Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:32])[C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:10]=2)[CH3:2].[N:46](OCCC(C)C)=[O:47]>C1COCC1>[CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:32])[C:23]3[C:24]([CH3:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:33](=[O:41])[C:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[N:46][OH:47])[CH:10]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)Cc3ccccc3)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Reactant: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCCCC(CC)Cn1c2ccc(C(=O)C(=NO)c3ccccc3)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
The mixture of 1-[11-(2-Ethylhexyl)-5-(2,4,6-trimethylbenzoyl)-11H-benzo[a]carbazol-8-yl]-2-phenyl ethanone (1.20 g, 2.03 mmol) and isoamyl nitrite (0.50 g, 4.26 mmol) in THF (6 ml) is bubbled with HCl gas for 1 minute. After stirring at room temperature for 4 hours, the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the crude is purified by column chromatography on silica gel eluting with a mixed solvent of n-hexane and CH2Cl2 (1:1) to obtain an off-white resin (0.69 g, 50%). The structure is confirmed by 1H-NMR spectrum (CDCl3) δ [ppm]: 0.79-0.90 (m), 1.19-1.45 (m), 2.19 (s), 2.28 (m), 2.42 (s), 4.75 (m), 6.97 (s), 7.35-7.41 (m), 7.57 (d), 7.63 (d), 7.70-7.79 (m), 7.98 (d), 8.35 (s), 8.63 (d), 8.72 (s), 9.54 (d).
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[Cl-].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([C:28]3C=CC=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:11]\[C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccc(-c2ccccc2[P+](C)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Reactant: O=Cc1ccncc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(/C=C\c2ccncc2)cc1OC1CCCC1
Yield: 11.9 %

Procedure:
A solution of sodium ethoxide [prepared from sodium (0.10 g, 4.50 mmol)] in ethanol (50 ml) was added over 5 min to a stirred mixture of 4-pyridine carboxaldehyde (0.44 g, 4.10 mmol) and (3-cyclopentyloxy-4-methoxyphenyl)-methyltriphenylphosphonium chloride (2.00 g, 4.08 g) in ethanol (30 ml). After 2h, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (75 ml) and brine (50 ml). The organic layer was separated, then dried (MgSO4) and concentrated in vacuo. A 1H n.m.r. spectrum indicated that the mixture consisted of a 3:2 mixture of (Z): (E)title compound (and triphenylphosphine oxide). A portion (0.6 g) of the mixture was subjected to chromatography (SiO2 ; hexane to EtOAc) to afford pure/Z-title compound (0.14 g) as a pale yellow solid m.p. (Found: C, 77.18; H, 7.16; N, 4.63. C19H21NO2 requires C, 77.26; H, 7.17; N, 4.74%); δH (300 MHz; CDCl3) 1.5-1.55 (2H, br m, cyclopentyl H's), 1.65-1.9 (6H, br m, cyclopentyl H's), 3.83 (3H, s, OMe), 4.44 (1H, br m, OCHCH2), 6.40 (1H, d, J 12.2 Hz, CH=CH), 6.65-6.80 (4H, m, ArH ortho to OMe+2×ArH meta to OMe+CH=CH), 7.15 (2H, ca. d, J 6.0 Hz, pyridine H2, H6); m/z 295 (M+, 22%), 228 (15), 227 (100), 226 (94), 198 (35), 184 (15), 166 (12), 43 (19), and 41 (29).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.C([CH2:11][S:12]([CH2:15][S:16]([CH2:19][C:20](O)=O)(=[O:18])=[O:17])(=[O:14])=[O:13])(O)=O>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:11]/[S:12]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:18])=[O:17])(=[O:14])=[O:13])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccsc1)CS(=O)(=O)/C=C/c1ccsc1
Yield: 55 %

Procedure:
A solution of thiophene-3-carbaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 55% yield. m.p. 150-152° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([O:14][CH2:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][O:7]2)=[CH:16][CH:17]=1)=[CH2:1]
Reactant: O=Cc1ccc(OCCC2OCCO2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccc(OCCC2OCCO2)cc1
Yield: 88.5 %

