Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=[CH2:5].[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][O:20][C:21]2[CH:29]=[CH:28][C:24]([CH:25]=[N:26][OH:27])=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]1[O:27][N:26]=[C:25]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:9]([CH3:8])[CH:18]=3)=[CH:29][CH:28]=2)[CH2:5]1
Reactant: C=CC(OC)OC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: COC(OC)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 100 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 3,3-dimethoxy-propene and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 4-[4-(5-dimethoxymethyl-4,5-dihydro-isoxazol-3-yl)-phenoxymethyl]-2-methyl-quinoline (0.4 g, 100%) as a crude oil. MS found: (M+H)+=393.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@:24]([OH:28])([CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][C@:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
(R)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 66.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (32.3 mg, 0.261 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial and treated with a mixture of DME (553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 45.3 mg, 0.065 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Silica, from 23% to 28% in 6 min) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=0.94 min, m/z=460.4 [M+H]+, m/z=458.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.67-1.83 (m, 2H) 2.96 (d, J=10.54 Hz, 1H) 3.03 (d, J=10.54 Hz, 1H) 3.18-3.26 (m, 1H) 3.38-3.47 (m, 1H) 4.75 (s, 1H) 7.36 (d, J=8.28 Hz, 2H) 7.82-7.90 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.79 (d, J=2.38 Hz, 1H) 8.89 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[C:15]1([CH2:14][O:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCOc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCCOc2cc(OCc3ccccc3)ccc21
Temperature: 60 °C
Yield: 64.5 %

Procedure:
A mixture of 8-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Preparation 26) (8.66 g, 48.3 mmol), benzyl bromide (6.32 ml, 53.2 mmol) and potassium carbonate (20.04 g, 145 mmol) in DMF (80 ml) was stirred and heated at 60° C. for 2 hours. The cooled reaction was diluted with EtOAc/water (300 ml of each) and the aqueous extracted with EtOAc (2×75 ml). Combined organics were washed with 3×100 ml of water, dried (magnesium sulphate), evaporated, triturated with ether and filtered off to give the title compound (8.39 g) as a white solid. MS (ES) C16H15NO3 requires 269; found 270 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:45][NH2:46]>O1CCCC1.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12]([NH:46][OH:45])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 87) (330 mg, 0.86 mmol) and N-methylmorpholine (160 μl, 1.46 mmol) in anhydrous tetrahydrofuran (14 ml) was cooled to 0° C., treated with isobutyl chloroformate (120 μl, 0.93 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (350 μl, 2.86 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 98:2 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a colourless oil (272 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[C:16]([NH:2][C:1]3[C:3]4[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=4[N:10]=[CH:11][N:12]=3)[CH:21]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4nc(C)ccc34)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
A solution of the product of Example 10B (28.4 mg, 0.151 mmol), and the product of Example 10E (53.3 mg, 0.151 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum, and the resultant residue triturated with methanol to provide the title compound as a tan solid (26.5 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.92 (s, 1 H), 9.63 (s, 1 H), 8.70 (d, J=8.09 Hz, 1 H), 8.55 (s, 1 H), 7.52 (d, J=8.46 Hz, 1 H), 7.38 (d, J=8.82 Hz, 2 H), 7.27 (s, 1 H), 7.06-7.18 (m, 3 H), 6.94 (d, J=8.46 Hz, 3 H), 6.61-6.72 (m, 2 H), 5.02 (s, 2 H), 3.75 (s, 3 H), 2.66 (s, 3 H); MS (ESI+) m/z 497.2 (M+H)+, (ESI−) m/z 495.3 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[P:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[P:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@@H]1CC[C@@H](C)N1c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: C[C@@H]1CC[C@@H](C)N1c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 84.8 %

