 7.06 (d, J=7.6, 1H), 6.91 (s, 1H), 6.77 (dd, J=8.3, 2.4, 1H), 3.23-3.14 (m, 3H), 3.11 (dd, J=12.0, 5.7, 1H), 2.95 (dd, J=9.7, 4.4, 1H), 2.80-2.70 (m, 1H), 2.37-2.29 (m, 1H), 2.05 (ddt, J=16.5, 12.9, 6.3, 1H), 1.94-1.84 (m, 1H), 1.82-1.60 (m, 2H), 1.47-1.29 (m, 2H); MS (ESI+) m/z 271 (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:15])[NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)C=CC=CC=1.[N:16]1([CH2:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[NH:9][C:8]([N:19]1[CH2:20][CH2:21][N:16]([CH2:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:18]1)=[O:15]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Product: O=C(Nc1nccs1)N1CCN(Cc2cnc3ccccc3c2)CC1

Procedure:
The title compound was prepared from thiazol-2-yl-carbamic acid phenyl ester and 3-piperazin-1-ylmethyl-quinoline in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 9.03 (d, J=2.0 Hz, 1H), 8.24-8.20 (m, 2H), 7.94 (d, J=8.1 Hz, 1H), 7.86-7.81 (m, 1H), 7.70-7.66 (m, 1H), 7.43 (d, J=3.3 Hz, 1H), 6.98 (d, J=3.5 Hz, 1H), 3.87 (s, 2H), 3.73-3.69 (m, 4H), 2.68 (bs, 4H).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6](=[O:20])[C:7]([N:11]1[C@H:14]([S:15][C:16](=[O:18])[CH3:17])[CH2:13][C:12]1=[O:19])=C(C)C>CO>[CH3:4][O:5][C:6](=[O:20])[C:7]([N:11]1[C@H:14]([S:15][C:16](=[O:18])[CH3:17])[CH2:13][C:12]1=[O:19])=[O:1]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SC(C)=O
Reactant: O=[O+][O-]
Solvent: CO
Product: COC(=O)C(=O)N1C(=O)C[C@H]1SC(C)=O

Procedure:
4 equivalents of ozone are introduced over a period of 60 minutes into a solution, cooled to -15°, of 150 mg of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 3 ml of methanol. The reaction mixture is rinsed with nitrogen, diluted with methylene chloride and washed for 2 minutes with a 5% aqueous sodium bisulphite solution. The organic phase is dried over sodium sulphate and concentrated in vacuo. IR spectrum of the resulting oily title compound (in methylene chloride): characteristic bands at 3.30-3.40, 5.52, 5.70, 5.83 (sh), 5.86, 6.98, 7.08 (sh), 7.40, 7.82-8.00 (broad, sh), 8.07, 8.19, 8.30 (sh), 8.46, 8.90, 9.22, 9.52, 9.91, 10.30 and 10.73μ. The product obtained can be used in the next stage without further purification.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>>[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH:49][CH:18]1[CH2:19][CH2:20][N:15]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: CN(C)CCN
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
The titled compound was prepared by the procedure as outlined in example 118, by reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) with N,N-dimethylethylenediamine (0.026 mL) and purified by HPLC and isolated as its tri-TFA salt; MS (ES+) 573.7 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]2[C:8]([NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[O-:25][CH2:26][CH3:27].[Na+]>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:25][CH2:26][CH3:27])[N:7]2[C:8]=1[NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC[O-]
Reactant: Clc1ccccc1-c1nc2cccc(Br)n2c1NC1CCCCC1
Agent: [Na+]
Product: CCOc1cccc2nc(-c3ccccc3Cl)c(NC3CCCCC3)n12

Procedure:
5-bromo-2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine 42 (152 mg, 0.376 mmol) was added to sodium ethoxide [generated in situ by addition of sodium metal (17.32 mg) to absolute ethanol (10 ml)]. The mixture was heated under reflux for 8 h. Excess solvent was removed in vacuo and the resultant mixture was treated with water before been extracted into ethyl acetate, dried over magnesium sulphate and filtered. Excess solvent was removed under reduced pressure to give an oil that was purified by column chromatography, eluting with hexane:ethyl acetate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CN(CCOCCN=[N+]=[N-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCOCCN)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
A solution tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 37.2 g of crude tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellow liquid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[CH:4]1)[CH3:2].Cl.C(N(CC)CC)C.[N-:24]=[N+:25]=[N-:26].[Na+]>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[NH:26][N:25]=[N:24][N:15]=2)=[CH:4]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1cc(-c2nnn[nH]2)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) was treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and was heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer was then washed with additional NaHCO3 (2×). The combined aqueous phases were acidified to pH 2 with 6N HCl. The resultant thick precipitate was extracted with hot EtOAc (3×) and the combined organic phases were washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.