Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:11][CH2:12]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+]>CN(C)C=O>[C:23]([O:26][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: ClCOC(COCc1ccccc1)COCc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(COCc1ccccc1)COCc1ccccc1
Temperature: 21 °C
Reaction time: 15 h

Procedure:
To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol from Preparation II (17.5 g, 55 mmol) in 400 ml of dimethylformamide at 0° C. under a drying tube was added sodium acetate (6 g). The solution was then warmed to 21° C. and magnetically stirred for 15 hours. The solvent was removed by evaporation at reduced pressure and the oily residue dissolved in 1 pound of diethylether. The ether solution was washed once with 750 ml of water, two times with 250 ml of water, and once with 250 ml of brine, dried over sodium sulfate and concentrated to give 19 g of 2-O-acetoxymethyl-1,3-di-O-benzylglycerol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])[CH:7]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[C:16]2=[S:17])[CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCNCCCNc1cc(Cl)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Yield: 24.9 %

Procedure:
A solution of the diamine of Step A (7.1 g) in dioxane (250 mL) and 1,1′-thiocarbonyldiimidazole (5.6 g) was refluxed under nitrogen for 2.5 hrs. Following the addition of para-toluenesulfonic acid monohydrate (11.9 g), the reaction mixture was heated at reflux for 48 hrs. The reaction was cooled and filtered and the filtrate was concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane provided a brown solid which was triturated with diethyl ether to give the title product (2.1 g, 25.0%) as a white solid, m.p. 111-112° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C:15]([OH:17])=[O:16])=[C:9]([O:23][CH3:24])[CH:8]=1.[O-][CH2:26]C.[Na+].C[O-].[Na+]>>[CH2:1]([O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][C:15]([OH:17])=[O:16])=[C:9]([O:23][CH3:24])[CH:8]=1)[CH3:26]
Reactant: CC[O-]
Reactant: CCCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC
Agent: C[O-]
Agent: [Na+]
Product: CCCCCC(CC(=O)O)c1ccc(OCCCOCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 50A, but using an ethanolic sodium ethoxide solution instead of a methanolic sodium methoxide solution, the title compound was obtained as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[K].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[OH:25]>CS(C)=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:25][C:18]2[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=2[Cl:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([O-:14])=[O:13]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A stirred solution of methyl 5-chloro-2-nitro-benzoate (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90°C for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3 × 100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2 × 30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101°-103°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1C=CC(N2C3C=CN=CC=3N=C2C)=NC=1)=[O:5])[CH3:2].N1C=CC=C(C(O)=O)C=1.[CH3:31][C:32]1[N:33]([C:41]2[N:46]=[CH:45][C:44]([C:47]([OH:49])=O)=[CH:43][CH:42]=2)[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:40]=1.CC1N(C2C=CC(C(O)=O)=CC=2)C2C=CN=CC=2N=1>>[CH3:31][C:32]1[N:33]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:49])=[CH:45][N:46]=2)[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:40]=1
Reactant: CCOC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Reactant: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cn1
Agent: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cc1
Agent: O=C(O)c1cccnc1
Product: CCOC(=O)CC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1

Procedure:
The method of Preparation 1, Method C, (b) was followed substituting the pyridine-3-carboxylic acid from (c) above for 4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoic acid. The title compound was an orange gum.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][N:8]([CH3:29])[C:9]1[N:20]2[C:12]([CH:13]=[N:14][C:15]3[N:16](COCC[Si](C)(C)C)[CH:17]=[CH:18][C:19]=32)=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([S:3]([CH2:6][CH2:7][N:8]([CH3:29])[C:9]1[N:20]2[C:12]([CH:13]=[N:14][C:15]3[NH:16][CH:17]=[CH:18][C:19]=32)=[CH:11][CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCN(C)c1ccc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)CCN(C)c1ccc2cnc3[nH]ccc3n12
Reaction time: 2 h
Yield: 100 %

Procedure:
(2-Ethanesulfonyl-ethyl)-methyl-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacen-8-yl]-amine (68 mg, 0.16 mmol) was taken up in methylene chloride (3 mL) and TFA (2 mL) and lightly capped and stirred for 2 hours. The volatiles were removed on the rotovap and the remainder was taken up in CH2C12 (25 mL). The volatiles were stripped and the remainder placed on a drying pump for 30 minutes. The material was taken up methylene chloride (2 mL) and ethylene diamine (2 mL) and stirred for 1.5 hours. Ethyl acetate (40 ml) and brine (40 mL) was added and the material shaken in a separatory funnel. The ethyl acetate phase was collected and washed with an equal volume of brine solution. The aqueous phases were back extracted with ethyl acetate (2×30 ml), the organics combined, dried (MgSO4), filtered and stripped. The crude was purified via preparative TLC using 7% MeOH in CH2Cl2 as eluant to provide 49 mg of (2-ethanesulfonyl-ethyl)-methyl-(3H-3,4,8a-triaza-as-indacen-8-yl)-amine as a green-black crystalline solid. MS (M+H)+=291.
Reaction SMILES: COC[C@@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.CC12C(C)(C)[C:28]([C:34]([O:36][CH2:37][C@@H:38]3[C@@H:40]([CH2:41][O:42]CC)[C@:39]3([CH3:59])[C:45]3[CH:54]=[CH:53][C:52]4[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=4[CH:46]=3)=O)(CC1)OC2=O>>[CH2:34]([O:36][CH2:37][C@@H:38]1[C@@H:40]([CH:41]=[O:42])[C@@:39]1([CH3:59])[C:45]1[CH:54]=[CH:53][C:52]2[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=2[CH:46]=1)[CH3:28]
Reactant: CCOC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 97 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 11b as the starting material afforded the title compound (25 mg, 97% yield) as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([C:25](O)=[O:26])=[N:10]1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([CH2:25][OH:26])=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.5 g of 1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid in 30 ml of THF, were added dropwise 43 ml of a 1M solution of borane in THF at room temperature. Then the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The organic layers were combined and dried over MgSO4, filtered and concentrated under reduced pressure. The product was obtained as a white solid and was used without further purification.
Reaction SMILES: C(C1C=CC=CC=1C(C1C=CC=CC=1C(O[CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16])=O)=O)(C)C.CC(CC)[C:33](=[O:47])[C:34]([O:36]CCC(C)CCC=C(C)C)=[O:35].O=C(CCC)C(OCCC(C)CCC=C(C)C)=O.C([C:71]1[CH:76]=[CH:75][C:74]([C:77](=[O:91])[C:78](OCCC(C)CCC=C(C)C)=O)=[CH:73][CH:72]=1)(=O)C.C(C1C=C(C(C)C)C=CC=1C(C1C=CC=CC=1C(OC/C=C(/CCC=C(C)C)\C)=O)=O)(C)C>CCCCCC>[O:47]=[CH:33][C:34]([O:36][C:71]1[C:72]([CH:13]=[CH:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:73][C:74]([C:77](=[O:91])[CH3:78])=[CH:75][CH:76]=1)=[O:35]
Reactant: CCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C
Reactant: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C(=O)c1ccccc1C(C)C
Reactant: CC(=O)c1ccc(C(=O)C(=O)OCCC(C)CCC=C(C)C)cc1
Agent: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C(=O)c1ccc(C(C)C)cc1C(C)C
Agent: CCCC(=O)C(=O)OCCC(C)CCC=C(C)C
Solvent: CCCCCC
Product: CC(=O)c1ccc(OC(=O)C=O)c(C=CC(C)CCCC(C)C)c1

Procedure:
UV/Vis (hexane): 384 (sh, 60), 367 (sh, 100), 343 (sh, 150), 310 (sh, 1230), 301 (sh, 1660), 266 (17910), 260 (18440). IR (neat): 3051w, 2964s, 2926s, 2872m, 2856m, 1736s, 1693s, 1607w, 1570m, 1500m, 1457m, 1434m, 1407m, 1379m, 1359m, 1318m, 1307m, 1260s, 1199s, 1176s, 1117w, 1075m, 992s, 959m, 861m, 832m. 1H NMR (360 MHz, CDCl3): 8.17-8.02 (m, 4H); 5.12-5.04 (m, 1H); 4.53-4.37 (m, 2H); 2.66 (s, 3H); 2.14-1.90 (m, 2H); 1.90-1.75 (m, 1H); 1.73-1.53 (m, 2H); 167 (s, 3H); 1.60 (s, 3H); 1.46-1.32 (m, 1H); 1.32-1.12 (m, 1H); 0.96 (d, J=6.3, 3H). 13C NMR (90.6 MHz, CDCl3): 197.19 (s); 185.55 (s); 163.25 (s); 141.33 (s); 135.67 (s); 131.57 (s); 130.28 (d); 128.56 (d); 124.34 (d); 65.19 (t); 36.91 (t); 35.26 (t); 29.43 (d); 26.94 (q); 25.70 (q); 25.35 (t); 19.37 (q); 17.67 (q). MS (EI): 330 (M+, 4); 312 (1); 302 (1); 281 (1); 269 (1); 194 (4); 193 (2); 183 (1); 176 (2); 165 (1); 161 (1); 155 (2); 149 (5); 148 (43); 147 (100); 138 (4); 137 (11); 133 (1); 132 (2); 123 (10); 120 (4); 119 (11); 110 (2); 109 (10); 105 (2); 104 (12); 96 (4); 95 (21); 91 (15); 83 (5); 82 (13); 81 (29); 77 (6); 76 (8); 69 (38); (5); 67 (11); 65 (3); 57 (3); 56 (3); 55 (12); 53 (3); 50 (3); 43 (15); 41 (30); 39 (5); 29 (4); 27 (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])=[C:4]([F:22])[CH:3]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH:40]=O)=[CH:34]3)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:40][C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:39][CH:38]=3)(=[O:11])=[O:10])=[C:4]([F:22])[CH:3]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccc(Cl)cc3F)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3ccc(Cl)cc3F)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[O:27])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1CCNCC1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CN1CCN(C(=O)CN2CC(C)(C)OCC2C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CC1
Yield: 12 %

Procedure:
The desired compound was prepared using [5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 1-methyl piperazine following Method F in 12% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[C:24]([O:30][CH3:31])=[C:23]([O:32][CH3:33])[CH:22]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:21]2[CH:22]=[C:23]([O:32][CH3:33])[C:24]([O:30][CH3:31])=[C:25]([NH2:27])[CH:26]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc(N)c(OC)c(OC)c2)cc1
Yield: 41.7 %

Procedure:
Following a reaction and purification procedure similar to those described in Example (1b), 950 mg of N-[1-(3,4-difluorophenyl)ethyl]-N-[(3,4-dimethoxy-5-nitrophenyl)-(4-methoxyphenyl)methyl]amine [prepared as described in step (a) above], 985 mg of nickel chloride hexahydrate and 330 mg of sodium borohydride were reacted. The crude product was purified by chromatography through a silica gel column using a 10:1 by volume mixture of toluene and ethyl acetate as eluant, to afford isomer A of the title compound (215 mg) as a yellow oil and isomer B of the title compound (370 mg) as a yellow oil, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]3[C:14]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH:18][C:5]3=[CH:4][C:3]1=2.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40].Cl>C(Cl)Cl>[C:39]([N:18]1[C:5]2[C:6](=[CH:7][C:8]3[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:32])([CH3:1])[C:3]=3[CH:4]=2)[C:14]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)=[N:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2)(=[O:41])[CH3:40]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Nc1ccccc1N=C3c1ccc(C(=O)O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2N=C(c2ccc(C(=O)O)cc2)c2cc3c(cc21)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution 4-(7,7,10,10-tetramethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]-cyclohepta[1,2-b]naphthalen-12-yl)benzoic acid (27) (0.47 mmol) and pyridine (1.2 mmol) in CH2Cl2 (4 mL) is treated with acetyl chloride (1.0 mmol) and stirred at room temperature for 6 h. The mixture is poured into 1 N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solid is purified by reversed-phase HPLC (0.1% TFA, 30-100% gradient CH3CN) to give the acid (29).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][C:29](O)=[O:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)Cc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)Cc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.20 g), 5-phenyl-4-isoxazolylacetic acid (0.84 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-5-phenyl-4-isoxazolylacetamide (1.58 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:5])[CH3:4].[H][H].Br[CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O>[C:3]([CH:6]([CH:19]([CH3:21])[CH3:20])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:5])[CH3:4]
Reactant: CC(C)Br
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(C(=O)Nc1ccccc1)C(C)C

