Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:19]1([CH:26]=[O:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:26]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:21][CH2:20]1)=[O:27]
Reactant: O=CN1CCCNCC1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCCN(C=O)CC2)n(-c2ccccc2)c2ccccc12
Yield: 97 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4]diazepane-1-carboxaldehyde as described in Example 1 to afford 2-(4-formyl-[1,4]diazepan-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (97% yield) as a yellow solid. LC/MS: MS 348 (M+H); RT 2.77 min; (CDCl3): 10.26 (1H, d), 8.22 (1H, d), 8.00 (0.5H, s), 7.86 (0.5H, s), 7.47-7.69(3H, m), 7.23-7.38 (3H, m), 7.17(1H, t), 6.97 (1H, d), 3.25-3.70 (8H, m), 1.50-1.73(2H, m).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25])([O-:20])=[O:19].[OH-].[Na+]>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:25][C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2cccc([N+](=O)[O-])c2)[nH]c1-c1ccc(F)cc1

Procedure:
Ethyl 5-(4-fluorophenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(4-fluorophenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[CH3:16])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][C:10]=2[CH3:16])=[N:4][CH:3]=1
Reactant: Cc1cc(N)ccc1Oc1ncc(Cl)cn1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccc(Oc2ncc(Cl)cn2)c(C)c1

Procedure:
2.0 g of 4-(5-chloro-2-pyrimidinyloxy)-3-methylaniline and 1.3 ml of triethylamine were dissolved in 20 ml of tetrahydrofuran, and 1.12 ml of valeryl chloride was dropwise added thereto under cooling with ice. The mixture was reacted at room temperature for 40 minutes under stirring. After completion of the reaction, the reaction product was poured into water and extracted with ethyl acetate. The extract layer was washed with a saturated aqueous solution of sodium chloride and dried over Glauber's salt. Then, ethyl acetate was distilled off to obtain 2.8 g of N-[4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl]valeramide (Intermediate Compound No. 13) (melting point: 146°-150° C.)
Reaction SMILES: C(NCC)C.C[Al](C)C.[CH2:10]([C:12]1[N:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16](=[O:24])[NH:17]2)[CH3:11].Cl.C[OH:32]>ClCCl>[CH2:10]([C:12]1[N:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[C:14]([OH:32])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16](=[O:24])[NH:17]2)[CH3:11]
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2[nH]c1=O
Reactant: CO
Agent: C[Al](C)C
Agent: Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
Diethylamine (0.63 ml) was added dropwise to a stirred solution of trimethylaluminium (2M solution in toluene; 3 ml) in dichloromethane (5 ml) under an atmosphere of argon. The mixture was stirred for 30 minutes then a solution of ethyl 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylate (548 mg) in dichloromethane (5 ml) was added dropwise. The resulting mixture was heated at reflux for 4 hours then cooled in ice. A mixture of 2M hydrochloric acid (1 ml) and methanol (1 ml) was added dropwise. The mixture was filtered and the filtrate was concentrated by evaporation to give a brown oil which was purified by flash chromatography, eluting with methanol/ethyl acetate (1:24 v/v), to give 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-N,N-diethylcarboxamide (B) (391 mg) as a solid, m.p. 56°-59° C.; NMR (CDCl3): 1.17(t, 3H), 1.25-1.4(complex m, 9H), 2.85(q, 2H), 3.07(q, 2 H), 3.32(q, 2H), 3.63(q, 2H), 6.95(s, 1H), 8.08(s, 1H), 12.28(s, 1H); mass spectrum (CI, ammonia): 302 (M+H)+ ; microanalysis, found C, 66.4; H, 7.6; N, 13.6%; C17H23N3O2.0.25H2O requires: C, 66.7; H, 7.7; N, 13.7%.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:27][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)Nc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
91 g (375 mmol) of 1-hexadecanol were added to a solution of 50 g (375 mmol) of p-tolyl isocyanate in 50 ml of toluene, and the resulting solution was heated under reflux for 8 h. After cooling to room temperature and stirring at this temperature for 12 h, the precipitated solid was filtered off. The colourless solid was washed twice with 10 ml of toluene each time and then dried in vacuo. 80 g (213 mmol, 57%) of the desired carbamate were obtained in the form of a colourless solid with a melting point of 75° C. The melting point agreed with literature data (75-76° C., Microchem J. 1962, 6, 179).
