Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[S:10][C:9]([N:11]([CH3:22])[CH:12]3[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]3)=[N:8][N:7]=2)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.[Cl:27]N1C(=O)CCC1=O>ClCCCl.CC(O)=O.C(=O)(O)[O-].[Na+]>[Cl:27][C:4]1[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[S:1][C:5]=1[C:6]1[S:10][C:9]([N:11]([CH3:22])[CH:12]2[CH2:17][C:16]([CH3:18])([CH3:19])[NH:15][C:14]([CH3:20])([CH3:21])[CH2:13]2)=[N:8][N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(c1nnc(-c2cc3ccccc3s2)s1)C1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(c1nnc(-c2sc3ccccc3c2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 90 °C
Yield: 44.5 %

Procedure:
A mixture of 5-(benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (37 mg, 0.096 mmol) and N-chlorosuccinimide (15.34 mg, 0.115 mmol) in DCE:AcOH (1:1) (1 mL) was heated at 90° C. for six hours. The reaction was cooled to RT, diluted with saturated sodium bicarbonate, extracted with ethyl acetate (3×), and DCM (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to a crystalline yellow solid. Purification by flash column chromatography (4 g silica gel, 1-17% 3.5 N ammonia in MeOH gradient in DCM over 30 column volumes) provided 5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine as a yellow solid (18 mg). LC/MS Rt=0.58 min. MS=420.9 (M−1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.84-7.99 (m, 2H), 7.47-7.60 (m, 2H), 4.53 (m, 1H), 3.14 (s, 3H), 1.83 (d, J=9.6 Hz, 2H), 1.55-1.68 (m, 2H), 1.38 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 5-bromo-3-pyridineacetic acid (500 mg, 2.314 mmol) in DMF (3 mL) is added TBTU (1.11 g, 3.472 mmol). Morpholine (0.61 mL, 6.94 mmol) is added dropwise and the mixture is stirred at room temperature for 18 h. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-4.5% MeOH in DCM as the gradient to afford 2-(5-bromo-pyridin-3-yl)-1-morpholin-4-yl-ethanone.
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]#[N:8])=O.CC([O-])(C)C.[K+].[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.O.[Cl-].[Na+].O>[C:7]([CH:6]=[C:27]1[CH2:28][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: -14 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Diethyl cyanomethyl phosphonate (745 g, 4.20 mol, 1.20 eqiv) and anhydrous THF (9 L) was added to a four-neck flask equipped with thermowell, addition funnel and nitrogen protection tube. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of t-BuOK in THF (3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the temperature<−5° C. The mixture was stirred for 3 hr at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (1, 600 g, 3.50 mol) in THF (2 L) was added over 2 hr while keeping the reaction temperature<−5° C. The reaction mixture was stirred at −5 to −10° C. over 1 hr and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated brine (4.5 L) and extracted with ethyl acetate (2×9 L). The combined organic layers were combined and washed with brine (6 L), dried over anhydrous Na2SO4. The organic solvent was removed under reduced pressure, diluted with dichloromethane (4 L) and adsorbed onto silica gel (1.5 kg). The product was purified by flash column chromatography (SiO2, 3.5 kg×2), each column was eluted with (8 L of heptane, 8 L of 5% AcOEt/heptane, 12 L of 10% AcOEt/heptane, 40 L of 25% AcOEt/heptane) to give the pure tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 4.62 (m, 2H), 4.72 (m, 2H), 5.41 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of aniline (9.31 g, 100 mmol) and triethylamine (15.2 g, 150 mmol) in THE (150 mL) is cooled to −40° C. before chloroacetic acid chloride (11.3 g, 100 mmol) is slowly added in portions such that the temperature does not rise above 0° C. After completion of the addition, the brown suspension is stirred at rt for 1 h. The dark purple mixture is poured onto water (300 mL) and extracted twice with EA (300 mL). The organic extracts are washed with sat. aq. NaHCO3, 0.5 N aq. HCl, followed by water, and evaporated. The brown residue is suspended in diethyl ether, filtered off, washed with additional diethyl ether and dried under high vacuum to give 2-chloro-N-phenyl-acetamide. LC-MS: tR=0.75 min, [M+1]+=170, 1H NMR (CDCl3): δ 8.22 (s br, 1H), 7.56-7.51 (m, 2H), 7.40-7.24 (m, 2H), 7.20-7.14 (m, 1H), 4.20 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>O1CCCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CCCCCc1ccc(-c2ccc(C=Cc3ccc(F)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCc3ccc(F)cc3)cc2)cc1

Procedure:
A solution of 9.5 g of 1-(p-fluorophenyl)-2-(4'-n-pentyl-biphenyl-4-yl)ethene [obtained by Heck coupling of 4-fluorostyrene with 4-bromo-4'-n-pentylbiphenyl] in 100 ml of tetrahydrofuran is hydrogenated in the presence of Pd/C until the take-up of H is complete. Customary work-up gives 1-(p-fluorophenyl)-2-(4'-n-pentylbiphenyl-4-yl)ethane, mp. 60°, cp. 109°.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][CH2:4][C@@H:5]1[CH2:8][CH2:7][C@H:6]1[C:9]([O:11]C)=[O:10].CO.[OH-].[Na+]>O>[F:1][CH:2]([F:13])[O:3][CH2:4][C@@H:5]1[CH2:8][CH2:7][C@H:6]1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)[C@@H]1CC[C@H]1COC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CC[C@H]1COC(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
To a solution of Intermediate 241A (100 mg, 0.515 mmol) in a 1:0.3:1THF:MeOH:water was added NaOH (41.2 mg, 1.030 mmol) and the resulting solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the aqueous layer was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 4 by adding an aqueous solution of 1.5 N HCl and extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4 and evaporated under vacuum to afford Intermediate 241B as yellow sticky liquid (80 mg, 86%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 6.35-6.95 (m, 1H), 3.74-3.89 (m, 2H), 2.85 (q, J=8.70 Hz, 1H) 2.63-2.77 (m, 1H) 1.95-2.10 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[CH2:15][C:14]2([CH3:23])[CH2:13][N:12]([CH3:24])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.Br.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[CH2:15][C:14]2([CH3:23])[CH2:13][N:12]([CH3:24])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCN(C)CC2(C)Cc2ccccc2C3)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC2(c3cccc(O)c3)Cc3ccccc3CC2(C)C1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a 10 mL single-necked flask was added 100 mg (0.31 mmol) of (±)-1,2,3,4,4a,5,10,10a-octahydro-4a-(3-methoxyphenyl)-2,10a-dimethylbenzo[g]isoquinoline (10) and 0.8 mL of glacial acetic acid and 0.8 mL of 48% HBr. This mixture was heated under reflux for 18 h and then cooled to room temperature. The pH was then adjusted to 10 with cooling starting with 50% NaOH and finishing with saturated NaHCO3. This was extracted 2 times with CHCl3 and 2 times with 3:1 n-butanol:toluene. Both extracts were dried over K2CO3, and then the solvent was removed. The material from both extracts was examined by 1H NMR and was shown to contain the desired product. The material from the CHCl3 layer was chromatographed on silica gel eluting with 25d% CMA-80 in CHCl3. This gave 27 mg of the desired pro duct (7) (28% yield). The residue was dissolved in MeOH, and to this was added 3 equivalents of 1N HCl in dry ethyl ether. The solvents were removed, and the residue crystallized from ether/MeOH. The butanol extracts contained 45 mg of the desired material giving an overall yield of 74.6%. MP ° C. 270-275 (dec). Anal. Calcd for C21H26NOCl.0.25H2O: C, 65.54; H, 7.20; N, 3.64. Found: C, 65.86; H, 7.15; N, 3.42. 1H NMR (DMSO) δ 1.014 (s, 3H); 1.587 (d, 1H, J=14.3 Hz); 2.072 (s, 3H); 2.358 (d, 1H, J17.4 Hz); 2.498 (d, 1H, J=17.4 Hz); 2.734 (s, 3H); 2.924-2.792 (m, 3H); 3.113 (d, 1H, J=13.1 Hz); 3.602 (d, 1H, J=18.78 Hz); 6.562 (d, 1H, J=8.0 Hz); 6.611 (m, 2H); 6.993 (t, 1H, J=7.5 Hz); 7.081 (d, 1H, J=7.5 Hz); 7.148 (t, 1H, J=7.8 Hz); 7.269-7.193 (m, 2H); 9.30 (s, 1H); 9.898 (bs, 1H). 