Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=3[CH3:18])=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)[nH]n1
Yield: 39.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.2 g, 0.728 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.112 g, 0.728 mmol), HOBt (0.128 g, 0.946 mmol), DIPEA (0.165 ml, 0.946 mmol) and EDCI (0.181 g, 0.946 mmol) using the method of Example 34(d) affording 0.117 g of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.54 (s, 3H), 2.55 (s, 3H), 4.31 (m, 1H), 4.44 (m, 1H), 4.62 (m, 1H), 6.44 (d, 1H), 7.51 (d, 1H), 7.54 (s, 2H), 11.14 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[NH:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[CH2:13]1[CH2:18][O:17][CH:16]=[CH:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[F:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:9]([CH:16]3[CH2:15][CH2:14][CH2:13][CH2:18][O:17]3)[CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: N#Cc1cc2[nH]cnc2cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1F)ncn2C1CCCCO1
Temperature: 85 °C
Yield: 73.5 %

Procedure:
A mixture of 6-fluoro-3H-benzo[d]imidazole-5-carbonitrile (1.78 g, 11.1 mmol), DHP (1.84 g, 22.2 mmol), and TsOH (212 mg, 1.1 mmol) in THF (20 mL) under nitrogen was heated at 85° C. overnight. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (50 ml×2). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting petroleum ether:EtOAc (5:1) to afford 5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-6-carbonitrile as white solid (2.0 g, 73.8%).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[CH:7]=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9](=[O:16])[NH:10]2)C=C.CN(C)[C:22]1[CH:27]=CC=C[CH:23]=1>>[CH2:27]([C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[C:12]([CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[C:8]([CH:17]([CH3:18])[CH3:19])=[CH:7]2)[CH:22]=[CH2:23]
Reactant: C=CCOc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Reactant: CN(C)c1ccccc1
Product: C=CCc1cc(C)c2[nH]c(=O)c(C(C)C)cc2c1O
Temperature: 202 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
5-Allyloxy-3-isopropyl-8-methylcarbostyril (1.85 g, 7.20 mmol) was suspended in N,N-dimethylaniline (20 ml). The suspension was heated and dissolved while stirring at 202° C. for 90 minutes. The reaction system was heated under reduced pressure until condensed. The resultant residue was recrystallized from methanol-ether-hexane to obtain 1.50 g of the title compound as pale yellow powdery crystals (81.1%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[NH2:16][OH:17].Cl.CCN(CC)CC>CCO>[F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[N:16][OH:17]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C(=NO)C(F)(F)F)c1
Yield: 79.5 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(3-nitro-phenyl)ethanone (4 g), NH2OH.HCl (5.037 g), and Et3N (20.44 g) in EtOH (80 mL) was refluxed for 4 days. After concentration, the residue was extracted with CH2Cl2. The organic layer was washed with water and dried over MgSO4. The crude product was purified by silica gel flash chromatography (30% ethyl acetate in hexanes) to give the title compound (3.4 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 84.3 %

Procedure:
Beginning with 0.200 gm (0.88 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.114 mL (0.96 mMol) 4-fluorobenzoyl chloride, 0.260 gm (84%) of the title compound were prepared as an ivory solid essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol. m.p.=215° C. (dec.) MS(m/e): 350(M+) Calculated for C20H19N4OF: Theory: C, 68.56; H, 5.47; N, 15.99. Found: C, 68.57; H, 5.66; N, 16.01.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][N:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[O:14])[CH2:12][C:5]=2[CH:4]=1)[NH2:2]>C1(=O)CCCCC1>[C:15]1(=[N:2][NH:1][C:3]2[N:8]=[N:7][C:6]3[CH2:9][CH2:10][N:11]([C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)=[O:14])[CH2:12][C:5]=3[CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1
Solvent: O=C1CCCCC1
Product: Cc1ccc(C(=O)N2CCc3nnc(NN=C4CCCCC4)cc3C2)cc1

