Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O)C.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1)([O-])=O>[Pd].O>[NH2:5][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cn2cncn2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A stainless steel vessel was inetted with nitrogen and connected via its vent to a mobile scrubber unit. The scrubber was charged with very dilute hydrochloric acid. The vessel was charged with 96% ethanol (40 kg) followed by 1-(4-nitrobenzyl)-1,2,4-triazole (9.62 kg). The vessel was re-inerted with nitrogen and a slurry of 10% Pd/C catalyst (Engelhardt type 4505, 192 g) in water added to the stirred batch via the addition funnel. The vessel, funnel and line were rinsed with water. Total water used was 16 l. The batch was well stirred and heated to 60° C. A solution of ammonium formate (13.95 kg) in water (30 l) was metered into the reactor over 1 hour. Batch temperature settled at 65° C. At the end of this addition, the batch was heated at 70°-75° C. for a further 1 hour. Tlc showed complete reaction and single spot formation. The batch was cooled to 60° C. and passed through a pressure filter coated with hyflo (1.5 kg) to another vessel. The reaction vessel, filter and lines were washed with water (10 l). A further batch of 1-(4-nitrobenzyl)-1,2,4-triazole (9.585 kg) was then reduced in the same way. This batch was filtered and added to the previously filtered batch together with a 10 l water wash of the vessel, filter and lines. The combined, filtered batch (215 l) was distilled at atmospheric pressure until 70 l of distillate had been removed (vapour temperature was 83° C. at this point). Water (30 l) was added and the distillation continued until the vapour temperature reached 95° C. (106 l total distillate). The pressure in the distillation vessel was then reduced to allow distillation at a boiling point of ≤70° C. A further 70 l of distillate was removed to leave a residual volume of 69 l. The batch had crystallised at this point and the slurry was cooled to ≤20° C. over 1 hour. The batch was gently stirred and aged overnight. The batch was cooled to 0° C., aged for 1 hour and then filtered. The solid was washed with water at 0°-5° C. (10 l). The batch was dried overnight at 50° C., in vacuo, with a nitrogen bleed to give 1-(4-aminobenzyl)-1,2,4-triazole in 96% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)#[N:11].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O.CO.C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COc1cncc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1cncc(-c2ccc(C#N)cc2)c1
Yield: 89 %

Procedure:
1.93 g (10.3 mM) of 3-bromo-5-methoxypyridine and 1.85 g (12.36 mM) of 4-cyanophenylboronic acid are mixed with 40 ml of toluene and 40 ml of methanol. 0.6 g (0.5 mM) of tetrakis(triphenylphosphine)palladium and 1.3 g (30.9 mM) of lithium chloride are added. 26 ml of 1 M sodium carbonate solution are then added. The mixture is refluxed for 5 hours and, after cooling, water and ethyl acetate are added to the reaction medium. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (94/6; v/v) as the eluent to give the expected product in the form of a beige solid with a yield of 89%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)[CH:18]=2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)cc1C(F)(F)F
Yield: 25 %

Procedure:
The product was synthesized according to General Procedure 1, described in Example 1, starting with 4-bromo-2-(trifluoromethyl)benzene sulfonyl chloride (17.8 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) yielding 5.6 mg (25%) of the title compound. MS (ESI+) calcd for C14H9BrF3N5O2S 446.961242, found 446.961472.
Reaction SMILES: [Si]([O:8][C:9]1[CH:22]=[C:21]2[C:12]([C@@:13]3([CH2:31][CH3:32])[C@H:18]([CH2:19][CH2:20]2)[CH2:17][C@@:16]([OH:29])([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:15](=[O:30])[CH2:14]3)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O1CCC[CH2:34]1>>[CH2:31]([C@:13]12[C:12]3[C:21](=[CH:22][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19][C@@H:18]1[CH2:17][C@:16]([C:23]1[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=1)([OH:29])[C@:15]([CH3:34])([OH:30])[CH2:14]2)[CH3:32]
Reactant: C1CCOC1
Reactant: CC[C@@]12CC(=O)[C@](O)(c3ccncc3)C[C@H]1CCc1cc(O[Si](C)(C)C(C)(C)C)ccc12
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccncc3)C[C@H]1CCc1cc(O)ccc12
Reaction time: 72 h
Yield: 13 %

