Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:9][C:10]([O:12][CH2:13][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:11])=[C:6]([CH3:8])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(O)cc(C)c1CC(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC(=O)OCc1ccccc1
Yield: 161.1 %

Procedure:
0.36 g of 2-(4-hydroxy-2,6-dimethylphenyl)acetic acid was treated with 184 mg of a 60% dispersion of sodium hydride in mineral oil and 0.72 g of benzyl bromide in 10 ml of dry dimethylformamide. The solvent was removed by evaporation and the residue was partitioned between water and methylene chloride. The organic layer was evaporated to give 0.63 g of crude product of melting point 54°-57° C. Recrystallization from aqueous methanol gave 0.58 g of pure benzyl 2-(4-benzyloxy-2,6-dimethylphenyl)acetate of melting point 62°-64° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[C:2]([CH3:1])=[CH:3][C:4]([NH2:7])=[N:5]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(N)nn1Cc1ccc(F)cc1

Procedure:
Prepared in analogy to example 10a) starting with 5-methyl-1H-pyrazol-3-ylamine and 4-fluorobenzyl bromide. The title compound was obtained as a white solid (Yield=14%). MS ISP (m/e): 206.1 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>CCOC(C)=O>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a vigorously stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (47.0 g, 238 mmol) in EtOAc (450 mL) at room temperature, anhydrous aluminum chloride (38.1 g, 286 mmol) was added in one portion. Then pyridine (77 mL, 954 mmol) was added drop wise at 45-50° C. for 30 min. The reaction mixture was refluxed for 2 h and allowed to cool down to 60° C. The reaction mixture was carefully poured into ice/concentrated HCl mixture (265 mL). After stirring at 50° C. for 1 h, the reaction mixture was cooled to 0° C. The formed precipitate was separated by filtration, washed with water, and vacuum-dried to afford the desired compound (29.4 g, 161 mmol, 67.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([N:12](CC)CC)C>C(#N)C>[C:10]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)#[N:12]
Reactant: CCN(CC)CC
Reactant: COc1ccc[n+]([O-])c1
Solvent: CC#N
Product: COc1cccnc1C#N

Procedure:
3-Methoxypyridine-1-oxide (25.2g, 209 mmol) was dissolved in acetonitrile (260 mL). Trimethylsilycyanide (66.35g, 669 mmol) and triethylamine (45.13g, 446 mmol) were added and the reaction mixture heated at reflux for overnight. The cooled solution was concentrated in vacuo to give a brown solid which was partitioned between CH2Cl2 and 3M Na2CO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chomatography using 1:1 EtOAc/hexanes as eluent. Compound 762B was isolated (17.63g, 63%) as a light yellow solid. HPLC: 96.2% at 1,37 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 134.88 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][NH2:11]>C1(C)C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:10][CH2:9][CH2:8][NH2:12]
Reactant: Clc1ncccn1
Reactant: NCCCN
Solvent: Cc1ccccc1
Product: NCCCNc1ncccn1
Yield: 164.1 %

Procedure:
2-chloro-pyrimidine (24.3 g) was added portionwise to a mixture of 1,3-propanediamine (85 g) in toluene (240 mL) while stirring at reflux temperature. The reaction mixture was stirred and refluxed for 3 hours. The reaction mixture was cooled, the precipitate was filtered off and the filtrate was evaporated. The residue was distilled in vacuo, yielding 53 g (65.7%) of N-2-pyrimidinyl-1,3-propanediamine (intermediate 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2ccc(N)cc2)CCCCC1
Solvent: ClCCl
Product: N#CC1(c2ccc(N)c(Br)c2)CCCCC1

Procedure:
The title compound was prepared from 1-(4-amino-phenyl)-cyclohexane carbonitrile (as prepared in the previous step) by bromination with NBS according to the procedure in Example 4, step (b), replacing CH3CN with CH2Cl2. 1H-NMR (CDCl3; 400 MHz): δ 7.49 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=8.4, 2.0 Hz), 6.76 (d, 1H, J=8.4 Hz), 2.16-2.08 (m, 2H), 1.90-1.73 (m, 8H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH4+]=[S:14]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](=[S:14])[NH2:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: N#CC1CCC2(CC1)OCCO2
Solvent: CO
Product: NC(=S)C1CCC2(CC1)OCCO2
Yield: 22.7 %