Procedure:
Sodium hydride (0.48 g. of a 50% w/w dispersion in mineral oil) was added to a solution of 2-acetylacetanilide (1.8 g.) in dry dimethylformamide (15 ml.) under an atmosphere of argon. The mixture was stirred at 35° until the evolution of hydrogen had ceased. 2-Bromopropane (1.12 ml.) was added, and the mixture was heated at 55°-60° for 110 hr. The mixture was cooled and then poured into water (100 ml.). The resulting solution was adjusted to pH 2 with 3N-hydrochloric acid and extracted with ethyl acetate (3×100 ml.). The ethyl acetate extract was dried (Na2SO4) and the ethyl acetate was evaporated in vacuo. The residual oil was chromatographed on silica gel (Kieselgel 60, 180 g.) using 20% v/v ethyl acetate in petroleum ether (b.p. 60°-80°) as eluant. The relevant fraction was evaporated in vacuo, and the residue was crystallised from cyclohexane to give 2-acetyl-2-isopropylacetanilide, m.p. 135°-7° .
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:22]([OH:24])=[O:23])=[CH:3]1)[N:13]=[C:12]([C:19]([OH:21])=[O:20])[CH:11]=[CH:10]3.C(=O)(O)[O-].[Na+:29]>O>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:22]([O-:24])=[O:23])=[CH:3]1)[N:13]=[C:12]([C:19]([O-:21])=[O:20])[CH:11]=[CH:10]3.[Na+:29].[Na+:29]
Reactant: CCCc1c2nc(C(=O)O)ccc2cc2c(=O)cc(C(=O)O)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1c2nc(C(=O)[O-])ccc2cc2c(=O)cc(C(=O)[O-])oc12
Yield: 94.7 %

Procedure:
The product of step (c) (hemihydrate 0.629 g) and sodium bicarbonate (0.3145 g) were stirred in water (70 mls) until a complete solution was formed. The solution was filtered and the filtrate freeze dried to give 0.658 g of the desired salt.
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20]CCCCCCC(O)CCCCCCCCCC.CCCCCCCCC(O)CCCCCCCCC>>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:20]
Reactant: CCCCCCCCCCCC(O)CCCCCC
Reactant: CCCCCCCCCCC(O)CCCCCCC
Agent: CCCCCCCCCC(O)CCCCCCCC
Product: CCCCCCCCCCCCC(O)CCCCC

Procedure:
7-octadecanol; 8-octadecanol; 9-octadecanol;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To a solution of 1-(4-amino-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.5 g, 5.5 mmol), in 1:1 acetone:water (12 mL) was added sodium bicarbonate (1.2 g, 13.7 mmol). The resulting solution was cooled to 0° C. and benzyl chloroformate (2.8 mL, 8.2 mmol, 50% solution in toluene) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:5 EtOAc:Pet. ether) to provide the title compound (2.05 g, 92%) as off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([OH:10])[CH3:9])[C:3]=1[OH:11].[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]1[C:18](=[O:19])[C:17](=[O:22])[C:16]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([OH:10])[CH3:9])[C:3]=1[OH:11])[CH3:13]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CC(O)c1cccc(N)c1O
Solvent: CCO
Product: CCOc1c(Nc2cccc(C(C)O)c2O)c(=O)c1=O
Temperature: 60 °C
Yield: 38 %

Procedure:
A mixture of 1.16 g (7.6 mmol, 1 eq) of 2-amino-6-(1-hydroxyethyl)phenol and 5.15 g (30.3 mmol, 4 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione in 50 ml of ethanol was heated at 60° C. for 18 hours. The reaction medium was evaporated and the residue was chromatographed on silica gel (column puriFlash IR-50SI/300G, Spot II) eluted with heptane/ethyl acetate (gradient). 800 mg of 3-ethoxy-4-[2-hydroxy-3-(1-hydroxyethyl)phenylamino]cyclobut-3-ene-1,2-dione were obtained in the form of an orange solid. Yield=38%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([NH:20][CH2:21][CH2:22][NH2:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][NH:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Product: COc1ccc([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)n1
Yield: 59 %

Procedure:
Starting from 2-chloro-6-methoxy-3-nitropyridine (5.0 g; commercial) and N-Boc-ethylenediamine (4.15 mL; commercial), and proceeding in analogy to Example 17, step 17.i, the title compound was obtained as a yellow solid (4.79 g; 59% yield).