Procedure:
A solution of (2R,4aR,10aR)-7-(tert-butyidimethylsilanyloxy)-4a-ethyl-2-hydroxy-2-pyridin-4-yl-1,4,4a,9,10,10a-hexahydro-2H-phenanthren-3-one (32 mg, 0.65 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. and treated with a 1.0 M solution of methyllithium/lithium iodide complex in tetrahydrofuran (0.65 mL, 0.65 mmol). The mixture was allowed to stir from −78° C. to room temperature over 3 days and was then quenched with saturated aqueous ammonium chloride solution and water. The mixture was extracted four times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to a solid that was triturated with hexane and diethyl ether. The title compound (3 mg, 13%) was isolated from the solid by chromatography on silica gel eluting with a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate. Mass spectrum (m/e) 354 (M++1).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C@H:9]([CH3:22])[C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2.O[C@@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)CC1)C[C@H]3C>>[CH3:22][C@@H:9]1[C:8]2[C@:3]([CH2:2][OH:1])([CH2:4][CH2:5][C@@H:6]([OH:23])[CH:7]=2)[C@@H:20]2[C@H:11]([C@H:12]3[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C@@H:15]([OH:21])[CH2:14][CH2:13]3)[CH2:10]1
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Agent: C[C@@H]1CC2=CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@H](O)CC[C@H]3[C@H]12
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)[C@@H](O)CC[C@@H]23)[C@@]2(CO)CC[C@@H](O)C=C12

Procedure:
Substituting 17β,19-dihydroxy-4,17α-dimethyl-4-androsten-3-one and 19-hydroxy-6α-methyl-4-androstene-3,17-dione for 17α,19-dihydroxy-7α-methyl-4-androsten-3-one above results in the preparation of 4,17α-dimethyl-4-androstene-3α,17β,19-triol and 6α-methyl-4-androstene-3α,17β,19-triol, respectively.
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C1(C)C=CC=CC=1>[NH2:1][C:9]1[C:10]([CH:11]=[O:12])=[C:5]([Cl:4])[N:6]=[CH:7][N:8]=1
Reactant: N
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ncnc(Cl)c1C=O
Temperature: 23 °C
Reaction time: 3.5 h

Procedure:
A solution of 7 M NH3 in MeOH (265 mL, 1.855 mol, 2.0 equiv) was added over 1.25 h to a solution of 4,6-dichloropyrimidine-5-carbaldehyde (163.7 g, 0.9301 mol) in toluene (3 L) at ambient temperature. The reaction temperature slowly increased from 20 to 26° C. and a yellow suspension formed. Mild cooling was applied to maintain the reaction temperature at below 26° C. The suspension was stirred at ambient temperature for 3.5 h before the solids were collected by filtration. The solids were washed with EtOAc (1 L). The filtrate was concentrated under reduced pressure, and the solids were triturated with toluene and n-heptane (2:1 v/v, 600 mL), filtered and dried to give 71.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde as a yellow solid. The original solid filtered from the reaction mixture contained additional amount of 4-amino-6-chloropyrimidine-5-carbaldehyde. The product was extracted from the filtered solid by stirring in EtOAc (1.25 L) for 1.5 h, filtering, then stirring in THF (750 mL) for 1 h and again filtering. Both EtOAc and THF filtrates were concentrated under reduced pressure, and the resulting solids were triturated with toluene and n-heptane (2:1 v/v, 450 mL), filtered and dried to give an additional 44.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde as a yellow solid. The combined yield of 4-amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 146.5 g theoretical) was 78.6%. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.71 (bs, 1H), 8.55 (bs, 1H), 8.39 (s, 1H) ppm; C5H4ClN3O (MW, 157.56), LCMS (EI) m/e 158 (M++H).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)ccc2[C@H]2CCc3cc(O)ccc3C2)cc1
Yield: 69.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.0 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(CCC(C)C)c1ccc(F)cc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CC(C)CCC(C)(C(=O)O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1C, substituting the compound of Example 22B for the compound of Example 1B. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, J=6.43 Hz, 6 H) 1.05 (m, 2 H) 1.51 (m, 4 H) 1.96 (m, 2 H) 7.02 (m, 2 H) 7.34 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:27]([O:29][CH3:30])=[O:28])=[N:11][N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)[C:13]=1[C:14](OC)=[O:15])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10]([C:27]([O:29][CH3:30])=[O:28])=[N:11][N:12]2[C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:24][C:14](=[O:15])[C:13]=12
Reactant: COC(=O)c1nn(-c2ccccc2[N+](=O)[O-])c(C(=O)OC)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nn2c(c1O)c(=O)[nH]c1ccccc12

