Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])[CH3:22]>C(Cl)Cl.[Cu]Cl>[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH3:22]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC(C)(C)C)c(OCC)c1)c1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.9 g (9.6 mmols) of N,N'-dicyclohexyl-carbodiimide, 1.06 ml (11.2 mmols) of absolute tert.butanol and 0.020 g (0.20 mmol) of copper(I) chloride was stirred for 60 hours at room temperature. Then, 6.6 ml of methylene chloride were added, and the resulting solution was added dropwise to a solution of 0.44 g (1 mmol) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid in 15 ml of methylene chloride. After 60 hours' stirring at 20° C., the precipitate which had formed was filtered off, washed with methylene chloride, and the methylene chloride solution was evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/ethyl acetate-9/1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([NH:13][CH3:14])[CH:10]([OH:15])[CH2:9]2)=[N:6][CH:7]=1.[CH:16](=O)[C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+].C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]3[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=3)[CH3:14])[C@H:10]([OH:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CNC1CN(c2ccc(Br)cn2)CC1O
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(CN(C)[C@@H]2CN(c3ccc(Br)cn3)C[C@H]2O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Dissolve 1-(5-bromo-pyridin-2-yl)-4-methylamino-pyrrolidin-3-ol (0.347 g, 1.28 mmol) in dichloroethane (10 mL) and add veratraldehyde (212 mg, 1.28 mmol), sodium triacetoxyborohydride (405 mg, 1.91 mmol) and acetic acid (125 mL, 2.18 μmol). Stir the mixture at room temperature overnight. Dilute with saturated sodium bicarbonate and extract the mixture with dichloromethane (3×). Dry the combined organic portions over sodium sulfate, filter, and evaporate. Purify the resulting residue by silica gel chromatography, eluting with 0-9% methanol (2N NH3)/CH2Cl2 to give 390 mg (72%) of the title compound as a white solid. MS/ES m/z (81Br) 424.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10](O)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:45]([SH:47])[CH3:46].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([S:47][CH2:45][CH3:46])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCS
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(O)c2c1[nH]c1ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(SCC)c2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-1-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (60 mg, 0.3 mmol) in DCM (2 mL) was added trifluoromethanesulfonic anhydride (50 mL, 0.6 mmol) at 0° C. and the mixture was stirred for 1 hour at 0° C. Ethanethiol (34 mL, 0.9 mmol) was added and the reaction mixture was stirred overnight at 20° C. Water was added and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was then washed with water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:19) to give the title compound (2 mg); 1NMR (CDCl3): δ 8.59 (1H, s), 8.77 (1H, d), 7.54 (2H, m), 7.36 (1H), 7.19 (1H, m), 7.06 (2H, m), 6.73 (1H, s), 4.41 (2H, m), 4.21-4.30 (3H, m), 2.59-2.69 (2H, m), 1.28 (3H, t), 1.19 (3H, t). MS (ES): 439 (MH+).
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([OH:53])=O)[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH:25]=[C:26]([F:28])[CH:27]=1.CCN(C(C)C)C(C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[F:28][C:26]1[CH:25]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:53])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH:23]=[C:22]([F:21])[CH:27]=1
Reactant: O=C(O)c1cc([C@@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([C@@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
TSTU (75.0 mg, 0.23 mmol) was added in one portion to a stirred solution of 8-[(2S)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (102 mg, 0.21 mmol, >98% enantiomeric purity, made from the first eluting ester enantiomer from chiral separation of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate—see below) and DIPEA (0.041 mL, 0.23 mmol) at room temperature The resulting mixture was stirred at room temperature for 1.5 h. Morpholine (0.037 mL, 0.42 mmol) was then added to the reaction mixture and stirring was continued over the week-end. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[(2S)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (64 mg, 57%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:16][CH3:17].O.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:16][CH3:17]
Reactant: CCOC(=O)c1ccc(Cl)c(NC)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1c(Cl)ccc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3.01 g (11.6 mmol) of ethyl 4-chloro-3-(methylamino)-2-nitrobenzoate were dissolved in 35 ml of tetrahydrofuran and 22 ml of water and this solution was admixed with 0.5 g (20.9 mmol) of lithium hydroxide. It was left with stirring for 8 h and then concentrated. The residue was taken up in water and washed with methylene chloride, and the aqueous phase was then adjusted to a pH of 1 using a KHSO4 solution. The precipitate was isolated by filtration with suction, washed with water, and dried under reduced pressure at 70° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=4)=[N:10][NH:11][CH:12]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1c[nH]nc1-c1ccc(C(F)(F)F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]nc3-c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 471 (M+H)+.
Reaction SMILES: [C:1]([N:8]([CH:10](O)[CH2:11][CH2:12][CH3:13])[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.O.[O:20]1CCC[CH2:21]1>>[C:1]([N:8]([CH3:9])[CH2:10][CH2:11][CH2:12][CH2:13][O:20][CH3:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC(O)N(C)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The resulting N-Boc-N-methyl amino butanol (4.00 g) was placed in a 200-mL threeneck flask, and after nitrogen substitution, the compound was dissolved in 35 mL of anhydrous tetrahydrofuran. The solution was added with 60% sodium hydride (1.77 g), and stirred at room temperature for 30 minutes. Then, the reaction mixture was added dropwise with 1.87 mL of methyl iodide and stirred on an oil bath at 50° C. for 1.5 hours. The reaction was stopped with water, and the organic layer was extracted with ethyl acetate, washed once with water and once with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 4.25 g of N-Boc-N-methyl-N-methoxybutylamine.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.C(OC([NH:30]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=3)=[CH:3][NH:2][N:30]=2)=[CH:8][CH:9]=1
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)n1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CSc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Yield: 93 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 4.13 g (13.0 mmol) of 3-dimethylamino-1-(4-fluorophenyl)-2-(2-methylthiopyrimidin-4-yl)-2-propen-1-one obtained in Example 66-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 3.44 g of the title compound as a white powder. (Yield: 93%)
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=34)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=34)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3ncn4cc(Cl)ccc34)nc12
Temperature: 25 °C
Yield: 29.6 %

Procedure:
To a solution of N-tert-butyl-2-(6-chloroimidazo[1,5-a]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (50 mg, 100 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (228 mg, 154 μL, 2.00 mmol) and the mixture stirred at room temperature. After 16 h the reaction mixture was concentrated, then the residue was redissolved in dichloromethane (2 mL), methanol (1 mL) and ammonium hydroxide (0.22 mL) and stirred at room temperature. After 2 h the reaction was concentrated in vacuo. The residue was purified by chromatography (silica, 30-100% of a 0.5:10:89.5 ammonium hydroxide:methanol:dichloromethane solution in dichloromethane). The collected material was concentrated, triturated with methanol and filtered to give N-tert-butyl-2-(6-chloroimidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (12 mg, 29.6 μmol, 30%) as a yellow solid. MS (M+H)+=369.1; 1H NMR (DMSO-d6) δ: 12.69 (s, 1H), 9.08 (s, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.34 (d, J=9.7 Hz, 1H), 8.30 (s, 1H), 7.84 (s, 1H), 7.05 (d, J=9.7 Hz, 1H); 1.52 (s, 9H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH:34]([S:36]([N:39]1[CH2:42][C:41]([F:44])([F:43])[CH2:40]1)(=[O:38])=[O:37])=[CH2:35]>>[F:44][C:41]1([F:43])[CH2:40][N:39]([S:36]([CH2:34][CH2:35][N:8]2[CH2:11][CH:10]([C:12]3[CH:33]=[CH:32][C:15]4[C:16]5[N:17]=[C:18]([C:24]6[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=6)[S:19][C:20]=5[CH2:21][CH2:22][O:23][C:14]=4[CH:13]=3)[CH2:9]2)(=[O:37])=[O:38])[CH2:42]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C=CS(=O)(=O)N1CC(F)(F)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N4CC(F)(F)C4)C3)ccc1-2

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and 1-ethenesulfonyl-3,3-difluoro-azetidine were reacted to give 454 isolated as a white solid (139 mg, 84%). LCMS: RT=8.30 min, [M+H]+=551. 1H NMR δ (ppm) (CDCl3): 8.32 (1H, d, J=8.18 Hz), 7.89 (1H, s), 7.08 (1H, dd, J=8.21, 1.87 Hz), 6.97 (1H, d, J=1.84 Hz), 5.93-5.83 (1H, m), 4.38 (2H, t, J=5.05 Hz), 4.31 (4H, t, J=12.10 Hz), 3.76 (2H, t, J=6.86 Hz), 3.75-3.63 (1H, m), 3.43-3.36 (2H, m), 3.23 (2H, t, J=6.61 Hz), 3.11 (2H, t, J=7.01 Hz), 2.92 (2H, t, J=7.00 Hz), 1.60 (6H, d, J=6.63 Hz)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]1[CH3:21])[CH2:9]2)=[O:4].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O.[BH4-].[Na+]>CO>[CH3:21][N:15]1[C@@:10]2([CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][CH2:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:22]=4)[CH:7]=3)[CH2:11]2)[C:18](=[O:19])[NH:17][C:16]1=[O:20]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN)cc1C2
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNCc3ccc4ccccc4c3)cc1C2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A stirred solution of 2-amino-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide from Step B (80.0 mg, 0.277 mmol) and 2-naphthaldehyde (65.0 mg, 0.416 mmol), in MeOH (3 mL) was heated to 50° C. After 5 hours, no additional formation of the intermediate imine could be observed, so the reaction was cooled to 0° C., prior to the introduction of sodium borohydride (21.0 mg, 0.555 mmol). After 10 minutes the reaction was complete. The bulk of the solvent was remove in vacuo, and the resulting residue was applied to a silica gel column for purification, eluting with DCM:MeOH (10% conc. NH4OH)—98:2 to 92:8. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=429 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(C)c1
Yield: 97 %

Procedure:
3,4-Dimethylbenzoic acid (64.4 g, 429 mmol) was dissolved in methanol (600 ml), and sulfuric acid (9 ml) was added, which was followed by reflux under heating for 5 hours. The reaction mixture was concentrated to 160 ml and water was added. The mixture was extracted with ethyl acetate, and the organic extract was washed successively with water, 10% aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 68.0 g of methyl 3,4-dimethylbenzoate (yield 97%).
Reaction SMILES: O[C:2]1([OH:14])[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([OH:13])[CH:7]=[CH:6][CH:3]1[CH:4]=[O:5].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:15]([O:13][C:8]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:2]([OH:14])[C:3](=[CH:6][CH:7]=1)[CH:4]=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC1=C(O)C=CC(C=O)C1(O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc(C=O)c1O
Yield: 71 %

Procedure:
A mixture of 2,4-dihydroxy-3-propylsalicylaldehyde (15.5 g), benzyl chloride (12.0 g), potassium carbonate (13 g) and potassium iodide (0.5 g) in dry acetone (350 ml) was heated under reflux for 24 hours. The solid was removed by filtration and the solution evaporated to dryness. The oil obtained was distilled and the fraction bp0.5 mm 220-224° was collected to yield 15.0 g of 4-benzyloxy-3-propylsalicylaldehyde.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>>[N:11]1([CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:6]=3[N:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc2oc(CN3CCCC3)nc2c1
Product: C[Si](C)(C)C#Cc1ccc2oc(CN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 18b from 5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole and ethynyl-trimethyl-silane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=2)[CH:10]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: O
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{3-chloro-4-[4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (1.2 g) and p-fluorobenzoic acid (0.8 g) in Eaton's acid (5 mL) was heated at 60° C. for 4 h. The resulting red solution was cooled to 0° C., water (30 mL) added and the suspension stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (2×), the combined organic layers washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), concentrated in vacuo and flashed chromatographed on silica gel (25-40% THF/hexanes) to afford the title compound of Step A as a off-white foam, 1.1 g. MS Calc.:481.9; Found:481.8.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[PH2](O)=O.ClC(C)C(O)=O.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:19]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: CC(Cl)C(=O)O
Agent: O=[PH2]O
Product: Cc1ccc(O)c(C(C)c2ccccc2)c1

Procedure:
The reaction was similarly carried out as Example 10 except that into a mixture of 32 g of p-cresol, 4 g of hypophosphorous acid and 6 g of α-chloropropionic acid was poured 36 g of styrene to give only 2-(α-methylbenzyl)-4-methylphenol, but not to detect other tert-butylated compounds.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl.[CH3:23][NH:24][O:25][CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To a solution of Boc-Glu(OtBu)-OH (15 g) in dichloromethane (150 ml) was added N,O-dimethyl-hydroxylamine hydrochloride (5.3 g) and [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate] (15.87 g) and the pH was adjusted to pH 8-8.5 by adding triethylamine. The reaction mixture was stirred for 16 h at room temperature. The mixture was washed successively with cold 0.3M hydrochloric acid solution, water, 5% aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: dichloromethane/methanol=98/2 v/v %) to yield Boc-Glu(OtBu)-NMeOMe (17.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7](S(Cl)(=O)=O)[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].Cl.N[C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([C:27]2[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:28]=2)(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(NS(=O)(=O)c2ccc(/C=C/C(=O)O)cc2)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 7 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.1 g, 2.55 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of 4-aminocinnamic acid hydrochloride (0.65 g, 43.3 mmol) and DMAP (0.44 g, 3.6 mmol) in pyridine (20 ml). The mixture was stirred for 7 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, petroleum ether/ethyl acetate/HOAc 1/1/0.1). Yield: 0.43 g=30% 13C (100 MHz, DMSO-d6) δ 167.68, 149.54, 147.56, 143.23, 139.25, 130.47, 130.33, 130.07, 129.89, 129.42, 129.21, 126.45, 123.19, 122.96, 122.71, 120.18, 118.42, 114.28, 113.74, 41.10
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][NH:14][C:13](=O)[C:12]=1[N+:18]([O-:20])=[O:19].FC(F)(F)S(O)(=O)=O.[CH3:29][O:30][CH2:31][CH:32]([NH2:35])[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:35][CH:32]([CH2:31][O:30][CH3:29])[CH2:33][CH3:34])[C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: CCC(N)COC
Reactant: COc1cc(Cl)c(-c2cc[nH]c(=O)c2[N+](=O)[O-])cc1F
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(COC)Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 13 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one (0.3 g, 0.70 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine (0.28 g, 2.79 mmol) were treated substantially as described in Part C of Example 19a to produce 35 mg (13%) of crude [4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine.