Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.O>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ClCCOCCCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCOCC1
Reaction time: 1 h
Yield: 35.1 %

Procedure:
NaH (420 mg, 10.5 mmol, 60%, w/w) was added to a solution of 2-(3,4-dichlorophenyl)acetonitrile (930 mg, 5 mmol) in DMSO (20 ml) at room temperature. After stirring for 40 minutes at room temperature (15° C.), 1-chloro-2-(2-chloroethoxy)ethane (786.5 mg, 5.5 mmol) was added. The mixture was stirred for another 1 hour, then poured into water (5.0 mL), and the mixture was extracted with EtOAc-toluene (2:1, 3×30 mL). The combined organic extracts were washed with 2N aq. HCl (30 mL), water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated to 5 mL. The precipitated solids were collected by filtration and washed with cold diethylether (10 mL) to afford the title compound (450 mg, yield 35%). 1H NMR (400 MHz, CDCl3): 7.58 (d, J=2.0 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.34 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 4.08-4.12 (m, 2H), 3.85-3.92 (m, 2H), 2.2.02-2.13 (m, 4H). LC-MS (M+H): m/z 229.1 (M-CN).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: CN
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: CNc1ccc([N+](=O)[O-])c(C)n1

Procedure:
6-Chloro-2-methyl-3-nitro-pyridine (0.6 g) was treated with methyl amine according to General Procedure U to give methyl-(6-methyl-5-nitro-pyridin-2-yl)-amine LCMS (m/z): 168. This was reduced under hydrogen atmosphere according to General Procedure Z to give 6,N*2*-dimethyl-pyridine-2,5-diamine (0.35 g), LCMS (m/z): 138. This was converted to 2-methyl-6-methylamino-pyridine-3-sulfonyl chloride according to General Procedure AA.
Reaction SMILES: FF.[CH3:3][O:4][C@@H:5]1[C@H:10]([O:11][CH3:12])[C@@H:9]([O:13][CH3:14])[C@H:8]([CH3:15])[O:7][C@H:6]1[O:16][N:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=3)[N:26]=2)=[CH:21][CH:20]=1.[F:37][C:38]([F:45])([F:44])[C:39]([F:43])=[C:40]([F:42])[F:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH3:3][O:4][C@@H:5]1[C@H:10]([O:11][CH3:12])[C@@H:9]([O:13][CH3:14])[C@H:8]([CH3:15])[O:7][C@H:6]1[O:16][N:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:40]([F:42])([F:41])[CH:39]([F:43])[C:38]([F:45])([F:44])[F:37])=[CH:32][N:31]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3ncn(-c4ccc(O)cn4)n3)cc2)[C@@H]1OC
Reactant: FC(F)=C(F)C(F)(F)F
Agent: FF
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)C(F)(F)F)cn4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Yield: 24 %

Procedure:
Fluoroalkylation conditions were based on a paper by Timperley et al. J. Fluorine Chem. 2006, 127, 249. A solution of 4-[1-(5-hydroxy-pyridin-2-yl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-oxime in 10 mL anhydrous DMF/THF (1:1) under a N2 atmosphere was cooled at 0° C. while an excess of hexafluoropropylene gas was added over 15 min. Following addition, triethylamine (15 uL, 0.109 mmol) was added and the reaction mixture warmed to ambient temperature before concentration to dryness. Chromatography (EtOAc/hexanes, 1:1) afforded Compound 94 (16 mg, 24%). 1H NMR (CDCl3) δ 9.17 (s, 1H), 8.39 (d, J=7.68 Hz, 1H), 8.21 (d, J=8.22 Hz, 2H), 8.19 (s, 1H), 8.08 (d, J=7.68 Hz, 1H), 7.74 (d, J=8.22 Hz, 2H), 6.97 (s, 1H), 5.63 (d, J=1.85 Hz, 1H), 5.17 (m, 1H), 3.78 (dd, J=3.28, 1.99 Hz, 1H), 3.63 (m, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 3.56 (s, 3H), 3.43 (dd, J=9.31, 3.36 Hz, 1H), 3.18 (t, J=9.48 Hz, 1H), 1.29 (d, J=6.26 Hz, 3H); EIMS 619 m/z (M+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH2:3][OH:4].[N:17]#[C:18]Br>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:18]([NH2:17])=[N:1]2)[CH3:8])=[CH:15][CH:14]=1
Reactant: N#CBr
Reactant: CC(C)(OC[C@H](N)CO)c1ccc(F)cc1
Product: CC(C)(OC[C@H]1COC(N)=N1)c1ccc(F)cc1

Procedure:
In analogy to example 1d, (R)-2-amino-3-[1-(4-fluoro-phenyl)-1-methyl-ethoxy]-propan-1-ol was reacted with cyanogen bromide to give (S)-4-[1-(4-fluoro-phenyl)-1-methyl-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine. Colourless oil. MS (ISP): 253.3 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: Cn1ccnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cn1ccnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 32.9 %

Procedure:
To a solution of tert-butyl 4-(1-methyl-1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (398 mg) in MeOH (4.0 ml) was added 5% Pd/C (wet; 40 mg) and the mixture was stirred at room temperature for 7 hours under hydrogen atmosphere (1 atm). After removal of Pd/C with cerite, the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column (n-hexane:EtOAc=80:20 to EtOAc only) to give tert-butyl 4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (132 mg) as a colorless oil.
Reaction SMILES: C1C2C(C[C@:15]([NH:58][C:59](=[O:64])[C:60]([NH2:63])([CH3:62])[CH3:61])([CH:55]([CH3:57])[CH3:56])[C:16]([N:18]([C@@H:20]([CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)[C@H:21]([O:48][CH3:49])[CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C@H:30]([O:46][CH3:47])[C@@H:31]([CH3:45])[C:32]([NH:34][C@H:35]([CH3:44])[C@@H:36]([OH:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:33])=[O:24])[CH3:19])=[O:17])C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[NH2:63][C:60]([CH3:62])([CH3:61])[C:59]([NH:58][C@@H:15]([CH:55]([CH3:57])[CH3:56])[C:16]([N:18]([C@@H:20]([CH:50]1[CH2:51][CH2:52][CH2:53][CH2:54]1)[C@H:21]([O:48][CH3:49])[CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C@H:30]([O:46][CH3:47])[C@@H:31]([CH3:45])[C:32]([NH:34][C@H:35]([CH3:44])[C@@H:36]([OH:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:33])=[O:24])[CH3:19])=[O:17])=[O:64]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)[C@@H]1CCCN1C(=O)C[C@@H](OC)[C@H](C1CCCC1)N(C)C(=O)[C@@](CC1c2ccccc2-c2ccccc21)(NC(=O)C(C)(C)N)C(C)C
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)[C@@H]1CCCN1C(=O)C[C@@H](OC)[C@H](C1CCCC1)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To above product (16) was added DEA (3 mL)/CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and dried over sodium sulphate. After concentrated in vacuo, the residue was purified by flash chromatography on silica-gel (MeOH/CH2Cl2, 1:10) to give the desired product 17 (121.0 mg, 58.4% for two steps). LC-MS: m/z 703.0[M+H]+; 1H NMR (400 MHz, DMSO) δ 8.41 (m, 2H), 7.30-7.11 (m, 5H), 4.80-4.10 (m, 4H), 4.00-3.50 (m, 3H), 3.35-2.65 (m, 14H), 2.44-1.90 (m, 4H), 1.89-1.60 (m, 5H), 1.60 (m, 20H), 1.15-0.70 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][O:25][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19]1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: OCC1CCCNC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: OCCOc1cccnc1OCC1CCCNC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 3-piperidinemethanol (65 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 52 mg (0.21 mmol, 53%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=[C:8]([S:14][CH3:15])[N:7]=1)=[O:5])C.Cl>C(O)C.C1COCC1.[Li+].[OH-]>[CH2:12]([C:10]1[N:9]=[C:8]([S:14][CH3:15])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)nc(SC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(C(=O)O)nc(SC)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
To a solution of 6-ethyl-2-methylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester (590 mg, 2.61 mmol) in ethanol (12 mL) and THF (12 mL), 2M aq. LiOH (4 mL) is added. The mixture is stirred for 12 h at rt before neutralizing with 1N aq. HCl. The aq. solution is extracted 3 times with ethylacetate and the combined org. layers are evaporated to dryness to give 510 mg of 6-ethyl-2-methylsulfanyl-pyrimidine-4-carboxylic acid as a white solid; LC-MS: tR=0.75 min, [M+H]+=199.02.
Reaction SMILES: C1C2C(COC([N:18]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:19]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])[C:61]([OH:63])=O>>[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])[C:61]([N:18]([C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:19]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:63]
Reactant: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)c1ccc(O)c(O)c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]-3,4-dihydroxybenzylamine (576 mg, 0.8 mmol, example 26, step A) as described for example 26 (step B) using 3,4-dihydroxybenzoic acid (178 mg, 1.2 mmol) instead of 4-hydroxy-3-nitrobenzoic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2/1% AcOH. The title compound was obtained as white crystals (190 mg, 32%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]#[N:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].NC1C=C[NH:19][N:18]=1>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([NH2:14])[NH:18][N:19]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)Oc1ccc(C(=O)CC#N)cc1
Product: CC(C)Oc1ccc(-c2cc(N)[nH]n2)cc1
Yield: 94 %