Procedure:
To a solution of 3.3 g (7.8 mmol) of the 1-((2R,5R)-2,5-dimethylpyrrolidinyl)-2-diphenylphosphinylnaphthalene in 100 ml of xylene were added 6.8 ml (49.14 mmol) of triethylamine and 4.7 ml (46.8 mmol) of trichlorosilane, and the mixture was slowly heated up to 120° C., at which the mixture was stirred for 6.5 hours. After cooling to room temperature, the reaction mixture was poured into 250 ml of 2N NaOH and extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane/acetone=20/1 by volume) to give 2.71 g of the title compound in a yield of 85%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[CH2:15][O:16][C:17]1[C:18]2[N:19]([C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:20]=[CH:21][CH:22]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[CH2:15][O:16][C:17]1[C:18]2[N:19]([C:23]([C:27]([NH:8][CH:6]3[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]3)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.8 mg (0.12 mmol) of 2,2,6,6-tetramethylpiperidine-4-amine were initially charged, and 32 mg (0.10 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 0.4 ml of DMF and 42 mg (0.13 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) in 0.2 ml of DMF were added. 20 mg (0.20 mmol) of 4-methylmorpholine were then added, and the reaction was stirred at RT overnight. The mixture was then filtered off and the filtrate was purified by preparative LC-MS (Method 12). The product-containing fractions were concentrated under reduced pressure. This gave 27 mg (59% of theory) of the target product.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38](=[N:40]O)[NH2:39])=[N:35][C:34]=1[CH3:42])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.ClCCl>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38]2[N:40]=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][N:39]=2)=[N:35][C:34]=1[CH3:42])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1nc(C(N)=NO)sc1C(=O)NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2noc(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of phenylacetic acid (0.05 g, 0.37 mmol) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (0.14 g, 0.83 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, and N-benzyl-2-(N′-hydroxy-carbamimidoyl)-4-methylthiazole-5-carboxamide (0.12 g, 0.41 mmol) was added. The reaction mixture was stirred for 17 hours, diluted with dichloromethane, washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white powder (0.01 g, 6%): mp 124-125° C.; 1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 10H), 6.16 (t, J=5.6 Hz, 1H), 4.60 (d, J=5.6 Hz, 2H), 4.29 (s, 2H), 2.76 (s, 3H); MS (ES+) m/z 391.5 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:33][CH:32]=1
Reactant: Clc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (56 mg, 1.4 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (250 mg, 1.27 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(4-chlorophenethyl)homopiperidine (380 mg, 1.40 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 2 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (5:1) and then with hexane and ethyl acetate (2:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5-[1-(4-chlorophenethyl)piperidine-2-ylmethyl]-5,11-dihydro-dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (160 mg, 29%).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[CH2:9][C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11]>>[CH3:5][O:4][P:3]([CH2:9][C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])([O:6][CH3:7])=[O:2]
Reactant: COP(OC)OC
Reactant: C=CCOC(=O)CCl
Product: C=CCOC(=O)CP(=O)(OC)OC
Reaction time: 4 h
Yield: 70.5 %

Procedure:
191 g of trimethylphosphite were added dropwise under stirring to 188 g of allyl chloroacetate (21/2 h) preliminarly heated to 118°. The reaction mixture was kept at this temperature for 4 h, whereupon it was subjected to a distillation to give 205 g of allyl dimethylphosphono-acetate, b.p. 118°/0.1 Torr.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([OH:24])=O.[C:25]1([CH2:31][O:32][C:33]([C:35]2([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:25]1([CH2:31][O:32][C:33]([C:35]2([NH:41][C:22]([C:14]3[S:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:24])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)=[O:34])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(O)c1cc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystal was collected by filtration and heated and dried under reduced pressure to obtain 10 g (91%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:18].[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[Cl:18][C:3]1[C:4]2[N:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:5]=2[CH:16]=[CH:17][C:2]=1[C:19]#[N:20]
Reactant: N#C[Cu]
Reactant: CCc1nc2c(Cl)c(Br)ccc2n1CC(F)(F)F
Solvent: CN1CCCC1=O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Temperature: 220 °C
Yield: 49.2 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1-(2,2,2-trifluoroethyl)-1H-benzimidazole (0.036 g, 0.106 mmol) and CuCN (0.020 g, 0.222 mmol) were combined in NMP (3 mL) and heated to 220° C. for 20 min in a microwave. The cooled mixture was partitioned between Et2O and water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.015 g): 1NMR (400 MHz, CDCl3) δ7.56 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.68 (q, J=8.2 Hz, 2H), 2.96 (q, J=7.4 Hz, 2H), 1.45 (t, J=7.4 Hz, 3H); MS (ESI) m/z 288 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([C@@H:19]([NH:18][C:14]([C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH3:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1
Yield: 95.2 %

