Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>O>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(O)cc2)no1)C(C)C
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccc(F)cc3)cc2)no1)C(C)C

Procedure:
To methyl 2-(3-(4-hydroxyphenyl)isoxazole-5-carboxamido)-3-methylbutanoate (150 mg) in, acetone (3 ml), potassium carbonate (78 mg) was added and stirred. To this 1-(bromomethyl)-4-fluorobenzene (0.07 ml) was added and the reaction mixture was refluxed for 2 hours and then cooled reaction. The mixture was filtered and filtrate was concentrated to obtain pale brown residue. To this residue, water was added and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized using DCM-Petroleum ether to obtain the title compound as white solid. Yield: 170 (84%); MS (ES+): m/z 427 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 9.18 (d, 1H), 7.88 (d, 2H), 7.68 (s, 1H), 7.53 (m, 2H), 7.23 (m, 2H), 7.18 (d, 2H), 5.17 (s, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[O:12])=[CH:7][CH:6]=1)[CH3:3].[CH2:14]([N:21]1[C:25]([CH:26]=O)=[CH:24][N:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[CH2:14]([N:21]1[C:25]([CH:26]=[CH:13][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=2)=[O:12])=[CH:24][N:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1ccc(C(=O)C=Cc2cncn2Cc2ccccc2)cc1

Procedure:
A solution of 4-isobutylacetophenone (2.0 g), 3-benzyl-3H-imidazole-4-carbaldehyde (2.1 g) and 48% sodium hydroxide (0.65 ml) in methanol (20 ml) is heated at 55-60° C. for 6 hours. The reaction mixture is then cooled in an ice bath. The resulting precipitate is filtered, and rinsed with methanol. The yield is 2.5 g.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>O1CCCC1>[CH2:19]([O:18][C:17](=[O:21])[CH2:16][C:12]1[CH:11]=[C:10]([Br:9])[CH:15]=[CH:14][N:13]=1)[CH3:20]
Reactant: Cc1cc(Br)ccn1
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(Br)ccn1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (2 mol/L in tetrahydrofuran/heptane/ethylbenzene, 3.00 mL) was added to a solution of 4-bromo-2-methylpyridine (2.00 g) and diethyl carbonate (1.8 mL) in tetrahydrofuran (30 mL) cooled to −70° C. The solution was stirred for 1 h prior to the addition of another portion of lithium diisopropylamide (2 mol/L in tetrahydrofuran/heptane/ethylbenzene, 3.00 mL). Stirring was continued at −70° C. for one more hour and then the reaction was quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 95:5→1:1) to give the title compound. Yield: 2.35 g (83% of theory); LC (method 3): tR=2.86 min; Mass spectrum (ESI+): m/z=244/246 (Br) [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][CH2:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][N:9]=1>>[Br:6][CH2:7][C:8]1[C:12]2[CH:13]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=[CH:16][C:11]=2[O:10][N:9]=1
Reactant: O=S(=O)(O)Cl
Reactant: BrCc1noc2ccccc12
Product: O=S(=O)(Cl)c1ccc2onc(CBr)c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
Chlorosulfonic acid (1.5 ml, 22 mmol) was slowly added to 3-Bromomethyl-benzo[d]isoxazole (1.0 g, 4.7 mmol) at RT under argon. The reaction was heated at 90° C. for 12 h and then left at RT for 6 h. The resulting viscous oil was quenched over ice, extracted with EtOAc, dried over MgSO4 and concentrated in vacuo to a brown oil (1.17 g, 80% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:15]4[CH:27]=O)[C:9]([CH3:29])=[C:8]([F:30])[CH:7]=2)[CH2:3][CH2:2]1.C([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.O1CCOCC1.C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:15]4[CH2:27][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:9]([CH3:29])=[C:8]([F:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CCCO)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CCCO)cc(CN3CCNCC3)c2c1
Reaction time: 24 h
Yield: 27.7 %

