Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: OC1CCNCC1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1cccc(F)c1
Yield: 46 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and 4-hydroxypiperidine to give the title compound in 46% yield; NMR Spectrum: 1.36 (d, 2H), 1.69 (d, 2H), 2.18 (t, 2H), 2.78 (m, 4H), 3.80 (s, 3H), 4.42 (t, 2H), 4.55 (d, 1H), 5.11 (s, 2H), 7.02 (d, 1H), 7.16 (m, 2H), 7.30 (m, 2H), 7.36 (d, 1H), 7.44 (q, 1H), 8.25 (s, 1H), 8.45 (s, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with EtOAc. The combined EtOAc layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1Cl

Procedure:
As described for Reference Example 21, 3.13 g of 2-chlorobenzoic acid is reacted with 40 ml of thionyl chloride to give 3.32 of product as an off-white semi solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:4]=1.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:14][C:15]3=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]3[N:21]=2)[CH:4]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: COc1ccnc(CCC(=O)O)c1
Product: COc1ccnc(CCc2nc3cc(C)cnc3[nH]2)c1

Procedure:
Similarly to Example 1, 0.428 g of 3-(4methoxypyridin-2-yl)propionic acid (starting material A1), 0.26 g of 2,3-diamino-5-methylpyridine (Lappin et al., J. Amer. Chem Soc. 72, 2806 (1950) and 8 g of PPA (4 hours at 140° C.) give 0.25 g of the title compound of m.p. 150–152° C. (crystallized from ethyl acetate). The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 269.3 and 559.1 Da.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:23])([F:22])[CH2:6][N:7]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)C>C(O)(=O)C.[Fe]>[Cl:21][C:14]1[N:15]=[CH:16][C:17]2[NH:18][C:4](=[O:3])[C:5]([F:23])([F:22])[CH2:6][N:7]([CH:8]3[CH2:11][CH2:10][CH2:9]3)[C:12]=2[N:13]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCC2)CC1(F)F
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
To a solution of 11.6 g (0.032 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2,2-difluoro-propionic acid ethyl ester in 100 mL of acetic acid was added 15.5 g (0.191 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and mixture was stirred for 10 minutes and then filtered. The organic layer was washed with ammonium hydroxide and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was washed with 50 mL of hexanes-ethyl acetate (90:10) and then air dried to give 6.8 g of 2-chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:8]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:44].[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([NH:53][C:54]([C:56]1[O:57][C:58]3[C:64](Br)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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]>[ClH:44].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52]1)[C@@H:47]([NH:53][C:54]([C:56]1[O:57][C:58]3[C:64]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[CH:8]=4)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: O=S(=O)(Oc1cccc(N2CCOCC2)c1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(N4CCOCC4)c3)c2o1

Procedure:
151.1 mg (0.49 mmol) of 3-(4-morpholinyl)phenyl trifluoromethanesulphonate (Example 17A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 144 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 32 mg (18% of theory) of the title compound.
Reaction SMILES: C1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10](F)=[C:11](N4C[C@H](C)N[C@H](C)C4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)CC1.N>>[O:24]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][CH:5]=[C:6]1[C:25]([OH:27])=[O:26]
Reactant: C[C@@H]1CN(c2cc3c(c(F)c2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H](C)N1
Agent: N
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
In a sealed tube, 1-cyclopropyl-5,6-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 28% aqueous ammonia were heated at 100° C. for 48 hours. The reaction mixture was concentrated under reduced pressure. A 1N aqueous solution of sodium hydroxide was added to the residue, and the insoluble matter was removed by filtration. A 10% aqueous solution of acetic acid was added to the filtrate to adjust its pH to 8, and it was then extracted with chloroform. The extract was dried and concentrated. Acetonitrile was added to the residue, and the mixture was cooled with ice. The crystals were collected by filtration and recrystallized from aqueous ammonia to give 5-amino-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 253°-254° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])([CH3:24])[CH3:23]>>[CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14](=[N:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[CH:26]=3)[C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C(=O)N1CCN(C2CCCCC2)CC1)c1cccs1
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cccc(N=C(C(=O)N2CCN(C3CCCCC3)CC2)c2cccs2)c1

Procedure:
Intermediate 12 was generated from 1-(4-cyclohexyl-piperazin-1-yl)-2-thiophen-2-yl-ethane-1,2-dione and 3-isopropylaniline using general method L.
Reaction SMILES: [OH:1][CH:2]([CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[C:3]#[N:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:37]([O:39][CH2:40][CH3:41])=[CH2:38].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:37]([O:39][CH:40]([O:1][CH:2]([CH:5]([O:18][CH3:19])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][CH:11]=1)[C:3]#[N:4])[CH3:41])[CH3:38]
Reactant: C=COCC
Reactant: COC(c1ccc(N2CCOCC2)cc1)C(O)C#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(C)OC(C#N)C(OC)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
To a solution of 2-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanenitrile (˜5.1 mmol) in anhydr CH2Cl2 (17 mL) under argon was added pyridinium para-toluenesulfonate (0.094 g, 0.37 mmol) and ethyl vinyl ether (17 mL, 178 mmol). The mixture was placed under a drying tube and stirred at room temperature for 16 hrs. Additional ethylvinyl ether (4 mL, 42 mmol) and pyridinium para-toluenesulfonate (0.11 g, 0.44 mmol) were added and the mixture stirred for 24 hrs more. Saturated aqueous NaHCO3 was added to the mixture then it was diluted with H2O and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by chromatography (20-35% EtOAc-hexanes containing 1% Et3N) gave 2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinophenyl)propanenitrile (0.606 g, 35% for three steps).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:12]=1)(O)=[O:9]>ClCCl>[ClH:4].[Cl:7][C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:12]=1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(-c2cccc3cccnc23)c2ccccc12
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1cn(-c2cccc3cccnc23)c2ccccc12
Temperature: 22 °C
Reaction time: 15 h
Yield: 115 %

Procedure:
0.6 cm3 (6.88 mmol) of oxalyl chloride is added to a suspension, cooled to a temperature in the region of 5° C., of 0.74 g (2.28 mmol) of 3-carboxy-1-(quinol-8-yl)-1H-indole hydrochloride in 15 cm3 of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.9 g of 3-chlorocarbonyl-1-(quinol-8-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])[CH2:13][CH:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH3:15])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])[CH2:13][CH:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH3:15])([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)CC(C)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)Nc1ccccc1C(=O)O)c1ccc2ccccc2c1

Procedure:
Prepared analogously to Example 2 from 3-(naphth-2-yl)-butanoic acid-N-(2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][CH2:14][Cl:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Br)ccc(O)c21
Reactant: OCCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1NCc2c(Br)ccc(OCCCCl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A suspension of Example 106D (250 mg, 1.1 mmol), 3-chloropropanol (0.095 mL, 1.1 mmol), and triphenylphosphine (350 mg, 1.3 mmol) in dichloromethane (5 mL) at 0° C., was treated dropwise with DEAD (0.21 mL, 1.3 mmol) over 10 minutes. The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature overnight, and concentrated. The residue was purified by silica gel chromatography with 50 to 60% ethyl acetate/hexanes to give 227 mg of the desired product which was contaminated with triphenylphosphine oxide. MS (ESI(+)) m/e 304,306 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][N:24]([CH2:26][C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)[CH:25]=2)O1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][C:27]4([OH:31])[CH2:30][CH2:29][CH2:28]4)[CH:25]=3)=[N:9]2)=[CH:4][N:3]=1
Reactant: Clc1ccc2cnc(Br)cc2n1
Reactant: CC1(C)OB(c2cnn(CC3(O)CCC3)c2)OC1(C)C
Product: OC1(Cn2cc(-c3ccc4cnc(Br)cc4n3)cn2)CCC1

