Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([OH:34])[CH2:30]3)[CH2:20][CH2:19]1>>[OH:34][CH:29]1[CH2:30][CH:31]2[N:26]([CH2:25][CH2:24][N:21]3[CH2:22][CH2:23][CH:18]([NH:17][C:11]([C:5]4[NH:6][C:7]5[C:3]([CH:4]=4)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=5)=[O:13])[CH2:19][CH2:20]3)[CH:27]([CH2:33][CH2:32]2)[CH2:28]1
Reactant: NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2C3CCC2CC(O)C3)CC1)c1cc2c(Br)cccc2[nH]1

Procedure:
This compound is synthesized from 4-Bromo-1H-indole-2-carboxylic acid and amine 24 analogously to the method described for 194 (see example 156).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(=O)(O)[O-].[Na+:44]>O1CCOCC1.[Pd].O>[CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O-:20])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:44]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC(=O)OCc3ccccc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SCC(=O)OCc3ccccc3)C[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of p-nitrobenzyl 2-benzyloxycarbonylmethylthio-6-(1-hydroxy)ethyl-carbapen-2-em-3-carboxylate (7.1 mg, 0.014 mmol) in dioxane (0.84 ml) is treated with ethanol (0.07 ml), water (0.49 ml) containing sodium bicarbonate (1.4 mg, 0.017 mmol), and 10% palladium on charcoal (7.1 mg) and the mixture is hydrogenated at 40 psi for 30 minutes. The mixture is diluted to 3 ml with water and centrifuged to remove the catalyst which is washed with more water (2×1 ml). The combined aqueous solution is washed with ethylacetate (4×2 ml), filtered through a cotton plug, concentrated in vacuo to ca. 1 ml, and lyophilized to provide the title compound as a powder: UV (0.1 M pH 7 phosphate buffer) 300 nm; electrophoresis (0.05 M pH 7 phosphate buffer, 2 KV, 25 ma, 20 mins) gives a single bioactive zone migrating 3.5 cm toward the anode.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([CH2:15][C@H:16]2[C@@H:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[C:11]([CH3:41])[CH:10]=1)=O)(C)(C)C.Cl>CO>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][O:21][C@H:20]1[CH2:19][NH:18][CH2:17][C@H:16]1[CH2:15][C:13]1[N:14]=[C:9]([NH2:8])[CH:10]=[C:11]([CH3:41])[CH:12]=1
Reactant: Cc1cc(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2OCCNCCc2cccc(Cl)c2)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(N)nc(C[C@@H]2CNC[C@@H]2OCCNCCc2cccc(Cl)c2)c1
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a solution of 21b (70 mg, 0.10 mmol) in MeOH (2 mL) was added 6 N HCl (4 mL) at room temperature. The mixture was stirred for 12 h and then concentrated. The crude product was purified by recrystallization (EtOH/H2O) to give inhibitor 10 (38 mg, 97%): 1H NMR (500 MHz, CDCl3) δ 2.26 (s, 1H), 2.55-2.65 (m, 1H), 2.78-2.85 (dd, J=7.0, 15.0 Hz, 1H), 2.88-2.95 (dd, J=8.0, 15.0 Hz, 1H), 3.02-3.07 (dd, J=15.5, 16.0 Hz, 1H), 3.25-3.33 (m, 2H), 3.39-3.43 (m, 3H), 3.71-3.74 (t, J=6.5 Hz, 2H), 3.89-3.96 (t, J=15.0 Hz, 2H), 4.29 (s, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 7.50-7.53 (dd, J=5.0, 7.5 Hz, 1H), 7.70-7.73 (d, J=8.0 Hz, 1H), 7.92-7.96 (ddd, J=2.0, 8.0, 8.0 Hz, 1H), 8.45-8.55 (d, J=5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.3, 29.1, 37.8, 42.0, 46.4, 46.9, 50.4, 50.6, 50.8, 53.3, 69.4, 108.0, 114.8, 115.1, 116.7, 118.7, 120.9, 121.0, 126.9, 139.1, 147.4, 149.2, 149.4, 149.6, 149.8, 152.5, 159.3; LC-TOF (M+H+) calcd for C20H28F2N5O 392.2262, found 392.2265.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:26][CH3:27])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:26]([N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:16]([NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1)=[N:17][C:9]=2[NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=1)[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1cnc2c(Nc3ccc(N)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Solvent: ClCCl
Product: CCn1cnc2c(Nc3ccc(NS(C)(=O)=O)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
trans-4-[6-(4-amino-phenylamino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (100 mg, 0.272 mmol) is suspended in 1 ml dichloromethane and treated with 22 μl (0.272 mmol) methanesulfonyl chloride. The reaction mixture is stirred at RT for 48 h. The crude product is recovered by filtration and purified by chromatography on silica gel (CH2Cl2/MeOH 95:5). N-{4-[9-ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6-yl-amino]-phenyl}-methane-sulfonamide is obtained as an amorphous material, 43 mg (36%); MS [M+H]+444; HPLC (System h) tR=4.63 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[Br:14]N1C(=O)CCC1=O.Cl>CN(C)C=O.CO>[Br:14][C:5]1[S:1][C:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(Br)s2)cc1
Reaction time: 2 h

Procedure:
In a two necked flask under argon, 0.75 g (3.98 mmol) of 4-(2-thienyl)benzaldehyde in 20 mL of dimethylformamide (DMF) are cooled to 0° C. 1.1 eq. (0.78 g, 4.38 mmol) of N-bromosuccinimide (NBS) are solubilised in a mixture of 10 mL of DMF and 10 mL of methanol. This solution of NBS (protected from light) is then added drop by drop (30 min) to the reaction medium. The temperature of the medium is then left to return to ambient temperature over 2 h. The medium is hydrolysed with a solution of 1 mol·L−1 HCl and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After filtration and evaporation to dryness, the reaction mixture is recrystallised with acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH:7]([CH:11]([C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.C=O>C(O)C>[C:1]([O:5][C:6](=[O:30])[C:7]([CH:11]([C:22]([N:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[CH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C(=O)O)C(CCCc1ccc(Cl)cc1)C(=O)N1CCCCC1
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(C(=O)OC(C)(C)C)C(CCCc1ccc(Cl)cc1)C(=O)N1CCCCC1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
2-[4-(4-Chloro-phenyl)-1-(piperidine-1-carbonyl)-butyl]-malonic acid tert-butyl ester (2.0 g, 4.6 mmol) was dissolved in ethanol (100 ml) and treated with piperidine (0.43 ml, 5.5 mmol) and 37% w/w formaldehyde (1.9 ml, 23 mmol). The reaction mixture was heated at 50° C. overnight. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (60 ml), and the solution was washed with water (3×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to give the 2-[4-(4-Chloro-phenyl)-1-(piperidine-1-carbonyl)-butyl]-acrylic acid tert-butyl ester as a colourless oil (750 mg, 41%). 1H-NMR: δ (CDCl3), 7.21 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz), 6.19 (1H, s), 5.71 (1H, s), 3.82 (1H, dd, J=4.9, 8.2 Hz), 3.64 (1H, m), 3.51-3.32 (3H, m), 2.67-2.50 (2H, m), 1.90 (1H, m), 1.61-1.38 (9H, m) and 1.48 (9H, s).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:48])([CH3:47])[CH2:10][O:11][C:12]1[CH:46]=[CH:45][C:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[C:33]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH:32]=[CH:31][C:30]=3[CH2:29]2)=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.O1CCCC1.N>ClCCl>[NH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[C:33]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[CH:32]=[CH:31][C:30]=3[CH2:29]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a solution of pivalic acid 6-{2-{[4-(2-tert-butoxycarbonylamino-2-methylpropoxy)benzyl]ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (90 mg) in dichloromethane (1.5 ml) was added trifluoroacetic acid (0.2 ml), and the solution was stirred for 1.5 hours at room temperature. The solution was neutralized by sequentially adding tetrahydrofuran and aqueous ammonia, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (72 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)=[CH:32][CH:31]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Reactant: Nc1ccc(-c2ccncc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Reaction time: 20 h
Yield: 37.9 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(pyridin-4-yl)aniline (60 mg, 0.352 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg, 0.097 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 440.3 (M+H); UV 201.7, 242.5, 278.7 nm; t 0.384 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[S].[CH2:11](N)[CH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:13][CH2:12][CH2:11][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NCCN
Reactant: N#Cc1cccc(Br)c1
Agent: [S]
Product: Brc1cccc(C2=NCCN2)c1

Procedure:
To a solution of 3-bromobenzonitrile (500 mg, 2.75 mmol) in ethylenediamine (3.5 mL) was added sulfur (44 mg, 1.4 mmol). The mixture was refluxed overnight then poured onto ice water, which caused the product to precipitate as a white solid. The product was isolated by vacuum filtration and dried in a vacuum oven (545 mg, 88%). 1H-NMR (CDCl3) δ 7.93 (t, J=1.7 Hz, 1H), 7.68 (ddd, J=7.8, 1.2, 1.2 Hz, 1H), 7.56 (dddd, J=7.8, 0.9, 0.9, 0.9 Hz, 1H), 7.26 (dd, J=10.5, 8.0 Hz, 1H), 3.78 (br s, 4H).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]I>C(O)C>[NH:4]1[CH:5]=[N:6][C:2]([S:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)=[N:3]1
Reactant: ICCCCCCCCI
Reactant: Sc1nc[nH]n1
Solvent: CCO
Product: c1nc(SCCCCCCCCSc2nc[nH]n2)n[nH]1
Yield: 35.2 %

Procedure:
20 mmole of 3-mercapto-1H-1,2,4-triazole (potassium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 1,8-diiodooctane was added dropwise to the solution of 3-mercapto-1H-1,2,4-triazole (potassium salt), and stirred overnight. After the solvent was evaporated in vacuum, the residual was washed with 50 ml pure H2O for three times, and then with 50 ml hexane for 3 times. At last, the residual was dried in oven at 60° C. for 24 hours. 1.1 g product was obtained as white solid. Yield: 30%. 1H NMR (DMSO): δ(ppm) 8.34 (2H, s), 3.04 (4H, t, JH-H=7.14), 1.61 (4H, m), and 1.23-1.32 (8H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][C:44]12[CH2:51][CH2:50][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])([CH2:48][CH2:49]1)[CH2:46][CH2:45]2>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:43][C:44]34[CH2:45][CH2:46][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])([CH2:50][CH2:51]3)[CH2:48][CH2:49]4)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Product: CCOC(=O)C12CCC(NC(=O)C34CCC(N(CC(=O)N5C[C@@H](F)C[C@H]5C#N)C(=O)OCc5ccccc5)(CC3)CC4)(CC1)CC2
Yield: 73.5 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (22.3 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)=[O:4]>CO.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)=[CH:23][CH:24]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 101.6 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (25 g, 109 mmol) and triethyl phosphate (24.3 ml, 142 mmol) was stirred at 150° C. for 24 h. The resulting mixture was purified by distillation (165-172° C., 1 mmHg) to obtain diethyl 4-(methoxycarbonyl)benzylphosphonate (21.5 g, 69%). To a mixture of diethyl 4-(methoxycarbonyl)benzylphosphonate (20.5 g, 71.5 mmol), 15-crown-5 (1.4 ml, 7.1 mmol) and THF (120 ml) was added sodium hydride (60% in oil, 2.9 g, 71.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11.9 g, 59.6 mmol) in THF (45 ml) was added dropwise to the resulting mixture over period of 10 min at 0° C. The mixture was stirred at room temperature for 20 h. The resulting mixture was poured into ice-water (200 ml) and the whole was extracted with ethyl acetate (100 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate(100 ml), saturated sodium chloride solution (100 ml) successively. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 200 g, ethyl acetate/hexane=1/10) followed by recrystallization from hexane to give tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6.9 g, 35%) as a colorless crystalline powder. A mixture of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was hydrogenated over 10% palladium carbon (50% wet, 1 g) for 5 h at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to obtain the title compound (6.1 g, 100%) as pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=1[NH:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]1)([O-])=O.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:17])[CH3:18])=[CH:6][C:5]=1[NH:22][C@@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:27][CH2:28]1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](Nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc2N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-methyl 4-(2-nitro-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate (2.77 g, 5.96 mmol) and palladium (10% on carbon) (0.634 g, 0.596 mmol). To this was added EtOH (48.5 mL) followed by ammonium formate (3.76 g, 59.6 mmol). The reaction mixture was stirred at RT for 2 hours and then diluted with EtOH and filtered through Celite® brand filter aid. The filter cake was washed sequentially with DCM (100 mL), EtOH (100 mL), and MeOH (100 mL). The filtrate was concentrated, re-diluted with DCM (100 mL) and washed with brine. The organic layer was collected, dried over sodium sulfate and concentrated to afford cis-methyl 4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate as a brown oil (2.58 g, 100% yield). MS m/z=435.2 [M+H]. Calc'd for C24H42N2O3Si: 434.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:10]([N:13]1[CH2:18][CH2:17][C:16]([C:25]#[N:26])([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH2:8][CH3:9].O.[OH-].[Na+]>C(OCC)C>[CH2:7]([S:10]([N:13]1[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH2:8][CH3:9]
Reactant: CCCS(=O)(=O)N1CCC(C#N)(N2CCCCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCS(=O)(=O)N1CCC(CN)(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of lithium aluminium hydride in diethyl ether (1 M, 1.6 mL) at −78° C. was added a solution of 1′-(propylsulfonyl)-1,4′-bipiperidine-4′-carbonitrile (0.40 g, 1.34 mmol) in diethyl ether (10 mL) over 30 min. The mixture was stirred cold for 1 h then allowed to warm to room temperature and stirred for 2 h. The resultant mixture was cooled in an ice-bath and to the mixture was added water (0.17 mL), 15% NaOH solution (0.17 mL) then water (0.17 mL). The resultant white granular solid was filtered off and the filter-cake rinsed twice with diethyl ether. The filtrate was evaporated to give {[1′-(propylsulfonyl)-1,4′-bipiperidin-4′-yl]methyl}amine as a clear oil which was used in the next step without further purification; m/z (ES+) 304 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12](Cl)=[O:13].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH3:9])=[CH:3][CH:4]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc(O)cc1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-aminophenol (3.27 g, 30.0 mmol) in dichloromethane (50 ml) were added 3,3-dimethyl-butyryl chloride (8.08 g, 60.0 mmol) and pyridine (4.85 ml, 60.0 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 35 ml) was added, the mixture was stirred at room temperature overnight and the solvent was removed by evaporation. Water (200 ml) was added and the solid material is collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (3.37 g) in methanol (50 ml) was added. After stirring for 2 days at room temperature water (300 ml) was added, the organic solvent was removed and the aqueous phase was acidified with 1 N HCl. The solids were collected and dried yielding the title compound (1.97 g, 31% yield, pink solid). The mother liquor was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with saturated sodium bicarbonate (2×250 ml), dried over sodium sulphate, filtered and evaporated yielding a second amount of the title compound (0.67 g, 10%). From the first aqueous extract another portion of product was isolated by extraction with ethyl acetate (4×250 ml). The combined organic phases were washed with water (400 ml), dried, filtered and evaporated yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a third amount of the title compound (2.11 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=O)=[CH:9][N:10]=2)[N:7]=1.[BH4-].[Na+].O.C([SiH](CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(C(=O)c2cnc3ccc(Cl)nn23)cc1
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2cnc3ccc(Cl)nn23)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The compound (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(4-methoxy-phenyl)-methanone (Stage 3.2, 2.04 g, 7.1 mmol) was suspended in ethanol (20 mL) with sodium borohydride (140 mg, 3.6 mmol) and stirred at rt for 7 h. Then water was added and the precipitate formed was filtered off. The yellow solid obtained was dried and then dissolved in TFA (50 mL). Triethylsilane (2.85 mL, 17.7 mmol) was added to the solution and it was stirred at rt for 30 min. the RM was poured into ice water. It was extracted with EtOAc and washed with aqueous 1 N sodium hydroxide solution then with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography with DCM and MeOH. The title compound was obtained As a white solid (tR 1.1 min (conditions 2), MH+=274).