Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][O:5][CH3:6].[Li+].CC([N-]C(C)C)C.[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29][O:30][C:31]1[C:39]2[CH:38]=[CH:37][S:36][C:35]=2[C:34]([CH:40]=[O:41])=[CH:33][CH:32]=1.Cl>C1COCC1.ClCCl.ClCCl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:5][CH3:6])[CH:40]([OH:41])[C:34]1[C:35]2[S:36][CH:37]=[CH:38][C:39]=2[C:31]([O:30][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:32][CH:33]=1
Reactant: COCC(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 3.17 ml methoxyacetic acid methyl ester (31.4 mmol) in 30 ml of THF, 17 ml of LDA (2M in THF/heptane/ethylbenzene, 34.2 mmol) were added dropwise within 15 min at −78° C. After stirring for additional 15 min, a solution of 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.7 mmol) in 70 ml of dichloromethane was added dropwise within 20 min. The dark brown reaction solution was stirred for additional 60 min, then warm up to room temperature within 150 min, cooled to 0° C. again and treated with 50 ml of ice water and 6 ml of conc. hydrochloric acid (pH 3). The organic layer was separated, washed with 25 ml water, dried over sodium sulfate and evaporated to dryness to yield 8.81 g of crude product as a brown oil. Flash chromatography (SiO2, dichloromethane/AcOEt=9/1) yielded 5.89 g (91%) of the title compound as a syn/anti mixture of 1:4 with a purity of 98.3% (GC area; method: column: DB-1 (15 m*0.32 mm); injector: 270° C.; detector: 320° C.; oven 150-310° C. (4° C./); carrier gas: H2 (60 KPa); samples silylated with BSTFA/pyridine. Retention times: starting material (aldehyde 1), 23.8 min; syn-alcohol 6, 28.1 min; anti-alcohol 6, 28.5 min) as a yellowish crystalline solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:28][C:29]1[O:33][C:32]([C:34]2([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:31][C:30]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:26][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:42][CH2:41][C:30]2[N:31]=[C:32]([C:34]3([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[O:33][C:29]=2[CH3:28])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 42. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, 2H, J=8.60 Hz), 7.08 (d, 2H, J=8.60 Hz), 6.89 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.99 (t, 2H, J=6.25 Hz), 2.33 (s, 3H), 2.16-2.08 (m, 2H), 1.62-1.32 (m, 8H), 1.42 (s, 3H), 1.32 (s, 3H); MS (ES+) calcd for C30H35NO6F3: Found m/e 562.3 (M+1, 100%)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([S:18]([NH2:17])(=[O:20])=[O:19])=[CH:22][CH:23]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(S(N)(=O)=O)cc3)nc12

Procedure:
4-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 4-(aminosulphonyl)benzeneboronic acid following general procedures as described in these Examples. MP 277-278° C., M+H=359.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:49])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:48])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([NH:39][CH2:40][CH2:41][C:42]([O:44]C)=[O:43])=[O:38])[C:34]4([CH3:47])[CH3:46])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:51])[CH3:50])(=O)C>CO.C1COCC1.[OH-].[Na+]>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:49])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:48])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])[C:34]4([CH3:47])[CH3:46])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:51])[CH3:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)NCCC(=O)OC)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)NCCC(=O)O)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
To a stirred solution of methyl 3-((1S,3R)-3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)propanoate (Example 37, 0.150 g, 0.211 mmol) in MeOH:THF (2:1) (7.5 ml), 2N NaOH (2.5 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated. The reaction mixture was acidified with 1N HCl, filtered, washed with water and dried under vacuum to afford the title compound as an off white solid. Wt: 0.030 g: Yield: 21.7%; 1H NMR (300 MHz, DMSO-d6): δ 7.61 (brm, 1H), 7.54 (d, 1H, J=7.2 Hz), 4.63 (s, 1H), 4.52 (s, 1H), 2.90-2.80 (m, 1H), 3.20-3.08 (m, 3H), 3.00-2.89 (m, 3H), 2.68-2.54 (m, 2H), 2.40-2.18 (m, 5H), 1.90-1.74 (m, 2H), 1.70-1.00 (m, 28H), 0.90, 0.86, 0.84, 0.75, 0.72, 0.64 (s, 15H); Mass: [M+1]+ 653 (2%), [M+Na]+ 675 (100%); IR (KBr, cm−1): 3408, 2947, 2868, 1724, 1652, 1636, 1523, 1376, 1250, 1194, 1108, 1074, 1033, 983, 881, 730; M.R: 188.6° C.-200.1° C.; HPLC: 99.35%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O1CCOCC1.[ClH:37]>C(O)(C(F)(F)F)=O.CO>[ClH:37].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[C:4]=23)[CH2:18]1
Reactant: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Yield: 55 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate was stirred in TFA (3 mL) for 30 minutes, and then the reaction was concentrated to dryness. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 12M column, 0-50% CH3CN/water gradient; 20 CV) to yield a solid. The solid was dissolved in a minimal amount of methanol and was added dropwise to a 4N HCl dioxane solution. The resulting solid was collected, rinsed with DCM and dried under high vacuum to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide hydrochloride (22 mg, 55%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.78 (d, 1H), 9.85 (s, 1H), 8.32 (br s, 3H), 8.27 (s, 1H), 7.93 (s, 1H), 4.09 (q, 2H), 3.68-3.58 (m, 1H), 3.53-3.38 (m, 3H), 3.49 (s, 3H), 3.32-3.26 (m, 1H), 3.02-2.96 (m, 1H), 2.24-2.18 (m, 1H), 1.92-1.82 (m, 2H), 1.56-1.46 (m, 1H); LCMS (APCI+) m/z 365, 382 (M)+, Retention time=1.89 minutes (Method 1).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[CH3:20][NH2:21]>O1CCCC1>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:21][CH3:20])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: CN
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Solvent: C1CCOC1
Product: CNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reaction time: 16 h

Procedure:
A solution of the product from Example 219 (0.3 g) in tetrahydrofuran (2 ml) containing methylamine (2.0 molar in THF: 0.81 ml) was stirred for 16 hours. The mixture was evaporated to dryness then purified (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to give the title compound (295 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH:8]=[CH:7]1.[Na].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1
Reactant: COCCCn1ccc2ccc(C(=O)OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Product: COCCCN1CCc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 1-(3-methoxypropyl)-1H-indole-6-carboxylate (1.5 g) and sodium cyanohydroborate (1.61 g) was added acetic acid (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was neutralized by adding sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→n-hexane/ethyl acetate=2/1) to give methyl 1-(3-methoxypropyl)indoline-6-carboxylate [REx(10-1)] (1.20) as a pale yellow oil.
Reaction SMILES: ClCCl.Cl[C:5]1[O:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:11])[N:9]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O>[C:33]1([C:5]2[O:6][CH:7]=[C:8]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]3[CH2:25][O:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:11])[N:9]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(-c3ccccc3)n2)C(COc2cccnc2)C1
Temperature: 80 °C

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (6.7 mg, 0.0082 mmol) was added to a mixture of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (69.5 mg, 0.164 mmol), benzeneboronic acid (40 mg, 0.33 mmol) and sodium carbonate (35 mg, 0.33 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 80° C. overnight. Upon cooling to room temperature, the reaction mixture was filtered through Celite®, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 44.8 mg (47%) of the TFA salt of the desired product. LC-MS: RT=8.49 min, [M+H]+=465.0.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:2][CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:17]=[O:19])=[CH:8][CH:7]=1)[CH2:13][CH2:14][Cl:15]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (18, 0.826 g, 2.7 mmol) in dry CHCl3 (10 mL), Et3N (1.5 mL) was added dropwise at −5-0° C. The resulting solution was added dropwise to a solution of triphosgene (0.296 g, 1 mmol) in dry CHCl3 (10 mL) at −5-0° C. The reaction mixture was stirred at room temperature for 30 min. The resulting solution was evaporated under reduced pressure to dryness to give crude isocyanate (19) as liquid. This solution was added dropwise into a suspension of known 4-hydrazino-6-methoxy-2-methylquinoline (0.36 g, 1.5 mmol)55 and Et3N (2 mL) in dry DMF (15 mL at 0° C. The reacting mixture was stirred at room temperature for 1.5 h. The resulting solution was evaporated under reduced pressure to dryness. The solid residue was triturated with a mixture of THF/ether (2:1 v/v) and the solid was collected by filtration, washed with little amount of cold chloroform and methanol, and dried to give N-{4-[bis(2-chloroethyl)amino]phenyl}-2-(6-methoxy-2-methyl-4-quinolinyl)hydrazinecarboxamide (BO-1228), 0.413 g (60%): mp 224-225° C.; 1H NMR (DMSO-d6) δ 2.68 (3H, s, Me), 3.68-3.70 (8H, m, 4×CH2), 3.94 (3H, s, OMe), 6.70 (2H, d, J=9.0 Hz, ArH), 6.84 (1H, s, ArH), 7.31 (2H, d, J=9.0 Hz, ArH), 7.61 (1H, dd, J=2.2 and 9.2 Hz, ArH), 7.91 (1H, d, J=2.2 Hz, ArH), 7.96 (1H, d, J=9.2 Hz, ArH), 9.01 and 9.11 (each 1H, s, exchangeable, 2×NH), 10.65 (1H, brs, exchangeable, NH). Anal. Calcld. for (C22H25Cl2N5O2): C, 57.14; H, 5.45; N, 15.15. Found: C, 57.40; H, 5.18; N, 15.52.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[C:26](OC)=[O:27])[O:8][CH2:9][CH:10]([NH:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:15])[CH3:11])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[CH2:26][OH:27])[O:8][CH2:9][CH:10]([NH:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:15])[CH3:11]
Reactant: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(COc1ccc(CO)c(CO)c1)NCC(O)c1cccc(Cl)c1
Yield: 47.4 %

