Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[C:12]([O:20][CH:21]([O:23][C:24]([NH:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+:41].C(#N)C>O>[C:12]([O:20][CH:21]([O:23][C:24]([NH:26][CH2:27][C@H:28]1[CH2:29][CH2:30][C@H:31]([C:34]([O-:36])=[O:35])[CH2:32][CH2:33]1)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Na+:41]
Reactant: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 2.096 g (6.0 mmol) of trans-4-{[1-(benzoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid 23 was reacted with 504.1 mg (6.0 mmol) of sodium bicarbonate (NaHCO3) in 20 mL of a mixture of acetonitrile and water (1:1) to yield 2.23 g (quant.) of the title compound 24 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.86 (m, 2H), 1.08-1.21 (m, 2H), 1.22-1.32 (m, 1H), 1.53 (d, J=5.6 Hz, 31-1), 1.59-1.84 (br. m, 5H), 2.73-2.86 (m, 2H), 6.88 (q, J=5.6 Hz, 1H), 7.47-7.56 (m, 3H), 7.64-7.70 (m, 1H), 7.89-7.94 (m, 2H). MS (ESI) m/z 373.10 (M+Na)+; 348.12 (M−H)−.
Reaction SMILES: O1CCCC1.C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O.CO>[CH2:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][OH:7])=[CH:14][CH:13]=1)[CH2:16][CH3:17]
Reactant: CCCc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(CO)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Dried tetrahydrofuran (50 ml) in which 10.4 g (58.4 mmol) of 4-n-propylbenzoic acid methyl ester synthesized in step (i) was dissolved was dropwise added to 50 ml of dried tetrahydrofuran containing suspension of lithium aluminium hydride (1.54 g: 40.5 mmol) at a temperature of not more than 10° C. with cooling with ice, and reaction was carried out at a room temperature overnight. After the completion of the reaction, an excess amount of lithium aluminium hydride was reacted with methanol with cooling with ice. Next water and an aqueous solution of hydrochloric acid were successively added to the reaction mixture, and the resultant was extracted with hexane. After the hexane phase was washed with water, hexane was removed from the hexane phase to give 8.63 g (57.5 mmol) of 4-n-propylbenzyl alcohol.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][N:12]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][N:12]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCCN(Cc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN1CCCN(Cc2ccc(N)cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Yield: 98 %

Procedure:
To a solution of compound (7) (1.22 g, 2.16 mmol) in absolute ethanol (100 ml) was added 5% Pd/CaCO3 (0.31 g) to which lead (Pb) had been added as an inhibitor. The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The combined filtrate was evaporated in vacuo to give an oily residue, which was then treated with Et2O to obtain an off-white solid of compound (9) (1.13 g, 98% yield). 1H NMR (500 MHz, CDCl3): δ 7.07-7.06 (dd, 2H), 6.67-6.65 (dd, 2H), 3.39 (s, 4H), 3.30-3.14 (m, 4H), 3.12-3.01 (m, 4H), 2.77-2.75 (m, 2H), 2.70-2.42 (m, 8H), 1.96 (brs, 2H), 1.80 (brs, 2H), 1.46-1.45 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 171.1, 170.7, 145.6, 130.7, 127.6, 115.0, 81.6, 81.2, 57.9, 55.4, 54.7, 54.1, 51.6, 51.5, 49.8, 49.7, 49.4, 46.0, 28.2, 24.3, 24.1, 22.5; HRMS (FAB) calculated for C29H52N5O4: 534.4019 [(M+H)+], measured value: 534.4024 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3](=[CH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH3:2].[CH2:24]([Mg]Br)[CH3:25]>>[CH2:24]([C:7]1([OH:11])[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])=[CH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)[CH3:25]
Reactant: CC[Mg]Br
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCC1CCCC1=O
Product: CCC(=CCCc1ccc2c(c1)OCO2)CCC1CCCC1(O)CC

Procedure:
2-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-cyclopentanone can be treated with ethylmagnesium bromide according to the procedure of Example 2, part (c) to give 1-ethyl-2-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]cyclopentanol [XV; Ar is 3,4-methylenedioxyphenyl, Y is C(C2H5)=CHCH2CH2, R' is C2H5, m is 1. ].
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:17]3[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:33])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[C:17]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([OH:33])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:7][CH2:6][S:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=2[CH:19]=1
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCSc1ccccc1
Temperature: 110 °C
Yield: 27 %

Procedure:
Mesylate (229) (55 mg, 0.11 mmol) prepared as decribed in example 171 was reacted with excess thiophenol (0.10 mL) according to the procedure described in example 179, except that triethylamine (2.0 mL) was added and the reaction was heated at 110° C. for 4 days. Addition of water was followed by extracted of the compound with with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness followed by chromatography on silica eluting with ethyl acetate/hexane (1:4 to 1:1) to give carbazole (242) (16 mg, 27%) as an orange powder, mp 262–264° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.37 (br s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.58 (m, 1H), 7.46 (m, 5H), 7.19 (m, 2H), 7.12 (m, 3H), 7.05 (m, 1H), 4.66 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H). Found: C, 63.64; H, 4.09; N, 4.98. C28H19ClN2O3S.1¾H2O requires: C, 63.39; H, 4.28; N, 5.28.
Reaction SMILES: CS(C)=O.F[C:6]1[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH3:21])[C:9]([C:19]#[N:20])=[C:10]2[C:14]=1[O:13][C:12]([C:15]([F:18])([CH3:17])[CH3:16])=[N:11]2.C(N(CC)CC)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>[Cl-].[Na+].O>[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][N:39]([C:6]2[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:8]([CH3:21])[C:9]([C:19]#[N:20])=[C:10]3[C:14]=2[O:13][C:12]([C:15]([F:18])([CH3:17])[CH3:16])=[N:11]3)[CH2:38]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)F)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)F)nc2c1C#N

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(1-fluoro-1-methylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-312) (128 mg, 410 μmol), triethylamine (74 μl, 533 μmol) and (3S)-3-(dimethylamino)pyrrolidine (62 μl, 492 μmol) was stirred at 90° C. for 2.5 hours. After cooling, saturated-brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=10:1, v/v) to obtain a rough product of the entitled compound, followed by suspension washing with diethyl ether to obtain the entitled compound as a pale yellow solid. The filtrate was concentrated, and the obtained solid was washed by suspension with isopropyl ether to obtain the entitled compound as a pale yellow solid (total 54 mg, 38%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:5]1
Reactant: [H][H]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1OC)C[C@@H](c1ccccc1)C[C@H]2CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 0.2 g (0.67 mmol) of 1 aminomethyl 3,4-dihydro-5,6-dimethoxy-3-phenyl naphthalene hydrochloride, from Step 2, of Example 2, in 5 mL of absolute ethanol was added 0.05 g of 10% palladium supported on carbon. The reaction mixture was sealed under a blanket of hydrogen and stirred overnight at ambient temperature. The reaction mixture was flushed with nitrogen before it was filtered through Celite filter aid and washed with 15 mL of absolute ethanol and 15 mL of methylene chloride. The filtrate was concentrated to give 0.2 g (100% yield) of [1R,3S]1-aminomethyl-5,6-dimethoxy-3-phenyl 1,2,3,4-tetrahydro-naphthalene hydrochloride, m.p. 230°-231° C. 1H NMR (d6 -DMSO) delta 2.15-2.25 (m, 1H), 2.5-2.65 (m, 1H), 2.8-2.95 (m, 2H), 3.0-3.1 (m, 1H), 3.1-3.4 (m, 1H), 3.45-3.5 (m, 1 H), 3.66 (s, 3H), 3.78 (s, 3H), 6.95 (d, 1H), 7.12 (d, 1H), 7.2-7.3 (m, 1H), 7.35-7.45 (m, 4H), 8.0 (br s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.S(Cl)(Cl)=O.[NH3:33]>CO>[CH3:26][C:4]1([CH3:27])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([NH2:33])=[O:25])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3]1
Reactant: N
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC(N)=O)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propionic acid (Step A of Example 185) and thionyl chloride followed by ammonia in MeOH. Yield: 5.3 mg (11%).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:8]=1[C:9]([NH:11][C@H:12]([C:20](=[O:36])[NH:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])(=O)C.Cl>CO.O1CCCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:7]([OH:6])=[C:8]([CH:37]=1)[C:9]([NH:11][C@H:12]([C:20](=[O:36])[NH:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
5N Aqueous sodium hydroxide (0.2 mL) was added to a solution of (S)-2-acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide (141.4 mg, 0.25 mmol) in a mixed solvent of methanol/tetrahydrofuran (2 mL+2 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by ethyl acetate/isopropyl ether/n-hexane to give the title compound (74.4 mg, 56.8%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41]>C(OCC)(=O)C>[Cl:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: ClCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Temperature: 30 °C
Yield: 71.4 %

Procedure:
A mixture of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3) (19.9 g, 56.5 mmol), cesium carbonate (36.9 g, 113 mmol), and DMSO (190 mL) was heated at 30° C. for 15, minutes, and then 1-bromo-6-chlorohexane (12.4 g, 62.2 mmol) was added. The reaction was heated at 30° C. for 4.5 h, diluted with ethyl acetate (2 L), washed with 1M pH 7 phosphate buffer (2 L), and then washed with water (2L×2). The organic layer was dried, filtered, concentrated, and then purified by silica gel chromatography (100% ethyl acetate) to give 19 g of 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 8.87 (s, 1H), 8.79 (s, 2H), 7.90 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.65 (t, 2H), 1.77 (m, 4H), 1.43 (m, 4H); MS (ESI): 470.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([CH3:17])[CH2:13]1)=[O:27])[CH3:30]
Reactant: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C)C1

Procedure:
To a solution of 3.0 g (R)-2-Methyl-piperazine-1-carboxylic acid benzyl ester hydrotrifluoroacetate in 17 ml dichloromethane were added at 0° C. 3.5 ml triethylamine and 1.2 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent. Yield: 3.0 g.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@:3]([OH:9])([CH3:8])[C:4]([NH:6][NH2:7])=[O:5].[N:12]#[C:13]Br.C(=O)(O)[O-].[K+]>O>[NH2:12][C:13]1[O:5][C:4]([C@@:3]([OH:9])([CH3:8])[C:2]([F:10])([F:11])[F:1])=[N:6][N:7]=1
Reactant: C[C@](O)(C(=O)NN)C(F)(F)F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: C[C@](O)(c1nnc(N)o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanohydrazide (3.0 g, 17.5 mmol) in water (17 ml) was added cyanogen bromide (1.87 g, 17.7 mmol) and potassium bicarbonate (1.82 g, 18.1 mmol). The reaction mixture was stirred 30 min at rt until a white precipitate was formed. The precipitate was filtered and washed with water followed by a mixture of ether-hexanes (1:1) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 6.57 (bs, 2H), 6.20 (bs, 1H), 1.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].F[C:14]1[CH:15]=[C:16]([CH3:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.O.C(OCC)(=O)C.[I-].[K+]>[CH3:23][C:16]1[CH:15]=[CH:14][C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:12][CH:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH:17]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(Nc2cc(C)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
Ethyl-4-amino-1-piperidine-carboxylate (18.3 g, 106 mmol) was added to a stirred suspension of 3-fluoro-4-nitrotoluene (15.0 g, 97 mmol), sodium carbonate (10.3 g, 97 mmol) and potassium iodide (0.16 g, 0.97 mmol) in dimethylformamide (150 mL). The mixture was heated to 50° C., stirred for 15 hours and then allowed to cool. The reaction mixture was diluted with water (200 mL) and ethyl acetate (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×200 mL). The organic extracts were combined, extracted with a 10% aqueous solution of citric acid (250 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with dichloromethane and then ethyl acetate/hexane (7:8) to give the title compound (25.0 g, 84% yield) as a yellow solid. (Rf: 0.3 (ethyl acetate/hexane 7:8))
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][CH:9]2[C@@H:14]([N:15]([CH3:17])[CH3:16])[CH2:13][C@H:12]([O:18][C@@H:19]3[C:24]4[C:25]([OH:40])=[C:26]5[C:33](=[O:34])[C:32]6[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=6[C:29](=[O:30])[C:27]5=[CH:28][C:23]=4[C@@H:22]([C:41]([O:43][CH3:44])=[O:42])[C@@:21]([OH:46])([CH3:45])[CH2:20]3)[O:11][C@H:10]2[CH3:47])C[C@H](O)[C@@H]1O.[OH-].[Na+]>Cl>[CH3:47][CH:10]1[O:11][CH:12]([O:18][CH:19]2[C:24]3[C:25]([OH:40])=[C:26]4[C:33](=[O:34])[C:32]5[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=5[C:29](=[O:30])[C:27]4=[CH:28][C:23]=3[CH:22]([C:41]([O:43][CH3:44])=[O:42])[C:21]([OH:46])([CH3:45])[CH2:20]2)[CH2:13][CH:14]([N:15]([CH3:17])[CH3:16])[CH:9]1[OH:8]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)C(O[C@H]4C[C@H](O)[C@H](O)[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Yield: 88.9 %

Procedure:
A solution of 100 mg of auramycin C in 50 ml of 0.5% hydrochloric acid was hydrolysed at room temperature for 60 minutes. The reaction mixture was neutralised by dilute sodium hydroxide solution, extracted with 100 ml of chloroform twice and concentrated in vacuo to a small volume. The concentrate was chromatographed with thin layer chromatography plates (chloroform:methanol, 5:1). The band containing auramycin D was scraped off and extracted with a solvent mixture of chloroform and methanol (4:1) and concentrated in vacuo to dryness yielding 72 mg of auramycin D.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccc(F)cc2)c1
Yield: 73.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(4-fluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 4-fluorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.052 g (71%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1.[I-].[Na+]>>[O:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: BrCC1CCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Product: O=Cc1ccc(OCC2CCCO2)cc1
Yield: 99.9 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and 2-(bromomethyl)tetrahydrofuran (541 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-((tetrahydrofuran-2-yl)methoxy)benzaldehyde (338 mg, quant. crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)C.Cl.[NH2:20][OH:21].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:21][N:20]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(-c2cc(O)no2)cc1
Yield: 70.1 %

Procedure:
α,β-Dibromo-4-isopropylcinnamic acid ethyl ester (9.5 g), hydroxylamine hydrochloride (2.2 g) and sodium hydroxide (5.2 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (3.6 g, 71%) as colorless crystals.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=O.[CH3:19][O:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24]>CC(O)=O>[CH3:19][O:20][C:21](=[O:26])[C:22]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[N:25][C:23]=1[CH3:24]
Reactant: CN(C)CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)/C=C(/C)N
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
5.57 g (19.76 mmol) of the above prepared 3-dimethylamino-1-(3-trifluoromethyl-phenyl)-propan-1-one hydrochloride and 2.28 g (1.00 eq.) of 3-aminocrotonic acid methyl ester were dissolved in 60 ml of AcOH and heated to reflux for 4 h. After cooling, the bulk of the solvent was evaporated i. V., the residue dissolved in AcOEt and washed with water and brine. Drying over sodium sulfate, evaporation of the solvents and flash chromatography (SiO2, hexane/AcOEt=89/11) delivered finally 2.00 g of the title compound as light yellow crystals of mp. 47-49° C. (dec.).