Procedure:
1.0 g of 3-hydrazino-5,6,7,8-tetrahydro-6-(p-toluoyl)pyrido[4,3-c]pyridazine and 10 cc of cyclohexanone are heated at reflux in an oil bath of 180° for 1 hour. The title compound has a M.P. of 208°-210° (decomp., from 95% ethanol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:10]([C:21]([O:23][CH3:24])=[O:22])[NH:9][C:8]1=[O:25].[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O1CCOCC1>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][C:11]1[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)[C:8](=[O:25])[NH:9][C:10]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1[nH]c(=O)n(CCCCCBr)c1Cc1ccc(F)c(F)c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c(=O)n(CCCCCN2CCC(c3ccccc3)CC2)c1Cc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a stirred solution of 1-(5-bromopent-1-yl)-5-(3,4-difluorobenzyl)-2,3-dihydro-4-methoxycarbonyl-2(1H)-imidazolone (0.167 g, 0.4 mmol) in dioxane (20 mL) was added 4-phenylpiperidine (0.128 g, 0.800 mmol), potassium carbonate (0.165 g, 1.20 mmol) and sodium iodide (0.358 g, 2.38 mmol), and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between ethyl acetate (25 mL) and water (5 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4.5:0.5) to yield 0.062 g (31%) of the required product as a colorless oil; 1H-NMR (CDCl3) δ1.25-2.44 (m, 13H), 3.13 (d, J=11.4 Hz, 2H), 3.26 (d, J=10.5 Hz, 2H), 3.53 (t, J=7.7 Hz, 2H), 3.85 (s, 3H), 4.10-4.12 (m, 1H), 4.21 (s, 2H), 6.90-7.30 (m, 8H). Hydrochloride salt (recrystallized from ether): yellow solid; m.p. 130-132° C. Analysis calculated for C28H34ClF2N3O3.0.80 CH2Cl2 : C, 57.46; H, 5.96; N, 6.98. Found: C, 57.18; H, 6.33; N, 6.76.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7](O)=[O:8].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:24]12([NH2:34])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CC(C)=O>[C:24]12([N:34]3[C:7](=[O:8])[CH2:2][CH2:3][C@H:4]3[C:5]([NH2:1])=[O:6])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCC(=O)N1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
10 g of (L)-pyroglutamic acid (77 mmol) and 10.7 ml of triethylamine are mixed with 100 ml of anhydrous acetone, 9.29 g of pivaloyl chloride (77 mmol) are run in slowly at -5° and then, after 15 minutes at 0° C., 11.65 g (77 mmol) of adamantanamine are added in several portions.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].CC1(C)CCCC(C)(C)N1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>C(#N)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:5][CH2:4][CH2:3][CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Fc1ccccc1CCl
Reactant: NCCC(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: OC(CCNCc1ccccc1F)c1ccccc1
Yield: 52.5 %

Procedure:
A mixture of 3-hydroxy-3-phenylpropylamine (7.0 g, 46 mM) and 2,2,6,6-tetramethylpiperidine (7.9 ml, 46 mM) in acetonitrile (100 ml) was treated with a solution of o-fluorobenzyl chloride (6.75 g, 46 mM) in acetonitrile (10 ml). After 24 hours the resulting precipitate was removed by filtration and washed with acetonitrile (2×10 ml). The combined filtrate and washings were evaporated under reduced pressure and the residue partitioned between 2N hydrochloric acid (50 ml) and ether (100 ml). The aqueous layer was basified and extracted with ether, the ether extracts dried and evaporated. Chromatography on Grade 3 silica using 2% methanol in chloroform as eluant followed by distillation gave the title compound (6.3 g) b.p. 156°-160° C. (0.2 mbar).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[NH:13]1[CH2:19][CH2:18][CH2:17][C@@H:14]1[CH2:15][OH:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.C(OCC)(=O)C>CN(C)C=O.ClCCl.C(OCC)(=O)C.CO>[NH2:8][CH2:9][C:10]([N:13]1[CH2:19][CH2:18][CH2:17][C@@H:14]1[CH2:15][OH:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: OC[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCC(=O)N1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
N-(tert-butoxycarbonyl)glycine (5.00 g, 28.5 mmol) and D-prolinol (3.50 g, 34.2 mmol) was dissolved in N,N-dimethylformamide (10 ml) and dichloromethane (100 ml), and the mixture was stirred at room temperature. At the same temperature, 1-hydroxybenzotriazole.monohydrate (7.70 g, 57.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (hereinafter to be indicated as WSC) (8.20 g, 42.8 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with diluted hydrochloric acid, diluted aqueous sodium hydroxide solution, water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure, the obtained oil was purified by silica gel column chromatography (methanol-chloroform) to give a crude product. This was dissolved in ethyl acetate (30 ml) and methanol (20 ml), 4N hydrochloric acid-ethyl acetate solution (20 ml) was added, and the mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure, and to the obtained concentrate was added a saturated aqueous potassium carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.00 g, yield 22%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O[CH3:22])(=O)=O>CO>[CH3:22][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: COS(=O)(=O)[O-]
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 9099 %

Procedure:
As in Example 2, a melt of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.051 g (0.000455 mol) of methyl sulfate was introduced and reacted over the course of 3 hours with 197.75 g (6.18 mol) of gaseous (vaporized at 160° C.) methanol. 9.7 g (86.7%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 95.2% (GC).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH:27]1([CH2:26][C@H:20]([NH:19][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:21](=[O:22])[N:23]([CH3:24])[CH3:25])[CH2:29][CH2:28]1
Reactant: CN(C)C(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-amino-3-cyclopropyl-N,N-dimethylpropanamide hydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%, 372.2278 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][C:23]1[N:24]([C:29]2[C:34](O)=[CH:33][CH:32]=[CH:31][N:30]=2)[C:25]([CH3:28])=[CH:26][CH:27]=1>>[CH3:28][C:25]1[N:24]([C:29]2[C:34]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]3[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][N:15]=3)=[CH:33][CH:32]=[CH:31][N:30]=2)[C:23]([CH3:22])=[CH:27][CH:26]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Cc1ccc(C)n1-c1ncccc1O
Product: Cc1ccc(C)n1-c1ncccc1OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 28 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-(2,5-dimethylpyrrol-1-yl)pyridin-3-ol (32 mg, 0.17 mmol) as the source alcohol. Chromatographic (30–40% ethyl acetate/hexane) purification yielded 22 mg (28%) of the titled compound. ESI-MS t/z 462 (MH+), 460 (M−H−).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:27](O)([C:29]([F:32])([F:31])[F:30])=O.[C:34]([O:38][C:39](=[O:70])[NH:40][C:41]1([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[C:60](=[O:61])[C:59]4[C:54](=[C:55]([NH2:63])[C:56]([NH2:62])=[CH:57][CH:58]=4)[O:53][C:52]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:47][CH:46]=2)[CH2:44][CH2:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35]>C(Cl)(Cl)(Cl)Cl.C1CCCCC1.C(OCC)(=O)C.ClCCCl>[C:34]([O:38][C:39](=[O:70])[NH:40][C:41]1([C:45]2[CH:46]=[CH:47][C:48]([C:51]3[C:60](=[O:61])[C:59]4[CH:58]=[CH:57][C:56]5[N:62]=[C:27]([C:29]([F:32])([F:31])[F:30])[NH:63][C:55]=5[C:54]=4[O:53][C:52]=3[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)=[CH:49][CH:50]=2)[CH2:44][CH2:43][CH2:42]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc(C(F)(F)F)[nH]c54)c3=O)cc2)CCC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
To a stirred solution of triphenylphosphine (126 mg, 0.48 mmol) in CCl4 (2 mL) at 0° C. was added triethylamine (67 μL, 0.48 mmol) and TFA (13 μL, 0.18 mmol). After 10 min, {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) was added and the temperature raised to 80° C. After 2 hours, 1,2-dichloroethane (1 mL) was added to aid solubility. The reaction mixture was stirred for a further 1 hour before cooling to RT. The solution was directly subjected to flash chromatography (SiO2, 40% ethyl acetate in cyclohexane) to give the title compound as an off-white solid (38 mg, 41%). LCMS (Method H): RT=4.20 min, [M+H]+=576.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:5])C>[OH-].[Na+]>[F:24][C:18]1[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:7]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]([CH3:15])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(C(=O)O)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 65 °C
Yield: 97.3 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (88 mg, 0.20 mmol), 1M aqueous sodium hydroxide solution (220 μl) and IMS (3 ml) was heated at 65° C. for 2 hours. After cooling to ambient temperature the solvent was evaporated, the resultant residue was dissolved in water and the pH of the solution was adjusted to 7 by the addition of 1N HCl solution. The precipitated solid was collected by filtration, washed with water (2 mL) then diethyl ether (2 mL) and left to air dry to provide the title compound as a yellow solid (80 mg, 92%). LCMS (method B): RT=2.11 min, M+H+=412.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:26][CH:27]3[CH2:29][O:28]3)[N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[NH3:30]>>[NH2:30][CH2:29][CH:27]([OH:28])[CH2:26][N:22]1[C:23]([CH3:25])=[CH:24][C:20]([C:17]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([CH:16]=2)[C:4]([NH:6][CH2:7][C:8]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:5])=[N:21]1
Reactant: N
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CC1CO1
Product: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CC(O)CN
Temperature: 67 °C