Procedure:
Following a procedure similar to that described in Example 1, but using 2.53 g of 2-{2-[3,4-bis(methoxycarbonyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 20), 0.91 g of lithium aluminum hydride and 100 ml of dry tetrahydrofuran, and then purifying the reaction product by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, 1.04 g of the title compound were obtained having an Rf=0.37 (thin layer chromatography over silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1Cl.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Yield: 70.2 %

Procedure:
To a stirred solution of 1,2-dichloro-3-nitrobenzene (0.96 g, 5.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0 mmol) in acetonitrile (5 mL) was added of K2CO3 (1.38 g, 10 mmol). The mixture was heated at reflux for 48 h. The solvent was removed under reduced pressure. The crude material was partitoned between EtOAc (100 mL) and H2O (20 mL). The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 70%). TLC (silica, 20% EtOAc/hexanes): Rf=0.45. MS (electrospray): exact mass calculated for C15H20ClN3O4, 341.1; m/z found, 364.1 [M+Na]+. 1H NMR (400 MHz, CDCl3) 7.56 (dd, J=8.2, 1.4 Hz, 1H), 7.50 (dd, J=8.2, 1.4 Hz, 1H), 7.13 (t, J=8.2 Hz, 1H), 3.38-3.56 (m, 4H), 3.06 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C([Li])CCC.CCCCCC.Cl.[C:35](=O)(O)[O-:36].[Na+]>O1CCCC1.CN(C)C=O>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:35]=[O:36])[CH:3]=3)[N:8]=2)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6-Bromo-2-(trans-4-tert-butyl-cyclohexyloxy)-quinoline (1.0933 g, 3.0176 mmol) in Tetrahydrofuran (24 mL) was added 1.6 M of n-Butyllithium in hexane (5.6 mL, 9.0 mmol) at −78° C. and the reaction was stirred for 15 min. N,N-Dimethylformamide (1.2 mL) was added and the reaction was stirred for 30 minutes. 1 M HCl was added and the reaction allowed to warm to RT. Saturated sodium bicarbonate solution was added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using hexanes/ethyl acetate (0-50%) as eluent to give product in 603 mg yield (64%). ESI-MS (M+H+): 312.20.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([CH:8]([OH:11])[CH2:9]Br)[N:7]=1.[OH-].[Na+]>>[F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:11][CH2:9]2)[N:7]=1
Reactant: OC(CBr)c1csc(C(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1nc(C2CO2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
5 g (0.018 mol) of 1-(2-Trifluoromethyl-thiazol-4-yl)-1-hydroxy-2-bromoethane are suspended in 4 ml of 50% strength sodium hydroxide solution and stirred for 5 minutes. The mixture is then diluted with ice-water and extracted by shaking with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo at 20° C., and the resulting oil is purified on a silica gel column using methylene chloride as eluant.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH:33]1([C:39]2[CH:71]=[CH:70][C:42]([C:43]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]4[CH:60]=[C:59]5[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]5=[O:61])=[CH:54][CH:53]=4)=[CH:48][CH:47]=3)=[O:44])=[CH:41][CH:40]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([C:39]2[CH:71]=[CH:70][C:42]([C:43]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]4[CH:60]=[C:59]5[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([OH:65])=[O:64])[C:58]5=[O:61])=[CH:54][CH:53]=4)=[CH:48][CH:47]=3)=[O:44])=[CH:41][CH:40]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C5CCCCC5)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C5CCCCC5)cc4)cc3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 174 was prepared analogous to compound of example 98 by hydrolysis of compound of example 173.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1.[C:45]([OH:48])(=[O:47])[CH3:46].[CH2:49](O)C>>[OH:40][CH:28]([CH2:46][C:45](=[O:48])[O-:47])[CH2:29][N+:31]([CH3:49])([CH3:36])[CH3:32].[CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1
Reactant: CC(=O)O
Reactant: CCO
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[N+](C)(C)CC(O)CC(=O)[O-]

Procedure:
Carnitine was synthesized as in example 2, except that the NADH regeneration system comprised, in addition to alcohol dehydrogenase, aldehyde dehydrogenase (E.C. 1.2.1.5) which oxidizes the aldehyde (formed by action of alcohol dehydrogenase on ethanol) to acetic acid. Two molecules of NADH were formed from one molecule of ethanol (instead of one in the preceeding example) and the reaction balance was strongly displaced in favour of NADH and acetic acid formation. It was thus no longer necessary to eliminate acetaldehyde as in the preceeding example. The conditions were thus those of example 2, except that 125 units of purified aldehyde dehydrogenase (Boehringer ref. 171.832) were added to the reaction medium and nitrogen bubbling was omitted. After 24 hours, 0.764 g of L-carnitine was formed with a yield of 77.5% with respect to dehydrocarnitine hydrochloride.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH:18]=O.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH2:18][NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCC(=O)NCc1ccc(Cl)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NCc1ccc(Cl)c(CNC2CC2)c1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Cyclopropylamine (1.28 mL, 18.2 mmol) was added to a sol. of N-(4-chloro-3-formyl-benzyl)-propionamide (2.74 g, 12.1 mmol) in MeOH (42 mL). The mixture was stirred overnight, and NaBH4 (918 mg, 24.3 mmol) was added in portions. The mixture was stirred for 4 h, and aq. 1M NaOH (70 mL) was added. The solvents were partially removed under reduced pressure, and the aq. residue was extracted with EtOAc (2×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2→MeOH/CH2Cl2 1:9) yielded the title compound (2.62 g, 81%). LC-MS: tR=0.58 min; ES+: 267.38.
Reaction SMILES: C([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]3[C:19]([C:20]([C:22]4[C:23]([C:28]5[CH:29]=[C:30]6[C:34](=[CH:35][CH:36]=5)[CH2:33][CH:32]([NH:37]C(=O)C)[CH2:31]6)=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=2)[CH2:6]1)(=O)C.Cl>>[NH2:37][CH:32]1[CH2:31][C:30]2[C:34](=[CH:35][CH:36]=[C:28]([C:23]3[C:22]([C:20]([C:19]4[C:14]([C:10]5[CH:11]=[C:12]6[C:7](=[CH:8][CH:9]=5)[CH2:6][CH:5]([NH2:4])[CH2:13]6)=[N:15][CH:16]=[CH:17][CH:18]=4)=[O:21])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:29]=2)[CH2:33]1
Reactant: CC(=O)NC1Cc2ccc(-c3ncccc3C(=O)c3cccnc3-c3ccc4c(c3)CC(NC(C)=O)C4)cc2C1
Agent: Cl
Product: NC1Cc2ccc(-c3ncccc3C(=O)c3cccnc3-c3ccc4c(c3)CC(N)C4)cc2C1

Procedure:
51 g of 2-acetylamino-indan-5-yl-3-pyridyl ketone are refluxed for 16 hours with 250 ml of half concentrated hydrochloric acid. The solution is concentrated and then adjusted to pH 12 using 15N sodium hydroxide solution. The precipitate formed is washed with water and recrystallised from 100 ml of isopropanol.