Procedure:
The title compound (D5) (405 mg) was prepared according to the general procedure for amides preparation starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (250 mg, available from Sigma Aldrich #516341), and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (235 mg). Reaction time: 18 hrs.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:7]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 99.8 %

Procedure:
2-Chloro-4-methoxy-5-nitropyridine (Frontier Scientific, Newark, Del.; 1.02 g, 5.40 mmol) and K2CO3 (895 mg, 6.48 mmol) were purged with argon, treated with DMF (10 mL) followed by 1-methylpiperazine (0.66 mL, 5.94 mmol). The reaction mixture was then heated to 60° C. for 3 h. The reaction mixture was cooled to RT and treated with water, extracted with EtOAc (2×100 mL), washed with brine (2×25 mL) and dried over MgSO4, filtered and concentrated affording crude 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol, 99% yield). m/z (ESI, +ve ion) 252.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1H, s), 5.97 (1H, s), 3.97 (3H, s), 3.70-3.78 (4H, m), 2.47-2.55 (4H, m), 2.36 (3H, s). Pd/C (10 wt. %, 586 mg, 0.55 mmol) and 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine (1.36 g, 5.39 mmol) were treated with EtOH (20 mL) and EtOAc (20 mL) and stirred at RT overnight (18 h) under an atmosphere of hydrogen (balloon). The reaction mixture was filtered through a pad of Celite, washed with MeOH, and concentrated to dryness affording 4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a) (1.22 g, 5.77 mmol, 99% yield) as a purple viscous oil. m/z (ESI, +ve ion) 223.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s), 6.17 (1H, s), 3.87 (3H, s), 3.37-3.45 (4H, m), 3.32 (2H, br. s.), 2.51-2.60 (4H, m), 2.36 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-:24])(=[O:23])C.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:26]=1.[C]=O>[Pd].C(O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([C:21]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cn2c1C
Agent: [Pd]
Agent: [C]=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1

Procedure:
A mixture of 4 g of 8-benzyloxy-6-bromo-2,3-dimethylimidazo[1,2-a]pyridine, 0.4 g of palladium( acetate, 1.33 g of triphenylphosphine, 10 ml of triethylamine and 50 ml of ethanol is heated for 16 h) a carbon monoxide atmosphere in an autoclave (5 bar), the volatile portions are stripped off in vaco and the residue is chromatographed on silica gel (eluent: ethyl acetate). 2.4 g of the title compound melting point 140-1° C. (diethyl ether) are obtained.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)C1CCC(Oc2ccc(N)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Reaction time: 0.5 h

Procedure:
Methyl chlorooxoacetate (45 μL, 0.48 mmol) was added in one portion to a stirred solution of ethyl 4-(4-aminophenoxy)cyclohexanecarboxylate (127 mg, 0.48 mmol) and pyridine (47 μL, 0.58 mmol) in DCM (5 mL) and the reaction mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was taken up in EtOAc (40 mL) and an aqueous solution of hydrochloric acid (1M, 20 mL) was added. The layers were separated and the organic layer was washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (152 mg, 91%) as a solid; 1H NMR (CDCl3) δ1.19 (3H, t), 1.39-1.45 (2H, m), 1.48-1.56 (2H, m), 1.97-2.03 (2H, m), 2.08-2.12 (2H, m), 2.23-2.31 (1H, m), 3.89 (3H, s), 4.07 (2H, q), 4.11-4.14 (1H, m), 6.80-6.84 (2H, d), 7.44-7.48 (2H, d), 8.66 (1H, s); MS m/e MR+ 350.