Procedure:
The product was prepared from 3-(4-isopropoxy-phenyl)-3-oxo-propionitrile according to general procedure for aminopyrazole synthesis (route A2). The solvent was removed under reduced pressure, water (10 mL) was added, and the title product (1.0 g, 94% yield) was precipitated as a yellow solid and used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20].Br[CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CCCCC(Br)C(=O)OCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(C(=O)OCC)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 70 °C
Yield: 94.2 %

Procedure:
To a solution of 6-amino-5-chloro-2-(methyloxy)-N-(4-piperidinylmethyl)-3-pyridinecarboxamide (step 1 in example 13, 4.0 g, 13 mmol) in dimethylformamide (70 ml) was added ethyl 2-bromohexanoate (3.1 g, 14 mmol), sodium iodide (2.0 g, 13 mmol) and triethyl amine (2.2 ml) at room temperature. The mixture was heated at 70° C. overnight. After cooled to room temperature, the mixture was poured into water (80 ml) and extracted with diethyl ether (200 ml×2), washed with water (100 ml×2), brine (100 ml). The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1) to give 5.4 g (93%) of the title compound as a clear colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[CH:36]([N:39]([CH:43]([CH3:45])[CH3:44])[CH2:40][CH2:41][NH2:42])([CH3:38])[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:42][CH2:41][CH2:40][N:39]([CH:43]([CH3:45])[CH3:44])[CH:36]([CH3:38])[CH3:37])=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: S=C(Cl)Cl
Reactant: CC(C)N(CCN)C(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NCCN(C(C)C)C(C)C)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, N,N-diisopropylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (13 mg, yield 17%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][CH:28]=2)=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 122.5 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (0.92 g), which is the product of Example 11, was reacted with aqueous sodium hydroxide solution (1N, 3.80 ml) and the reaction mixture was treated to give the title compound (1.06 g) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[CH2:10]1[CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([NH2:20])=[C:13]([NH2:21])[C:12]=2[O:11]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:20][C:14]3[CH:15]=[CH:16][C:17]4[O:18][CH2:19][CH2:10][O:11][C:12]=4[C:13]=3[N:21]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: CCc1cc(C=O)[nH]n1
Reactant: Nc1ccc2c(c1N)OCCO2
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3c4c(ccc3[nH]2)OCCO4)[nH]n1

Procedure:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 134 mg of 3,4-ethylenedioxy-1,2-phenylenediamine, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm, C18 phase, dimensions 100×25 mm, flow rate 20 m/min, elution gradient acetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 60 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: C(OC(N1CC[CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH2:18]C)CC1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:50][O:51][C:52](=[O:57])C(Br)(C)C>CC#N>[CH3:50][O:51][C:52](=[O:57])[C:17]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([CH3:18])[CH3:14]
Reactant: COC(=O)C(C)(C)Br
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C

Procedure:
A mixture of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (30 mg, 0.0922 mmol), Cs2CO3 (75 mg, 0.23 mmol) and 2-bromo-2-methylpropionic acid methyl ester (36 uL, 0.277 mmol) in CH3CN (2 mL) was heated at reflux temperature for 2 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid methyl ester as a colorless gum (40 mg, quantitative). LCMS: RT 3.25 min [M+H]+ 426.1
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>>[Br:15][C:12]1[CH:13]=[N:14][C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[N:10][CH:11]=1
Reactant: Brc1cnc(NCc2ccccc2)nc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1

Procedure:
The subtitle compound was prepared by the method of example 38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and ethanesulphonyl chloride, yield 0.31 g.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[N:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[CH:12]=[C:11]([CH3:19])[N:10]=1.[NH:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1>O1CCCC1>[NH2:5][C:6]([NH2:8])=[O:7].[NH:20]1[CH:24]=[CH:23][C:22]([S:2]([NH:5][C:6]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[CH:12]=[C:11]([CH3:19])[N:10]=2)=[O:7])(=[O:4])=[O:3])=[CH:21]1
Reactant: c1cc[nH]c1
Reactant: Cc1cc(OC(F)F)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2cc[nH]c2)n1
Product: NC(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5.7 g of chlorosulfonylisocyanate are added dropwise at 0°-5° C. to a solution of 7 g of 2-amino-4-difluoromethoxy-6-methylpyrimidine in 100 ml of absolute tetrahydrofuran. The yellowish solution is stirred for 10 minutes at 0° C., then 5.6 ml of pyrrole are added and the reaction mixture is stirred for 17 hours at 20°-25° C. The solvent is evaporated off and the residue is taken up in a mixture of 25 ml of methanol, 50 ml of water and 3.2 g of sodium hydroxide. The solution is shaken vigorously for 10 minutes, washed with two 50 ml portions of methylene chloride and acidified with glacial acetic acid. The acid aqueous solution is then extracted with ethyl acetate. The organic extracts are dried over magnesium sulfate and concentrated to give a 1:1 mixture of two isomers in 20% yield. This mixture of isomers is chromatographed over silica gel with a 4:1 mixture of petroleum ether/ethyl acetate, affording N-(2-pyrrolylsulfonyl)-N'-4-difluoromethoxy-6-methylpyrimidin-2-yl)urea with a melting point of 189° C. (compound 4.1) and N-(3-pyrrolylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea with a melting point of 173°-174° C. (compound 4.8).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CCN(C(C)C)C(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27](/[CH:3]=[CH:2]/[CH2:1][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[C:5]2[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)cc1
Reactant: C=CCN(Cc1ccc(OC(F)(F)F)cc1)c1ccc(C(C)=O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(/C=C/CN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Yield: 56.9 %

Procedure:
A mixture of 1-(6-{allyl[4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone (10 g; 28.5 mmol), 4-bromo-anisole (5.6 g; 29.9 mmol), palladium (II) acetate (0.14 g; 0.63 mmol) and tri-o-tolylphosphine (0.57 g; 1.88 mol) in 11 ml of MeCN and 8 ml of DIEA was heated to reflux overnight. Upon cooling, the mixture was concentrated and the residue partitioned between ethyl acetate and 1N NaOH. The organic phase was dried over sodium sulfate and concentrated. Purification by flash chromatography eluting with dichloromethane afforded 1-(6-{[(2E)-3-(4-methoxyphenyl)prop-2-enyl][4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone (7.4 g; 54% yield).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][C:18]([O:20]C)=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>Cl>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[C:8]3[CH:16]=[CH:17][C:18]([OH:20])=[N:19][C:7]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]=2[N:11]=1
Reactant: COc1ccc2c3cnc(N)nc3n(C3CCCC3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ncc2c3ccc(O)nc3n(C3CCCC3)c2n1
Temperature: 140 °C

Procedure:
Compound 268 (150 mg, 529 μmol) was dissolved in conc. hydrochloric acid (2 mL). The reaction was heated with microwave energy (300 W) for 40 min. at 140° C. The resulting solution was added to aqueous NaHCO3 (20 mL, 50% sat.) and extracted with dichloromethane+10% methanol (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give an orange tar. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-100% ethyl acetate+2.5% TEA) afforded compound 272 as a tan solid, 120 mg (84%).