Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N+:7]([O-:18])=[CH:6][CH:5]=1>>[OH:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N+:7]([O-:18])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: [O-][n+]1ccc(Cl)c2ccc(C(F)(F)F)cc21
Agent: [K+]
Product: [O-][n+]1ccc(O)c2ccc(C(F)(F)F)cc21

Procedure:
A mixture of potassium hydroxide (50.4 g), 4-chloro-7-trifluoromethylquinoline-1-oxide (21.8 g) and industrial methylated spirit (800 ml) was heated under reflux for 150 minutes. The solvent was evaporated, the residue was triturated with water (600 ml) and filtered. The filtrate was neutralised with glacial acetic acid (150 ml) with cooling and the resultant precipitate collected by filtration, washed with water (50 ml) and dried. The crude product was crystallised from methanol to give the novel compound 4-hydroxy-7-trifluoromethylquinoline-1-oxide, m.p. 208°-210°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1.[CH2:27]([O:29][CH2:30][C:31](Cl)=[O:32])[CH3:28]>>[CH2:27]([O:29][CH2:30][C:31]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:26])[C:9](=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)=[O:32])[CH3:28]
Reactant: CCOCC(=O)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Product: CCOCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
10.0 g of 11β,17,21-trihydroxy-1,4-pregnadiene-3,20-dione is reacted analogously to Example 2(a) with ethoxyacetic acid chloride, worked up, and purified, thus isolating 10.4 g of 21-ethoxyacetoxy-11β,17-dihydroxy-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:4]=1[NH2:5].[Br:11]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Br:11][C:8]1[C:7]([CH3:10])=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)c(C)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a cooled (0° C.) solution of 2-methoxy-5-methylaniline (500 mg, 3.64 mmol) in DMF (5 mL) was added slowly, over 10 minutes, a solution of N-bromosuccinimide (662 mg, 3.72 mmol) in DMF (2.5 mL). The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. The reaction mixture was diluted with brine (25 mL) and extracted with EtOAc (25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in cyclohexane to give the title compound (679 mg, 86%). 1H NMR (500 MHz, CDCl3): δ 6.93 (s, 1H), 6.62 (d, J=0.5 Hz, 1H), 3.83 (s, 3H), 3.73 (br s, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(NCc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
To a solution of 4-(benzylamino)phenol (200 mg, 1 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (48 mg, 1.2 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, 1 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (169 mg, 44%).
Reaction SMILES: [H-].[Na+].[Br-].[Br:4][C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:39]=2)[CH2:34][CH2:33]1.Cl>CS(C)=O>[Br:4][C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[CH:7]=[C:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([O:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:39]=2)[CH2:36][CH2:37]1
Reactant: COC(=O)c1ccc(N2CCC(=O)CC2)cc1Oc1ccccc1
Reactant: Brc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCC(=Cc3ccccc3Br)CC2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylsulfoxide (22.88 mL) with sodium hydride (0.332 g) was heated to 70 OC for 1 hour, then cooled to room temperature and (2-bromobenzyl)triphenylphosphonium bromide (3.40 g) was added in several portions, and then stirred at room temperature for 1 hour. A solution of methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate (1.8 g) in dimethylsulfoxide (5.20 mL) was then added and the reaction was heated to 70° C. over the weekend. The reaction was acidified with 1M aqueous HCl solution and extracted with ether. The combined extracts were washed thoroughly with water and brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with 0-20% ethyl acetate in hexanes.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21]C#N)[CH2:16]1>>[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: N#CCCN1CCC(O)C1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC(O)C3)cc12
Yield: 5.4 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (4.10 g) and 3-(3-hydroxypyrrolidin-1-yl)propionitrile (1.5 g), 3-(2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (157.5 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]C2C=CC=CC=2)=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH2:21][C:22]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:23])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1ccc(Nc2ccccc2)cc1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(N2CCN(C(=O)NCC(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 171, [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid, 4-fluorophenylaniline, iPr2NE, HATU, are reacted to afford the product. LC-MS: 456 (M++1). 1H NMR (CDCl3): δ 3.05–3.3 (m, 4H), 3.6–3.8 (m, 4H), 4.0–4.2 (m, 2H), 4.65–4.9 (s, 2H), 6.1–6.2 (s, 1H), 7.0–7.1 (m, 2H), 7.2 (m, 1H), 7.3 (m, 2H), 7.6–7.7 (s, 1H), 7.7–7.8 (m, 1H), 8.6–8.7 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:22][C:23](OCC)([O:26]CC)[C:24]#[CH:25])[CH3:21].O.CC1C=CC(S(O)(=O)=O)=CC=1>C(#N)C.CCOC(C)=O.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.[Cu]I>[Cl:1][C:2]1[C:3]([C:25]#[C:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2cccc(Cl)c2I)CCOCC1
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C#Cc1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of ethyl 4-(3-chloro-2-iodophenyl)-tetrahydro-2H-pyran-4-carboxylate (0.57 g, 1.4 mmol) and TEA (1.8 mL, 13 mmol) in 10 mL ACN was degassed by vacuum and back filled with nitrogen 3 times. The mixture was treated with 3,3,3-triethoxyprop-1-yne (0.37 g, 2.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.051 g, 0.072 mmol) and copper(I) iodide (0.028 g, 0.14 mmol) and stirred at 55° C. for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with 50 mL EtOH and 10 mL water. The mixture was treated with 4-methylbenzenesulfonic acid hydrate (0.105 g, 0.551 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with 100 mL EtOAc, washed with 20 mL saturated NaHCO3, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (10-25% EtOAc/hexane) to give 0.5 g yellow oil. MS m/e: (M+H)+ 365.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])O[CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:21].C(O)(=O)C>C(O)C.O>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[C:11]([OH:12])=[CH:10][C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:21][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1coc(C(C)(C)C)cc1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc(C(C)(C)C)cc1O
Temperature: 95 °C
Yield: 76 %

