Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)n1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: c1ccc(COc2cccc(N3CCCC3)n2)cc1
Yield: 95.3 %

Procedure:
In a dried microwave reactor, 526 mg (2.0 mmol) of 2-(benzyloxy)-6-bromopyridine and 1.70 ml (20 mmol) of pyrrolidine were placed, and the mixture was reacted using microwave at 150° C. for 10 min. The reaction mixture was mixed with 20 ml of water, extracted twice with 100 ml portions of ethyl acetate, and the organic layer was separated dried over anhydrous and kept under a reduced pressure to remove the solvent. The residue thus obtained was subjected to column chromatography using 10% ethyl acetate/hexane as an eluent to obtain 485 mg (yield 95%) of 2-(benzyloxy)-6-(pyrrolidin-1-yl)pyridine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]2[CH2:13][S:12][C:11]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=4[NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:10]2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41].O>ClCCl>[Cl:23][C:19]1[CH:20]=[C:21]2[C:16](=[C:17]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=1)[NH:15][C:14]([C:11]1[S:12][CH2:13][C@@H:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:3]3)[N:10]=1)=[CH:22]2
Reactant: N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
The compound (85 mg, 0.19 mmol) prepared in Example 115 was dissolved in dichloromethane (10 ml). Diisopropylethylamine (0.13 ml, 0.75 mmol) and acetyl chloride (0.013 ml, 0.19 mmol) were added thereto, and the mixture was stirred for 30 min at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39 mg, Yield 42%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)([CH3:42])[C:39](O)=[O:40])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:38]([CH3:42])([C:39]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:40])[CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NCCC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(C)(CCNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Reaction time: 8 h
Yield: 62.4 %

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoic acid (27.0 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred overnight, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), eluted by a mixture of EtOAc and hexane (60:40) to give tert-butyl 3-(4-chlorophenyl)-3-methyl-4-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobutylcarbamate as a clear oil (27 mg, 74%). LCMS (APCI+) [M+H]+ 528.1; Rt: 3.38 min.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][C:21]=2[F:30])=[C:14]([CH3:31])[N:13]=1>C1COCC1.CCOC(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[F:30])=[C:14]([CH3:31])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminium hydride (1M in hexanes, 8.8 mL) was added dropwise over 10 min to a suspension of the product from example 22 step (iii) (0.78 g) in THF (10 mL) at 0° C. The mixture was allowed to warm to rt and stirred for 1 h. EtOAc (10 mL) was added and then the mixture stirred for 10 min before being added to ice/water (100 mL). The mixture was stirred for 30 min and then diluted with EtOAc (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to afford the subtitle compound, 0.3 g. 1H NMR (DMSO-d6); δ 7.11 (d, 1H), 7.04 (d, 1H), 6.89 (s, 1H), 6.84 (dd, 2H), 5.27 (t, 1H), 4.46 (d, 2H), 3.92 (s, 2H), 2.21 (s, 3H)
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]#[N:29])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(C#N)cc12
Temperature: 120 °C
Yield: 76 %