13C NMR (DMSO) δ 156.7, 146.4, 135.5, 133.3, 128.5, 128.4, 128.2, 126.2, 125.7, 117.6, 114.3, 113.5, 59.2, 49.4, 38.6, 35.4, 35.2, 31.0, 28.7, 22.8.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][CH2:26][C:27]([NH2:29])=[O:28].CCN(C(C)C)C(C)C>CCO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:24][CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC(N)=O
Reactant: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(NCCC(N)=O)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of the compound of Example 1 Step 4 (2.0 g, 5.5 mmol) in EtOH (50 mL) was treated with 3-amino-propionamide hydrochloride (1.72 g, 13.8 mmol) and DIEA (0.53 g, 27.7 mmol). The resulting mixture was stirred at reflux for 6 h, then cooled to room temperature and concentrated under vacuum. The crude product was dissolved in CH3OH and purified by preparative reverse-phase HPLC (CH3OH/H2O) on a YMC S10 ODS 50×500 mm column to afford the desired product as a yellow glass (0.96 g, 49%); 1H NMR (CD3OD): δ 7.37 (m, 5H), 5.65 (d, J=16.5 Hz, 1H), 5.30 (d, J=16.5 Hz, 1H), 4.70 (t, J=6.0 Hz, 1H), 3.15 (m, 1H), 2.94 (m, 1H), 2.59 (s, 3H), 2.49 (m, 2H), 1.93 (m, 2H), 0.89 (t, J=7.5 Hz, 3H); LC/MS (ESI): 370 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH:30][C:31]([NH2:33])=[S:32])=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[Cl-].[Na+]>CN(C)C=O>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([C:9](=[O:11])[C:8]2[CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]=2[O:13][CH2:14][O:15][CH3:16])[NH:30][C:31]([NH2:33])=[S:32])=[CH:27][CH:28]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Reactant: COc1ccc(NNC(N)=S)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)N(NC(N)=S)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
5-isopropyl-2,4-bis(methoxymethoxy)-benzoic acid (IM3-a: 16.4 g, 54.5 mmol), 4-methoxyphenylthiosemicarbazide (F53-02: 11.3 g, 57.3 mmol), dimethylformamide (150 mL) and 1-hydroxybenzotriazole monohydrate (8.11 g, 60.0 mmol) were placed in a 500 mL eggplant shaped flask. The reaction mixture was cooled to 0° C. and mixed with a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (11.5 g, 60 mmol) in dimethylformamide (100 mL). The mixture was stirred for 4 hours and allowed to come to room temperature. After completing the reaction, saturated sodium chloride solution (500 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (500 mL). The organic layer thus obtained was washed 4 times with saturated sodium chloride solution (500 mL) and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was distilled under reduced pressure, and the solids obtained were suspended in hexane (1000 mL) for purification and collected by filtration. The solids thus obtained were dried under reduced pressure to obtain the title compound (F53-03: 21.9 g, 83.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=1)=[O:21].Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cnc(SC)nc2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cnc(SC)nc2)c1F
Reaction time: 18 h
Yield: 125.1 %

