Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=1)[CH3:2].[C:17]([C:19]1[O:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1)#[N:18].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:24]([C:22]2[O:23][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[O:25])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=1)[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CCOc1ccc(N)c(N2CCCCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 54 %

Procedure:
Using a procedure similar to Example 3, step (d), 4-ethoxy-2-piperidin-1-yl-phenylamine (64 mg, 0.29 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (66.6 mg, 0.430 mmol) in the presence of DIEA (111 μL, 0.63 mmol) to afford 53 mg (54%) of the title compound as a light yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 9.49 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=2.7 Hz), 7.22 (d, 1H, J=2.8 Hz), 6.77 (d, 1H, J=2.8 Hz), 6.67 (dd, 1H, J=2.8, 8.9 Hz), 2.82 (m, 4H), 4.02 (q, 2H, J=7.0 Hz), 2.82 (m, 4H), 1.80-1.82 (m, 4H), 1.64 (br s, 2H), 1.41 (t, 3H, J=7.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C19H21N3O3, 340.1 (M+H), found 340.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH3:18])=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1>>[CH3:18][O:17][C:13]1[C:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)[CH:7]=3)=[N:9][NH:10][C:11]=2[CH:16]=[CH:15][N:14]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1nccc2c1c(-c1ccnc(Cl)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1nccc2[nH]nc(-c3ccnc(-c4cnn(C)c4)c3)c12
Yield: 57 %

Procedure:
Prepared according to the procedure described in Example 116, by reacting 3-(2-chloropyridin-4-yl)-4-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give the title compound (30.5 mg, 57% over two steps). LC-MS (Method G): m/z=307.0 (M+H)+; 3.06 min. 1H-NMR (400 MHz, DMSO): δ 13.89 (br s, 1H), 8.60 (d, J=5.2, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.97 (d, J=6.0, 1H), 7.75 (dd, J=5.2, 1.5 Hz, 1H), 7.23 (d, J=6.0, 1H), 4.05 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[OH-].[Na+].[CH3:12]I>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: CI
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)ccc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
2-Chloro-5-methylphenol (50 mmol, 7.13 g), NaOH pellets (60 mmol, 2.4 g), and methanol (50 ml) were stirred together until a homogeneous solution was obtained. The flask was cooled to 0° C., and methyl iodide (60 mmol, 3.77 ml) was added. The reaction was warmed over 2 hours to ambient and stirred for 16 hours. Reaction was still incomplete by thin layer chromatography; additional NaOH (˜300 mg) and CH3I (˜5 ml) was introduced, and stirring continued for another 24 hours. TLC again indicated incomplete conversion, so additional time and reagents were again applied. The mixture was at length concentrated, diluted with water (50 ml), and extracted with methylene chloride (2×25 ml). The combined organic layer was dried (MgSO4), filtered through silica, and concentrated to afford the title compound as an oil (5.09 g, 65%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=O)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:48][O:49][NH2:50]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH:34]=[N:50][O:49][CH3:48])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 21.7 %

Procedure:
To a solution of (2R,3 R,4R,5S,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-oxoethyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.35 mg, 0.61 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.24 mL, 3.04 mmol), and O-methylhydroxylamine hydrochloride (151 mg, 1.82 mmol). The reaction mixture was refluxed for 2 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (25 mL). The organic layer was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.0:9.0 Acetone:Pet. Ether) to afford the title compound (80 mg, 22%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:15][C:16]=3[CH3:17])[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>COCCO.O>[CH3:17][C:16]1[CH:15]=[C:14]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([NH:35][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:34])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:26]
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Reactant: C[C@@H](N)c1ccccc1
Solvent: COCCO
Solvent: O
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(NC(C)c3ccccc3)c21
Temperature: 115 °C
Yield: 83.1 %

Procedure:
A mixture of 4-chloro-5-[3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (37 mg, 0.1 mmol) and (R)-(+)-1-phenylethylamine (121 mg, 1 mmol) in 2-methoxyethanol (0.5 mL) was heated at 110-120° C. for 1.5 hours. The reaction was diluted with water and filtered. The precipitate was washed with water, little ethanol, ethyl acetate, hexane and dried to give 38.1 mg (81%) of the title compound as a yellow solid. MS 459 [M++1].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:39]=[CH:38][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C>C(OCC)(=O)C.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:38][CH:39]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC3CCNCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A mixture of tert-butyl 4-[(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenoxy)methyl]piperidine-1-carboxylate (1.5 g, 2.8 mmol) and 4 M hydrochloric acid-ethyl acetate solution (20 mL) in ethyl acetate (100 mL) and methanol (100 mL) was stirred at room temperature for 16 h. Solvent was removed in vacuo and 1 M sodium hydroxide solution was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid (1.1 g, 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C:19]([Cl:34])=[CH:18][N:17]=1>>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to Example 179. The product was isolated as a light brown solid (40 mg, 40%). LCMS (m/e) 466 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.67 (d, 1H, J=8.6 Hz), 8.29 (d, 1H, J=7.8 Hz), 8.12 (s, 1H), 7.79 (s, 1H), 7.50 (m, 2H), 7.10 (t, 1H, J=7.6 Hz), 6.94 (m, 2H), 6.13 (m, 1H), 4.02 (t, 2H, J=4.5, 5.1 Hz), 3.52 (m, 2H), 2.08 (m, 2H), 1.70 (t, 2H, 5.6, 6.1 Hz), 1.39 (s, 6H) 1.27 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1C(O)=O)=O.C(=O)=O.[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]3[C:8](=[C:22]([C:28]([O:30][CH3:31])=[O:29])[C:23]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14]3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C#CC(=O)OC
Agent: O=C=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Yield: 91 %

