Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8](N)=[O:9])([CH3:4])[CH3:3].P([O-])([O-])([O-])=[O:13].O=[Si]=O>>[OH:11][C@H:6]([CH2:7][C:8](=[O:13])[O-:9])[CH2:5][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: O=P([O-])([O-])[O-]
Reactant: C[N+](C)(C)CC(O)CC(N)=O
Agent: O=[Si]=O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]

Procedure:
Cells were collected by centrifugation from 300 ml of the culture broth obtained by cultivating the strain CA28-50A in the same medium as used in Example 9 containing 0.5% DL-carnitinamide and ground in a 50 mM phosphate buffer solution (pH 7.0) together with quartz sand followed by centrifugation to obtain 30 ml of a cell-free extract. Living cells and a cell-free extract were each added to a reaction solution containing 0.2% DL-carnitinamide in the same concentration as that in the growth culture medium in terms of the original cell amount and the resulting mixtures were allowed to stand for the reaction at 26° C. Analytical data on the reaction time and the amount of L-carnitine formed are shown in Table 7 below.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.COC1C=CC(C[N:52]2[C:56]3[CH:57]=[CH:58][C:59]([NH2:61])=[CH:60][C:55]=3[N:54]=[CH:53]2)=CC=1.COC1C=CC(CN2C3C=C(N)C=CC=3N=C2)=CC=1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:61][C:59]3[CH:58]=[CH:57][C:56]4[NH:52][CH:53]=[N:54][C:55]=4[CH:60]=3)=[N:3][CH:4]=[C:5]([CH2:34][N:35]3[CH2:36][CH2:37][N:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:6]=2)[N:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: COc1ccc(Cn2cnc3cc(N)ccc32)cc1
Agent: COc1ccc(Cn2cnc3ccc(N)cc32)cc1
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3[nH]cnc3c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 246 using 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and a mixture of 1-(4-methoxybenzyl)-1H-benzo[d]imidazol-5-amine and 1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-amine regioisomers, and was isolated as yellow amorphous solid (5.5%). m/z (ESI, +ve ion) 495.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.29 (1H, br. s.); 12.04 (1H, br. s.); 8.72 (1H, d, J=2.5 Hz); 8.39 (1H, br. s.); 8.25 (1H, d, J=2.3 Hz); 8.11 (1H, s); 7.80-7.86 (1H, m); 7.72 (1H, br. s.); 7.51 (1H, br. s.); 7.37 (1H, br. s.); 3.50 (2H, s); 3.11 (4H, d, J=4.5 Hz); 2.87 (3H, s); 2.50 (4H, s); 2.47 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25].O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:24]([O:26][CH3:27])=[O:25])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-fluorobenzoylamino)piperidine (0.25 g) in dichloromethane (5 ml) were added in turn pyridine (0.14 ml) and methyl chloroformate (87 μl) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. To the mixture was added N,N-dimethylaminopyridine (0.13 g) and allowed to stir for another 1 hour. The reaction mixture was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 4-(4-fluorobenzoylamino)-1-methoxycarbonylpiperidine (0.265 g).
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([CH2:17][C:18]3[N:28]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]4[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=4[CH:19]=3)[C:13](=[O:34])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:28]1[C:21]2[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:17][N:14]1[C:13](=[O:34])[CH2:12][C:11]2([CH2:10][CH2:9][NH:8][CH2:36][CH2:35]2)[C:15]1=[O:16]
Reactant: CC(C)(C)Cn1c(CN2C(=O)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc2cnc(C#N)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Cn1c(CN2C(=O)CC3(CCNCC3)C2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.5 g, 3.1 mmol) in dichloromethane (20 ml), TFA (5 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 2 h. After removal of the solvent, saturated sodium bicarbonate is added to the residue and the mixture is extracted with dichloromethane. The combined extracts are washed with H2O, brine, dried over magnesium sulfate and concentrated under vacuum to give desired product, 7-(2,2-dimethyl-propyl)-6-(1,3-dioxo-2,8-diaza-spiro[4.5]dec-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:22])[C@H:4]([NH:20][OH:21])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7].[C:23](OC(=O)C)(=[O:25])C>C(O)=O>[CH3:1][O:2][C@H:3]([CH3:22])[C@H:4]([N:20]([OH:21])[CH:23]=[O:25])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:7])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NO