Procedure:
In another 2 liter flask, 57.2 g of methyl triphenylphosphonium bromide was placed. 500 ml of anhydrous ether was poured and then, stirred. To the resulting solution was slowly added 18.0 g of potassium tert-butoxide and reacted at room temperature for 3 hrs. 23.7 g of the above 4-(2-[1,3]-dioxolan-2-yl-ethoxy)benzaldehyde was dissolved in 200 ml of anhydrous ether and was slowly added to the reaction mixture and then subjected to reaction at room temperature for 4 hrs. After completion of the reaction, the produced solid by-product was filtered off and washed with distilled water and saturated saline. The organic phase washed was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The reaction mixture was purified by Silica gel column chromatography to obtain 20.8 g of 2-[2-(4-vinylphenoxy)ethyl]-[1,3]-dioxolan, represented by the following formula: ##STR10##
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: COC(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 69.9 %

Procedure:
Using methyl anthranilate (3.02 g, 20.0 mmol) and 4-nitrobenzoic acid (3.67 g, 22.0 mmol), the procedure of Reference Example 16 was repeated to obtain 4.20 g (72.9%) of the title compound in the form of light yellow prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](OCC)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[BH4-].[Li+].O.Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([CH2:15][OH:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(CO)ncn2-c2ccc(F)cc2C1=O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
15.0 g (49.5 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are dissolved under argon in 450 ml of boiling absolute tetrahydrofuran (filtered over Alox) and added dropwise at 50° C. to a solution of 1.1 g (49.5 mmol) of lithium borohydride in 50 ml of absolute tetrahydrofuran. The mixture is stirred at 40° C. for 4 hours and at the boiling point for 2.5 hours. Subsequently, the mixture is decomposed at 40° C. with 20 ml of water and 20 ml of concentrated hydrochloric acid/water (1:1) and stirred at room temperature overnight. After removal of the tetrahydrofuran in vacuo, the residue is treated with 14 ml of concentrated ammonia. The mixture is left to crystallise in the cold and separated material is filtered off under suction and washed with water. After recrystallisation from ethanol, there is obtained 8-fluoro-4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[ 1,5-a][1,4]benzodiazepin-6-one of melting point 221°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH:23]N)=[O:22])=[C:10]2[CH3:25])[CH:5]=[CH:6][CH:7]=1>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1cccc(Cl)c1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 675 mg (1.9 mmol) of 1-[(3-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide and 500 mg of Raney Ni in 25 mL of ethanol was heated to maintain reflux for 3.5 hours and cooled to room temperature. The ethanol was decanted and the Raney Ni washed twice with methylene chloride. The combined solvents were filtered, concentrated at reduced pressure and the residue chromatographed on silica gel (eluted with EtOAc) to give 503 mg (77% yield) of 1-[(3-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide, mp, 171-173° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>ClCCl>[CH3:15][N:16]([CH3:17])[S:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:13])=[O:12]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
To a solution of (3-Nitrophenyl)methanesulfonyl chloride (1.0 g, 0.0042 mol) in dry dichloromethane (25 mls) at room temperature dimethylamine (2M in THF, 5.3 ml, 0.105 mol) was added dropwise. The mixture was stirred for 3 hours then filtered through silica, then evaporated to give N,N-Dimethyl-C-(3-nitro-phenyl)-methanesulfonamide, 1.0 g, 1H NMR CDCl3 2.84 (6H, s, 2×CH3), 4.29 (2H, s, CH2), 7.60 (1H, m, ArH), 7.79 (1H, d, ArH), 8.25 (2H, m, ArH)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a suspension of glycine ethyl ester hydrochloride (1.2 eq.) in DCE was added TEA (2 eq.) The reaction was stirred for 10 min at 20° C. then 4-chlorobenzaldehyde (1 eq.), acetic acid (4 eq.) and sodium triacetoxyborohydride (2 eq.) were added. The reaction was stirred for 15 h at 20° C. The crude was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous layer was then extracted twice with DCM. The organic layers were combined, washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to afford (4-chloro-benzylamino)-acetic acid ethyl ester.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH:6]([CH3:28])[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=O>C1COCC1>[CH3:28][CH:6]([CH2:7]/[CH:8]=[CH:39]\[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][Br:29])[CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=CCCCCCCCCCBr
Reactant: CC(CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C/C=C\CCCCCCCCCBr)CC(=O)O
Yield: 58.4 %

Procedure:
68.1 g (149 mmol) of (4-carboxy-3-methyl-butyl)-triphenylphosphonium bromide were placed in 150 ml of THF and treated with 33.4 g (298 mmol) of potassium t-butylate in 50 ml of THF. 35 g (149 mmol) of 10-bromodecanal were added to this mixture After usual work up 111.8 g of crude product were obtained and, after chromatography, 29 g of 3-methyl-5Z-15-bromopentadec-5-enoic acid were obtained having the following characteristics:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[O:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[O:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH:10][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=1)=[O:24])=[O:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CNC(=O)c1oc(C(C)(C)C)cc1N
Solvent: Cc1ccccc1
Product: CNC(=O)c1oc(C(C)(C)C)cc1NC(=O)Nc1ccc(F)cc1
Reaction time: 14 h
Yield: 63.2 %

Procedure:
To a solution of N-methyl-3-amino-5-tert-butylfuran-2-carboxamide (0.15 g, 0.76 mmol) in anh. toluene (2 mL) at the reflux temp. was slowly added 4-fluorophenyl isocyanate (0.10 g, 0.76 mmol, 1.0 equiv). The resulting solution was allowed to stir at the reflux temp. for 14 h, cooled to room temp., and concentrated under reduced pressure. The residue was purified by flash chromatography (15 g SiO2, gradient from 50% CH2Cl2/hexane to 100% CH2Cl2, then to 20% EtOAc/CH2Cl2) to afford N-(2-methylcarbamoyl-5-tert-butylfuryl)-N′-(4-fluorophenyl)urea (0.16 g, 61%): mp 109-11° C., TLC (30% EtOAc/CH2Cl2) Rf0.21; 1H NMR (CDCl3) δ1.29 (s, 9H), 2.89 (d, J=4.8 Hz, 3H), 6.02 (br q, J=4.8 Hz, 1H), 6.98 (app td, J=16.6, 4.1 Hz, 2H), 7.01 (s, 1H), 7.34-7.39 (m, 2H), 8.05 (br s, 1H), 9.14 (s, 1H); 13C NMR (CDCl3) δ25.5, 28.7 (3C), 33.1, 100.7, 115.6 (d, JC-F=23.2 Hz, 2C), 121.5 (d, JC-F=7.3 Hz, 2C), 128.3, 134.5 (br s), 152.4, 158.9 (d, JC-F=242.9 Hz, 1C), 161.6, 165.8; FAB-LRMS m/z (rel abundance) 334 (M+H, 100%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(O)C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in the previous step) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[N:39](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:19]2[CH:18]=1>CO.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[NH:39][C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][C:35]([F:37])([F:38])[F:36])=[CH:30][CH:29]=3)=[C:19]2[CH:18]=1
Reactant: COc1cc2c(-c3cc4c(CNCc5ccc(SC(F)(F)F)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(-c3cc4c(CNCc5ccc(SC(F)(F)F)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 97 %

Procedure:
0.265 cm3 of 5N potassium hydroxide is added to a solution of 0.04 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine in 2 cm3 of methanol, at a temperature in the region of 20° C. The reaction medium is refluxed for 6 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm3 of water. The solid formed is filtered off on a sinter funnel, washed twice with 3 cm3 of water and then dried under vacuum to give 0.030 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine, the characteristics of which are as follows:
Reaction SMILES: [CH:1]([O-:4])([CH3:3])[CH3:2].[CH:5]([O-:8])([CH3:7])[CH3:6].C([O-])(C)C.[Al+3:13].[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16]>>[CH:1]([O-:4])([CH3:3])[CH3:2].[CH:5]([O-:8])([CH3:7])[CH3:6].[C:14]([O-:18])(=[O:17])[CH:15]=[CH2:16].[Al+3:13]
Reactant: C=CC(=O)O
Agent: CC(C)[O-]
Agent: [Al+3]
Product: C=CC(=O)[O-]
Temperature: 32 °C

Procedure:
Into the flask described hereinabove there were placed 204.2 grams of aluminium tri-iso-propanolate to which 72 grams of acrylic acid were added during 8 minutes at room temperature (25° C.). The procedure was as set forth hereinabove. Owing to the reaction heat, the temperature increased to 32° C. The resultant product was a white, solid substance. The rotary evaporator heating then was switched on and gradually heated to 70° C. At the same time the vacuum was gradually adjusted to 24 mbar. The isopropanol was thereby expelled yielding a white powder.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][CH:6]=1.[C:17](N1C2C(=CC=CC=2)C(CC(O)=O)=C1)(=[O:19])[NH2:18]>>[C:17]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([CH2:4][C:3]([OH:2])=[O:16])=[CH:6]1)(=[O:19])[NH2:18]
Reactant: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Reactant: NC(=O)n1cc(CC(=O)O)c2ccccc21
Product: COc1ccc2c(c1)c(CC(=O)O)cn2C(N)=O

