Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28]>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:28][CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCc4ccccn4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-pyridin-2-ylmethyl-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and C-pyridin-2-yl-methylamine (0.84 mL, 8.1 mmol) in a manner analogous to Example 406. Product isolated as a light yellow powder (207 mg, 67%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.68 (d, J=6.5 Hz, 1H), 8.51 (m, 1H), 8.38 (d, J=7.7 Hz, 2H), 8.04 (d, J=7.9 Hz, 2H), 7.87 (d, J=7.7 Hz, 1H), 7.73 (t, J=15.5, 7.9 Hz, 1H), 7.46-7.37 (m, 2H), 7.24 (m, 1H), 7.04 (t, J=14.2, 6.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.28 (s, 3H). MS=380 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(F)c(C)c2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as off-white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH2:19]([N:21]([CH2:35][CH3:36])[C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:24]([C:23]3[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:22]=3[N:21]([CH2:35][CH3:36])[CH2:19][CH3:20])=[O:25])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-diethylamino-5-methanesulfonyl-benzoic acid (Example 2.5) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 501.4 (M+H+; 100%)
Reaction SMILES: C1(C[O:8][C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][O:16][S:17](=[O:20])(=[O:19])[NH2:18])=[CH:11][CH:10]=2)C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][O:16][S:17](=[O:19])(=[O:20])[NH2:18])=[CH:11][CH:10]=1
Reactant: NS(=O)(=O)OCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: NS(=O)(=O)OCCOc1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a solution of 25.8 g (0.08 mole) of sulfamic acid 2-[4-(phenylmethoxy)phenoxy]ethyl ester in 150 ml of tetrahydrofuran was added 0.5 teaspoon of 10% palladium on carbon catalyst and the mixture was hydrogenated in a Parr bottle at 40° C. overnight. The catalyst was removed and a fresh 0.5 teaspoon of 10% palladium on carbon catalyst was added and the mixture was hydrogenated at 40° C. for 3 hr whereby hydrogen uptake ceased. The catalyst was removed by filtration through Celite® and the filtrate was evaporated under reduced pressure to give a viscous oil that solidified upon standing. The solid was recrystallized from ethyl acetate-chloroform to yield 18.0 g (97%) of a shiny, white solid, mp 92°-93° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[C@@H:13]([CH2:14][F:15])[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[C@@H:13]([CH2:14][F:15])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CF)[C@](C)(NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@]1(C)CNC[C@@H]1CF

Procedure:
To a solution of (3S,4S)-3-(tert-butoxycarbonylamino)-4-fluoromethyl-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidine (1.35 g, 4.01 mmol) in ethanol (30 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 1.30 g), and the suspension was stirred in an oil bath at 40° C. for 12 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 932 mg (quantitative) of the crude target compound as a colorless transparent syrup substance.
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][CH:18]=[CH:17][C:16]=1I.[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[C:16]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(F)cc1
Yield: 83.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-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 0.058 g (84%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]1>ClCCl.O>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]2)=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: OC1CCCNC1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN1CCCC(O)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and 3-piperidinol (1.54 g, 15.2 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, the reaction was stirred at RT overnight under balloon H2 pressure. The catalyst was removed via filtration and the solvent was removed under reduced pressure to yield 1-{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-3-piperidinol as a white solid (3.0 g, 92%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 1.09 (m, 1 H), 1.44 (m, 1 H), 1.62 (m, 1 H), 1.74 (m, 1H), 2.14(br, 1H), 2.47(s, 1H), 2.74(br, 2H), 2.95 (m, 4H), 3.50(s, 2H), 3.68(s, 3H), 4.04 (t, J=6.13 Hz,2 H), 4.71 (s, 2H), 6.68 (s, 1 H), 7.51 (s, 1 H).
Reaction SMILES: IC1C=CC(C)=C2C=1C(=O)NC2.NC1C=CC=C2C=1C(=O)NC2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.C[C:54]1[CH:62]=[CH:61][C:60]([C:63]2[N:64]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C:65]3[C:70]([CH:71]=2)=[CH:69][C:68]([CH2:72][N:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)=[CH:67][CH:66]=3)=[C:59]2[C:55]=1[CH2:56][NH:57][C:58]2=[O:86]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:82]([O:81][C:79]([N:64]1[C:65]2[C:70](=[CH:69][C:68]([CH2:72][N:73]3[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78]3)=[CH:67][CH:66]=2)[CH:71]=[C:63]1[C:60]1[CH:61]=[CH:62][CH:54]=[C:55]2[C:59]=1[C:58](=[O:86])[NH:57][CH2:56]2)=[O:80])([CH3:85])([CH3:83])[CH3:84]
Reactant: Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(I)c2c1CNC2=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cccc3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 56 %

Procedure:
In a similar manner to Step 2 of Example 1, a mixture of 7-iodo-4-methylisoindolinone and 7-iodoisoindolinone (10/1, 40.5 mg, 0.149 mmol) was dissolved in acetonitrile (3.24 mL), and the solution was treated with Compound BD (107 mg, 0.298 mmol), palladium acetate (2.7 mg, 0.012 mmol), tri(o-tolyl)phosphine (7.3 mg, 0.024 mmol) and triethylamine (0.208 mL, 1.49 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain a mixture of 4-methyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone and 7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (38.2 mg, ratio 92.9/7.1, yield 56%). 4-methyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N+:8]([O-:17])[C:7]=1[O:18][CH3:19])=[O:5])C.[OH-].[Na+]>CO>[CH2:13]([C:9]1[C:10](=[O:12])[NH:11][C:6]([C:4]([OH:5])=[O:3])=[C:7]([O:18][CH3:19])[N+:8]=1[O-:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Yield: 99.4 %

Procedure:
A solution of 932 mg of 6-ethoxycarbonyl-3-isobutyl-5-methoxy-1,2-dihydropyrazine-2-one 4-oxide dissolved in 21 ml of methanol and 10 ml of an aqueous 1N sodium hydroxide solution was stirred for 4 hours at room temperature. The reaction mixture was made acidic with 10% hdyrochloric acid. The resulting crystals were collected by filtration and dissolved in chloroform-methanol. The solvent was removed by evaporation to obtain 830 mg of 3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one-6-carboxylic acid 4-oxide (Compound B-34) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[N:16]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:7]=2)[N:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:12]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCN(C)CC2)n1
Temperature: 130 °C
Yield: 42 %

Procedure:
5-(1-((2-Chloropyrimidin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (50.0 mg, 0.114 mmol) was dissolved in DMSO (0.5 ml) and 1-methylpiperazine (0.127 ml, 1.142 mmol) was added. The reaction was heated at 130° C. overnight and purified by prep-HPLC (MeCN/H2O 20%-50% MeCN, containing 0.1% TFA). The product was taken up in EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated to afford the desired compound as a yellow solid (24 mg, 42%). MS (ES+) C22H22F3N9O2 requires: 501. found 502 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.33-8.24 (m, 3H), 7.33 (d, J=8.3 Hz, 2H), 6.32 (d, J=4.9 Hz, 1H), 5.33 (s, 2H), 3.84-3.70 (m, 4H), 2.64 (s, 3H), 2.47-2.38 (m, 4H), 2.32 (s, 3H).
Reaction SMILES: O([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])S(C(F)(F)F)(=O)=O.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:39])[C:25]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH:33]([C:36]#[N:37])[C:34]#[N:35])=[CH:28][C:27]=1[CH3:38].C[O-].[Na+]>C(Cl)Cl.CO>[CH3:19][C:20]1[C:25](=[C:26]2[C:31]([CH3:32])=[CH:30][C:29](=[C:33]([C:34]#[N:35])[C:36]#[N:37])[CH:28]=[C:27]2[CH3:38])[C:24]([CH3:39])=[CH:23][N:22]([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:21]=1
Reactant: Cc1cncc(C)c1-c1c(C)cc(C(C#N)C#N)cc1C
Reactant: CCCCCC(CCC)COS(=O)(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(CCC)CN1C=C(C)C(=c2c(C)cc(=C(C#N)C#N)cc2C)C(C)=C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
To a solution of 2-propyl-1-heptanol (0.81 g, 5.1 mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of trifluoromethanesufonic anhydride (1.77 g, 6.10 mmol) in the same solvent (5 mL). After stirring at room temperature for 20 min, the reaction mixture was poured into ice (40 mL) and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield nearly pure 2-propyl-1-heptyl triflate as a purple liquid (1.40 g, 94.1%). The 2-propyl-1-heptyl triflate (0.319 g, 1.10 mmol) was next added dropwise to a solution of 15 (0.275 g, 1.00 mmol) in dry CH2Cl2 (10 mL), and the reaction mixture was stirred at room temperature for 12 h. A solution of sodium methoxide in methanol (2.4 mL, 0.5 M) was then added dropwise to the resulting solution of pyridinium salt 17. The color of the mixture immediately changed from yellow to purple. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting purple solid was then partitioned between water (20 mL) and CH2Cl2 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was next purified by flash chromatography on silica gel eluting with 4:100 methanol: CH2Cl2, to give 0.278 g (66.9%) of the title compound as an orange solid: mp 276-278° C.; 1H NMR (400 MHz, DMSO-d6): δ 8.969 (s, 2H), 6.591 (s, 2H), 4.421 (t, 2H, J=5.6 Hz), 2.114 (m, 1H), 2.067 (s, 6H), 1.704 (s, 6H), 1.229-1.190 (m, 12H), 0.836 (m, 6H); 13C NMR (125 MHz, DMSO-d6): δ 159.170, 142.273, 142.082, 137.669, 132.328, 125.659, 122.083, 117.561, 63.995, 38.500, 32.713, 31.339, 30.165, 27.600, 25.025, 21.849, 19.165, 18.846, 16.653, 14.188, 13.897; MS (high resolution, EI): m/z 415.2985 [M+]; calcd, 415.2987; Anal. Calcd. for C28H37N3·1/3 H2O: C, 79.76; H, 9.00; N, 9.97. Found; C, 79.92; H, 8.87; N, 9.97.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)O)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].N1C=CC=CC=1.[F:40][C:41]([F:52])([F:51])[C:42]([O:44]C(=O)C(F)(F)F)=[O:43].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[C:5]([CH2:17][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]([O:44][C:42](=[O:43])[C:41]([F:52])([F:51])[F:40])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCC(Oc1ccccc1)(C(=O)OCC)C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(OC(=O)C(F)(F)F)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[(4-Benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-hexanoic acid ethyl ester (13.4 mmol) in anhydrous CH2Cl2 (100 mL) and pyridine (134 mmol) was cooled to 0° C. and treated with trifluoroacetic anhydride (26.9 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. An aqueous solution of 1N HCl (150 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 2-(4-benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoic acid ethyl ester as an oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[O:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCCOc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
25.6 g of anhydrous aluminum trichloride are suspended in 64 ml of 1,2-dichloroethane, and 28.6 g of 4-methoxybenzoyl chloride are added. Then, while stirring vigorously, 31 g of methyl 4-phenoxybutyrate are slowly added. The reaction mixture is subsequently stirred at 50° C. for 4 hours, allowed to cool and poured into ice-water. The oily organic layer and the aqueous phase are separated, the organic phase is washed with water, and a little methanol is added to induce crystallization. The product which has separated out is filtered off with suction and recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2].Br[C:38]1[N:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([CH:53]3[CH2:56][N:55]([CH3:57])[CH2:54]3)=[CH:49][CH:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:38]2[N:39]=[C:40]([NH:46][C:47]3[CH:48]=[CH:49][C:50]([CH:53]4[CH2:54][N:55]([CH3:57])[CH2:56]4)=[CH:51][CH:52]=3)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2]
Reactant: CN1CC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CN(C)C4)cc3)n2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 80.3 %

Procedure:
To a sealed tube was charged a mixture of (2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl Acetate 247b (100 mg, 0.19 mmol), 5-bromo-1-methyl-3-(4-(1-methylazetidin-3-yl)phenylamino)pyrazin-2(1H)-one 298d (68 mg, 0.19 mmol), PdCl2(dppf) (14 mg, 0.019 mmol), K3PO4 (60 mg), and NaOAc (30 mg) in MeCN (5 mL) and water (1 mL). It was heated at 110° C. for 2 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 298e (100 mg, 82%). MS: [M+H]+ 656.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[Cl:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[C:31]([O:33][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COC3CCCCO3)c(COc3ccc(C#N)c(Cl)c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
2.5 g 5-Chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole and 1.48 g 2-chloro-4-hydroxybenzonitrile were dissolved in 20 ml dimethylformamide. 4.82 g Cesium carbonate were added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with 200 ml ethyl acetate and washed five times with portions of 50 ml water and brine. The organic phase was dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.0 g crude 2-chloro-4-[2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-ylmethoxy]-benzonitrile. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]>>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:15][CH2:16]2)[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cc1cc(Cl)nc(N2CCN(S(C)(=O)=O)CC2)n1
Yield: 41 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and 1-methanesulfonyl-piperazine. The title compound was isolated as a yellow solid in a yield of 41%. MS ISP (m/e): 291.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.81 (s, 1H), 3.80-3.70 (m, 4H), 3.20-3.15 (m, 4H), 2.90 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([NH:32][CH3:33])[CH2:19]1)=[O:17].C(N(C(C)C)C(C)C)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([N:32]([S:43]([CH3:46])(=[O:45])=[O:44])[CH3:33])[CH2:19]1)=[O:17]
Reactant: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentyl}-amide (36 mg) in acetonitrile (2 ml) were added N-ethyldiisopropylamine (0.03 ml) and mesyl chloride (0.01 ml). The reaction mixture was stirred at r.t. for 3 hrs, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 92:8) to give 5-chloro-thiophene-2-carboxylic acid [(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-(methanesulfonyl-methyl-amino)-cyclopentyl]-amide (32 mg) as off-white solid. MS 567.2 ([M+H]+).