Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:25][CH3:26])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.BrC[CH:44]1[CH2:46][CH2:45]1>ClCCl.O1CCOCC1>[CH2:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C@H:10]([O:25][CH3:26])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:44]2[CH2:46][CH2:45]2)[CH2:16][CH2:17]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Reactant: BrCC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CO[C@H](CN1CCN(CC2CC2)CC1)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (2.10 g, 4.60 mmol) was dissolved in 30 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The resulting solution was concentrated under reduced pressure. The residue was added with 40 mL of acetonitrile. In an ice-water bath, the resulting solution was added with triethylamine (2.09 g, 20.70 mmol), stirred for 0.5 hours followed by the addition of bromomethyl-cyclopropane (0.88 g, 6.47 mmol). The reaction solution was stirred for 12 hours. The resulting solution was concentrated under reduced pressure, added with 20 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2S)—N,N-dibenzyl-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-methoxy-propan-1-amine 35c (1.52 g, yield: 81.3%) as a brown oil.
Reaction SMILES: [CH2:1]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:4](=[O:5])[C@@H:3]([OH:11])[C@@H:2]1[OH:12].C(O)(=O)C1C=CC(O)=C(O)C=1>>[C:8]([OH:10])(=[O:9])[C:7]1[CH:1]=[C:2]([OH:12])[C:3]([OH:11])=[C:4]([OH:5])[CH:6]=1
Reactant: O=C(O)C1=CC(=O)[C@@H](O)[C@H](O)C1
Agent: O=C(O)c1ccc(O)c(O)c1
Product: O=C(O)c1cc(O)c(O)c(O)c1
Reaction time: 36 h

Procedure:
Alternatively, the 3-dehydroshikimic acid was added slowly with the glucose feed. The glucose feed solution was prepared by mixing 100 mL of a solution containing 18 g of 3-dehydroshikimic acid, with a 200 mL solution containing 120 g of glucose. An oxygen sensor controlled dissolved oxygen levels via addition of the solution containing glucose (0.4 g/mL) and 3-dehydroshikimic acid (0.06 g/mL, 0.35 mmol/mL). The rate of addition of the previous feed solution was about 8 mL/h and as a result approximately 0.5 g of 3-dehydroshikimic acid was added to the culture medium every hour. By the end of the fermentation run, the total amount of 3-dehydroshikimic acid added to the growing cells was 18 g, producing 6.3 g/L of gallic acid at 48 h in a 45% (mol/mol) yield based on added 3-dehydroshikimic acid. Significant amounts of protocatechuic acid (1.8 g/L) as well as unreacted 3-dehydroshikimic acid (4.2 g/L) were present at the end of the run (FIG. 5). A 20 mL aliquot of fermentation broth was taken at 24 h, 36 h, and 48 h for determination of PHB hydroxylase activity. Although pobA* activities were stable throughout the fermentation, the majority of gallic acid was produced in stationary phase (after 24 h). Interestingly, the concentration of protocatechuic acid showed an initial increase reaching a maximum value of 3.4 g/L at 36 h, after which the concentration of protocatechuic acid steadily decreased to 1.8 g/L at 48 h (FIG. 5).
Reaction SMILES: [BH4-].[Na+].[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:9][CH2:10][O:11][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1.Cl>C(O)(C)C>[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:9][CH2:10][O:11][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[N:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1
Reactant: COc1ccc(CCO[C@H]2CCCC[C@@H]2N2CCC(=O)C2)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CCO[C@H]2CCCC[C@@H]2N2CCC(O)C2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a chilled (0° C.) suspension of sodium borohydride (1.53 g, 40 mmol) in isopropanol (60 mL) was added slowly a solution of Compound 18 (6.14 g, 16 mmol) in isopropanol (40 mL). The resultant mixture was stirred at 0° C. for another 30 min and then was allowed to warm up to room temperature for 1 h. The reaction mixture was cooled to 0° C. again and slowly hydrolyzed with 1 M HCl aq (80 mL). The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The organic solvent was evaporated in vacuo, the residual aqueous layer was diluted with water to 150 mL and extracted with diethyl ether (1×150 mL) and dichloromethane (3×150 mL). The combined dichloromethane extracts were concentrated to 120 mL and treated with 0.25 M aq sodium hydroxide (100 mL). The aqueous layer was separated and extracted twice more with dichloromethane (2×150 mL). The combined dichloromethane extracts were dried over sodium sulfate and evaporated in vacuo. Purification by dry-column chromatography (ethyl acetate-hexanes, 2:1 to 4:1, +0.5% v/v isopropylamine) provided 2.0 g (36% yield) of the title compound as a free base. 1.9 g of the free base was partitioned between dichloromethane (24 mL) and 0.5 M HCl aq (24 mL). The aqueous layer was separated and extracted thrice more with dichloromethane (3×24 mL). The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Azeotropic distillation with benzene (2×25 mL) and drying under high vacuum provided the title compound as an off-white hygroscopic solid (1.58 g). 1H NMR (400 MHz, free base, CDCl3) δ 6.80-6.70 (m, 3H, Ar), 4.20-1.10 (m, 22H, Aliph), 3.80 (2×s, 6H, 2×CH3O); 13C NMR (75 MHz, APT, free base, CDCl3) δ 148.56 (+), 147.25 (+), 131.83 (+), 120.66 (−), 112.25 (−), 111.00 (−), 79.30 (−), 79.11 (−), 70.96 (−), 70.73 (−), 69.62 (+), 69.50 (+), 63.28 (−), 59.67 (+), 59.35 (+), 55.80 (−), 55.71 (−), 48.70 (+), 48.44 (+), 36.35 (+), 34.33 (+), 34.17 (+), 28.81 (+), 28.76 (+), 27.09 (+), 27.03 (+), 23.30 (+), 23.22 (+), 22.92 (+), 22.86 (+); HRMS (EI) mass calcd for C20H31N2O: 349.22531. found: 349.22578 (100%); HPLC (Zorbax Extend C18, 150×4.6 mmm, 5μ; 20-70% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 95.8%; CE 99.8%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.C(OC([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].C(=O)=O>ClCCl.C(OC)(C)(C)C>[F:23][C:24]([F:29])([F:28])[C:25]([O-:27])=[O:26].[S:1]1[C:2]2[C:19]3([CH2:20][CH2:21][NH2+:16][CH2:17][CH2:18]3)[O:8][CH2:7][CH2:6][C:3]=2[CH:4]=[CH:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: OCCc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C=O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C([O-])C(F)(F)F
Product: c1cc2c(s1)C1(CC[NH2+]CC1)OCC2
Temperature: 25 °C
Yield: 95 %