Procedure:
N-Cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxypropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide (Example 10e, 0.34 g) and 1-Boc-piperazine (0.30 g) were stirred together in DCE (10 ml) the overall pH of the reaction was adjusted to pH 6 by dropwise addition of glacial acetic acid. The mixture was stirred for 24 h, sodium triacetoxyborohydride (0.51 g) was added, and the resulting mixture was stirred at room temperature for 24 h. A solution of HCl in dioxan (5 mL of 4M) was added and the reaction mixture stirred for 2 h, evaporated to dryness and the residue purified by reverse phase preparative HPLC (Phenomenex column using a gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.11 g).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:15]1([CH2:20][CH2:21][C:22](O)=[O:23])[CH:19]=[CH:18][N:17]=[CH:16]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N:15]1([CH2:20][CH2:21][C:22]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:23])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: O=C(O)CCn1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCn1ccnc1)N1c2ccccc2Sc2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 19.9 g of phenothiazine, 14 g of 3-(imidazol-1-yl)-propionic acid, 20.6 g of dicyclohexylcarbodiimide, and 200 ml of ethyl acetate is stirred for 30 minutes at 0°, and then for 3 hours at 20°. It is worked up in the customary manner to give 10-[3-(imidazol-1-yl)-propionyl]-phenothiazine, melting point 150°-152°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:39])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C=O.C#C.C(NC(=O)[O-])(C)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:39])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:31][CH2:32]3)[C:19]([OH:21])=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(N)(CC#CCN1CCN(c2ccccc2)CC1)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: C#C
Agent: C=O
Agent: CC(C)(C)NC(=O)[O-]
Product: COc1ccc(-c2ccc(S(=O)(=O)C(N)(CC#CCN3CCN(c4ccccc4)CC3)C(=O)O)cc2)cc1

Procedure:
Methyl 2-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-6-(4N-phenylpiperazin-1N-yl)-hex-4-ynoate: N-Phenyl-1,4-piperazine (478 mg, 2.95 mmol) is coupled with paraformaldehyde (96 mg, 3.21 mmol wrt. monomer) and free acetylene 38e (1.0 g, 2.68 mmol) as described for compound 31a to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:18][OH:19].C(N(CC)CC)C>C(O)C.O>[OH:19][N:18]=[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:3]2([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[CH:16][CH:15]=1)[NH2:14]
Reactant: NO
Reactant: COC1(c2ccc(C#N)cc2)CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: COC1(c2ccc(C(N)=NO)cc2)CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4-(4-methoxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1, 200 mg, 0.921 mmol), hydroxylamine hydrochloride (141 mg, 2.03 mmol) and triethylamine (205 mg, 2.03 mmol) in ethanol (5 mL) was stirred and heated at reflux for 4 h. After being cooled to rt, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic extract was successively washed with brine and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the title compound was obtained (229 mg, 99%): 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.68 (d, 2H), 7.39 (d, 2H), 5.80 (s, 2H), 3.71-3.67 (m, 4H), 2.88 (m, 2H), 1.93-1.89 (m, 4H); DCI(NH3)-MS m/z 251 (MH)+; HPLC RT (Method G) 2.95 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)[CH3:2].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
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: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3cnn(C)c3)cc2CN2CCOC2=O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
{3-[4-Bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.1 g, 0.23 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.06 g, 0.27 mmol), and potassium carbonate (0.1 g, 0.66 mmol) were combined in DME (3 mL) and H2O (1 mL) and degassed with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) was added, and the reaction was stirred at 80° C. for 2 hours to give the title compound, which was directly as a crude solution in the hydrolysis step.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH3:16])=[N:8][C:7]2=[O:17])([O-])=O.[I:18]C1C=C(C(O)=O)C(N)=CC=1>>[I:18][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH3:16])[NH:8][C:7]2=[O:17]
Reactant: CCCc1nc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Nc1ccc(I)cc1C(=O)O
Product: CCCc1nc2ccc(I)cc2c(=O)[nH]1

Procedure:
Following the procedure described as in the preparation of 6-nitro-2-propylquinazolin-4(1H)-one above. 25 g of 5-iodoanthranilic acid was converted into the title compound. 1H-NMR (CDCl3, 200 MHz): δ1.02 (t, 3H, J=7.4 Hz), 1.81 (m, 2H), 2.63 (t, 2H, J=7.4 Hz), 7.40 (d, 1H, J=8.6 Hz), 8.07 (dd, 1H, J=2, 8.7 Hz).1H, J=8.6 Hz), 8.07 (dd, 1H, J=2, 8.7 Hz).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([NH:18][C:19](=[O:37])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:22][CH:21]=2)[CH:6]=1)=[O:4].C(O)C.Cl>C(OCC)(=O)C>[OH:4][CH2:3][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([NH:18][C:19](=[O:37])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][CH:25]=2)[CH:6]=1
Reactant: CCOC(=O)COc1ccc(C=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(CO)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
Under ice cooling 0.2 g of sodium borohydride was added to a mixture of 2.8 g of ethyl 4-formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 64 and 30 ml of ethanol. The mixture was stirred for 2 hours and 50 ml of ethyl acetate was added thereto. The mixture was rendered acidic with diluted hydrochloric acid. The ethyl acetate layer was fractionated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 2.06 g of ethyl 4-hydroxymethyl-2-[p-(4phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16](=O)[CH2:17]Br)[C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][NH:21][C:22]([NH2:24])=[S:23]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[N:24]=[C:22]([NH:21][CH3:20])[S:23][CH:17]=3)[C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(C(=O)CBr)c(=O)[nH]c2c1
Reactant: CNC(N)=S
Solvent: CO
Product: CNc1nc(-c2cc3ccc(C(=O)OC)cc3[nH]c2=O)cs1

Procedure:
This compound was made analogous to Example 8733, step G. 3-(2-Bromo-acetyl)-2-oxo-1,2-dihydro-quinoline-7-carboxylic acid methyl ester (497 mg, 1.5 mmol) and 1-methyl-2-thiourea (130 mg, 1.4 mmol) in MeOH were heated to 150° C. for 400 seconds in the microwave. MS m/z: 316 (M+1), 314 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[C:13]#[N:14].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:18][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(N)c(Nc2ccc(F)cc2F)c1
Yield: 38.5 %

Procedure:
A mixture of 3-(2,4-difluorophenylamino)-4-nitrobenzonitrile (3.5 g), iron powder (3.5 g) and ammonium chloride (0.35 g) in ethanol (50 ml) and water (25 ml) was refluxed for 1 hour. The insoluble material was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to dryness. The residual oil (3 g) was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate to give a powder of 4-amino-3-(2,4-difluorophenylamino)benzonitrile (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:21][C:20](=[O:23])[N:19]([CH2:28][C:27]#[CH:26])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(CCl)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A solution of 3.6 g (11.0 mmol) of 3-chloro-2-[3-(2-chloroacetylamino)-4-hydroxyphenyl]-5-trifluoromethylpyridine in 50 ml of anhydrous dimethylformamide was added dropwise at 0° C. to a suspension of 0.4 g (12 mmol) of sodium hydride (80% strength in mineral oil) which had been freed of mineral oil and 50 ml of anhydrous dimethylformamide. After stirring for 15 minutes, 1.3 g (11.0 mmol) of propargyl bromide were added dropwise to this mixture. The reaction mixture was then slowly allowed to warm to about 20° C. room temperature, stirred for a further three hours and then poured into 500 ml of ice water. The aqueous phase was extracted three times with 200 ml of ethyl acetate each time. The combined organic phases were washed twice with a little water, dried over sodium sulfate and then concetrated. Chromatographic purification of the residure on silica gel (eluent: cyclohexane/ethyl acetate 4:1) gave 1.9 g (47%) of colorless crystals of m.p.: 136-137° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])([CH3:3])[CH3:2].[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26]O)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][O:10][C:9](=[O:11])[CH2:8][O:7][C:6]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1cc(OCC(=O)O)cc(C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)cc(C(C)C)c2)cc1
Yield: 97.8 %

Procedure:
A mixture of 3-isopropyl-5-methylphenoxyacetic acid (prepared above, 6.0 g, 28.8 mmol), 2-(p-toluenesulfonyl)ethanol (5.77 g, 28.8 mmol), and p-toluenesulfonic acid hydrate (p-TsOH.H2O) (0.5 g) in 100 mL of toluene was refluxed with Dean-Stark trap for 3 h. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution (2×), dried over MgSO4, and concentrated to give 3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 64, 11.0 g, 98%) as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:56])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.CC(O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:56])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][OH:38])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-(2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoic acid methyl ester (3.88 mmol) in THF (25 mL) at 0° C. was added a mixture of HOAc:1M TBAF (in THF) (2.3 mL:5.8 mL) and the reaction mixture was allowed to stir at rt for 18 h. Extractive workup followed by trituration with 5% EtOAc/hex gave the desired 4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester with slight impurity as an off-white solid (92%, over 3 steps).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[CH:10]2)=[C:4]([Cl:20])[CH:3]=1.C(ON=O)(C)(C)C.[ClH:28]>C(#N)C.[Cu](Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:28])[CH:3]=[C:4]([Cl:20])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[CH:10]1
Reactant: Cl
Reactant: Nc1cc(Cl)c(-n2cnc(C(F)(F)F)cc2=O)c(Cl)c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=c1cc(C(F)(F)F)ncn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-amino-2,6-dichlorophenyl)-4-trifluoromethylpyrimidin-6-one (as prepared in Preparation 1) (0.9 g) in acetonitrile (10 ml) was added dropwise to a stirred suspension of copper (II) chloride (0.37 g) and t-butylnitrite (1.46 g) in dry acetonitrile (8 ml) while the temperature was maintained between 0° and 5° C. After the addition was complete, the reaction mixture was stirred for a further 1 hour at 5° C., and then allowed to warm slowly to ambient temperature. The reaction mixture was then poured into 20% aqueous hydrochloric acid and extracted into diethyl ether. The combined organic extracts were washed with 20% aqueous hydrochloric acid, dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated under reduced pressure. The residual oil was flushed through a plug of silica gel using petroleum ether (boiling range 60°-80° C.) containing diethyl ether (25% by volume) as eluent. Recrystallisation of the so generated white solid from petroleum ether (boiling range 60°-80° C.) gave 1-(2,4,6-trichlorophenyl)-4-trifluoromethylpyrimidin-6-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:30]1[O:31][C:27]([N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[O:20])=[CH:28][CH:29]=1)=[O:33]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-n2ccccc2=O)o1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2ccccc2=O)o1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-(2-oxo-2H-pyridin-1-yl)-furan-2-carboxylic acid. MS: 447.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2Oc2cncc(Cl)c2)cc1

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.41 g) and 4-methoxybenzenesulfonyl chloride ((0.30 g ) were combined to provide the title compound (0.236 g) as a crystalline solid following flash chromatography and trituration with ether.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)CCCNC(=O)COc1ccc(CCCCN)cc1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)CCCNC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (292 mg, 0.75 mmol) 5 was added to a solution of compound 4 (200 mg, 0.65 mmol), DIPEA (0.39 mL, 2.25 mmol), and ethanol (5 mL). The reaction mixture was stirred at 65° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (80:18:2 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 6 (190 mg, 56%) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.65 (m, 6H), 2.15 (s, 6H), 2.32 (m, 2H), 2.64 (m, 2H), 3.27 (m, 8H), 4.49 (s, 2H), 6.89 (d, 2H), 7.15 (d, 2H). m/z (ESI) 520.