Procedure:
6-tert-Butyl-4-oxo-4H-pyran-3-carboxylic acid ethyl ester (300 mg, 1.34 mmol, prepared according to the literature procedure by McCombie, S. W. et al. J. Org. Chem. 1991, 56, 4963-4967) and ammonium acetate (300 mg, 4.16 mmol) were combined in ethanol/water (8 mL/3 ml). Acetic acid was added and reaction mixture was heated at 95° C. for 30 min. It was concentrated and basified with aqueous sodium hydroxide and extracted with methylene chloride (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6-tert-butyl-4-hydroxy-nicotinic acid ethyl ester as a white solid (230 mg, 76%). LR-MS: 224 [(M+H)+]
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:23][N:24]([CH3:37])S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S)=CC=1.O>CN(C=O)C.C(Cl)(Cl)Cl.CO>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:23][NH:24][CH3:37])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC[C@H](NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12)c1ccccc1
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a solution of 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(1R)-2-{methyl[(2-nitrophenyl)sulfonyl]amino}-1-phenylethyl]imidazo[1,2-a]pyridine-3-carboxamide in 3 ml of DMF were added 140 mg of potassium carbonate and 50 mg of 4-methylbenzenethiol, followed by stirring for 3 hours. To the reaction mixture were added water and chloroform/methanol (9/1) to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 80 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(1R)-2-(methylamino)-1-phenylethyl]imidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:12])[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][N:24]3[C:27]([C:30]4[CH:31]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:33]=[CH:34][CH:35]=4)=[CH:28][N:29]=[C:23]3[CH:22]=2)O1>>[CH3:12][C:8]1([C:4]2[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][N:24]4[C:27]([C:30]5[CH:31]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:42])([F:44])[F:43])=[O:38])[CH:33]=[CH:34][CH:35]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:10][O:9]1
Reactant: CC1(C)OB(c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)OC1(C)C
Reactant: CC1(c2cccc(Br)c2)CCO1
Product: CC1(c2cccc(-c3ccn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)c2)CCO1

Procedure:
2-(3-Bromophenyl)-2-methyloxetane may be coupled with 1-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea according to procedure E3.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=4[F:38])=[O:29])=[CH:23][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[NH:11][CH:10]=1)=[O:8])C.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:38][C:32]1[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=1[NH:30][C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[NH:11][CH:10]=[C:9]([C:7]([NH:6][CH2:5][CH:4]=[O:3])=[O:8])[CH:13]=3)[CH:19]=2)=[CH:26][CH:25]=1)=[O:29]
Reactant: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC=O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}1H-pyrrole-3-carboxamide (580 mg, 1.03 mmol) in 10 ml of THF was added 1 ml of 2M HCl. The mixture was heated under nitrogen at 60 C. for 2 hours, cooled to room temperature, and poured into 100 ml of water. Saturated NaHCO3 solution was added until pH=8. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide as light brown solid. Yield: 450 mg, 90%.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)C(OC(C)(C)C)=O)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1.Cl>O1CCOCC1>[O:1]=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Yield: 88.7 %

Procedure:
(±)-3-Oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (0.158 g, 0.25 mmol) was treated with 4 M HCl in dioxane (3 mL) at RT for 1 h, then the solution was concentrated. ODS chromatography (gradient 5-60% CH3CN/H2O containing 0.1% TFA over 1 h), concentration and lyophilization gave the title compound (0.117 g, 82%): MS (ES) m/e 528.4 (M+H)+. Anal. Calcd for C28H28N3O4.1 CF3CO2H.1.5 H2O: C, 53.89; H, 4.82; N. 6.28. Found: C, 53.55; H, 4.55; N, 6.04.
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]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 80 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 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 0.057 g (80%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[F:15][C:16]([F:18])([F:17])[CH:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1cc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(C(O)C(F)(F)F)cn1
Yield: 47.1 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-1H-pyrazole-4-carbaldehyde (300 mg, 2.72 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (75 mg, 0.54 mmol) and (trifluoromethyl)trimethylsilane (0.442 mL, 2.99 mmol), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=10/1) was performed to give 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-4-yl)ethanol (Compound DJ) (231 mg, yield: 47%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9]C)=O.[NH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][NH:11][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: COC(=O)c1cccn1C
Reactant: NCCO
Product: Cn1cccc1C(=O)NCCO

Procedure:
A mixture of 5.5 parts of methyl 1-methyl-1H-pyrrole-2-carboxylate and 2.4 parts of 2-aminoethanol is stirred and refluxed for 2 hours. The reaction mixture is evaporated till dry. Benzene is added twice to the residue and evaporation is continued each time till dry. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is taken up in petroleumether and upon scratching, the product solidifies. It is filtered off and dried, yielding 1.9 parts of N-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carboxamide; mp. 78.1° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][Cl:32].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:29][CH2:30][CH2:31][Cl:32])(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1.02 g (2.92 mmol) of Compound 27 obtained in Example 27 was dissolved in 25 ml of dimethylformamide under argon atmosphere, 129 mg of sodium hydride (60% oil dispersion) and 2.9 ml of 1-bromo-3-chloropropane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Recrystallization from ethyl acetate/acetonitrile afforded 434 mg (35%) of 2-[4-[N-acetyl-N-(3-chloropropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[CH:20]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[CH:22]1([CH:20]([O:21][CH3:29])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:19])[F:17])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of (2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclopentyl)-methanol (126.8 mg, 0.33 mmol) in THF at 0° C. was added sodium hydride (39.2 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (100 μL, 1.6 mmol) was added. The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in hexanes) to afford the title compound as a colorless oil (120 mg, 91%). 1H NMR (400 MHz, CDCl3) δ ppm 0.13 (s, 6H) 0.96 (s, 9H) 1.11-1.21 (m, 1H) 1.30-1.40 (m, 1H) 1.44-1.70 (m, 5H) 1.77-1.86 (m, 1H) 2.13-2.23 (m, 1H) 3.15 (s, 3H) 4.20 (d, J=7.88 Hz, 1H) 4.77 (d, J=13.69 Hz, 1H) 4.89 (d, J=13.28 Hz, 1H) 7.46-7.55 (m, 2H) 7.77 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])=[CH:14][CH:13]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(CNc2cc(C#N)ccn2)cc1
Temperature: 25 °C

Procedure:
To pyridine (500 mL) were added 2-chloroisonicotinonitrile (22.0 g, 159 mmole), para-methoxybenzylamine (25 g, 114% Meq.), and NaHCO3 (30 g). The mixture was heated under reflux overnight. After cooling to RT, the mixture was filtered and the filter cake was rinsed with CH2Cl2. The combined filtrate was concentrated to dryness in vacuum to form a yellow solid. This solid is then recrystallized in EtOAc to give a light yellow crystalline compound and the mother liquor was concentrated and subjected to EtOAc again (repeating three times) to yield the desired compound.