Procedure:
To a solution of dimethyl 4-benzyloxy-1-(2-nitrophenyl)-1H-pyrazole-3,5-dicarboxylate (2.0 g, 4.85 mmol) in MeOH (100 mL) was added palladium on carbon (200 mg). The mixture was then stirred and purged with hydrogen gas. The mixture was stirred at ambient temperature under 1 atmosphere of hydrogen gas for 72 hours. The mixture was filtered through celite and the filter cake was washed with MeOH. The filtrate solvent was removed under reduced pressure. Trituration of the residue in a small volume of MeOH gave the product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 11.65 (s, 1H), 9.74 (s, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.25-7.34 (m, 2H), 3.88 (s, 3H); ES MS (M+1)=260.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55]>C(#N)C>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]([N:56]([CH2:57][CH3:58])[CH2:54][CH3:55])=[O:20])[CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1
Reactant: CCNCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCN(CC)C(=O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1

Procedure:
[6-(Biphenyl-4-sulfonylamino)-pyridin-2-yl]-acetic acid (0.35 g) in acetonitrile (5 mL) was treated at RT with N,N-ethyldiisopropylamine (0.16 mL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.252 g) then diethylamine (0.05 mL), and the mixture was stirred at RT for 16 h. It was then partitioned between cold diluted aqueous HCl and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/EtOAc 1:1) to give 2-[6-(biphenyl-4-sulfonylamino)-pyridin-2-yl]-N,N-diethyl-acetamide as a yellow solid (0.168 g). MS (ESI−): 422.2 ([M−H]−).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([OH:29])=[O:28]>CO>[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([O:29][CH3:1])=[O:28]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: COC(=O)c1c(O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dicyclohexyicarbodiimide (1.20 Kg, 5.8 mol, 1.1 eq) was added portionwise over 4.5 hours to a cooled, mechanically-stirred slurry of 2-hydroxy-1-naphthoic acid (1.00 Kg, 5.3 mol) in methanol (3 L) under nitrogen. The internal temperature was maintained between 10 and 15° C. during the addition. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 hours. The methanol was removed under reduced pressure and the residue taken up in ethyl acetate (5 L) and heated with stirring to 64° C. (internal temperature) and then allowed to cool once again to ambient temperature. The mixture was filtered, and the solid washed with ethyl acetate (0.7 L). The ethyl acetate solutions were combined and concentrated under reduced pressure. The residue (2.5 Kg) was recrystallised from ethanol-water (9:1, 3.3 L) and dried under vacuum at ambient temperature. Yield 0.92 Kg, 85%
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N:28]([CH3:30])[CH3:29])C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:30][N:28]([CH3:29])[C:10]1[C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=[CH:26][C:9]=1[OH:8])[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:27]
Reactant: CN(C)c1c(OCc2ccccc2)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)c1c(O)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 3-benzyloxy-4-dimethylaminoestra-1,3,5(10)-trien-17-one (86, 0.271 g, 0.67 mmol) in THF (10 mL) was added 10% palladium on carbon (0.200 g). The reaction mixture was stirred for 1 h under a hydrogen atmosphere at room temperature. After the catalyst was filtered, the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (5:1→3:1, v/v) to afford 0.171 g of 87 (81% yield) mp: 155-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[C:24](=[O:29])[N:23]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH:22]=[CH:21]2.O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[CH3:28])[C:24](=[O:29])[N:23]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(C)cc3c2=O)cc1
Temperature: 80 °C
Yield: 88.6 %

Procedure:
A solution of 3.2 g (15.9 mmol) 1-tert-butoxycarbonyl-4-hydroxypiperidine in 110 mL dimethylacetamide was stirred with 1.36 g (45.4 mmol) of 80-% sodium hydride for 1 h at room temperature. Then a suspension of 4.5 g (15.1 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in dimethylacetamide was added. The reaction mixture was heated to 80° C. for 2 h during which time a clear solution was obtained. The reaction mixture was slowly added to 160 mL water and after 1 h of stirring the product was isolated by filtration and dried over night in vacuum. 6.4 g of 4-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[CH3:28]O>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]([O:21][CH3:28])=[O:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC

Procedure:
A solution of the product from step (iv) (135 mg) in MeOH (5 ml) and 4M HCl in dioxane (0.5 ml) was stirred at rt for 18 h. The solvent was evaporated and the residue purified by RPHPLC to give the title compound as a solid, 31 mg.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][CH2:6]2)#[N:2].Cl.[NH2:30][OH:31].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:5](=[C:4]([CH3:28])[C:3]([C:1]([NH:30][OH:31])=[NH:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20]
Reactant: NO
Reactant: CCOC(=O)CCCC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 32 h
Yield: 86.4 %

Procedure:
A mixture of 1,1-dimethylethyl 6-cyano-1-[4-(ethyloxy)-4-oxobutyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 26; 533 mg, 1.38 mmol), hydroxylamine hydrochloride (575 mg, 8.27 mmol) and sodium bicarbonate (695 mg, 8.27 mmol) in ethanol (15 ml) was stirred at 80° C. for 32 h. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalent of each) were added, and heating was continued at 80° C. overnight. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalent of each) were added, and heating was continued at 80° C. for 5.5 h. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalent of each) were added, and heating was continued at 80° C. overnight. The mixture was cooled to room temperature and the solid was filtered off and washed with ethanol. The filtrate and washings were combined, most of the solvent removed, and the residue dissolved in ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (500 mg) as a pale yellow foam.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][CH:20]=1)[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][CH:20]=1)[CH3:18]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1cnc(C(=O)O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCc1cnc(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)[nH]1
Yield: 55 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.20 g, 0.87 mmol), 5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1b) (85 mg, 0.44 mmol), WSC hydrochloride (0.55 g, 2.87 mmol) and DMAP (115 mg, 0.94 mmol), to obtain 85 mg of the title compound as a pale yellow solid (55%).
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[CH:18]([OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1
Reactant: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(2-methyl-3-oxo-3-phenylpropyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (Example 246, step C) in 5 mL of EtOH/water (1:1)) is added 15 mg of Degussa Pd/C and the resulting mixture is hydrogenated at 1 atm for 4 h. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound: (M−1)−=375.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([C:14](=O)[CH3:15])=[CH:12][C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[CH3:17][Mg]Br>C1COCC1>[CH:14]([C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1)([CH3:15])[CH3:17]
Reactant: C[Mg]Br
Reactant: COc1cc2c(cc1C(C)=O)N(C)CCO2
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)C)N(C)CCO2
Temperature: 0 °C
Yield: 30 %

Procedure:
1-(7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethanone (10.48 g, 0.473 mol) was dissolved in 25 mL dry THF and the reaction mixture was stirred at 0° C. under nitrogen. Methyl magnesium bromide (22 mL of 3M solution in Et2O, 0.15 mol) was added dropwise, and the reaction mixture was stirred at 0° C. for two hours. The reaction was quenched by dropwise addition of 50 mL 10% aqueous ammonium chloride, followed by water. The aqueous mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was taken up in 95 mL acetic acid, and the reaction mixture was stirred at room temperature under nitrogen. Ammonium formate (14.92 g) and 10% Palladium on activated carbon (1.0 g) were added, and the reaction mixture was heated to 120° C. for three hours. The reaction mixture was cooled, solids were removed by filtration, and the filtrate was diluted with water, and made neutral by addition of solid sodium bicarbonate. The resulting aqueous solution was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure to yield 9.97 g of 6-Isopropyl-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine.