Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N([O-])=O.[Na+].O.[I-:23].[K+]>Cl.CC(C)=O.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([I:23])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(I)cc1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a 0° C. suspension of the 2-phenyl-4-aminobenzoic acid methyl ester prepared in Example 210B (4.54 g, 20 mmol) in 6.0 N HCl (20 mL) and acetone (10 mL) was added dropwise a solution of sodium nitrite (1.66 g, 24 mmol) in a minimum amount of water. After 30 minutes, potassium iodide (6.64 g, 40 mmol) in a minimum amount of water was added dropwise to the reaction mixture. The internal temperature of the reaction mixture was maintained under 5° C. for both additions. The reaction mixture was then stirred at ambient temperature for one hour. The reaction mixture was diluted with ether (200 mL), washed with water, sodium bisulfite (10% aqueous solution), water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (8% ethyl acetate-hexane) to give 4-iodo-2-phenylbenzoic acid methyl ester (3.98 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.77 (m, 2H), 7.55 (d, 1H), 7.38 (m, 3H), 7.27 (m, 2H), 3.63 (s, 3H). Ms (CI+): 356 (M+NH4)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]1([CH2:21][N:22]2[CH:31]=[C:30]([CH2:32][N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:46]4[CH:51]=[C:50]([C:52](=[O:57])[NH:53][CH:54]5[CH2:56][CH2:55]5)[CH:49]=[C:48]([F:58])[C:47]=4[CH3:59])[CH:28]=3)[C:23]2=[O:60])[CH2:20][CH2:19][CH2:18]1)(C(C)(C)C)(C)C>C(Cl)Cl>[CH:54]1([NH:53][C:52](=[O:57])[C:50]2[CH:51]=[C:46]([C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:60])[N:22]([CH2:21][C:17]3([CH2:16][OH:15])[CH2:18][CH2:19][CH2:20]3)[CH:31]=[C:30]4[CH2:32][N:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[C:47]([CH3:59])=[C:48]([F:58])[CH:49]=2)[CH2:56][CH2:55]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO)CCC3)cc(CN3CCNCC3)c2c1
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Trifluoroacetic Acid (3 mL, 38.94 mmol) was added to a solution of tert-butyl 4-[(2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl}-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27d 0.099 g) in DCM (9 mL) at room temperature. The reaction was stirred for 30 min before azeotroping with toluene (3×10 mL). The residue was passed through SCX resin, eluting with methanol to remove impurities, and then ˜0.7 N methanolic ammonia to elute product, which was then purified by preparative HPLC (Sunfire column using a 95-30% gradient of 0.3% aqueous ammonia in acetonitrile as eluent). The solvents were removed and the residue triturated with diethyl ether to leave the title compound (0.022 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:13]([CH2:12][O:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[C:17]([CH3:18])[O:16][N:15]=2)=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid methyl ester (540 mg, 1.42 mmol) in THF (5.4 mL) was added a solution of lithium hydroxide monohydrate (118 mg, 2.83 mmol) in water (5.4 mL) followed by methanol (2 mL) and the resulting mixture stirred at room temperature overnight. The mixture was then evaporated and acidified with HCl (1 N) and the mixture cooled to 0° C. for 30 min. A solid formed which was filtered off, washed with water and dried to afford the title compound (321 mg, 69%) which was obtained as a white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH:1]1([C:4]2[C:8]([CH:9]([OH:10])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:7][N:6]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-n2cc(C=O)c(C3CC3)n2)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C(O)CC(C)C)c(C3CC3)n2)cc1
Yield: 82 %

Procedure:
3-Cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.8 g) synthesized above was dissolved in tetrahydrofuran (10 mL), isobutylmagnesium bromide (1M tetrahydrofuran solution, 12 mL) was added dropwise at 0° C. In the same manner as in Example 1(6), the title object compound (1.8 g, 82%) was obtained as a white solid.
Reaction SMILES: C1(CNC(C2NC=C(C([C:15]3[C:16]([C:21]4[CH:26]=CC(F)=CC=4)=[N:17][O:18][C:19]=3C)=O)C=2)=O)CC1.[F:28][C:29]1[CH:30]=[C:31]([C:36]2[C:40]([C:41]([C:43]3[CH:44]=[C:45]([C:48](=[O:53])C(Cl)(Cl)Cl)[NH:46][CH:47]=3)=[O:42])=[C:39]([CH3:54])[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35]>>[O:18]1[CH2:26][CH2:21][CH:16]([NH:17][C:48]([C:45]2[NH:46][CH:47]=[C:43]([C:41]([C:40]3[C:36]([C:31]4[CH:32]=[CH:33][C:34]([F:35])=[C:29]([F:28])[CH:30]=4)=[N:37][O:38][C:39]=3[CH3:54])=[O:42])[CH:44]=2)=[O:53])[CH2:15][CH2:19]1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCOCC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and tetrahydro-pyran-4-yl amine(commercially available) in 41.5 yield. (m/e): 416.1 (MH+; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4](I)[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([C:19]#[C:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:3]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Cc1cc(Cl)cc(I)c1N
Product: Cc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N
Yield: 68.4 %

