Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]=[O:18].[OH-].[K+]>CS(C)=O>[OH:18][CH2:17][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[C:7](=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 100 parts of benzoin in 240 parts of dimethyl sulfoxide was added dropwise over 10 minutes to a dispersion of 17 parts of paraformaldehyde having a purity of 75% and 2.6 parts of potassium hydroxide in 580 parts of dimethyl sulfoxide and the mixture was agitated for further 15 minutes to effect the reaction which was terminated with addition of diluted hydrochloric acid followed by the admixture of the reaction mixture with 900 parts of water. The thus obtained aqueous solution was extracted with ethyl acetate and the ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride and concentrated by evaporating the solvent under reduced pressure to give 113 parts of α-hydroxymethyl benzoin. The yield was more than 99% of the theoretical value.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:30][C:31]=3[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C#N)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Crude 4-(4-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester from above was dissolved in methylene chloride (10 mL) and to the resulting solution was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (454 mg), triethylamine (247 μL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 337 mg). The reaction mixture was stirred at room temperature for 3 hr. Another portion of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 eq) was added. The reaction mixture was stirred at 50° C. for 3 hr and at room temperature for 3.5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded 4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (240 mg, 25% yield) as a yellow solid. LCMS calcd for C27H26F3N5O4 (m/e) 541, obsd 542 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].C(O)(C(F)(F)F)=[O:13].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:13])=[C:4]([F:10])[C:3]=1[CH3:11]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(Br)ccc(C#N)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Br)ccc(C(N)=O)c1F
Yield: 94 %

Procedure:
4-Bromo-2-fluoro-3-methylbenzonitrile (11 g, 51.4 mmol) in a 100 mL mixture of TFA-sulfuric acid (4:1, V/V) was stirred at 40° C. for 16 h. After complete conversion of starting material, the reaction mixture was poured into iced-cold water. The resulting solid was filtered off and washed with water and dried to give the desired product (11.24 g, 48.4 mmol, 94% yield) as a white solid. MS (ESI) m/z 234.1 [M+2]+.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].C([O:9][C:10](=O)[CH:11]([C:20]#[N:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])C>C(O)C>[NH2:5][C:4]1[N:6]=[C:20]([NH2:21])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[C:10]([OH:9])[N:3]=1
Reactant: CCOC(=O)C(C#N)c1cccc(Cl)c1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(O)n1

Procedure:
Sodium (1.2 g, 0.052 mol) was added in portions to absolute ethanol (50 ml) with stirring. After the sodium had dissolved guanidine hydrochloride (3.69 g, 0.039 mol) was added followed by ethyl-2-cyano-2-(2,3-dichlorophenyl)acetate (5 g, 0.0195 mol). The mixture was refluxed for 8 hours, EtOH was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was extracted with 2N NaOH and the extract was neutralised with 2N HCl with cooling. The precipitated solid was filtered and dried to give the title compound. (0.22 g), mp. 275° C. (decomp). Microanalysis: Calcd: for 0.25 hydrate: C, 43.56; H, 3.09; N, 20.33; C, 43.76; H, 3.09; N, 20.03.
Reaction SMILES: O[C:2]([CH2:16][CH2:17][CH3:18])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=O.[NH2:19][C:20]([NH2:22])=[O:21].Cl>C(O)C>[CH2:16]([C:2]1[NH:22][C:20](=[O:21])[N:19]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)[CH:3]=1)[CH2:17][CH3:18]
Reactant: CCCC(O)=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(=O)[nH]1
Yield: 72.1 %

Procedure:
A stirred mixture of 3-hydroxy-1-(3-trifluoromethylphenyl)-hex-2-en-1-one (259 mg), urea (90 mg), HCl (0.15 mL, 5M) and ethanol (5 mL) was heated at reflux for 16 h. Further urea (60 mg) and HCl (0.15 mL, 5M) were added and heating continued at reflux for 24 h. The mixture was allowed to cool and the solvent was evaporated at reduced pressure. The residue was dissolved in a mixture of ethyl acetate (20 mL) and water (20 mL), the organic layer was separated and further washed with a solution of saturated sodium carbonate (20 mL) followed by water (20 mL). The ethyl acetate extract was then dried over sodium sulphate and evaporated at reduced pressure to afford 6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one as a brown solid (204 mg). MS m/z 283.0 (M+1), 100%.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[C:1]([C:5]1[O:9][C:8]([C:10]([NH:16][NH2:17])=[O:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncc(C(C)(C)C)o1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cnc(C(=O)NN)o1
Temperature: 85 °C
Yield: 96.1 %

Procedure:
To a mixture of ethyl 5-tert-butyl-1,3-oxazole-2-carboxylate (28 g, 142 mmol) in ethanol (200 mL) is added hydrazine hydrate (7.1 g, 142 mmol). The reaction mixture is heated at 85° C. for 3 h. The solvent is evaporated and the residue is washed with n-pentane to afford the title compound (25 g, 96%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:19](I)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:19]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C[S@@](=O)(=NC(=O)c1cnc(N)c(I)c1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing (S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (345 mg, 0.86 mmol) in 6.0 mL DMF at room temperature was added triethylamine (0.36 mL, 2.6 mmol), trimethylsilylacetylene (0.24 mL, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.09 mmol), and copper(I) iodide (16 mg, 0.09 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated. Then added 30 mL ethyl ether to the dark oil, filtered to remove the dark precipitate. The organic extracts were concentrated and the residue was purifed by chromatography (silica gel, ethyl ether/EtOAc) to the title compound as a tan foam (317 mg, 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:20]=[CH:19][S:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:31][CH2:32][CH2:33][S:34]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:20]=[CH:19][S:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12

Procedure:
3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide was prepared according to the procedure for intermediate 11. 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.09 mmol) was reacted with triethyl amine (0.025 mL, 0.18 mmol) and 2-chloroethylsulfonyl chloride (0.012 mL, 1.08 mmol) to give 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9]
Reactant: C=Cc1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: C=Cc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 76.9 %

Procedure:
With 10.0 g of 1-bromo-2-vinyl benzene and 4.72 g of 5-chloroisatin as starting materials, 5.71 g of the title compound (light brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: C[C:2]1[CH:34]=[C:5]2[N:6]=[CH:7][C:8]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:9]([C:10]3[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:12][CH:11]=3)[N:4]2[N:3]=1.CC1[N:37]=C(N)NN=1>>[CH3:34][C:2]1[N:37]=[C:5]2[N:6]=[CH:7][C:8]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[C:9]([C:10]3[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:12][CH:11]=3)[N:4]2[N:3]=1
Reactant: Cc1n[nH]c(N)n1
Reactant: Cc1cc2ncc(-c3ccncc3)c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n2n1
Product: Cc1nc2ncc(-c3ccncc3)c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n2n1

Procedure:
Following the procedure for the preparation of 2-[4-(2-Methyl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline but substituting 5-Methyl-2H-[1,2,4]-triazol-3ylamine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.55 (m, 2H), 8.21(d, J=8.3 Hz, 1 H), 8.06 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.1 Hz, 1H), 7.73 (m, 1H), 7.64 (d, J=8.3 Hz, 1 H), 7.55 (m, 1H), 7.42 (d, J=8.7, 2H), 7.08 (m, 4H), 5.39 (s, 2H) 2.60 (s, 3H); MS: (M+H m/z=445.2).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[C:12]3[C:8]=2[C:9]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:10]([C:22]([O:24]CC)=[O:23])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:29]([CH2:28][CH2:27][C:9]1[C:8]2[C:12](=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:11][C:10]=1[C:22]([OH:24])=[O:23])([OH:31])=[O:30]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 4,6-diphenyl-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (4.42 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×25 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 243-245° C. 1H-NMR (DMSO-d6) δ 2.07 (m, 2H, 2′-H); 2.83 (m, 2H, 1′-H); 7.09 (d, 1H, 2J=1.6 Hz, 7-H); 7.34 (t, 1H, 3J=7.4 Hz, ph-ring), 7.44 (m, 7H, Ph-ring), 7.66 (d, 2H, 2J=0.9 Hz, 5-H); 7.68 (d, 1H, 1.6 Hz, Ph-ring); 11.72 (s, 1H, NH); 12.33 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 20.3 (C-2′); 34.9 (C-1′); 109.5 (C-4); 120.9 (C-6); 121.7 (C-3); 123.8 (C-2); 125.5 (C-3a); 127.0 (C-2″, C-6″); 127.3 (C-4″′); 127.5 (C-4″); 128.0 (C-3″′, C-5″′); 129.0 (C-3″, C-5″); 129.1 (C-2″′, C-6″′); 135.4 (C-7a); 137.3 (C-4), 137.4 (C-6); 140.8 (C-1″); 141.0 (C-1″′); 163.1 (2′-CO2H); 173.4 (2-CO2H). LC-MS (m/z): 386 [M-NH4+]+, 366 [M]+, 384 [M]−. Purity (LC-MS): 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
43.0 g (125 mmol) of the compound of Example 56A are provided in 504 ml of 1,4-dioxane, 94 ml (188 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 39.5 g (100% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To the product from step (iv) (1.25 g) in THF (100 mL), methyl 2-(4-formylphenyl)acetate (0.818 g) was addded followed by sodium triacetoxyborohydride (0.885 g) and acetic acid (3 drops) and stirred at rt for 16 h. The reaction was quenched with water, extracted with DCM washed with sat. NaHCO3 (200 mL), dried and solvent removed. The resulting residue was dissolved in methanol and purified on SCX to give the subtitle compound (0.73 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(I)cc1

Procedure:
The title compound is prepared in analogy to example 16a from 4-iodobenzoyl chloride, N,N-dimethylamine and triethylamine in CH2Cl2 as a yellowish oil, MS (ESI) 276.0 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:7]1[N:11]2[CH2:12][C@H:13]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[N:9][CH:8]=1)(=[O:6])[CH3:5]>O1CCCC1>[F:32][C:26]1[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=1[C@H:13]1[CH2:12][N:11]2[C:7]([C:4]([OH:6])([CH3:1])[CH3:5])=[CH:8][N:9]=[C:10]2[C@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14]1
Reactant: CC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)O)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Methylmagnesium bromide (3.0 M in ether; 90 μL, 0.27 mmol) was added to a solution of tert-butyl (6S,9R)-3-acetyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (22 mg, 0.05 mmol) in tetrahydrofuran (1 mL) at 0° C., and the reaction mixture was allowed to warm to ambient temperature. After 30 min, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (15 mg). MS 422.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)CN
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and isobutylamine (0.372 mL, 3.71 mmol) the title compound was obtained as an off-white foam (90 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.61-7.78 (m, 1H), 7.26-7.42 (m, 3H), 7.14-7.27 (m, 3H), 6.04-6.22 (m, 1H), 2.89-3.07 (m, 2H), 1.72-1.85 (m, 1H), 1.37 (s, 9H), 0.82 (d, J=6.4 Hz, 6H). MS (ESI): 576.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH:28]1([CH2:34][NH2:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([NH:35][CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: NCC1CCCCC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NCC3CCCCC3)c2)cc1
Yield: 105.5 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and cyclohexylmethylamine (0.143 g, 1.26 mmol) were used to afford 0.60 g of the required product. Percentage purity (LCMS): 97.6%, (M+1)=451.1+1.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:2]1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC#N.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([S:4][C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][N:8]([CH3:19])[C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccccc1SC1CC1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN(Cc1ccccc1SC1CC1)C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1C (1.68 g, 5.47 mmol) in CH3CN (55 mL) was added potassium carbonate (1.13 g, 8.20 mmol), tetrabutylammonium bromide (88 mg, 0.27 mmol) and methyl iodide (3.40 mL, 54.7 mmol) and the reaction was heated to reflux overnight. After cooling to rt and concentrating, the remaining residue was dissolved in ethyl acetate and washed with water (3×) and brine. The organic layer was dried (MgSO4), filtered and concentrated to provide ID (1.50 g) as a yellow oil. LC-MS: 321.95 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[Cl:10].[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38](NCC2C=CC(F)=CC=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:18][NH:19][C:20]([C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH2:36][OH:37])[C:25]([C:38]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([Cl:10])[CH:4]=2)=[O:39])=[CH:24][N:23]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Reactant: NCc1ccc(F)c(Cl)c1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 38.7 %

Procedure:
4-Fluoro-3-Chloro benzylamine (0.060 g, 1.29 mmol, 2 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.050 g, 0.141 mmol, 1 eq) (compound 1c of example 1) were heated in DMF at 90° C. for 120 min. The crude product was purified by silica gel (100% ethyl acetate) yielding 0.03 g of N2,3-bis(benzyloxy)-N5-(3-chloro-4-fluorobenzyl)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide as a white solid; MS-ESI m/z 573 [MH]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[NH:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:16]([C:24](O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:24](=[O:25])[C@H:16]([NH:15][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: COc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Yield: 81435.5 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step f) using 4-(2-methoxyphenyl)piperidine (Maybridge) (2.68 g, 0.014 mol), Boc-D-PheOH (Advanced ChemTech) (3.71 g, 0.014 mmol), HOAT (Aldrich) (1.9 g, 0.014 mol) and EDC (Advanced ChemTech) (4.02 g, 0.021 mol). Purification by silica gel chromatography (1:1 EtOAc:hexane) provided the title compound as a colorless oil (5.0 g). MS (ESI, pos. ion) m/z: 439 (M+1). Calc'd for C26H34N2O4: 438.56.