Procedure:
was prepared from 5-methoxy-3-indolylacetic acid methyl ester according to the protocol described scheme A8 for the preparation of (1-carbamoyl-1H-indol-3-yl)-acetic acid. Rf, TLC (EtOAC)=0.2; MS (LC/MS): 248.9 [M+H]+, 271.0 [M+Na]+, 247.1 [M−H]−, 495.1 [2M−H]−, 204.1 [M−CONH2]−; tR (HPLC conditions f): 1.54 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([F:12])=[C:4]([Cl:13])[N:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([F:12])=[C:4]([Cl:13])[N:3]=1
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: OCc1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
To a solution of methyl 2,6-dichloro-5-fluoro-3-pyridinecarboxylate (3 g, 13.39 mmol) in DCM (12 ml) at 0° C. under N2 was added dropwise DIBAL-H (1.5 M solution in toluene, 19.20 ml, 28.8 mmol). The reaction mixture was stirred at 0° C. for 20 h. TLC (DCM) showed starting material remaining. Then, more DIBAL-H (1.5 M solution in toluene, 10 ml) was added. The reaction was stirred at 0° C. for 20 h. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was treated with 1N HCl solution and extracted 3 times with EtOAc. The combined organic phases were washed with sat. NaCl, dried over Na2SO4 and concentrated to give 1.5 g (53%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29])([O-:21])=[O:20]>C(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([C@H:3]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:2][NH:1][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N+:19]([O-:21])=[O:20])(=[O:29])=[O:30])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3.3 g, 9.78 mmol) was dissolved in DCM (32.6 mL) at 0° C., then TEA (1.405 mL, 10.08 mmol), and 2-nitrobenzene-1-sulfonyl chloride (2.169 g, 9.78 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified to yield N—((S)-2-(3-bromo-5-fluorophenyl)-2-((S)-1,1-dimethylethylsulfinamido)ethyl)-2-nitrobenzenesulfonamide. LCMS (m/z): 522.1/524.1 (MH+), 0.94 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[NH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=O.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:39]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
HATU (230 mg, 0.605 mmol) and aniline (0.063 mL, 0.691 mmol) was added to a solution of 3-aminobenzoic acid hydrochloride (100 mg, 0.576 mmol) and N,N-diisopropylethylamine (0.217 mL, 1.267 mmol) in 1.5 mL of DMF. The reaction solution was stirred at RT for 3 h. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 20% to 45%. Desired fractions were collected and the solvents were removed under reduced pressure. The residue was passed through 2 g SCX column and washed by 2M NH3 in MeOH to provide 3-amino-N-phenylbenzamide (42 mg, 0.198 mmol, 34.4% yield) as a light-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([OH:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([OH:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1O
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1O
Yield: 81 %

Procedure:
Methyl N-tert-butoxycarbonylaminomethyl-2-hydroxybenzoate (8.7 g, 30.9 mmoles) was dissolved in dry tetrahydrofuran (100 mL), and potassium trimethylsilanolate (4.4 g, 30.9 mmoles, 90% pure) was added. The yellow solution was refluxed for 24 hours, during which time a tan precipitate formed and the solvent turned light brown. The mixture was evaporated to dryness, and the solid was dissolved in cold water (100 mL). The brown solution was chilled in an ice bath, and saturated aqueous potassium hydrogen sulfate solution was used to titrate the stirred solution to pH 2-3. An off-white solid precipitated during the titration. The solid was filtered, washed with cold water, and dried in vacuo over potassium hydroxide to afford 6.7 g, (81% yield) of crude N-tert-butoxycarbonylaminomethyl-2-hydroxybenzoic acid (m.p. 141-144° C., decomposes with effervescence on melting, open capillary, uncorrected).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)CCN
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN(C)C

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with N,N-dimethylethane-1,2-diamine using an analogous method to that described for the equivalent step in Example 1 to give N′-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N,N-dimethylethane-1,2-diamine; 1H NMR Spectrum: (DMSO-d6) 2.12 (s, 6H); 2.37 (t, 2H); 2.65 (t, 2H); 3.85 (s, 2H); 3.97 (s, 3H); 7.21 (s, 1H); 7.28 (t, 1H); 7.51 (m, 2H); 8.32 (s, 1H); 8.43 (s, 1H); 9.78 (s, 1H); Mass Spectrum: (M+H)+ 404.