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodo-6-methyl-phenylamine (1.5 g, 5.61 mmol) and 1-chloro-2-ethynyl-benzene (920 mg, 6.73 mmol) to afford 4-chloro-2-(2-chloro-phenylethynyl)-6-methyl-phenylamine (1.06 g, 68%) as an off white solid. LC-MS (ESI): 276 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([Li])CCC.[F:12][C:13]1([F:20])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>C1COCC1>[F:12][C:13]1([F:20])[CH2:18][CH2:17][C:16]([C:2]2[CH:3]=[N:4][NH:5][CH:6]=2)([OH:19])[CH2:15][CH2:14]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: Ic1cn[nH]c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cn[nH]c2)CCC(F)(F)CC1
Yield: 38.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 8a by using 4-iodo-1H-pyrazole (5.82 g, 30.0 mmol), butyl lithium (2.69 M solution in hexane; 22.3 mL, 60.0 mmol), 4,4-difluorocyclohexanone (4.43 g, 33.0 mmol) and THF (120 mL), to yield the title compound (2.32 g, 55%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.[CH3:35][S:36]([O-:38])=[O:37].[Na+].[OH-].[Na+].Cl>C(O)C.C(O)(C)C>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: CS(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CS(=O)(=O)Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.102 mmol) and sodium methanesulfinate (10.42 mg, 0.102 mmol) in ethanol (0.8 ml) were heated under microwave irradiation to 100° C. for 30 mins then 150° C. for 30 min, followed by 150° C. for a further 30 mins. Additional sodium methanesulfinate (10.42 mg, 0.102 mmol) was added and the reaction heated to 150° C. for a further 30 mins. The solvent was removed and the resultant beige solid treated with isopropanol (1 ml) and 2M aqueous sodium hydroxide (1.003 ml, 2.006 mmol) and stirred at 20° C. for 20 h. The mixture was neutralised with 2M aqueous hydrogen chloride, evaporated to dryness and azeotroped with isopropanol (2 ml). The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and shaken vigorously. The aqueous phase was pipetted off, then the heterogeneous solution was treated with methanol (5 ml), absorbed onto Florisil and the solvents removed. The Florisil was placed on top of a silica cartridge (10 g) and eluted with 0-3% methanol/dichloromethane. Appropriate fractions were combined and concentrated to give a beige solid, 16 mg. Further purification by Mass Directed Automated Preparative HPLC afforded the title compound as a white solid (5 mg).
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>CO>[C:1]1([NH:7][C:8](=[S:11])[NH:9]/[N:10]=[CH:12]/[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=S)Nc1ccccc1
Reactant: O=Cc1cccnc1
Solvent: CO
Product: S=C(N/N=C/c1cccnc1)Nc1ccccc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
4-Phenylthiosemicarbazide (890 mg, 5.3 mmol, 1.0 equiv) was added to a stirred solution of nicotinaldehyde (500 μL, 5.3 mmol, 1.0 equiv) in methanol (2.5 mL) at 23° C. The resulting pale yellow solution was heated to 65° C. and stirred for 3 h. The cooled reaction mixture was concentrated under vacuum. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as off-white crystals (1.3 g, 93%): mp 208-210° C.; IR (KBr thin film) 3442 (w), 3298 (m), 3125 (w), 2940 (w), 2791 (w), 1594 (s), 1532 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.22 (s, 1H), 9.03 (d, J=2 Hz, 1H), 8.59 (dd, J=5, 2 Hz, 1H), 8.38 (dt, J=8, 2 Hz, 1H), 8.18 (s, 1H), 7.55 (m, 2H), 7.45 (dd, J=8, 5 Hz, 1H), 7.21 (m, 1H); ESIMS m/z 257 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]1[CH:14]2[CH:15]3[CH:19]=[CH:18][CH:17]([CH:13]2[CH:12]=[CH:11]1)[CH2:16]3.C(OC(C1CC2CC1C=C2)=O)(C)(C)C.C1CC=CC=1>>[C:6]([O:5][C:1]([CH:2]1[CH2:3][CH:10]2[CH2:11][CH:12]1[CH:13]1[CH:14]2[CH:15]2[CH2:16][CH:17]1[CH:18]=[CH:19]2)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1=CCC=C1
Agent: CC(C)(C)OC(=O)C1CC2C=CC1C2
Product: CC(C)(C)OC(=O)C1CC2CC1C1C3C=CC(C3)C21
Yield: 40 %

