Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)C1C=CC=CC=1.S1CC(=O)NC1=O.[CH:16](=[C:23]1[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.[Pd]>[CH2:16]([CH:23]1[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)S1
Agent: [Pd]
Agent: O=C1CSC(=O)N1
Solvent: O=Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccccc2)S1

Procedure:
Benzaldehyde (10.6 g) and 2,4-thiazolidinedione (11.7 g) were reacted together by a procedure analogous to that described in Example 1. The resulting material, 5-benzylidene-2,4-thiazolidinedione (18.5 g) was dissolved in dioxan (300 ml) and hydrogenated over 10% Palladium-charcoal (18.5 g) at 200 psi, overnight. The mixture was filtered through diatomaceous earth, the filter cake thoroughly washed with dioxan, and the combined dioxan solutions evaporated to afford the title compound, mp 83°-86° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.Cl>O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
An eggplant flask was charged with 4-fluoro-3-nitrobenzoic acid (2.51 g, 13.56 mmol), aniline (2.52 g, 27.12 mmol), and ethanol (9.5 mL), and this was heated to reflux with stirring for 16 hours. After cooling to room temperature, the mixture was poured into dilute hydrochloric acid (1 M, 50 mL), diluted with distilled water (100 mL), was left to stir as is at room temperature for 30 minutes. The precipitated crystals were filtered off, and washed successively with dilute hydrochloric acid (1 M, with approx. 3 mL 3 times), distilled water (approx. 5 mL 2 times), and with diethyl ether (approx. 3 mL). The crystals obtained were dried at reduced pressure with heating to yield the title compound (3.39 g, quant.) as a reddish-orange solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:31]=[C:30]4[C:26]([C:27]([S:45]([CH3:47])=[O:46])=[CH:28][N:29]4[C:32]4[N:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[F:44])=[CH:34][N:33]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:17]2)(=O)=O)=CC=1>CN(C=O)C>[N:1]([C@@H:20]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([S:45]([CH3:47])=[O:46])=[CH:28][N:29]3[C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[CH:34][N:33]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:19]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)c3ccc4c(S(C)=O)cn(-c5ncc(-c6ccccc6F)cn5)c4c3)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CC[C@@H](N=[N+]=[N-])C3)ccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium azide (0.31 g, 4.79 mmol) was added to a solution of 68a) (0.75 g, 1.37 mmol) in DMF (8.65 mL) and the resulting mixture was stirred at 60° C. for 2 h. After cooling to ambient temperature, the reaction mixture was poured onto water and extracted with dichloromethane (3×30 mL). The organic phase was dried over sodium sulfate and concentrated. The remnant was purified by flash column chromatography [silica; 2.5% methanol in dichloromethane]. White solid. Yield: 0.4 g (59% of theory). HPLC-MS (method 4): Rt=3.04 min; m/z [M+H]+=490.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.Cl.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2cc(F)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1ccc2cc(F)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-fluoro-2-naphthyl)carbamic acid ethyl ester (548 mg, 2.35 mmol), N-chlorosuccinimide (313 mg, 2.35 mmol) and 1 M HCl in acetic acid (2.35 mL, 2.35 mmol) in acetic acid (20 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature, water (10 mL) is added. The resulting precipitate is removed by filtration to give N-(1-chloro-6-fluoro-2-naphthyl)carbamic acid ethyl ester as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(O)CO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](CC(O)CO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (4R)-4-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-5,5-dimethyl-hexane-1,2-diol, 191a, (0.140 g, 0.257 mmol) in THF (10 mL) was added sodium methoxide (0.055 g of 25% w/w solution, 0.257 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH/CH2Cl2) followed by preparative HPLC to afford 10 mg pure desired product: 1H NMR (400 MHz, d6-DMSO) δ 8.61 (dd, J=9.9, 2.6 Hz, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=4.1 Hz, 1H), 4.66 (d, J=10.4 Hz, 1H), 4.43 (s, 1H), 4.29 (d, J=4.1 Hz, 1H), 4.04 (s, 1H), 3.35 (s, 1H), 3.26 (d, J=6.1 Hz, 2H), 1.69 (t, J=12.3 Hz, 1H), 1.59-1.45 (m, 1H), 0.96 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.76 minutes (M+H) 392.46.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
3-fluoro-4-methylphenol (3.66 g, 29.0 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. HNO3 70% (3.7 mL, 58 mmol) was diluted with H2O (33 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture, which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 6.85 (d, J=11.0 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C(O)(C)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:19]=[CH:18][N:17]=[C:16]2[O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
