Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([OH:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:16][C:15]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][C:6]=3[C:7]=2[N:8]=1)=[O:17]
Reactant: CO
Reactant: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 85 °C
Yield: 57 %

Procedure:
To a stirred mixture of 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (20.0 g, 61.3 mmol) in MeOH (280 mL), was added H2SO4 (45.1 g, 450 mmol) dropwise at room temperature. Then the mixture was heated to reflux (85° C.) mixture was filtered and the solid was washed with saturated aqueous NaHCO3 solution, dried in vacuo to afford 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (12 g, 57%) as a yellow solid which was directly used for the next step without any further purification. LC-MS: 341.8 (M+2).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.O[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[N:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[Cl:4][C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[N:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.5 g of oxalyl chloride in 5 ml of dry acetonitrile is added dropwise to anhydrous dimethylformamide at -30°. After 20 minutes, 7.0 g of ethyl 4-hydroxy-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate is added at -30°. Reaction temperature is kept between -20° and -30° for 30 minutes, then allowed to warm up to room temperature and evaporated to dryness. Residue is taken up in chloroform, washed with cold sodium bicarbonate aqueous solution, dried over magnesium sulfate, treated with decolorizing charcoal and evaporated to dryness to yield ethyl 4-chloro-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate, m.p. 200°-210°.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]([C:7](=[O:33])[CH2:8][C:9]([CH3:32])([CH3:31])[CH2:10][N:11]1[C:28](=[S:29])[N:14]2[C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[O:18][C:19]=3[CH:20]=[C:13]2[C:12]1=[O:30])[CH3:6].O.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2[O:18][C:19]3[CH:20]=[C:13]4[C:12](=[O:30])[N:11]([CH2:10][C:9]([CH3:31])([CH3:32])[CH2:8][C:7]([N:5]([CH2:4][C:3]([OH:34])=[O:2])[CH3:6])=[O:33])[C:28](=[S:29])[N:14]4[C:15]=3[CH:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CN(C)C(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(CC(=O)O)C(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 40 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Compound 20 was dissolved in TFA (1.5 ml) and water (0.75 ml) was added thereto. The resulting mixture was stirred at 40° C. for 16 hours. After cooling the mixture to room temperature, water and chloroform were added, followed by addition of 10% NaHCO3 (20 ml), while maintaining an acidic pH of the solution. The organic layer was separated, washed twice with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure to give an orange solid. Chromatography purification was carried out using with a 8:2 ethyl acetate:methanol mixture as eluent to give Compound 21 (38.3 mg, 88% yield) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:25]1(C2C=CC=CC=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:30]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:25]=[CH:26][C:27]([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:24])=[CH:8][CH:9]=3)[N:35]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5ccccc5)cc4)oc3C)cc2)C(=O)O)cc1C

Procedure:
A mixture of 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (Ex. 32, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-dimethyl-phenoxy)-2-methyl-propionic acid 1H NMR (400 MHz, CDCl3) δ 8.23–8.21 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.67–7.62(m, 3H), 7.50–7.42 (m, 3H), 7.38–7.34 (m, 1H), 7.19 (d, 2H, J=8.8 Hz), 6.95 (d, 1H, J=8.2 Hz), 6.82 (d, 2H, J=8.8 Hz), 6.71 (d, 1H, J=2.8 Hz), 6.63 (dd, 1H, J=8.2, 2.8 Hz), 4.20 (t, 2H, J=6.4 Hz), 3.24 and 3.13 (d of Abq, 2H, J=14.0 Hz), 3.01 (t, 2H, J=6.4 Hz), 2.39 (s, 3H), 2.16 (s, 6H, 1.38 (s, 3H). IR (KBr) 3480, 2980, 1717, 1611, 1512, 1248, 1118 cm−1. HRMS (ES+) m/z exact mass calcd for C36H36NO5 562.2593, found 562.2598.
Reaction SMILES: C([O-])(=O)CCC([O-])=O.C(O)(=O)CCC(O)=O.NC1N=C(C2N=C([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:49][O:48][CH2:47]5)[CH2:42][CH2:41]4)=[CH:36][CH:35]=3)C3N(C=CN=3)C=2)C=NC=1.[Al]>[Cu]>[O:48]1[CH2:49][CH:46]([N:43]2[CH2:42][CH2:41][N:40]([C:37]3[CH:38]=[CH:39][C:34]([NH2:33])=[CH:35][CH:36]=3)[CH2:45][CH2:44]2)[CH2:47]1
Reactant: Nc1cncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Agent: [Cu]
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])CCC(=O)[O-]
Product: Nc1ccc(N2CCN(C3COC3)CC2)cc1
Reaction time: 0 h