Reaction SMILES: CON(C)[C:4]([CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5].[CH3:22][C:23]([CH3:27])=[CH:24][Mg]Br>C1COCC1>[F:13][C:10]1([F:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:7]([CH2:6][C:4](=[O:5])[CH:22]=[C:23]([CH3:27])[CH3:24])[CH2:11]1
Reactant: CON(C)C(=O)C[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Reactant: CC(C)=C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)=CC(=O)C[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a THF (23 ml) solution of (R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate (1.4 g, 4.54 mmol) over ice bath, 2-methyl-1-propenylmagnesium bromide solution (0.5 M in THF, 45 ml, 22.7 mmol) was added dropwise over 1 hour. Remove ice bath, stifling was continued for another 3 hours. The reaction was quenched with 1N HCl (aq., 30 ml) at 0° C., and was stirred at room temperature for 30 minutes. Two layers were separated, aqueous layer was extracted with EtOAc (25 ml×2), organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Product was purified by silica gel chromatography (Hexane/EtOAc, linear gradient from 100:0 to 80:20). Compound (R)-tert-butyl 4,4-difluoro-2-(4-methyl-2-oxopent-3-enyl)pyrrolidine-1-carboxylate was obtained as a light yellow oil: 1.10 g (79.5% yield).
Reaction SMILES: [OH:1][C:2]([C:4]1([O:15][C@@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[C@H:9]([NH:10]C(C)=O)[C@@H:7]([OH:8])[CH2:6]1)[OH:5])=[O:3].[O:22]([C@@H:34]1[C@@H:40]([CH2:41][OH:42])[O:39][CH:37]([OH:38])[C@H:36]([NH:43][C:44]([CH3:46])=[O:45])[C@H:35]1[OH:47])[C@@H:23]1[O:31][C@H:30]([CH2:32]O)[C@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]1[OH:25].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[Cl-].[K+].CC(N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)C[C@@H]1O)=O.[Na+].C1N(CCO)CCN(CCS(O)(=O)=O)C1.C=CC(N)=O>O>[OH:1][C:2]([C@@:4]1([O:15][C@@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[C@H:9]([NH2:10])[C@@H:7]([OH:8])[CH2:6]1)[O:5][CH2:32][C@H:30]1[O:31][C@@H:23]([O:22][C@@H:34]2[C@@H:40]([CH2:41][OH:42])[O:39][CH:37]([OH:38])[C@H:36]([NH:43][C:44]([CH3:46])=[O:45])[C@H:35]2[OH:47])[C@H:24]([OH:25])[C@@H:26]([OH:27])[C@H:28]1[OH:29])=[O:3]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: C=CC(N)=O
Agent: CC(=O)N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Solvent: O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO[C@]3(C(=O)O)C[C@H](O)[C@@H](N)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Temperature: 25 °C
Yield: 97 %

Procedure:
NeuAc (0.92 g, 3 mmol), Galβ1,4GlcNAc (1.1 g, 3 mmol), CMP (0.1 g, 30 μmol), ATP (16 mg, 3 μmol), PEP (2.8 g, 6 mmol), MgCl2.6H2O (0.61 g, 3 mmol), MnCl2.4H2O (0.15 g, 0.8 mmol), KCl (0.22 g, 3 mmol), NMK or MK (450 U), PK (6,000 U), PPase (300 U), CMP-NeuAc synthetase (24 U), and Siaα2,6Gal sialyl transferase (4 U) were mixed with 150 ml of HEPES buffer (0.2M, pH 7.5) to form a reaction mixture and the reaction mixture maintained under argon at about 25° C. for about 48 hours. After the disappearance of NeuAc (determined by thin-layer chromatography) the reaction mixture was reduced in volume to 20 ml by lyophilization and the lyophilized reaction mixture applied to a Bio Gel P2 (200-400 mesh) column with water as the mobile phase. The trisaccharide-containing fractions were eluted, collected and lyophilized to give pure Neuα2,6Galβ1,4GlcNAc in 97 percent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([C:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (250.0 mg, 0.5099 mmol, prepared in Example 7, step B), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (315.3 mg, 1.020 mmol), tetrakis(triphenylphosphine) palladium (117.8 mg, 0.1020 mmol), Na2CO3 (1.275 ml, 2.550 mmol) and DME (25 mL). The reaction mixture was stirred at 100° C. overnight, then partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (273.3 mg, 98%). LRMS (APCI pos) m/e 546 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(N2CCCCC2)C=CC=1N)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42 %

Procedure:
5-Amino-2-nitro-benzoic acid (compound A′) (910 mg) was dissolved in methanol (50 ml). Thionyl chloride (0.74 ml) was added dropwise to the solution on an ice bath, and a reaction was allowed to proceed under reflux with heating for 12 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling to room temperature and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-amino-2-nitro-benzoic acid methyl ester (410 mg, yield 42%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:22]1[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]1[OH:33])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:34]([C:37]1[N:41]=[CH:40][NH:39][N:38]=1)([O-:36])=[O:35]>>[OH:32][C@H:24]1[C@@H:23]([OH:33])[C@H:22]([N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][C:19]([N:39]2[CH:40]=[N:41][C:37]([N+:34]([O-:36])=[O:35])=[N:38]2)=[N:20][C:12]=3[NH:11][C@H:8]([CH2:9][OH:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][C@@H:25]1[NH:27][C:28](=[O:31])[CH2:29][OH:30]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])c1nc[nH]n1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(-n4cnc([N+](=O)[O-])n4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound can be prepared from N-{(1S,2R,3S,4R)-4-[6-((S)-1-benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate GC) and 3-nitro-1,2,4-triazole, as described for N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
D3 (600 mg) was treated with 2 M aq. NaOH (25 ml) and MeOH (25 ml). This mixture was stirred overnight then heated to 50° C. for 6 hours. The MeOH was then evaporated and the remaining solution acidified and extracted with EtOAc (×3). The combined organic solutions were washed with brine and evaporated to give the crude residue C(302 mg) as an off-white solid. This was triturated with cold MeOH to give the title compound (162 mg) as a grey solid. δH (d6-DMSO, 400 MHz): 2.80 (2H, t), 4.46 (2H, t), 6.64 (1H, d), 7.49-7.59 (6H, m), 7.72 (1H, d), 7.85 (1H, dd), 8.22-8.25 (1H, m), 8.31-8.34 (1H, m). MS (ES): C24H16F3N3O3S requires 483; found 484 (MH+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1.C[O:18][B:19](OC)[O:20]C.Cl>C1COCC1>[O:15]=[C:13]1[NH:12][C:11]2[CH:16]=[C:7]([B:19]([OH:20])[OH:18])[CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: COB(OC)OC
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(B(O)O)ccc2o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Add n-BuLi (1.6M in hexanes, 8.76 mL, 14.02 mmol) portionwise (exotherm) to a solution of 5-bromo-3H-benzooxazol-2-one (1.00 g, 4.67 mmol) in dry THF (28 mL) at −78° C. under N2. Stir at −40° C. for 1 h and add trimethylborate (1.94 g, 18.68 mmol) at once. Warm up to room temperature overnight. Add 1N aqueous HCl (50 mL) and stir for 3 h at room temperature. Extract into ethyl acetate, dry (MgSO4) and concentrate organics to a brown solid. Triturate with hexanes/toluene and collect 766 mg (92%) of the title compound as a brown powder. MS (ES) 179 (M+H), 177 (M−H); HPLC shows 80% purity.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([N:14](C(OC)=O)[C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=3[Cl:25])=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl>CO>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=3[Cl:25])=[N:12][N:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)N(c1ccc(C(F)(F)F)cc1Cl)c1nnnn1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(-n2nnnc2Nc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 95.2 %

Procedure:
A mixed solution of 1-(4-trifluoromethylphenyl)-5-(2-chloro-4-trifluoromethyl-N-methoxycarbonyl-anilino)tetrazole (1.2 g), methanol (15 ml) and potassium hydroxide (0.4 g) was stirred at room temperature for 3 hours. After the completion of the reaction, hydrochloric acid (5%; 80 ml) was added thereto. The precipitated crystals were collected by filtration and washed with water to obtain 1-(4-trifluoromethylphenyl)-5-(2-chloro-4-trifluoromethylanilino)tetrazole (1.0 g).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3].[CH:10]([OH:13])([CH3:12])[CH3:11]>O1CCOCC1>[CH:10]([O:13][C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3])([CH3:12])[CH3:11]
Reactant: O=C(Cl)N1CCNC1=O
Reactant: CC(C)O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N1CCNC1=O

Procedure:
14.9 parts by weight of N-chlorocarbonylimidazolid-2-one in 100 parts by volume of i-propanol and 100 parts by volume of dioxane were warmed to 50° C for 3 hours After stripping off the solvent, the residue was recrystallized from acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([OH:15])=[O:14])[O:12][C:7]=2[CH:6]=1.C1(NC2CCCCC2)CCCCC1.Br[CH2:43][C:44]([O:46][CH3:47])=[O:45].O>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([O:15][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:14])[O:12][C:7]=2[CH:6]=1
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Reactant: COC(=O)CBr
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)C1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) (0.4 g) was dissolved in DMF (0.2 ml) and dicyclohexylamine (0.2 ml) was added thereto, followed by stirring at 60° C. for 15 minutes. Then methyl bromoacetate (0.2 g) was added, the mixture further stirred at 60° C. for 3 hours, to the reaction mixture was added water (20 ml), and the mixture was extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and then dried over magnesium sulfate, followed by an evaporation of the solvent under a reduced pressure. The residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:19][C:16]1[S:15][C:14]([C:12]2[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:28]4[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.31 g, 0.74 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.81 mmol) according to the general procedure III. Obtained as a light yellow solid (0.075 g, 23%). MS (ISP) 434.2 [(M+H)+]; mp 228° C.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:30][CH2:29]2)=[O:17])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1.C(N(CC)CC)C.[C:52](Cl)(=[O:55])[CH2:53][CH3:54]>ClCCl>[C:11]([C:9]1[CH:10]=[C:5]([NH:4][C:52](=[O:55])[CH2:53][CH3:54])[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:32][CH2:33]2)=[O:17])[CH:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)C4CCCN4C)CC3)c2n1C
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@@H]5CCCN5C)CC4)c3n2C)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg of 1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(3-amino-5-tert-butyl-2-methoxy-phenyl)-amide trihydrochloride are dissolved in 2 ml of dichloromethane and combined successively with 160 μl triethylamine as well as 25 μl propionyl chloride. The mixture is stirred for 2 hours at ambient temperature, the solvents are eliminated in vacuo and the residue is purified by preparative HPLC (method 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23](O)=[O:24])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([Cl:33])=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.6 g (1.553 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)-benzoic acid were suspended in 20 ml of dichloromethane with magnetic stirring, the mixture was placed in a bath at 0° C. and then 0.408 ml (4.66 mmol) of oxalyl chloride were added drop wise, finally a few drops of dimethylformamide were added. The cold bath was withdrawn and then the mixture was stirred at r.t. for 2 h. The reaction medium was concentrated in vacuo and immediately used in the next step.