Procedure:
In a microwave vial was degassed with argon for 15 min. a mixture of 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (50 mg, 0.118 mmol), zinc cyanide (14 mg, 0.118 mmol) in dimethylformamide (1.5 ml). Tetrakis(triphenylphosphine)palladium (4 ma, 0.003 mmol) was added and the vial was sealed and heated at 120° C. under microwave irradiation for 10 min. The mixture was diluted with ethyl acetate, washed with a 5% aqueous solution of ammonia, brine and dried over sodium sulfate. The solution was concentrated and purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-20%) to yield 6-cyano-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (33 mg, 76%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]2[N:22]=[CH:23][CH:24]=[CH:25][C:15]1=2.CC(C1C=C(C(C)C)C(S([N:41]=[N+:42]=[N-:43])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>C1COCC1>[N:41]([CH:19]1[C:20](=[O:21])[N:14]([CH3:13])[C:15]2[CH:25]=[CH:24][CH:23]=[N:22][C:16]=2[CH2:17][CH2:18]1)=[N+:42]=[N-:43]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CN1C(=O)CCCc2ncccc21
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN1C(=O)C(N=[N+]=[N-])CCc2ncccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 2.5 eq of diisopropylamine in 50 mL of dry THF was cooled to −78° C. While stirring, 2.4 eq of n-BuLi (2.5 M in hexanes) was added dropwise. The reaction mixture was warmed to 0° C. After stirring for 30 min, the solution was cooled to −78° C. and 1.0 eq of 97 dissolved in 20 mL of dry THF was added. After stirring at −78° C. for 30 min, 1.5 eq of trisyl azide was added. The mixture was stirred, as it warmed to rt. After 17 hrs, 4.5 eq of 17 M glacial acetic acid was added and stirred at rt for 5 hrs. The reaction mixture was rotary evaporated and 30 mL of saturated NaHCO3 was added. The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and flash chromatographed on silica using EtOAc as eluent. After concentration and drying under vacuum of the fractions containing product, a brownish colored solid was obtained as 98.
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].[C:5]([O:8][C@H:9]1[C@@H:14]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:13][C@H:12]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:10]12[CH3:11])[C@:28]1([CH3:29])[C@H:23]([CH2:24][C@H:25]([OH:39])[C@@H:26]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:27]1)[CH2:22][CH2:21]3)(=[O:7])[CH3:6]>ClCCl>[Br-:4].[C:5]([O:8][C@H:9]1[C@@H:14]([N+:15]2([CH2:3][CH:2]=[CH2:1])[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:13][C@H:12]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:10]12[CH3:11])[C@:28]1([CH3:29])[C@H:23]([CH2:24][C@H:25]([OH:39])[C@@H:26]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:27]1)[CH2:22][CH2:21]3)(=[O:7])[CH3:6]
Reactant: C=CCBr
Reactant: CC(=O)O[C@H]1[C@@H](N2CCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Solvent: ClCCl
Product: C=CC[N+]1([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCOCC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2OC(C)=O)CCCC1
Product: [Br-]

Procedure:
2-propenyl bromide (1.95 ml) was added to a solution of (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16(1-pyrrolidinyl)-androstane-3,17-diol 17-acetate (1.35 g) in dichloromethane (27 ml) and the solution was sealed in a pressure bottle at room temperature for 22 h. The solvent was removed under reduced pressure with the minimum of heating and the crude solid (1.59 g) was chromatographed on alumina (Fluka type 5016A). The pure fractions were combined, taken up in dichloromethane (15 ml) and diethyl ether (100 ml) was added to precipitate pure 1-[(2β,3α,5α,16β,17β)-17-acetyloxy-3-hydroxy-2-(4-morpholinyl)-androstan-16-yl]-1-(2propenyl)-pyrrolidinium bromide (1.14 g), m.p. 161°-169° C.; [α]D20 =+18.7° (c 1.03 in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([NH2:12])[N:8]=1.C(N[C:16]([C:18]1S[CH:20]=[CH:21][C:22]=1[Cl:23])=O)#N.Cl.NO.O.N1C=CC=[CH:30][CH:29]=1>>[Cl:23][C:22]1[CH:21]=[CH:20][C:29]([CH:30]=[N:12][C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[O:11][N:10]=2)=[CH:16][CH:18]=1
Reactant: Nc1noc(-c2sccc2Cl)n1
Reactant: c1ccncc1
Reactant: N#CNC(=O)c1sccc1Cl
Agent: Cl
Agent: NO
Solvent: O
Product: Clc1ccc(C=Nc2noc(-c3sccc3Cl)n2)cc1
Yield: 37 %

Procedure:
5-(3-Chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-ylamine: A solution of N-cyano-3-chloro-thiophene-2-carboxylic acid amide (467.5 mg, 2.5 mmol), hydroxylamine hydrochloride (174 mg, 2.5 mmol) in pyridine (5 mL) was heated at 100° C. for 8 h. It was cooled and poured into water (80 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water, 1N HCl, dried with Na2SO4, and concentrated. The crude residue was purified by column chromatography (hexane:ethyl acetate, 10:1) to yield 189 mg (37%) of title compound. 1H NMR (CDCl3): 7.56 (d, J=5.4 Hz, 1H), 7.09 (d, J=5.4 Hz, 1H), 4.49 (brs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23]N=3)=[CH:17][CH:16]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)([CH3:6])[CH3:5].[CH3:34]OC(=O)C(C1C=CC(S)=C(OC)C=1)(C)C>>[CH3:1][O:2][C:3](=[O:33])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:34]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(S)c(OC)c1
Reactant: COC(=O)C(C)(C)c1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c(OC)c1
Product: COC(=O)C(C)(C)c1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(OC)c1
Yield: 34 %

Procedure:
Compound 47A was prepared analogously to compound 21D using the product prepared from compound 21C. Yield was 34% after flash column purification. MS m/z 475 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:24]([O:28][C:29]([C:30]1[O:17][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 140 °C
Yield: 71.8 %

Procedure:
To a solution of 4-benzyloxy-2-hydroxy-benzaldehyde (5.56 g, 24.4 mmol) in DMF (20 mL) is added K2CO3 (6.73 g, 48.8 mmol), bromo-acetic acid tert-butyl ester (4.75 g, 24.4 mmol), and DBU (1.0 mL). The mixture is heated to 140° C. for 2 hours and cooled to room temperature. The mixture is quenched with water (200 mL) and extracted with EtOAc (100 mL). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography cluting with 15% EtOAc/Hexanes to provide the title compound (5.68 g, 72%). LC-ES/MS m/e 269.0 (acid, M+1)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[CH3:19][N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1>>[Cl:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@H:3]([CH3:4])[CH2:2][NH:1][C:25]([C:23]3[N:22]=[CH:21][N:20]([CH3:19])[CH:24]=3)=[O:26])[N:6]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](CNC(=O)c1cn(C)cn1)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 14.4 %

Procedure:
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg, 1.15 mmol) was coupled with 1-methyl-1H-imidazole-4-carboxylic acid (174 mg, 1.38 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 61 mg (14%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.45 (d, 3H), 3.52-3.72 (m, 4H), 3.67 (s, 3H), 4.63-4.75 (m, 1H), 6.95 (d, 1H), 7.62 (dd, 1H), 7.89 (d, 1H), 7.99 (s, 1H), 8.00 (s, 1H), 8.10 (t, 1H), 8.18 (t, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20](=[O:23])[NH:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[N:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction scheme 1 shows that the compounds of formula I can be, for example, prepared starting from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester which is reacted in a first reaction step with tert-butylcarbazate to give 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester (starting compound A7). Compound A7 is reduced with, for example, the boran tetrahydrofurane complex to give 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (starting compound A6). Treatment of compound A6 with concentrated hydrochloric acid results in the formation of piperidin-4-yl-hydrazine dihydrochloride (starting compound A5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30](Cl)=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=2)=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:30]3[CH:31]=[CH:32][C:27]([C:26](=[O:37])[NH:25][C:22]4[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=4)=[CH:28][C:29]=3[N+:34]([O-:36])=[O:35])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(S)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of the product of Example 89C (39.9 mg, 0.160 mmol) in anhydrous ethanol (2 mL) under a nitrogen atmosphere was treated with the product of Example 10A (56.8 mg, 0.160 mmol) and anhydrous sodium acetate (66 mg, 0.800 mmol) at room temperature, then heated at reflux for 2 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (50 mL) and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel flash chromatography using methylene chloride as eluent afforded the title compound as a yellow solid (77 mg, 85%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C[O:8][C:9]([C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)=[O:10].[OH:18][C:19]([CH3:52])([CH3:51])[CH2:20][C@@:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:26][C:25](=[O:27])[N:24]([C@H:28]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH3:29])[CH2:23][CH2:22]1>CN(C)C=O>[OH:18][C:19]([CH3:51])([CH3:52])[CH2:20][C@@:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:26][C:25](=[O:27])[N:24]([C@H:28]([C:30]2[CH:31]=[CH:32][C:33]([C:14]3[N:13]=[N:12][C:11]([C:9]([OH:8])=[O:10])=[CH:16][CH:15]=3)=[CH:34][CH:35]=2)[CH3:29])[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (1.46 mL) was added to a mixture of 6-chloropyridazine-3-carboxylic acid methyl ester (0.38 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.70 g) in N,N-dimethylformamide (8 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) dichloromethane complex (72 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling the mixture to ambient temperature, water and 1 M hydrochloric acid were added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/F3CCO2H) to afford the title compound as an oil that solidifies while standing. Yield: 0.36 g (52% of theory); Mass spectrum (ESI−): m/z=474 [M−H]−.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([O:17][C:18]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][C:19]=1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(#N)C.CCOCC>[CH2:10]([O:17][C:18]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:31][C:19]=1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:29])=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCO
Reactant: O=C(Cl)CCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Solvent: CC#N
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)CCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Yield: 53.6 %

Procedure:
0.66 g (5 mmol) of 1-octanol was dropwise added to the solution of 1.5 g (3.2 mmol) of 6-{N-[2,5-di(benzyloxy)benzoyl]amino}hexanoyl chloride in 15 ml of anhydrous acetonitrile and 0.29 g (3.7 mmol) of anhydrous pyridine during 5 minutes under cooling and stirring at 0°-5° C. The reaction mixture was stirred at room temperature for 10 hours, then evaporated under reduced pressure to dryness at a temperature below 50° C. The residue obtained was dissolved in 40 ml of ether and was successively washed with water, 2% sodium hydroxide solution and finally with water, then dried and evaporated under reduced pressure. The residue was purified on a silicagel column by using ethyl acetate as eluent to give 0.96 g (54%) of the aimed compound, m.p.: 48°-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][O:11][CH2:12][CH3:13])=[C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:5]=[C:4]([CH3:20])[N:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:10][O:11][CH2:12][CH3:13])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: CCOCC(=O)Nc1c(NCC(C)C)cc(C)nc1Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOCc1nc2c(Cl)nc(C)cc2n1CC(C)C
Temperature: 110 °C

Procedure:
N-(2-Chloro-4-(2-methylpropylamino)-6-methylpyridin-3-yl]-2-ethoxyacetamide (26.43 g), anhydrous toluene (400 ml), and phosphorus oxychloride (74 ml) were combined and heated to 110° C. for 16 hours. HPLC analysis of the resulting reaction mixture indicated 30% completion. The reaction mixture was heated to reflux for an additional 24 hours when the reaction was found to be complete. The resulting reaction mixture was cooled, and the phosphorus oxychloride and toluene were removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate and water, and the aqueous layer was made basic with sodium carbonate. The basic aqueous layer was washed with ethyl acetate (2×). The organic layers were combined, dried with magnesium sulfate, and concentrated to a black oil under reduced pressure. The oil was extracted with hot hexane. The resulting hexane solution was filtered hot, and the filtrate was cooled to below 0° C. overnight The resulting orange and black crystals were washed with cold hexane. NMR analysis of the resulting product (14.02 g) indicated only minor impurities, and the product was carried on to the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2ccnn2)cc1
Temperature: 25 °C

Procedure:
4-Nitrobenzylbromide (25.4 g, 0.12mol) was added to a solution of 1H-1,2,3-triazole (8.12 g, 0.12 mol) and triethylamine (11.88 g, 0.12 mol) in anhydrous acetonitrile. The mixture was refluxed for 1 h, cooled to room temperature and the precipitated NEt3. HBr filtered off. The solvent was removed under vacuum and the residue chromatographed through silica gel eluting with CH2Cl2 (100) to CH2Cl2 /MeOH (95.5) to give 2-products. The more polar product was identified as the title-1-isomer (13 g, 54%); mp 114°-116° C. δ (250 MHz, CDCl3) 5.72 (2H, s, CH2), 7.38 (2H, d, J=9 Hz, Ar--H), 7.64 (1H, s, Ar--H), 7.78 (1H, s, Ar--H), 8.18 (2H, d, J=9 Hz, Ar--H). The less polar, minor isomer was identified as the 2-alkylation product (2.25 g, 9%), mp 112°-113° C. δ (250 MHz, CDCl3) 5.72 (2H, s, CH2), 7.40 (2H, d, J=9 Hz, Ar--H), 7.66 (2H, s, Ar--H), 8.18 (2H, d, J=9 Hz, Ar--H).