Procedure:
The reaction was carried out in the same manner as in the Synthesis Example 1(1), except for using t-butyl acrylate, dicyclopentadiene, and 5-t-butoxycarbonylbicyclo[2.2.1]hept-2-ene at a molar ratio of 3:1(as cyclopentadiene):1 as reaction raw materials, to obtain 8-t-butoxycarbonyltetracyclo[4.4.0.12,5.17,10]dodec-3-ene of the following formula (16) at an yield of 40%.
Reaction SMILES: N1([C:6]([C:8]2[N:9]=[CH:10][C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:7])C=CN=C1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][OH:39])[CH:31]=1>C1(C)C=CC=CC=1>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[CH2:21][N:12]1[C:11]2[CH:10]=[N:9][C:8]([C:6]([O:39][CH2:38][CH2:37][CH2:36][C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[O:7])=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=C(c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1)n1ccnc1
Reactant: OCCCc1cccnc1
Solvent: Cc1ccccc1
Product: O=C(OCCCc1cccnc1)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A suspension of 3-(1-imidazolylcarbonyl)-9-(2,5-dichlorobenzyl)-9H-β-carboline (505 mg, 1.20 mmol) and 3-pyridinepropanol (8.2 g, 60 mmol) was heated at 80° C. in toluene (15 mL) for 22 hours. The resulting solution was cooled to room temperature, and extracted several times with water before drying the organic phase with Na2SO4. Evaporation of the solvent followed by preparative thin layer chromatography of the resulting crude material with hexane/ethyl acetate (6:4) as eluent furnished the desired product (470 mg, 80% yield) as a pale yellow solid. 1H NMR (CDCl3) δ8.91 (s, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.31 (d,J=8.0 Hz, 1H), 7.67 (AB q, J=7.4 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.42-7.48 (m, 3H), 7.22-7.28 (m, 2H), 6.60 (s, 1H), 5.70 (s, 2H), 4.53 (t,J=6.5 Hz, 3H), 2.87 (t, J=7.7 Hz, 3H), 2.26 (t, J=7.3 Hz, 3H); MS (ACPl; (M+H)+) m/z 490.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=1)=[O:39])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][C@@H:20]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([O:23]C)=[O:22])=[O:18])[CH:13]=2)[CH:7]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[C:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][C@H:20]([NH:19][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:34]=[CH:35][C:36]([NH:37][C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=4)=[O:39])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18])[C:21]([OH:23])=[O:22])([CH3:31])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate (120 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 1 ml of 1M NaOH (1 mmol) solution. The mixture was stirred at room temperature for 30 minutes, and poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid as white solid. Yield: 100 mg, 85%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[N:13]=[CH:12][C:11]=2[C:10]([CH3:23])([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[O-2].[Mn+4].[O-2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[N:13]=[CH:12][C:11]=2[C:10]([CH3:22])([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(O)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
A mixture of 6-(1-hydroxy-2-methyl-propyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.366 g, 1.14 mmol), DCM (50 mL) and manganese (IV) oxide (9.6 g, 110 mmol) was stirred at 20° C. for 18 h, then solids were removed by filtration and the filtrate evaporated in vacuo to give a solid. Chromatography (SiO2; gradient elution with 0-40% EtOAc in 40-60 petroleum ether) gave the title compound (0.299 g) as a colourless solid. MS: [M+H]+=319.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14](Cl)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[CH3:23][NH2:24]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([CH2:23][NH2:24])[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: Fc1ccc2nn3c(Cl)c(-c4ccccc4)c(Cl)nc3c2c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NCc1c(-c2ccccc2)c(Cl)nc2c3cc(F)ccc3nn12
Temperature: 100 °C
Yield: 46.4 %

Procedure:
2 g (7.5 mmol) 2,4-Dichloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-0, step 2) and 7.5 mL (15 mmol) of a 2M solution of methylamine in tetrahydrofuran were dissolved in 16.8 mL N,N-dimethylformamide and heated in the microwave for 20′ at 100° C. The solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 960 mg (46.4%) of the desired compound.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([NH2:13])[CH:2]=1.C(=O)(O)[O-].[Na+].[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:9](=[O:11])[C@H:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([NH2:13])=[CH:2][CH:1]=1)[NH2:12])[CH3:20]
Reactant: CCO
Reactant: Nc1ccc(C[C@H](N)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 80 °C

Procedure:
About 40 g of dried L-4-amino phenylalanine was mixed with 1000 mL of ethanol. The reaction mass was dehydrated by distilling out about 20% of the ethanol added. To the dried reaction mixture about 300 g of dry hydrochloric acid gas was purged in. The reaction mass was warmed to about 80° C. and the reaction was promoted by removing condensation (water formed in the reaction) by distillation. The progress of the reaction was monitored by HPLC analysis. Upon completion of the esterification reaction, the reaction mass was neutralized with sodium bicarbonate and the precipitated inorganic salt was removed, isolated, washed with ethanol, and the filtrate was collected. The filtrate was concentrated by distillation and dehydrated to a thick mass. (the weight of reaction mass residue was 41 g; its purity 98%.)
Reaction SMILES: CS[C:3]1[C:9]2=[N:10][N:11]=[N:12][N:8]2[CH2:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>>[CH3:24][N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:3]2[C:9]3=[N:10][N:11]=[N:12][N:8]3[CH2:7][C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[N:4]=2)[CH2:19][CH2:20]1
Reactant: CN1CCC(N)CC1
Reactant: CSC1=Nc2ccccc2Cn2nnnc21
Product: CN1CCC(NC2=Nc3ccccc3Cn3nnnc32)CC1
Yield: 49 %

Procedure:
To a solution of 5.0 g. (22 mmol.) of 11-Methylthio-5H-tetrazolo[5,1-c][1,4]benzodiazepine in 15 ml. of 4-amino-1-methylpiperidine is heated at 115° C. for 18 hours. The excess amine is evaporated and the resulting solid is triturated with water. Recrystallization from ethanol-water gives the title product in 49% yield (m.p. 112°-114° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.[CH:22]([C:24]1[N:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:34]#[N:35])=[C:27]2[O:36][CH:37]([CH3:39])[CH3:38])=O>CC(O)=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:22][C:24]2[N:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][C:28]([C:34]#[N:35])=[C:27]3[O:36][CH:37]([CH3:39])[CH3:38])[C:9](=[O:11])[N:10]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc12
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (prepared as described below), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (50.2 mg, 0.21 mmol) (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 80° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in AcOEt, re-filtered through a paper filter to give 6-[2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a light brown solid (19.2 mg, 24.9%). HR-ES (+) m/e calcd for C23H17FClN5O2S (M+H)+ 482.0849. found 482.0848.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(Cl)(Cl)Cl.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])O.[Na+]>O.N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)COS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 108.1 %

Procedure:
Under cooling in an ice bath, 2,2-dimethyl-1-propanol (1.55 g) was added to a chloroform (20 mL) solution that contained 3-bromobenzenesulfonyl chloride (3.00 g) and pyridine (1.86 g), and the obtained solution was then stirred at a room temperature for 60 hours. Thereafter, water and a saturated sodium hydrogencarbonate aqueous solution were added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The obtained solid was washed with n-hexane, so as to obtain the title compound (3.90 g) in the form of a colorless solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:13]=1[CH:14]=[O:15].O>O1CCCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:13]=1[CH:14]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:15]
Reactant: c1ccoc1
Reactant: COc1cccc(Cl)c1C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(Cl)c1C(O)c1ccco1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 96.6 %

Procedure:
To a solution of furan (10.7 mL, 147 mmol) in anhydrous tetrahydrofuran (100 mL) under an N2 atmosphere at −10°C. was added n-butyl lithium (65 mL of a 2.5M solution in hexanes, 162 mmol) dropwise over 35 minutes (the internal temperature was maintained at less than −7°C.). The mixture was stirred at this temperature for 1 hour 35 minutes before adding a solution of 2-chloro-6-methoxy-benzaldehyde (27.6 g, 162 mmol) in anhydrous tetrahydrofuran (100 mL) dropwise over 1 h 30 (internal temperature approx −5°C.). On completion of addition, the reaction mixture was warmed to room temperature and stirred at this temperature for 18 hours. Water (100 mL) was added then the mixture was diluted with EtOAc (100 ml). The phases were separated and aqueous phase was extracted into EtOAc (2×100 ml). The combined organics extracts were washed with brine (50 ml), dried over MgSO4 and concentrated to a yellow oil. The crude product was adsorbed onto silica and purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product (33.9 g, 97%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (d, 1H), 7.25-7.21 (m, 1H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.34-6.29 (m, 2H), 6.06 (dt, 1H), 4.38 (d, 1H), 3.87 (s, 3H).