Procedure:
Step 3 To a solution of tert-butyl N-[(1R)-1-(4-chloro-2-fluoro-3-{[2-(methylsulfanyl)pyrimidin-5-yl]carbonyl}phenyl)propyl]carbamate (20.0 mg, 0.04 mmol) in DCM (1 mL) was added 4M HCl in dioxane (0.04 mL, 0.16 mmol, 4 eq) and the reaction stirred for 18 h. The mixture was concentrated and then triturated with diethyl ether (˜5 mL) and the pale green solid filtered off and dried in a vacuum oven to give (1R)-1-(4-chloro-2-fluoro-3-{[2-(methylsulfanyl)pyrimidin-5-yl]carbonyl}phenyl)propan-1-amine (17.0 mg).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][C:16]([CH3:18])=O)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>O.C1(C)C=CC=CC=1>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16]([Cl:28])[CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Cc1cc(C)nc(Nc2ccccc2)n1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 94.3 %

Procedure:
Into a 500 ml reaction flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel, 48.3 g (0.2 mol) of 2-anilino-4-methyl-6-acetonyl-pyrimidine and 200 ml of toluene were charged and dissolved. To this solution, 61.4 g (0.4 mol) of phosphorus oxychloride was dropwise added from the dropping funnel. The mixture was reacted at a temperature of from 88° to 90° C. for further 6 hours. The reaction mixture was cooled and put into a water/toluene solution and subjected to liquid separation. The toluene layer was washed with an aqueous sodium carbonate solution and then with water. The toluene layer was concentrated to obtain 49 g of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine having a melting point of from 63° to 66° C. The yield was 94.4%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:30]([CH3:32])[CH3:31])[C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=2)[C@H:10]([CH2:33][N:34]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:30]([CH3:31])[CH3:32])[C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=2)[C@H:10]([CH2:33][NH2:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN=[N+]=[N-])C(C)C)ccc1C
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN)C(C)C)ccc1C

Procedure:
According to the procedure described for Example 130/reaction step C, by hydrogenation of (3S,4R)-3-azidomethyl-4-({isopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.68 g, 7.31 mmol), dissolved in MeOH (80 mL), in the presence of Pd/C 10% (1.0 g; Engelhard 4505) at room temperature under atmospheric pressure to give, after filtration and drying in vacuo, the title compound as oil. MS: 478.2 [M+H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.28 min.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI>C1COCC1.O.CCOCC>[CH3:1][C:13]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)C1CCCCCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: CC1(C(=O)O)CCCCCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diisopropylamine (7.47 g, 73.8 mmol) in dry THF at -78° C. under nitrogen was added n-butyllithium(2.5M, 29.5 ml, 73 8 mmol). The mixture was stirred for 10 minutes before cycloheptanecarboxylic acid (2.10 g, 14.8 mmol) was added dropwise and the reaction stirred at -78° C. for a further 10 minutes before refluxing for a further 2 hours. The reaction was cooled to 0° C. and methyl iodide (5.76 g, 40.6 ml) was added dropwise before refluxing for a further 1 hour before cooling to room temperature. The reaction mixture was poured onto an admixture of water/ether (100 ml/SO ml) and the aqueous layer was separated, acidified with dilute hydrochloric acid (2M) and extracted with ether (5×25 ml). The combined ether layers were washed with water (2×50 ml) and saturated sodium chloride solution (50 ml) before being dried over MgSO4. Filtration and evaporation of solvent under reduced pressure yielded the 1-methylcycloheptanecarboxylic acid which was recrystallised from hexane (2.20 g, mp 46° C.). The title compound was produced by the method of Example 24 using this acid in place of the 1-methylcyclopentanecarboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:10]=[CH:23]/[CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: O=C/C=C/c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 11) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:21]=[CH:22][C:12]([O:11][C:8]4[N:7]=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: O=C1CCCC1
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)nc1
Reaction time: 0.5 h

Procedure:
N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (150 mg, 0.5 mmol) was dissolved in 2.5% acetic acid in methanol (5 ml) and treated dropwise with cyclopentanone (0.09 ml, 1 mmol). The mixture was stirred for 30 minutes and then (polystyrylmethyl)trimethylammonium cyanoborohydride (2.04 mmol/g, 490 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, applied to a SCX cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.25:2.25:97.5) to afford the title compound (E223). MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]2[CH2:2][OH:1])=[CH:16][CH:17]=1
Reactant: OC[C@H]1CCCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCCN1CCc1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 4-chlorophenethyl tosylate (931 mg, 3.00 mmol), sodium carbonate (320 mg, 3.00 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 10 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-1-(4-chlorophenethyl)-2-hydroxymethylpiperidine in the form of a light yellow oil (354 mg, 56%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)C>C(Cl)Cl>[F:3][C:4]([F:13])([F:14])[CH:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(O)C(F)(F)F

Procedure:
To a suspension of 91.2 g (2.4 mol) of sodium borohydride in 6 l of CH2Cl2 cooled at +2° C., are dropwise added 1473 g of ethyl 4,4,4-trifluoroacetoacetate while keeping temperature between +4° and +7° C. After the introduction, 100 ml of absolute ethanol are added while keeping temperature at +3° C. The reaction medium is washed with bicarbonated water. The organic phase is concentrated and the product is distilled at 78° C. under 10 mm Hg.