Procedure:
3-Thiopheneethanol (123.03 mL, 1.11 mol) is added to a solution of N-tert-butoxycarbonyl-4-piperidone (185 g, 928.48 mmol) in dichloromethane (1300 mL) and stirred at room temperature. Then trifluoroacetic acid (280.82 mL, 3.71 moles) is added dropwise (5 min) while cooling with an ice/water bath (internal temperature=14° C.-30° C., caution: CO2 evolution). The reaction mixture is gradually warmed to ambient temperature and stirred at that temperature for 20 hr. The solvent is evaporated to provide a beige crystalline solid upon cooling in vacuo. The solid is slurried in methyl t-butyl ether (200 mL), filtered, washed with methyl t-butyl ether (2×1000 mL) and dried under vacuum to afford 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-ium trifluoroacetate as a white solid in 95% yield. MS=(m/z): 210 (M+1). 10 M sodium hydroxide (220.36 mL, 2.20 mol) is added to a stirred suspension of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-ium trifluoroacetate (285 g, 881.44 mmol) in dichloromethane (1 L) with cooling (ice/water bath) and the resulting mixture is stirred till a biphasic mixture is obtained. The phases are separated and the aqueous layer is extracted with dichloromethane (2×200 mL). Combined organics are concentrated under vacuum to obtain a thick oil which is triturated with water to obtain a light yellow precipitate. The precipitate is filtered, washed with water (300 mL) and hexane (200 mL) and dried under vacuum at 35° C. for 20 hr. to yield the title compound as a light yellow solid in 86% yield. MS (m/z): 210 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[C:36]2[C:31](=[N:32][CH:33]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:35]=2)[N:30]([CH3:46])[C:29]1=[O:47]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[C:36]6[N:28]([CH2:27][CH2:26][O:25][CH3:24])[C:29](=[O:47])[N:30]([CH3:46])[C:31]6=[N:32][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCCn1c(=O)n(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Product: COCCn1c(=O)n(C)c2ncc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cc21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-(2-methoxy-ethyl)-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 69.1.1) to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=499 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.15-8.05 (m, 3H), 7.97-7.91 (m, 1H), 7.64-7.60 (m, 1H), 7.57-7.53 (m, 1H), 4.11-4.03 (m, 2H), 3.90 (s, 31-1), 3.67-3.62 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H), 3.23 (s, 3H), 1.98 (s, 3H))
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:41][F:42])[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br.C(O)(=O)C>C(O)(=O)C>[CH2:1]([O:17][CH2:18][CH:19]([CH2:41][F:42])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(CF)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCOCC(CO)CF
Reaction time: 0.01 h
Yield: 0.9 %

Procedure:
A solution of 0.750 g (123 mmol) of 10 in 5 ml glacial acetic acid was cooled to 0°. To this was added 2 ml of HBr-acetic acid and the mixture was stirred at 0° for 45 seconds. The solution was filtered and the filtrate was poured into ice water and the mixture was partitioned between methylene chloride and water. The aqueous layer was washed with two portions of methylene chloride and the organic extracts were washed with aqueous Na2CO3 and water, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel using hexane-ethyl acetate eluent (9:1, v/v) to afford 0.388 g (88%) of the title compound (11) as a colorless wax, m.p. 34°. NMR (CDCl3, (CH3)4Si); δ0.90 (t, 3H, J=6 Hz), 1.25 (s, br, 26H), 1.59 (m, 2H), 2.10 (s, br, --OH), 2.19 (d of septets, 1H, JH--H)=6 Hz, JH--F =21 Hz), 3.45 (t, 2H, J=6.5 Hz), 3.63 (d, 2H, J=6 Hz), 3.85 (d, 2H, J=6 Hz, CH2OH), 4.64 (d of d, 2H, JH--H =6 Hz, JH-F=47 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1

Procedure:
Reaction of 4-fluorobenzonitrile with the compound of Example 4, step 1 following the procedure, of Example 1, step 2. affords the title compound, 4-[4-(2-Benzylamino-ethyl)-phenoxy]-benzonitrile, (2.7 g): 1H NMR (CDCl3, 300.00 MHz): 7.65-7.58 (m, 2H), 7.41-7.25 (m, 7H), 7.06-6.98 (m, 4H), 3.86 (s, 2H), 3.01-2.83 (m, 4H), m/z=328.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[NH:36][CH:35]=[CH:34]2>CC(N(C)C)=O>[CH3:41][O:40][C:39]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][NH:36]2)=[CH:32][C:31]=1[O:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2[nH]ccc2cc1O
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3OC)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 38.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.6 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (248 mg, 1.8 mmol) and 5-hydroxy-6-methoxyindole (127 mg, 0.78 mmol) in DMA (4.0 ml) was stirred at 95° C. for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature, filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) and the resulting oil triturated with diethyl ether to give 4-(6-methoxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (106 mg, 38%).
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+].[Na+].OCl.[Zr:19]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Zr+4:19].[Na+:14]
Reactant: [Zr]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: OCl
Agent: [Na+]
Product: [Zr+4]

Procedure:
The above sodium citrate solution was added to 500 g of zirconium hydroxychloride solution which contains 20.0% ZrO2. The reaction batch was mixed continuously while the sodium citrate was being added. A clear solution of sodium zirconium citrate was obtained after the addition of sodium citrate solution was completed. The pH of the solution product was 6.2.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc([N+](=O)[O-])cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc([N+](=O)[O-])ccc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy- 6-nitro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride. Add excess trifluoracetic acid and stir overnight at room temperture. Concentrate the reaction in vacuo, dilute with ethyl acetate and rinse with saturated sodium bicarbonate, dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-[(phenacyl)methylamino]-2-carbethoxy-6-nitroindole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21](O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O>CO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(O)c2ccccc2)cn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2)cn1
Reaction time: 6 h
Yield: 60.5 %

Procedure:
To product from step 2 (50 mg, 0.13 mM) was added Pd/C, 10% (40 mg, wt) in MeOH/AcOH (1.5 ml, 6:4) and stirred under H2 (H2 balloon, atm pr) for 6 h. 10% NaOH (5 mL) was added to quench the reaction. EtOAc was added and the mixture was filtered and dried down to give the title compound (29 mg, 83%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35]C(OC(C)(C)C)=O)[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[C:16]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[Cl:46]CCl.CO>>[ClH:46].[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH2:35])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[C:16]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OCCCOC)c(OCCCOC)c1)C(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OCCCOC)c(OCCCOC)c1)C(C)C
Product: Cl