Procedure:
X-ray powder diffraction (XRPD) analysis of the monomesylate (MSA) and succinate forms of the compound of Example 2 herein were conducted on a diffractometer (PANanalytical XPERT-PRO, PANalytical B.V., Almelo, Netherlands) using copper radiation (Cu Kα, λ=1.5418 Å). Samples were prepared for analysis by depositing the powdered sample in the center of an aluminum holder equipped with a zero background plate. The generator was operated at a voltage of 45 kV and amperage of 40 mA. Slits used were Soller 0.02 rad., antiscatter 1.0°, and divergence. The sample rotation speed was 2 sec. Scans were performed from 2 to 40° 2-theta. Data analysis was performed by X'Pert Highscore version 2.2c (PANalytical B.V., Almelo, Netherlands) and X'Pert data viewer version 1.2d (PANalytical B.V., Almelo, Netherlands). The XRPD patterns for Mono MSA Forms I & II were obtained using the instrument setting as follows: 45 KV, 40 mA, Cu Kα, λ=1.5418 Å, scan range 2.-40°, step size 0.0167°, counting time: 15.875 s. The XRPD patterns for Succinate Forms I & II were obtained using the instrument setting as follows: 45 KV, 40 mA, Cu Kα, λ=1.5418 Å, scan range 2.-40°, step size 0.0084°, counting time: 95.250 s.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH:12]=[N:11][C:10]=23)=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[I-].[Na+]>CN(C=O)C.O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:17][CH:16]=4)[CH:12]=[N:11][C:10]=23)=[CH:2]1
Reactant: Oc1ccc(-c2cnc3c(-c4ccsc4)cnn3c2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(-c2cnn3cc(-c4ccc(OCCN5CCOCC5)cc4)cnc23)cs1
Yield: 64.7 %

Procedure:
A solution of example 3 (11 mg, 0.038 mmol), cesium carbonate (37 mg, 0.11 mmol), N-(2-chloroethyl)morpholine hydrochloride (7 mg, 0.11 mmol), and sodium iodide (0.013 mmol) in DMF (3 mL) was heated at 60° C. under argon for 16 h. The reaction mixture was then poured into water (25 mL) and washed with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4), concentrated, and purified by flash chromatography [50% Hexanes/CHCl3(NH3)] to give the title compound as a yellow solid [10 mg, 65%, mp =149-151° C., Rf=0.39 (100% CHCl3(NH3))]: 1H NMR (CDCl3) δ8.77 (d, 1H, J=2.2Hz), 8.75 (d, 1H, J=2.2Hz), 8.36 (s, 1H), 7.90 (dd, 1H, J=2.9, 1.3 Hz), 7.69 (dd, 1H, J=4.9, 1.3Hz), 7.52 (d, 2 H, J=8.8Hz), 7.43 (d, 1H, J=4.9, 2.9Hz), 7.06 (d, 2 H, J=8.8Hz), 4.18 (t, 2 H, J=5.7Hz), 3.76 (t, 4 H, J=4.6Hz), 2.85 (t, 2 H, J=5.7 Hz), 2.61 (t, 4 H, J=4.6Hz); FAB MS (M++1) Anal Calcd. for C22H22N4O2S : C, 65.00; H, 5.46; N, 13.78. Found C, 64.98; H, 5.55; N, 14.02.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl.[N:29]1([C:34](=N)[NH2:35])C=CC=N1>CN(C=O)C>[F:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:34](=[NH:29])[NH2:35])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: N=C(N)n1cccn1
Reactant: FCCOCc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCN(c2ccc(COCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of 1-(4((2-fluoroethoxy)methyl)-phenyl)piperazine hydrochloride (50 mg, 0.12 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in DMF (1 mL) was added 1H-pyrazole-1-carboximidamide hydrochloride (29 mg, 0.20 mmol). The reaction stirred at room temperature for 24 h. The next day, the reaction mixture was concentrated to yield a crude oil, which was purified via HPLC using a Phenomenex Luna C-18 (2) column (10μ, 250×21.2 mm, gradient method 15-55% B over 20 min., where B=90% ACN in water using 0.1% formic acid as a modifier and A=water using 0.1% formic acid as a modifier) with a flow rate of 20 mL/min afforded 4-(4-((2-fluoroethoxy)methyl)phenyl)piperazine-1-carboximidamide as a white solid (20 mg, 41% yield based on recovered starting material). 1H NMR (300 MHz, DMSO-d6): δ 7.58 (br s, 4H), 7.211 (d, 2H, J=8.5 Hz), 6.96 (d, 2H, J=8.6 Hz), 4.61 (m, 1H), 4.45 (m, 1H), 4.41 (s, 2H), 3.67 (m, 1H), 3.58 (dd, 4H, J=4.2, 3.9 Hz), 3.22 (m, 5H); 19F NMR (282.4 MHz, DMSO-d6): δ−221.39 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 156.1, 149.8, 128.9, 115.4, 84.1 (81.9), 71.8, 68.6 (68.4), 47.5, 44.7; HRMS calcd for C14H21FN4O: 281.177216 found 281.17720.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15].[OH-:16].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([NH2:15])=[O:16]
Reactant: [OH-]
Reactant: N#Cc1c(N)cccc1-c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1c(N)cccc1-c1ccccc1
Yield: 73 %

Procedure:
A solution of 3-aminobiphenyl-2-carbonitrile (4 g, 20 mmol) in ethanol (20 mL) and aqueous NaOH (8 g, 200 mmol) was heated at 100° C. in the microwave reactor for 1 h 30 min. After this time, the ethanol was evaporated under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic extracts were concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 3-aminobiphenyl-2-carboxamide (3.1 g, 72% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.40-7.30 (m, 5H), 7.15 (br s, 1H), 7.11 (t, 1H, J=8 Hz), 6.72 (dd, 1H, J=0.8, 8 Hz), 6.52 (dd, 1H, J=0.8, 8 Hz), 5.13 (s, 1H). LCMS Method W: retention time 1.28 min; [M+1]=213.0.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: O=C1[C@H]2C[C@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 65B (200 g, 0.90 mol, 1 equivalent) in 2-ethoxyethanol (3.2 L), benzylamine (120 mL, 1.09 mol, 1.2 equivalents) was added. To this mixture, triethylamine (152 mL, 1.08 mol, 1.28 equivalents) was added, and the mixture was refluxed for 20 hours. The reaction mixture was cooled and concentrated under reduced pressure to afford crude product. This crude material was purified by column chromatography on silica gel using a mixture of methanol-ethyl acetate gradient (0-10%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (m, 1H), 2.46 (m, 1H), 3.50 (m, 2H), 3.73 (d, 1H, J=16), 3.76 (m, 1H), 4.00 (d, 1H, J=16), 4.45 (d, 1H, J=15), 4.50 (m, 2H), 4.72 (d, 1H, J=15), 7.30 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3cc(F)ccc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71 %

Procedure:
(2R,4S)-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (505 mg, 1.43 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature for 22 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2,5-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one 299 mg (71%). 1H NMR (600 MHz, cd3od) δ 1.49 (q, 1H), 1.71 (dq, 1H), 1.99-2.08 (m, 2H), 2.82-3.00 (m, 4H), 3.24-3.31 (m, 1H), 3.31-3.37 (m, 1H), 5.50 (s, 1H), 6.99-7.13 (m, 3H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1244
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[N:19]1([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: ClC(c1ccccc1)c1ccc2cccnc2c1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccc3cccnc3c2)n2ccnc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 33.2 %

Procedure:
A mixture of 3.4 parts of 7-[chlorophenylmethyl]quinoline, 4.5 parts of 1H-imidazole and 72 parts of N,N-dimethylformamide was stirred for 6 hours at 80° C. The reaction mixture was evaporated to dry and the residue was taken up in water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 1.27 parts (33.2%) of 7-[(1H-imidazol-1yl)phenylmethyl]quinoline; mp. 110.7° C. (compound 36).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[N:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[N:30][CH:29]=1
Reactant: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cncc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1ccc(N)c(CCc2cncc(N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into the reaction flask was added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-methylpyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.030 g, 0.054 mmol), methanol (0.6 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at rt overnight and concentrated to give the desired product (21 mg, 95%). LCMS for C18H20ClN6 (M+H)+: m/z=355.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:34]=[CH:33][C:19]([O:20][C:21]2[C:30]3[N:29]=[C:28]([CH3:31])[C:27](=[O:32])[NH:26][C:25]=3[N:24]=[CH:23][CH:22]=2)=[CH:18][C:17]=1[F:35]>>[F:35][C:17]1[CH:18]=[C:19]([O:20][C:21]2[C:30]3[N:29]=[C:28]([CH3:31])[C:27](=[O:32])[NH:26][C:25]=3[N:24]=[CH:23][CH:22]=2)[CH:33]=[CH:34][C:16]=1[NH:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:14]
Reactant: Cc1nc2c(Oc3ccc(N)c(F)c3)ccnc2[nH]c1=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)ccnc2[nH]c1=O
Yield: 81 %

Procedure:
Method F2 was used with 2-fluoro-5-trifluoromethyl-phenylisocyanate and 8-(4-amino-3-fluorophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one to afford the title compound, yield 81%.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:28])[C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[NH:14][C:15](=[O:27])[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH3:17]>C1COCC1>[Cl:12][C:11]1[CH:10]=[C:9]([Cl:13])[CH:8]=[C:7]2[C:6]=1[C:5](=[O:28])[C:16]([CH3:17])([C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[C:15](=[O:27])[NH:14]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a suspension of sodium hydride (50 mg, 1.25 mmol, 60% in mineral oil) in dry THF (20 mL) was added a solution of 4,6-dichloro-2-[2-(4-nitro-phenyl)-propionylamino]-benzoic acid methyl ester (0.20 g, 0.50 mmol) in THF anhydride (5 mL) at 0° C. The reactant was stirred for 5 hours, and the reaction was quenched by addition of 0.5M HCl solution (30 mL). The resultant was extracted with ethyl acetate (50 mL×3), washed with water (50 mL×2) and brine (50 ml×2) and dried over magnesium sulfate anhydride. After evaporation of solvent, the pure objective compound (0.18 g, 99%) was obtained as pale yellow solid by a recrystallization (dichloromethane:EtOAc 3:1): 1H NMR (200 MHz, CDCl3) δ 1.79 (s, 3H, CH3), 6.80 (d, J=1.8 Hz, 1H, ArH), 7.15 (d, J=1.8 Hz, 1H, ArH), 7.38 (d, J=9.0 Hz, 2H, ArH), 8.18 (d, J=9.0 Hz, 2H), 8.43 (s, 1H, NH); MS(EI) m/e 364 [M+].
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Br.[Br-].[OH2:14]>CO>[OH:14][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccccc1
Reactant: O
Agent: Br
Agent: BrBr
Agent: [Br-]
Solvent: CO
Product: O=C(CO)c1ccccc1
Temperature: 60 °C

Procedure:
About 13 parts of bromine was added with stirring to a mixture of 474.6 parts of acetophenone in about 640 parts of methanol, while the mixture was stirred and maintained at a temperature between 5°-10° C. Hydrogen bromide gas was then introduced into the mixture until bromide coloration disappeared, at which point an additional amount of bromine was added over a 2 hour period to make a total of 631.3 parts. There was then added 71 parts of water while the mixture was stirred and externally cooled for a period of about 30 minutes. An excess of about 2700 parts of water was then slowly added to effect the precipitation in the form of crystals of α-bromo acetophenone from the mixture. The crystals were decanted by means of a vacuumed siphon, washed, then neutralized with a 20% sodium hydroxide solution, and decanted to dryness. There was then added about 940 parts water, 1600 parts of methanol, 333 parts of sodium bicarbonate and a sodium formate solution prepared from 161 parts of a 90% formic acid and sufficient sodium hydroxide to neutralize the acid. The mixture was heated to 60° C. with vigorous stirring for 7 hours after which time it was cooled to ambient temperature and filtered. Based on method of preparation and gas chromatographic analysis of the mixture, there was produced α-hydroxyacetophenone in quantitative yields.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][NH:12][C:11]=2[C:15]([NH2:17])=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[CH:13][NH:12][C:11]=2[C:15]([NH2:17])=[O:16])=[CH:8][CH:9]=1
Reactant: NC(=O)c1[nH]cnc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]cnc1-c1ccc(N)cc1
Yield: 97.8 %

Procedure:
To a suspension of 0.009 g (0.081 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol is added, at a temperature in the region of 20° C., 0.04 g (0.172 mmol) of 5-(4-nitrophenyl)-3H-imidazole-4-carboxamide. After hydrogenating for 3 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered. The catalyst is rinsed with twice 2 cm3 of methanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.034 g of 5-(4-aminophenyl)-3H-imidazole-4-carboxamide in the form of a brown solid; EI: m/z=202: M+; Cl: m/z=203: [M+H]+; ES+: m/z=203: [M+H]+; ES−: m/z=201: [M−H]−.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:50]=[C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:52]=1)[C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][N:42]=1)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:54]([O:53][C:51]1[CH:50]=[C:37]([CH:36]=[C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:52]=1)[C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:46])=[CH:43][N:42]=1)=[O:39])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C(O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Yield: 25 %

Procedure:
Diisopropylethylamine (DIPEA, 0.23 ml, 1.3 mM) then 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC, 126 mg, 0.66 mM) were added to a solution of 2-dimethylaminoethylamine (0.57 ml, 0.53 mM) and 6-{[3,5-Di-(benzyloxy)benzoyl]amino}nicotinic acid (0.20 g, 0.44 mM) in dichloromethane (10 ml) under argon at ambient temperature. After 16 hours the reaction mixture was evaporated in vacuo and then chromatographed on SiO2 using a gradient elution of 10 to 25% methanol in dichloromethane. The fractions containing product were evaporated to give a cream solid (0.052 g, 25%); 1H NMR δ (d6-DMSO): 2.67 (6H, s); 3.11 (2H, m); 3.62 (2H, m); 5.18 (4H, s); 6.88 (1H, s); 7.27-7.52 (12H, br m); 8.18-8.36 (2H, m); 8.90 (1H, s); 10.20 (1H, br s).