Solvent: O=CO
Product: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)N(O)C=O
Reaction time: 8 h

Procedure:
(2S,3R)-N-[3-Methoxy-1-(3-quinolylmethanesulfonyl)-2-butyl]hydroxylamine (300 mg) was dissolved in a premixed solution of acetic anhydride (2 ml) and formic acid (6 ml) and stood overnight. The reaction was evaporated and then re-evaporated from chloroform (2×5 ml). The residue was redissolved in methanol (5 ml), treated with potassium carbonate (639 mg) and stirred for 45 min and then evaporated. The residue was redissolved in water (5 ml) and the pH adjusted to 7 with 1M hydrochloric acid. After extraction with MDC (2×5 ml), the combined extracts were dried (MgSO4) and evaporated. The residue was chromatographed (acid washed silica gel, 3% MeOH/MDC) to give the title compound (232 mg). MS (APCI+ve ion) 353 (MH+); 1H NMR δ[(CD3)2SO] 9.9 and 9.7 (1H, 2xs rotamers), 8.83 (1H, m), 8.38 (1H,d,J=2 Hz), 8.32 and 8.0 (1H,2xs rotamers), 8.03 (2H, m), 7.81 (1H, t, J=8 Hz), 7.66 (1H, t, J=8 Hz), 4.85 and 4.22(1H, 2xs rotamers), 4.76 (2H, m), 3.7–3.3 (3H, m), 3.25 (3H, s), 1.15 (3H, m rotamers).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([OH:27])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccn2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 2-bromopyridine (488 μL, 5 mmol) in ether (10 mL) was added dropwise butyl lithium (1.6M hexane solution, 3.125 mL, 5 mmol) at −78° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-formylpiperidine (1066 mg, 5 mmol) in ether (10 mL) at −78° C. The mixture was stirred for 18 hours while the temperature is elevated to room temperature. The reaction mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:2) to give the titled compound as yellowish oily substance (913 mg). Yield 62%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:29]=1.BrBr>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH:35]([CH2:34][C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)[C:36]([OH:38])=[O:37]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: CCOC(=O)CCc1cccnc1
Agent: BrBr
Product: O=C(O)C(Cc1cccnc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from 2,6-dibromo-4-(6-bromo-benzo[b]naphtho [2,3-d]thiophen- 1 -yl)-phenol (Example 21) and 3-pyridin-3-yl-propionic acid, ethyl ester (Example 104). White solid: NMR (DMSO-d6); δ8.98 (s, 1 H), 8.82 (d., J=5 Hz, 1 H), 8.57 (d, J=8 Hz, 1 H), 8.28 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.96 (dd, J=8, 6 Hz, 1 H), 7.82 (d, J=2 Hz, 1 H), 7.79 (m, 1 H), 7.78 (d, J=2 Hz, 1 H),7.62 (dd, J=8, 1 Hz, 1 H), 7.57-7.50 (m, 2 H), 7.27 (dd, J=8, 1 Hz, 1 H), 6.67 (d, J=8 Hz, 1 H), 5.45 (dd, J=6, 2, 1 H), 3.60 (m, 2 H); MS (+FAB): [M+H]+, 3 bromine isotope pattern, 710, 712, 714, 716; Anal. Calc. for C30H18Br3NO3S.HCl: C, 48.13, H, 2.56, N, 1.87. Found: C, 48.12, H, 2.86, N, 1.65.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Na+].[Cl-].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CNC
Reactant: BrCC1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Product: CN(C)CC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Bromomethyl)tetrahydro-2H-pyran (0.50 g, 2.8 mmol) was dissolved in dimethylamine (40% in water, 5 mL) and the reaction mixture was stirred at RT for 18 hours. The mixture was saturated with NaCl and extracted into Et2O (2×). The combined organic extract was dried (K2CO3), filtered and concentrated in vacuo to give the title compound as a colourless oil (0.40 g).
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24]([CH2:32][CH3:33])C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl>ClCCl>[CH2:32]([NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[C:7]3[C:6]4[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=4[S:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:19][CH2:20]1)[CH3:33]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (230 mg, 0.48 mmol, 1.00 equiv) in dichloromethane (4 mL) was added hydrochloric acid (12 M, 0.5 mL) at 0° C. and the resulting solution was stirred for 3 hr at 0° C. The resulting mixture was concentrated under vacuum. The crude product (180 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 100 mM NH4HCO3 and CH3CN (6.0% CH3CN up to 60% in 20 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[(3R)-12-[[4-(ethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (114.4 mg, 63%) as a white solid. MS (ES): m/z 375 [M+H]+. 1H-NMR (300 MHz, CD3OD): δ 8.47 (1H, s), 5.29 (1H, m), 4.82 (1H, m), 3.07-3.10 (1H, m), 2.93-2.99 (2H, m), 2.58-2.73 (4H, m), 2.23-2.23 (4H, m), 2.03-2.18 (2H, m), 1.66 (2H, m), 1.40-1.30 (2H, m), 1.03-1.18 (3H, t).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[CH:14][CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]([CH3:12])[CH2:8][Si:9]([CH:13]([Si:9]([Cl:10])([Cl:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Reactant: C=CCCC=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC([Si](Cl)(Cl)CC(C)c1ccccc1)[Si](Cl)(Cl)CC(C)c1ccccc1
Yield: 66 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 21.3 g (0.097 mole) of 3-(phenyl)-1,1-dichloro-1-silabutane and 100 μl of 1% chloroplatinic acid solution in isopropanol were placed and then 3.2 g (0.039 mole) of 1,5-hexadiene was added dropwise for 5 min. The solution was reacted for 15 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation gave 13.4 g (185°-187° C./0.03 mmHg) of bis{(2-phenylpropyl)dichlorosilyl}hexane in 66.0% yield.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][C:13]1([CH3:32])[O:17][CH:16]([CH2:18][O:19][C:20]2[C:29]([CH3:30])=[CH:28][C:23]([C:24]([NH:26]O)=[NH:25])=[CH:22][C:21]=2[CH3:31])[CH2:15][O:14]1>>[CH3:12][C:13]1([CH3:32])[O:17][CH:16]([CH2:18][O:19][C:20]2[C:21]([CH3:31])=[CH:22][C:23]([C:24]3[N:26]=[C:8]([C:6]4[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=4)[O:10][N:25]=3)=[CH:28][C:29]=2[CH3:30])[CH2:15][O:14]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: Cc1cc(C(=O)O)sc1C=O
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine; LC-MS: tR=1.16 min; [M+1]+=429.16; 1H NMR (D6-DMSO): δ1.34 (s, 3H), 1.38 (s, 3H), 2.34 (s, 6H), 2.65 (s, 3H), 3.79-3.93 (m, 3H), 4.10-4.15 (m, 1H), 4.42-4.49 (m, 1H), 7.75 (s, 2H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3cc(Cl)cc(Cl)c3)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 3,5-dichlorophenylboronic acid (191 mg, 1.0 mmol) to afford after chromatographic purification the title compound (85 mg, 38%). 1H NMR (CDCl3, 300 MHz) δ 7.35 (s, 2H), 7.21-7.23 (m, 1H), 7.13 (s, 1H), 7.10 (s, 1H), 3.82-4.22 (m, 2H), 3.65-3.75 (m, 1H), 2.84-3.52 (m, 7H), 1.80-1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].O>C(O)C.C(OCC)(=O)C.C(OCC)C.[Fe]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:23]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(N)ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Temperature: 90 °C
Yield: 25.9 %

Procedure:
To a solution of morpholine-4-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]amide (775 mg) in ethanol (50 ml) were added electrolytic iron powder (505 mg), ammonium chloride (967 mg) and water (10 ml), followed by stirring to heat at 90° C. for 20 min. The reaction mixture was cooled down to room temperature, and filtered to remove an insoluble portion, which was then washed with water and N,N-dimethylformamide in this order. The filtrate was concentrated under a reduced pressure to give a residue, which was then partitioned between ethyl acetate:tetrahydrofuran=1:1 (200 ml) and water (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then suspended in ethyl acetate (5 ml), and diluted with diethyl ether (30 ml). The solid was filtered, and dried under aeration to provide the titled compound (184 mg, 26.1%) as colorless powder. The mother liquor was concentrated to give a residue, which was suspended in diethyl ether (30 ml). The solid was filtered, and dried under aeration to further provide the titled compound (207 mg, 29.3%) as pale yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C@H:24]([CH2:26][OH:27])[NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:25][C@H:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][OH:27])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml) was added dropwise thionyl chloride (14.1 ml, 19 mmol). The reaction mixture was heated at 90° C. for 2 hours, cooled to ambient temperature and volatiles removed under reduced pressure to afford crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH2Cl2 and added dropwise over 30 min., to a vigorously stirred solution of (R)-(-)-2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) in CH2Cl2 (200 ml) cooled to 0° C. The reaction mixture was allowed to warm ambient temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1 L) and water (1 L). The aqueous layer was separated, extracted with ethyl acetate (2×500ml) and the combined organic phase washed with 1N HCl (500 ml), aqueous 4% NaHCO3 solution (500 ml) and brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 88%) as pale yellow solids.
Reaction SMILES: [C:1]([CH:11]1[NH:18][C:16](=[O:17])CCCC1)([CH:3]1NC(=O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=O.N[C:20](N)(N)[CH2:21][CH2:22]CCCCCC>C(OCC)(=O)C>[N:18]([CH2:11][CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:20][CH2:21][CH3:22])=[C:16]=[O:17]
Reactant: CCCCCCCCC(N)(N)N
Reactant: O=C1CCCCC(C(=O)C2CCCCC(=O)N2)N1
Solvent: CCOC(C)=O
Product: CCCCCC(CCC)CN=C=O
Temperature: 25 °C

Procedure:
302.4 g (1.2 mol) carbonyl-bis-caprolactam was dissolved in 400 ml ethyl acetate at 78° C. In one hour 69.3 g (0.4 mol) triamino nonane, dissolved in 100 ml ethyl acetate, was added dropwise. The reaction was monitored by means of TLC. After 3 hours the clear solution was cooled to room temperature and extracted 4 times with 500 ml water (with some NaCl). The solution was then dried with NaSO4. The NaSO4 was removed by filtration and the ethyl acetate was removed by means of the rotavapor. The product was dried at 75° C. and in a vacuum. Caprolactam-blocked of 1,8-diisocyanato, 4-(isocyanatomethyl) nonane was obtained pure, as a lightly coloured oil (yield=99%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([F:17])=[CH:5][CH:4]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([F:17])=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3cc(F)ccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3cc(F)ccc13)CCCC2O
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a cooled suspension of 5.0 g of 9-amino-3,4-dihydro-6-fluoroacridin-1(2H)-one in 85 ml of tetrahydrofuran was added 22 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour and then quenched with 8 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate, and the combined organics were dried over anhydrous magnesium sulfate. This was filtered and concentrated to obtain 5.0 g of powder, mp 203°-206° C. d. This was recrystallized from tetrahydrofuran/hexane to obtain 3.95 g of an analytically pure powder, mp 207°-209° C. d.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[NH:12][CH:11]=[C:10]([C:13](=[O:20])[CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]=1)=[O:7].[CH3:25][S:26][CH2:27][CH2:28]Cl.O>CCCCCC.CN(C=O)C>[Cl:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH2:25][S:26][CH2:27][CH3:28])[CH:11]=[C:10]([C:13](=[O:20])[CH2:14][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])[CH:9]=1)=[O:7]
Reactant: CCN(CC)CC(=O)c1c[nH]c(C(=O)c2ccccc2Cl)c1
Reactant: CSCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCSCn1cc(C(=O)CN(CC)CC)cc1C(=O)c1ccccc1Cl
Temperature: 65 °C

Procedure:
0.2 g (0.0045 moles) of 60% NaH in oil was washed with hexane and 3 mL of DMF was added. To the suspension was added a solution dropwise of 1.2 g (0.0035 moles) of 1-[5-(2-chlorobenzoyl)-1H-pyrrol-3-yl]-2-(N,N-diethylamino)ethanone in 8 mL of DMF. After stirring for 10 m, 1.5 mL (0.0070 moles) of chloroethyl methyl sulfide was added and the reaction heated to 65° C. for 4 h. Water was added and extracted with Et2O, the organics were washed with water, brine and dried (Na2SO4). The solvent was evaporated in vacuo. The resulting oil was passed through a Biotage Flash 40 L, silica gel (97:3:0.1 CH2Cl2:MeOH:NH40H), then treated with ethereal HCl. After recrystallizing from 2-PrOH, 0.11 g of Compound 16; mp 157-158° C. CIMS m/z=393 (MH+). 1HNMR (300 MHz, DMSO-d6) δ 8.3 (Ar, 1H); 7.6-7.4 (Ar, 4H); 6.9 (Ar, 1H); 4.7 (m, 4H); 3.3(s,3H); 3.2 (m, 4H); 2.9 (m, 2H); 1.2 (t, 6H). Anal calc'd for C20H25CIN2O2S.HCl: C, 55.94; H, 6.1; N, 6.52. Found: C, 55.77, H, 6.12; N, 6.31.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7]OCCO.[H-].[Na+].C(O)C[CH2:20][OH:21].BrC1C=CC=CC=1CBr>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:20][OH:21]
Reactant: OCCCO
Reactant: OCCOCCOCc1ccccc1Br
Agent: BrCc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCOCc1ccccc1Br

Procedure:
The reaction and work up was conducted as described in the preparation of compound 415. Starting materials were NaH (60% in oil, 0.86 g, 22 mmol) in THF (80 mL), 1,3-propanediol (8.67 mL, 120 mmol), 2-bromobenzylbromide (5.0 g, 20 mmol) dissolved in 4 mL dry THF and tetrabutylammonium iodide (0.07 g, 0.2 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:1->2:1 as the eluent to afford the title compound as a pale yellow oil.