3-Aminophenol (338 mg, 3.09 mmol) was treated with cesium carbonate (2 g, 6.2 mmol) in anhydrous isopropanol (10 mL) and the mixture stirred at room temperature for 30 minutes. 4-(2-(4-chloro-6-methoxyquinazolin-7-yloxy)ethyl)morpholine from the previous step (1 g, 3.09 mmol) was added and the mixture stirred at 80° C. for 2 h. Cesium carbonate was filtered off, washed with isopropanol and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol 9:1) to afford 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline (236 mg, 22%) as a brownish solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.09 (t, 1H), 6.50-6.37 (m, 3H), 5.30 (bs, 2H), 4.34-4.30 (m, 2H), 3.91 (s, 3H), 3.60 (s, 4H), 2.82-2.70 (m, 2H) 2.59-2.42 (m, 4H); LC-MS (ESI) m/z 397 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([OH:27])=[O:26])=[C:21]([CH2:23][OH:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:10].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[S:19][C:20]=1[C:25]([OH:27])=[O:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(CO)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Solvent: c1ccncc1
Product: CC(=O)OCc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylic acid (Example 237; 100 mg, 0.23 mmol) was dissolved in pyridine (2 ml) and cooled to 0° C. Acetic anhydride (21.8 μl, 0.230 mmol) was added and mixture was stirred at room temperature for 1 h. The mixture was diluted with
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=[C:37]([OH:41])[CH:36]=2)C(F)=CN=1.CC1OC(C)=CC=1CN>>[CH3:36][C:37]1[O:41][C:23]([CH3:22])=[CH:24][C:25]=1[CH2:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:17]([F:18])=[CH:16][N:15]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Cc1cc(CN)c(C)o1
Product: Cc1cc(CNc2ncc(F)c(Nc3cccc(O)c3)n2)c(C)o1
Yield: 59 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and (2,5-dimethyl-3-furyl)methylamine (80 mg, 0.63 mmol) gave N2-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 59%). 1H NMR (acetone-d6): δ 2.14 (s, 6H), 4.37 (d, J=4.2 Hz, 2H), 5.96 (s, 1H), 6.77 (d, J=6.6 Hz, 1H), 7.23-7.28 (m, 2H), 7.44 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 9.05 (br, 1H), 9.75 (br, 1H); 19F NMR (282 MHz, acetone-d6): δ −165.77; LCMS: ret. time: 19.23 min.; purity: 94.89%; MS (m/e): 329.08 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[CH:28]1([C:31]([N:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=2[C:7]2[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:27])[CH:6]=2)[CH2:25][CH3:26])=[O:32])[CH2:30][CH2:29]1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-33) was prepared by following the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)=[O:26])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2cccnc2Br)nc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2cccnc2Br)nc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
The 6-(2-bromopyridine-3-yloxy)pyridine-3-amine (200 ml, 1.24 mmol) and indole-3-carboxylic acid (200 mg, 1.24 mmol) were dissolved in DMF (5 ml), DCC (280 mg, 1.37 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (100 mg, 20%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1)([CH3:3])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(C)C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(C)C)ccc1C(C)=O

Procedure:
4′-isopropyl-2′-hydroxyacetophenone (33.4 g, 187.4 mmol) is dissolved in acetone (233 ml). Following addition of K2CO3 (51.8 g, 374.8 mmol) and methyl iodide (23.33 ml, 374.8 mmol) the batch is heated at reflux for three days. The reaction mixture is cooled and filtered through a glass fibre filter and the residue is washed with cold acetone. The solvent is removed and the residue is chromatographed (silica gel, eluent: ethyl acetate/hexane). This isolates 31.85 g (88.4%) of the desired compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[N:26]1[CH2:27][CH2:28][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[CH2:24][CH2:25]1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3c(F)cccc3F)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2c(F)cccc2F)CC1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)-sulfonyl]-4-(2,6-difluorophenyl)piperazine to give 1-(2,6-difluorophenyl)-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26][CH:27]5[CH2:28][CH2:29][N:30]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:31][CH2:32]5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCN(S(C)(=O)=O)CC3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 50 mg, 0.085 mmol) and methanesulfonyl chloride (7.9 μL, 0.102 mmol) using a similar method to that employed for Example 27 (30 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.[H-].[Na+].S(OCC)(O[CH2:29][CH3:30])(=O)=O>CN(C=O)C.O>[CH2:29]([N:12]1[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:11]1[CH3:16])[CH3:30]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)CC(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)=C1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) was dissolved in DMF (9 mL) and sodium hydride (60% dispersion in mineral oil, 0.112 g, 1.40 equiv) was added. After the reaction had stirred for 20 minutes at room temperature, diethyl sulfate (0.314 mL, 2.40 mmol, 1.20 equiv) was added and the reaction was heated to 100° C. for 4 hours. The reaction was diluted with H2O and extracted with EtOAc. The organic phase was washed four times with H2O and once with satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.627 g (92%) of the title compound as an oil. MS (ES+) m/e 342 [M+H]+
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=O)[CH2:2][CH3:3].C[O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=1>>[CH2:8]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13]([OH:23])=[O:12])=[CH:17][CH:18]=1)=[O:7])[CH2:9][CH3:10]
Reactant: CCCC(CCC)C(=O)O
Reactant: COC(=O)C=Cc1ccc(N)cc1
Product: CCCC(CCC)C(=O)c1ccc(C=CC(=O)O)cc1

Procedure:
This compound, a precursor to compounds 9 and 10, was synthesized from 2-propyl-pentanoic acid (0.78 mL, 4.9 mmol) and 3-(4-amino-phenyl)-acrylic acid methyl ester (0.86 g, 4.9 mmol) according to Methods a and b aforementioned. Total yield, 1.05 g (70% for 2 steps); 1H NMR (CDCl3, 10% DMSO-d6) δ 9.49 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.55 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 6.31 (d, J=15.9 Hz, 1H), 2.40 (m, 1H), 1.7-1.1 (m, 8H), 0.87 (t, 6H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.[ClH:22].CCOCC>CO>[ClH:21].[ClH:22].[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a methanol solution (80 mL) of the 3-[(tert-butoxycarbonyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.38 g, 20.5 mmol), was added 1 M HCl-Et2O (100 mL). The resulting mixture was stirred at 25° C. for 15 hours. The solvent was removed under reduced pressure to provide a solid, which was purified by recrystallization (methanol/acetonitrile=1:2, 130 mL) to thereby afford 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (4.939 g, 85%) as a white powder. 1H NMR (d6-DMSO, 300 MHz) δ 3.15 (br, 1H), 3.3-3.75 (br-m, 4H), 3.9 (br, 1H), 4.05 (br, 1H), 4.44 (br, 1H), 4.54 (br, 1H), 7.5-7.7 (m, 4H), 8.45 (br, 1H), 8.60 (br, 1H); the purity was determined by RPLC/MS (>99%). ESI/MS m/e 211.0 (M++H, C11H16ClN2).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][OH:37])=[CH:33][C:32]=2[CH:38]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][O:37][C:39](=[O:41])[CH3:40])=[CH:33][C:32]=2[CH:38]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2cc(OCc3oc4cccc(OCC5CCCN(Cc6cccnc6)C5)c4c3C)ccc2o1

Procedure:
A solution of [5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-yl]-methanol (Example 50, 21 mg), acetic anhydride (100 μl) and pyridine (300 μl) was stirred at room temperature for one hour. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution and water. The organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give acetic acid 5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-ylmethyl ester (22 mg) as a colorless oil. FAB-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 1.25-2.23 (7H, m), 2.12 (3H, s), 2.23 (3H, s), 2.78 (1H, m), 2.97 (1H, br d, J=11 Hz), 3.47 (1H, d, J=13 Hz), 3.57 (1H, d, J=13 Hz), 3.86 (1H, dd, J1=9 Hz, J2=7 Hz), 3.94 (1H, dd, J1=9 Hz, J2=5 Hz), 5.09 (2H, s), 5.18 (2H, s), 6.55 (1H, d, J=8 Hz), 6.72 (1H, s), 7.00 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.04 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.16 (1H, d, J=2.5 Hz), 7.20 (1H, dd, J1=8 Hz, J2=5 Hz), 7.38 (1H, d, J=9 Hz), 7.66 (1H, br d, J=8 Hz), 8.48 (1H, br d, J=5 Hz), 8.53 (1H, br s).
Reaction SMILES: [C:1]([CH2:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH2:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH:25][C:9](=[O:11])[C@@H:8]([CH2:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
A suspension of 3.0 g (12 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0.184.550) and 2.66 g (11 mmol) of L-histidine methyl ester dihydrochloride in 40 ml of dimethylformamide is treated at room temperature under a nitrogen atmosphere with 3.45 g (34 mmol) of triethylamine and 4.58 g (12 mmol) of HBTU. The reaction mixture is stirred at room temperature for 5 hours and subsequently evaporated in a high vacuum. The residue is dissolved in 500 ml of ethyl acetate and washed in succession with 100 ml of water, three times with 100 ml of saturated sodium bicarbonate solution each time and 100 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate, evaporated under reduced pressure and the yellowish crude product obtained is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol which contains 0.1% ammonia. In this manner there are obtained 3.6 g of N-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine methyl ester as a colourless foam, MS: 399 (M)+.