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-methyl-1-oxiranylmethyl-1H-pyrazol-3-yl)-benzamide (0.4 g, 0.96 mmol) in methanolic ammonia (20 mL, 7.0 N) was heated to 67° C. in a sealed tube for 16 h. The mixture was concentrated in vacuo, and the residue was triturated with diethyl ether-ethyl acetate to afford the title compound (0.12 g). LCMS (m/z) 435.3 M+1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH:13]=[N:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)[C:3]=1[C:4](O)=[O:5].[CH3:26][Li].Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[N:14]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]([CH3:26])[C:7]=2[C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: [Li]C
Reactant: COc1cc(CN=Cc2c(F)c(Cl)nc(Cl)c2C(=O)O)cc(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)cc(OC)c1
Reaction time: 2 h
Yield: 9.5 %

Procedure:
To a mixture of 2,6-dichloro-4-((3,5-dimethoxybenzylimino)methyl)-5-fluoronicotinic acid (5.8 g, 25.3 mmol) in THF (120 mL) was added methyl-lithium (60.0 mL, 126.6 mmol) drop wise at −78° C. After the addition was completed, the mixture was stirred for an additional 2 h. The reaction mixture was acidified with 1N HCl to pH 7 and THF was removed under reduced pressure. The mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and purified by silica gel chromatography eluting with PE-EtOAc (5:1) to give the title compound as a white solid (0.93 g, 16%). 1H-NMR (CDCl3, 400 MHz) δ 1.58 (d, J=6.8 Hz, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 4.35 (d, J=14.4 Hz, 1H), 4.52 (q, J=6.8 Hz, 1H), 5.07 (d, J=14.4 Hz, 1H), 6.43-6.45 (m, 2H), 7.28 (d, J=9.2 Hz, 1H). [M+H] calc'd for C17H15Cl2FN2O3, 386. found, 385.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(N)CC
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CCC(CC)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (750 mg, 1.48 mmol) and 3-aminopentane (520 μl, 4.44 mmol) as starting materials.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]1([C:13]2[O:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:7]1([C:13]2[O:22][C:21]3[CH2:20][CH2:19][CH2:18][N:17]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:16][C:15]=3[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(-c2cc3c(o2)CCCNC3)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CCCc2oc(-c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1.8 g. of cyclopropylcarbonyl chloride in 50 ml. of dry chloroform is added dropwise to a cooled mixture of 3.1 g. of 2-phenyl-4,6,7,8-tetrahydrofuro[3,2-c]azepine and 1.7 g. of triethylamine in 50 ml. of dry chloroform. After addition, the reaction mixture is stirred at ambient temperature for 20 hours, washed with water and dried. The chloroform is removed and the residue is triturated with n-hexane to produce a solid product. The product is recrystallized from n-hexane to give 2-phenyl-5-cyclopropylcarbonyl-4,6,7,8-tetrahydrofuro[3,2-c]azepine, m.p. 108°-110°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[N:12]=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:15]=1)=[O:10]>C1COCC1.C(OC)(C)(C)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]2[CH:15]=[C:11]([C:9](=[O:10])[CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:17][CH:18]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(CN1CCOCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Yield: 81.2 %

Procedure:
Morpholine (0.04 ml, 0.426 mmol) was added to a solution of 2-bromo-1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanone I-7g (63 mg, 0.142 mmol) in THF (3 ml). The resultant solution was stirred at 23° C. for 12 hours, diluted with 50 ml methyl tert-butyl ether, and washed with 25 ml water. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was co-evaporated with hexanes once to afford 1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-2-morpholin-4-yl-ethanone 7A-1 (52 mg, 81%) as a solid.