Procedure:
A solution of N-(3,4-dichlorobenzoyl)proline (28.813 g 0.1 mol) in acetic anhydride (100 mL) and dimethyl acetylenedicarboxylate (50 mL) was stirred in a flask equipped with a reflux condenser and a gas bubbler to monitor CO2 evolution during the reaction. The mixture was heated to 120° C. over a 15-min period, during which time CO2 evolution occurred at an increasingly rapid rate; the temperature was maintained for 1 h after the rate of gas evolution had substantially decreased. The reaction mixture was concentrated in vacuo and the residue, which solidified on cooling, as twice crystallized from hot methanol (500 mL) to yield 33.35 g (91%) of dimethyl 2,3-dihydro-5-(3,4-dichlorophenyl)-1H-pyrrolizine-6,7-dicarboxylate as analytically pure fine white needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2o1
Yield: 89.9 %

Procedure:
6-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzofuran-2-carboxylic acid ethyl ester (1.58 g, 4.31 mmol) and 1-bromopinacolone (1.16 g, 6.47 mmol) and K2CO3 (1.78 g, 12.9 mmol) in acetone (50 mL) are reacted analogous to Example 30-D to give the title compound (1.80 g, 90%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1.OS(O)(=O)=O.CCOC(C)=O>CN1C(=O)CCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:17][CH:18]4[CH2:20][CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: Clc1nc(NC2CC2)c2c(n1)C(c1ccccc1)CC2
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc(NC3CC3)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 97 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (175 mg, 0.612 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (151 mg, 0.674 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.046 mL, 0.857 mmol). The mixture was stirred at 97° C. for 20 hours. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/water and water, dried over Na2SO4, and finally removed. The residue was purified via Biotage (12 g, hexanes-80% EtOAc) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (200 mg, 0.423 mmol, 69.1% yield). LC-MS (M+H)+=473.10. 1H NMR (500 MHz, CDCl3) δ ppm 7.81 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.5 Hz), 7.44 (1H, s), 7.27-7.35 (2H, m), 7.19-7.25 (3H, m), 6.99-7.06 (2H, m), 6.95 (1H, d, J=8.2 Hz), 4.89 (1H, br. s.), 4.20 (1H, t, J=8.2 Hz), 3.45 (3H, s), 2.92 (1H, td, J=6.7, 3.1 Hz), 2.76-2.86 (1H, m), 2.59-2.75 (2H, m), 2.07-2.14 (1H, m), 0.85-0.91 (2H, m), 0.63-0.70 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CCCO1
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (1.95 g, 12.2 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.66 g, 13.5 mmol). The mixture was stirred at reflux for 2 h. The resulting suspension was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 50% MeOH/acetone (75 mL). The suspension was stirred at reflux for 5 min. The solid material was filtered and washed with acetone (2×25 mL). This allowed the isolation of compound O, 1.74 g (51%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7](O)([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[ClH:15]>[Cl-].[Zn+2].[Cl-]>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([Cl:15])([CH3:9])[CH3:8])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The alcohol from step A above (54 g, 0.27 mol) is treated with ethereal HCl (1.3 L, 1M) followed by anhydrous zinc chloride (53 mL, 1M in ether) and the reaction allowed to stir for 22 h at room temperature. The reaction is then washed with water, aqueous 2 N NaOH, dried over MgSO4, concentrated and purified by silica gel chromatography (8:1 hexane to ethyl acetate) to give 4-trifluoromethyl-α,α-dimethylbenzyl chloride of sufficient purity to carry to the next step; yield: 50.5 g (85%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].[H][H].S(=O)(=O)(O)O>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: [H][H]
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccc(CO)o2)cc1

Procedure:
To a heated suspension of 5-(4-nitrophenyl)-2-furancarboxaldehyde (176 g., 0.8 m.) and 1000 ml of ethanol was added a suspension of sodium borohydride (82 g.) in 1500 ml of ethanol. The solids dissolved and the solution turned very dark. The solution was stirred without external heating until hydrogen ceased to be evolved (22 hours). Upon stirring, the material solidified (pH 9-11). To the suspension was added a 5 percent sulfuric acid solution until the solution was just acidic (600 ml., pH 5-6). The dark mixture was dissolved upon heating at 60°-70° C. for 1 hour. After cooling, the solids were filtered and the filtrate was diluted with water to ppt. the product. The solids were extracted with boiling SDA-32 and the extracts were diluted with water. Total yield of 5-(p-nitrophenyl)-furfuryl alcohol was 150 grams (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=383.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17]CC)=[O:16])(=[O:11])=[O:10].C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11]
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the product of Step A was added ethanol (8 mL) followed by a solution of NaOH (0.483 g, 12.06 mmol) in water (8 mL). The reaction was stirred at ambient temperature for 45 minutes. To the mixture was added 1 N HCl (23 mL) and the mixture was stirred overnight. The solids were collected by filtration, washed with water (1×5 mL) and dried by vacuum filtration to give 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: 1H-NMR: (400 MHz, DMSO-d6) δ ppm 13.97 (bs, 1H), 10.62 (bs, 1H), 8.26 (dd, 1H, J=1.6, 1.6, 3.2 Hz), 8.16 (ddd, 1H, J=8.1, 1.1, 1.1 Hz), 7.90 (ddd, 1H, J=8.1, 1.4, 1.4 Hz), 7.68 (dd, 1H, J=7.8, 7.8 Hz), 7.25-7.1 (m, 4H); MS (ESI) m/z 294.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14]CN(CC)CC2)=[O:7])=[CH:4][C:3]=1[Cl:19].[N:20]1(CCN)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:14][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:7])=[CH:4][C:3]=1[Cl:19]
Reactant: NCCN1CCCC1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Product: Nc1ccc(C(=O)NCCN2CCCC2)cc1Cl

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 2-pyrrolidin-1-ylethanamine (Aldrich; 1.885 g, 16.5 mmol), as a tan coloured solid (2.67 g, 66%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[Br:28][C:29]1[CH:36]=[CH:35]C(C#N)=[CH:31][CH:30]=1>C1COCC1>[Br:28][C:29]1[CH:36]=[CH:35][C:27]([C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(Br)cc3)cc12
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
To N,N-diisopropylamine (2.54 mL, 18 mmol) in anhydrous THF (15 mL), under N2 at −78° C. was added n-BuLi dropwise (2.5M in n-hexanes, 7.2 mL, 18 mmol) and the reaction mixture maintained at this temperature for 30 minutes. A solution of N,N-diethyl-2,3-dimethyl-benzamide (1.23 g, 6 mmol) in anhydrous THF (15 mL) was added dropwise to give a deep red solution. After 20 minutes at −78° C., 4-bromobenzonitrile (1.09 g, 6 mmol) in anhydrous THF (15 mL) was added dropwise and the reaction mixture allowed to stir at this temperature for 2.5 h. The reaction mixture was quenched by adding dropwise onto ice, upon which a pale yellow solid precipitated out. The solid was triturated with iso-hexane/EtOAc (2:1), filtered and dried in vacuo to afford 3-(4-bromo-phenyl)-5-methyl-2H-isoquinolin-1-one as a pale yellow solid (1.1 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:7]=1.C(N(CC)CC)C.[Cl:33][C:34]1[C:42]([O:43][CH3:44])=[C:41]([O:45][CH3:46])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][N:19]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:36]([C:35]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([O:43][CH3:44])[C:34]=2[Cl:33])=[O:37])[CH:7]=1
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Reactant: CC(C)CCNCc1nc2ccccn2c1Cc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccn3c2Cc2cc(Br)ccc2O)c(Cl)c1OC
Temperature: 45 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of 90 mg (0.25 mmol) ({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(3-methylbutyl)amine in 4 mL dichloromethane at 0° C. is treated with triethylamine 50 mg (0.50 mmol) and then 2-chloro-3,4-dimethoxybenzoylchloride 110 mg (0.50 mmol). The solution is stirred overnight and the volatiles removed by rotary evaporation. The residue is dissolved in 4 mL methanol and treated with 2 mL 1M sodium hydroxide. The solution is heated to 45° C. for 1 hr and the volatiles removed by rotary evaporation. The mixture is acidified with 1M hydrochloric acid, extracted with 3×5 mL ethyl acetate and the combined extracts washed with 5 mL brine. The combined extract is dried over anhydrous MgSO4 and the solvent removed in vacuo to yield 120 mg (80%) N-({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 602.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([C@@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][C:28]([OH:29])=[C:17]([OH:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Yield: 50 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3,4-dihydroxy-L-phenylalanine to provide the title compound in 50% yield as yellow needles (recrystallization from acetone/toluene).