Procedure:
Analogously to Example 1, the title compound is prepared starting from 66 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[3,4-di(3-methoxypropyloxy)phenyl]-octanoic acid (N-butyl)amide. This yields the tide compound: Rf (dichloromethane/methanol=9:1)=0.21; Rt (I)=40.0 minutes; FAB-MS (M+H)+ =539.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])[CH:5]=1.[OH-].[Na+].Cl>CO>[CH3:22][O:21][CH2:20][CH2:19][N:17]([CH3:18])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]([OH:23])=[O:2]
Reactant: COCCN(C)c1cc(C(=O)OC)ccc1N1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN(C)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Reaction time: 8 h

Procedure:
To a solution of 150 mg (0.47 mmol) of 3-[(2-methoxy-ethyl)-methyl-amino]-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester in 5 mL of methanol were added 0.9 mL (0.93 mmol, 2 eq.) of 1N NaOH solution and the reaction mixture left standing overnight at room temperature. The solution was then added with 0.47 mL of 2N hydrochloric acid, the solvent evaporated, and the residue dried at 70° C. under vacuum. The compound was used as such in the subsequent step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15]Cl.[Cl-].[Na+]>O1CCCC1>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)nc2)CC1

Procedure:
6.5 g (0.217 mol) of 80% strength sodium hydride in white oil are suspended in 170 ml of tetrahydrofuran and a solution of 15.3 g (0.1 mol) of 6-chloro-pyridine-3-acetonitrile in 60 ml of tetrahydrofuran is added dropwise. The mixture is stirred until completion of gas evolution, cooled and a solution of 14.3 g (0.1 mol) of 1-bromo-2-chloro-ethane in 15 ml of tetrahydrofuran are added dropwise at 5°-20° C. The mixture is stirred for 2 hours at room temperature, poured into concentrated sodium chloride solution and extracted using ether. The crude product, freed from solvent, is taken up in ethyl acetate and filtered through a bed of 200 g of silica gel. 14.3 g of a brownish, semi-crystalline material are thus obtained, which is purified by bulb tube distillation. 5.8 g (32.5% of theory) of an oil, which solidifies on cooling, are distilled at an apparatus temperature of 130°-140° C. and 0.08 mbar.
Reaction SMILES: S([CH2:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:7])(O)(=O)=O.[Na].[Cl:36]CC(O)=O>>[Cl:36][CH2:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:7]
Reactant: O=C(O)CCl
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCOC(=O)CS(=O)(=O)O
Agent: [Na]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCOC(=O)CCl
Temperature: 93 °C

Procedure:
The reactor is then heated to a temperature of 93° C. and maintained at a temperature of between 90° C. and 97° C. for about 11 hours. HPLC analysis of the resulting slurry indicates that the sodium lauryl-myristyl sulfoacetate is substantially free of monochloroacetic acid and its salts.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]3[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])=[N:21][CH:22]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>CCO>[ClH:35].[ClH:35].[OH:28][NH:27][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]1[CH:19]=[N:18][C:17]([NH:16][C@@H:12]2[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[CH:22][N:21]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-[5-({(3R)-1-[3-phenylpropyl]-3-piperidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (265 mg) in EtOH (1.5 mL) was added 2N—HCl solution in EtOH (1.5 mL). The reaction mixture was stirred for 2 hours at ambient temperature. IPE (1.5 ml) was added to the mixture. The resulting solid was collected by filtration to give (2E)-N-hydroxy-3-[5-[{(3R)-1-(3-phenylpropyl)-3-piperidinyl}amino]-2-pyrazinyl]acrylamide dihydrochloride (148 mg).
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl.[CH:12]([OH:15])([CH3:14])[CH3:13]>>[CH:12]([O:15][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na]
Product: CC(C)OCc1ccncc1

Procedure:
3.4 g of sodium are dissolved in 120 ml of isopropanol and 11 g (0.067 mol) of 4-chloromethylpyridine-hydrochloride are added. The reaction mixture is refluxed for 10 hours under nitrogen, with stirring, then after cooling it is made weakly acidic with dilute hydrochloric acid and concentrated by evaporation under reduced pressure. The residue is made alkaline with 40% potassium carbonate solution and extracted with ether. After drying with anhydrous sodium sulphate the organic phase is concentrated by evaporation. The crude product is then distilled.