Procedure:
The 1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.16 g, 6.94 mmol, Tetrahedron, 2002, 58(8), 1557), ammonium sulfide (20 wt. % in water, 2.84 mL, 8.33 mmol) and MeOH (14 mL) were heated in a CEM® microwave at about 130° C. for about (250 psi maximum pressure, 10 min ramp, 300 max watts). The mixture was concentrated under a stream of air and the resulting material was purified by flash chromatography on silica gel using EtOAc/heptane (7:3) as an eluent to give the title compound (0.317 g, 23%) as a light yellow solid: LC/MS (Table 1, Method a) Rt=1.68 min; MS m/z: 202.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]>Br>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([N:8]4[C:9](=[O:10])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7]4)=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(C)C)c4=O)cc3)CC2)cc1
Agent: Br
Product: CC(C)Cn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 91 %

Procedure:
This compound was synthesized as a white amorphous solid from 4f (64.0 mg, 0.152 mmol) in 48% aqueous HBr (1.5 mL) in 91% yield by following general procedure 1.4: MALDI-MS: 394.2 (M+H+), 416.2 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Se](=O)=O>O1CCOCC1.C(O)C>[OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=[Se]=O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(O)c(C=O)n1
Yield: 57.3 %

Procedure:
3-Hydroxy-6-methyl-2-pyridine methanol (20.0 g, 0.14 mol) and selenium dioxide(8.0 g, 72 mmol) were dissolved in 140 mL of 1,4-dioxane and 280 mL of absolute ethanol. The resulting mixture was heated at 80°-85° C. for 12 h. The selenium precipitate was removed by filtration and the filtrate was concentrated to dryness in vacuo. The dark red residue was sublimed at 90° C. and 14 mmHg for 6 h to obtain 11.0 g (56%) of pure product, m.p. 101°-102° C.; 1H NMR (CDCl3) δ: 10.50 (br s, 1H), 10.03 (s, 1H), 7.27 (s, 2H); 2.53 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3][CH2:2]1.[F:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:27](=[O:28])[CH2:26][F:25])[C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)CF
Reactant: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Solvent: ClCCl
Product: O=C(CF)N(Cc1cccc2c1OCO2)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl)amine (0.16 g, 0.50 mmol) dissolved in DCM (2 mL) was added TEA (0.20 g, 2.00 mmol, 0.28 mL). The reaction was cooled to 0° C. and fluoroacetyl chloride (0.10 g, 1.00 mmol, 0.07 mL) was added. The mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1-5% B, 80 g, 4.0 CV, 60 mL/min) to afford 160 mg (84%) of N-(benzo[1,3]dioxol-4-ylmethyl)-2-Fluoro-N-(2-phenyloxy-phenyl)acetamide as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 4.67 (1H, d, J=2 Hz, FCH), 4.83 (1H, d, J=2 Hz, FCH), 4.74 (1H, d, J=14 Hz, ArCH), 5.12 (1H, d, J=14 Hz, ArCH), 5.63 (1H, d, J=1 Hz, OCHO), 5.79 (1H, d, J=1 Hz, OCHO), 6.66-6.88 (6H, m, ArH), 6.96-7.06 (2H, m, ArH), 7.12-7.38 (4H, m, ArH).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C(N(C(C)C)C(C)C)C.OC1C=CC=C[N+]=1[O-].[NH2:29][C:30]1[C:35]([C:36](O)=[O:37])=[CH:34][C:33]([C:39]2[CH:40]=[N:41][N:42]([CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:43]=2)=[CH:32][N:31]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[NH2:29][C:30]1[C:35]([C:36]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=2[OH:11])=[O:37])=[CH:34][C:33]([C:39]2[CH:40]=[N:41][N:42]([CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:43]=2)=[CH:32][N:31]=1
Reactant: CN1CCC(n2cc(-c3cnc(N)c(C(=O)O)c3)cn2)CC1
Reactant: COc1ccc(N)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(-c3cnn(C4CCN(C)CC4)c3)cnc2N)c(O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.2 %

Procedure:
2-amino-5-methoxy-phenol hydrochloride (210 mg), N-ethyl-N-isopropyl-propan-2-amine (0.208 ml) and 2-hydroxypyridine-1-oxide (221 mg) were added to a stirred solution of 2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylic acid (300 mg) dissolved in DMF (5 ml) under nitrogen. 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (382 mg) was added portionwise to this mixture and the resulting solution was stirred at 25° C. for 48 hours. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 2-amino-N-(2-hydroxy-4-methoxy-phenyl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide (190 mg). NMR Spectrum: (DMSOd6) 1.88-2.10 (m, 6H), 2.20 (s, 3H), 2.82-2.90 (m, 2H), 3.71 (s, 3H), 4.06-4.15 (m, 1H), 6.42 (dd, 1H), 6.49 (d, 1H), 6.99 (bs, 2H), 7.26 (d, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 8.30 (d, 1H), 8.39 (d, 1H), 9.51 (bs, 1H), 9.58 (bs, 1H) Mass spectrum: M+H+ 423
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26]>[Cu]I>[CH3:18][C:6]1[C:5]2[C:9](=[CH:10][C:2]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Solvent: C1CCNCC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
To a pressure tube was added 4-(6-bromo-3-methylindazol-1-yl)pyrimidin-2-amine (0.5 g, 1.64 mmol), piperidine (3.5 mL) tetrakis(triphenylphosphine)palladium (113.98 mg, 0.1 mmol), copper(I) iodide (18.79 mg, 0.1 mmol) and ethynyl(trimethyl)silane (0.47 ml, 3.29 mmol). The mixture was purged with nitrogen for 2 minutes and then stirred at 65° C. for 1.5 hr. The reaction mixture was concentrated in vacuo, DCM (5 mL) was added and the concentration repeated (×2). The mixture was purified by column chromatography (Biotage, 3-8% MeOH gradient in DCM) to give the title intermediate as a white solid (116 mg): 1H NMR (250 MHz, DMSO) delta 0.28 (9H, s), 2.57 (3H, s), 7.03 (3H, d, J=5.5), 7.38 (1H, d, J=8.2), 7.84 (1H, d, J=8.2), 8.26 (1H, d, J=5.5), 8.90 (1H, s); LC-MS: m/z=+322.50 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[NH2:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][C:31](=[O:33])[NH2:32].[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][C:31](=[O:33])[NH2:32])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Temperature: 2.5 °C

Procedure:
34.60 g (200 mmol) of quinoline-2-carboxylic acid (Benechim S. A.) were suspended in 350 ml of ethyl acetate (Fluka) while stirring and under a protective gas at 0 to 5° C. and treated with 25.0 ml (200 mmol) of pivaloyl chloride (Fluka). 28.0 ml (200 mmol) of triethylamine (Fluka) were added to the white suspension within 30 minutes, with the temperature being held at 0 to 5° C. Subsequently, the suspension was stirred at 0 to 5° C. for 30 minutes. The white suspension was filtered and the filter cake was washed with 100 ml of cooled (0-5° C.) ethyl acetate (Fluka). The filtrate contained the resulting 2,2-dimethylpropionic acid-quinoline-2-carboxylic acid anhydride having the following characteristics: melting point: 47° C.; MS: [M+H]+258; IR: 1750 cm−1, 1775 cm−1. The cooled (0−-5° C.), light yellow filtrates were combined and treated within 5 minutes while stirring intensively with a pre-cooled solution of 30.0 g (200 mmol) of L-asparagine (Fluka), 8.0 g (200 mmol) of sodium hydroxide (Fluka) and 16.80 g (200 mmol) of sodium bicarbonate in 350 ml of cold, deionised water (0-5° C.), with the temperature being held at between 0 and 5° C. Subsequently, the cooling was removed and the light green two-phase system was stirred at room temperature for about 17 hours. The aqueous phase of the now colourless two-phase system was treated with 200 ml of methanol (Merck) while stirring and under argon. Then, 49 ml of 25% hydrochloric acid (Merck) were added dropwise to pH 3.0. In so doing, the temperature rose to 28° C. and crystallization set in. The white suspension was stirred at room temperature for one hour, subsequently cooled to 0-5° C. and stirred at this temperature for a further hour. The filtered-off filter cake was washed with a total of 80 ml of cold, deionised water (0-5° C.) and dried in a rotary evaporator at 5° C./10 mbar for 6 hours. Yield: 47.52 g (83%) of N-(2-quinolylcarbonyl)-L-asparagine in the form of white crystals [melting point: 209° C. (decomposition), HPLC analysis 99.8% (area)].
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH: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]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(SC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a beige solid. UPLC-MS (Condition 3) tR=1.06 min, m/z=486.1 [M+H]+, m/z=484.4 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.85 (d, J=11.29 Hz, 1H) 3.16-3.27 (m, 2H) 3.35-3.43 (m, 1H) 4.18-4.25 (m, 1H) 4.90 (d, J=3.64 Hz, 1H) 7.70 (d, J=8.78 Hz, 2H) 7.88-7.96 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.41 (t, J=2.07 Hz, 1H) 8.80 (d, J=2.38 Hz, 1H) 8.91 (d, J=2.13 Hz, 1H) 9.03 (d, J=1.88 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.ClC[CH2:28][CH2:29][NH2:30]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH2:30][CH2:29][CH2:28][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH:8]=2)[C:4]([Cl:3])=[CH:5]1
Reactant: NCCCCl
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(Cl)c[nH]c2c1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(Cl)cn(CCN)c2c1)C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
Sodium hydroxide (103 mg) and tetrabutylammonium hydrogensulfate (15 mg) were added to a solution of tert-butyl [(3-chloro-1H-indol-6-yl)methyl]cyclopropylcarbamate (275 mg) in acetonitrile (7.0 ml) and the mixture was stirred at room temperature for 20 minutes. 3-Chloropropylamine hydrochloride (149 mg) was added to the reaction mixture and it was heated under reflux for 16 hours. Sodium hydroxide (103 mg) and 3-Chloropropylamine hydrochloride (149 mg) were added and the mixture was further heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, insoluble materials were filtered through Celite and the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform/methanol=20/1 to 10/1) to give tert-butyl {[1-(2-aminoethyl)-3-chloro-1H-indol-6-yl]methyl}cyclopropylcarbamate (257 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:34][N:33]=2)=[CH:28][CH:27]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:40]3[CH2:39][CH2:38][CH:37]([C:35]4[O:34][N:33]=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=5)[N:36]=4)[CH2:42][CH2:41]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC2CO2)C1
Reactant: Clc1ccc(-c2noc(C3CCNCC3)n2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCC(c3nc(-c4ccc(Cl)cc4)no3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.069 g. 0.20 mmol) was dissolved in CH2Cl2 (1 mL), and 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4 mmol) was added, followed by Yb(OTf)3 (0.031 g, 0.22 mmol). The mixture was stirred at room temperature for 16 h. Preparative TLC (silica, 7.5% MeOH/CH2Cl2) afforded 84 mg (69%) of the title compound. MS (electrospray): exact mass calculated for C31H34Cl2N6O3, 608.21; m/z found, 609.2 [M++H]. 1H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers): 8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42 (d, J=8.6 Hz, 2H), 7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB quartet J=15.6 Hz, 1H), 4.62 (br s, 1H), 4.25-4.13 (m, 2H), 4.10-3.98 (m, 2H), 3.90-3.70 (m, 2H), 3.04-2.71 (m, 5H), 2.51-2.40 (m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:28])([F:27])[F:26])[C:18]=3[N:17]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:26])([F:27])[F:28])[C:18]=3[N:17]=2)[CH2:9]1
Reactant: [H][H]
Reactant: O=C(Cc1nc2c(C(F)(F)F)cccc2[nH]1)N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1nc2c(C(F)(F)F)cccc2[nH]1)N[C@@H]1CCNC1
Yield: 82.1 %

Procedure:
In a round-bottom flask, a slurry of N-[(3R)-1-benzylpyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide (800 mg, 1.99 mmol) and Palladium (10%) on Carbon (10 mg) in MeOH was purged with hydrogen gas for 2 min.; the reaction was then subjected to 1 atm of hydrogen gas overnight. The flask was purged with argon, then the mixture was filtered, concentrated and subjected to flash chromatography (ethyl acetate) to afford N-[(3R)-pyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide (510 mg, 83%), as a white solid.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]([CH3:33])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][CH:18]1[CH2:22][C:21](=[O:23])[O:20][CH:19]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])(C)(C)C.[NH2:35][C:36]1[C:44]([F:45])=[C:43]([F:46])[C:39](C(O)=O)=[C:38]([F:47])[C:37]=1[F:48].O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:25]([O:24][CH:19]1[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:5])[C:39]2[C:38]([F:47])=[C:37]([F:48])[C:36]([NH2:35])=[C:44]([F:45])[C:43]=2[F:46])[CH3:33])=[O:32])[CH2:22][C:21](=[O:23])[O:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1c(F)c(F)c(N)c(F)c1F)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 73 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 4-amino-2,3,5,6-tetrafluoro-benzoic acid according to the procedure used to prepare 98a to afford 58 mg of title compound (73% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.30-1.50 (m, 3H), 1.62-2.35 (m, 4H), 2.45-3.12 (m, 2H), 3.50-3.90 (m, 2H), 4.20-4.95 (m, 5H), 5.42 (s, 0.4H), 5.52 (s, 0.1H), 5.64 (d, 0.4H), 5.82 (d, 0.1H), 7.25-7.65 (m, 5H). Analytical HPLC: 16.56, 16.90 min. LC-MS (ES+): m/e=567.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]3)[CH:12]=1)(C)[C:3](O)=O.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:39][C:2]([C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]3)[CH:10]=[N:9][CH:8]=1)([CH3:3])[CH3:1]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(C(C)(C)N)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 59 [D], 2-methyl-2-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)propanoic acid (example 72 [C]) was reacted with diphenylphosphoryl azide in presence of TEA and then sodium trimethylsilanoate (1 M in THF) to give the title compound as a light brown amorphous solid. MS: 296.5 (M+H+).