Procedure:
The title compound was prepared according to the method described for Preparation 58 using 7-Bromo-2-chloro-1,6-naphthyridine (Preparation 61) and 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)cyclobutanol (Preparation 131).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:11]=2[CH2:12][N:13]([CH2:19][CH3:20])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(Cl)Cl.O>C(N(CC)CC)C.[Cu](I)I.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>[CH2:19]([N:13]([CH2:12][C:11]1[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:10]=1[C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:3]=1)[C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])[CH3:20]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC)C(=O)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C#C[Si](C)(C)C)cnc1OC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarboxylic acid [2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amide (0.215 g, 0.47 mmol), (trimethylsilyl)acetylene (0.07 mL, 0.47 mmol), and copper iodide (0.012 g, 0.05 mmol) were combined in triethylamine (2 mL), and the solution was purged with N2 for 25 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.039 g, 0.05 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was worked-up with CH2Cl2 and H2O, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give cyclopropanecarboxylic acid ethyl-[2-(2-methoxy-5-trimethylsilanylethynyl-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[Br:15].[H-].[Na+].CI.[C:20]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Br:15][C:3]1[CH:4]=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][CH3:20]
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CNc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4-amino-3-bromo-5-nitrobenzotrifluoride (5.25 g, 18.4 mmol) in DMF (40 mL) was added NaH (883 mg, 60% suspension in mineral oil, 22.1 mmol). After 30 min MeI (1.38 mL, 22.1 mmol) was added. The reaction mixture was allowed to stand at room temperature for 1 h, then was poured into a solution of saturated aqueous NaHCO3 and brine. The resulting suspension was extracted twice with CH2Cl2, and the combined extracts were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (5% EtOAc in hexanes, then 8% EtOAc in hexanes) provided the title compound as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.12 (br s, 1H), 7.86 (d, J=2.0 Hz, 1H), 6.47 (br s, 1H), 3.07 (d, J=5.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3-fluorobenzyl chloride gave the title compound. ES-MS m/e (%): 507.4 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[Cl:33][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:35]3[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=3)[C:19](=[O:34])[NH:20]2)=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(-c4ccccn4)c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(-c4ccccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-pyridin-2-yl-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 2.0 dry methylene chloride was added a few drops of anisole followed by 2.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1.5 hours, the solvents were removed in vacuo and the resulting residue purified by reverse-phase mplc (C-8, methanol:0.1% aqueous trifluoroacetic acid, 55:45) to give the title compound (112 mg). MASS: 488 (M+H)
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:33][N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)[N:13]([CH:40]([CH3:42])[CH3:41])[N:12]=1)C1C=CC=CC=1>[Pd]>[CH:40]([N:13]1[C:14]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:31][N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH2:33]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:15][C:11]([NH2:10])=[N:12]1)([CH3:42])[CH3:41]
Reactant: CC(C)n1nc(NC(=O)OCc2ccccc2)nc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Agent: [Pd]
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Reaction time: 72 h

Procedure:
A suspension of (1-isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-yl)-carbamic acid benzyl ester (157 mg, 0.25 mmol) in IMS (25 mL) was treated with a slurry of palladium on carbon (50 mg, 50% in water) and the mixture was stirred under an atmosphere of hydrogen for 3 days. More palladium on carbon was added and the mixture stirred for another 18 hours before being filtered through celite. The filtrate was concentrated in vacuo and the residue purified by reverse-phase preparative HPLC (Gemini C18 column, gradient 10-90% MeOH in H2O+0.1% HCO2H) to give 463 as a white solid after freeze drying (43 mg, 35%). LCMS: RT=6.30 min, [M+H]+=489. 1H NMR δ (ppm) (DMSO-d6): 8.22 (1 H, d, J=8.18 Hz), 7.14 (1 H, dd, J=8.25, 1.81 Hz), 6.99 (1H, d, J=1.77 Hz), 5.67-5.59 (1 H, m), 5.54 (2H, s), 4.30 (2 H, t, J=5.02 Hz), 3.63-3.50 (3 H, m), 3.10 (4 H, t, J=6.28 Hz), 3.01 (3 H, s), 2.78 (2 H, t, J=6.83 Hz), 1.42 (6 H, d, J=6.58 Hz). 2 Protons obscured by water peak
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][N:50]=[CH:51][CH:52]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccncc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-4-ylmethanamine, the title compound was obtained as a colorless solid in 60% yield: mp 146-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=6.0 Hz, 2H), 7.29-7.24 (m, 4H), 7.07-7.01 (m, 2 H), 6.21 (br s, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.45 (s, 2H), 4.08 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 426.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([CH3:24])[CH:22]=2)[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: Cc1cccc(CBr)c1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
A mixture of the product from Example 38b (28 mg, 0.085 mmol), 3-methylbenzyl bromide (13 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the tile compound (32 mg, 100%).