Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[CH2:13][N:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH:10]([CH3:20])[N:9]1[CH2:21][CH2:22][CH2:23][NH-:24]>C(OCC)C.C1COCC1>[CH3:7][CH:8]1[CH2:13][N:12]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:11][CH:10]([CH3:20])[N:9]1[CH2:21][CH2:22][CH2:23][NH2:24]
Reactant: CC1CN(c2ncccn2)CC(C)N1CCC[NH-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1CN(c2ncccn2)CC(C)N1CCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
50 mg (1.54 mmol) of LiAlH4 were added to a solution of 0.2 g (0.77 mmol) of 3-[2,6-dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamide in 5 ml of diethylether and 5 ml of THF. The mixture was stirred one hour at room temperature and one additional hour at reflux, then the reaction was quenched by successive addition of 50 ul of water, 50 ul of 15% aqueous NaOH and 3×50 ul water. The mixture was diluted with diethyl ether, filtered, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silicagel (CH2Cl2, EtOH, NH4OH: 45, 5, 1) to afford 0.037 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18]O)[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][F:27])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](CO)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@@H](CF)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
(4R)-3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(hydroxymethyl)-1,3-oxazolidin-2-one (0.71 g, 2.0 mmol), prepared in Example 71, was dissolved in 20 mL methylene chloride and cooled to 0° C. (Diethylamino)sulfur trifluoride (0.295 mL, 2.20 mmol) was added dropwise. The mixture was warmed to 25° C. and stirred for 2.5 h. The reaction was quenched with water and saturated NaHCO3 and the mixture was extracted with methylene chloride. The organics were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (8% acetone/hexane) afforded the title compound (243 mg, 34%) as a white solid. mp 148-150° C. HRMS: calcd for C13H10BrFN2O2S+H+, 356.97031; found (ESI, [M+H]+), 356.9705. Analytical HPLC: retention time 10.2 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH 3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].CN(C=O)C.I[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH3:19])=[CH:4][C:3]=1[Cl:9]
Reactant: CCI
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc(Br)c(Cl)c1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
The 4-Bromo-3-chloro-phenol (24 mmol, 5 g) in anhydrous THF (50 mL) was added to a stirred solution of NaH (60%) in mineral oil, 120 mmol, 4.8 g) in THF (100 mL) and DMF (42 mL) under N2 at room temperature. This solution stirred for 30 minutes. The iodethane (240 mmol, 19.2 mL) was then added. The solution was stirred and was refluxed overnight. The reaction was cooled and quenched with 1 N HCl (150 mL), extracted into CH2Cl2 (2×150 mL), dried over MgSO4, concentrated in vacuo, and distilled under vacuum yielding 1-bromo-2-chloro-4-ethoxybenzene as a brown oil (4.59 g, 81%). 1H NMR (CDCl3, 300 MHz): δ7.42 (1H, d, J 8.7 Hz), 6.96 (1H, d, J 2.9 Hz), 6.64 (1H, dd, J 8.8 and 2.5 Hz), 3.95 (2H, q, J 7.0 Hz), 1.39 (3H, t, J 7.0 Hz.)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1/[N:19]=[C:20](\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)/[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[C:22]=1[OH:36])([CH3:9])[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:17])[CH3:18])[C:11]=1[NH:19][CH:20]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[C:22]=1[OH:36])([CH3:8])[CH3:9]
Reactant: COc1ccccc1-c1cc(C)cc(/C(=N/c2c(C(C)C)cccc2C(C)C)c2ccccc2)c1O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(C)cc(C(Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)c1O
Reaction time: 4 h
Yield: 64.2 %

Procedure:
To a suspension of 0.34 g (8.0 mmol) of LiAlH4 in 25 mL of THF, 1.19 g (2.50 mmol) of 35 was added. The obtained mixture was stirred for 4 hr, and then a saturated aqueous solution of Na2SO4 was added. The organic layer was separated, and the aqueous layer was washed by 2×50 mL of diethyl ether. The combined organic extract was evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 20:1, vol.) to yield 0.77 g (64%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH2:9](I)[CH3:10].[Li+].CC([N-]C(C)C)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][CH3:10]
Reactant: CCI
Reactant: Brc1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(Br)cccc1Br
Temperature: -78 °C
Reaction time: 2.75 h

Procedure:
A three necked round-bottom flask was purged with argon and then filled with dry THF (1.2 l), 1,3-dibromo benzene (121 g, 0.514 mol) and ethyl iodide (95.4 g, 0.611 mol). The mixture was cooled to −78° C. and LDA (64.2 g, 0.697 mol) (2 M in THF/n-heptane/ethyl benzene) was added slowly in a way that the temperature did not rise above −65° C. After stirring for 2.75 h the reaction was poured onto 1 l sat. aq. NH4Cl solution and stirred vigorously for 20 min. Two times extraction with DCM yielded colorless oil (167 g) which was used in the next step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2([NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[N:27]5[C@@:28]([CH2:41][C:42]6[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=6)([CH3:40])[C:29](=[O:39])[N:30]([C:31]6[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=6)[C:26]5=[N:25][CH:24]=4)=[O:22])[CH2:19][CH2:18]3)=[O:16])[CH2:13][CH2:12]2)[CH:6]=1.CCN(C(C)C)[CH:53]([CH3:55])[CH3:54].BrCCCBr>CC(N(C)C)=O.CCOC(C)=O>[N:3]1([CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]3([NH:14][C:15]([C:17]4([NH:20][C:21]([C:23]5[N:27]6[C@@:28]([CH2:41][C:42]7[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=7)([CH3:40])[C:29](=[O:39])[N:30]([C:31]7[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=7)[C:26]6=[N:25][CH:24]=5)=[O:22])[CH2:18][CH2:19]4)=[O:16])[CH2:12][CH2:13]3)[CH:6]=2)[CH2:55][CH2:53][CH2:54]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Reactant: CCN(C(C)C)C(C)C
Agent: BrCCCBr
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN6CCC6)ccn5)CC4)CC3)n21
Temperature: 100 °C
Yield: 13 %

Procedure:
To the solution of (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide dihydrochloric acid salt (60 mg, 0.081 mmol) in dry DMA (5 mL) was added DIPEA (0.071 mL, 0.405 mmol) followed by 1,3-dibromopropane (0.0415 mL, 0.405 mmol). The reaction mixture was heated in the microwave at 100° C. for 2×10 min. Diluted with EtOAc (50 mL). Washed with saturated NaHCO3 (2×25 mL). Layers were separated. The organic layer was dried, filtered, and concentrated. The resultant crude product was purified by prep-TLC using 5% MeOH/DCM as the eluent. The prep TLC plate looked messy, presumably due to the significant existence of DMA. The product fraction was collected and redissolved in EtOAc (50 mL), washed with water (3×15 mL), dried, filtered, and concentrated. The crude product was purified by prep-TLC using 5% MeOH/DCM as the eluent to afford 7.5 mg of the title compound as a light yellow solid, m/z 709.8 [M+1]+.
Reaction SMILES: C[O-].[Na+].[C:4]([O:10]C)(=O)[C:5]([CH3:8])([CH3:7])[CH3:6].[C:12](#[N:14])[CH3:13].Cl>O.C1(C)C=CC=CC=1.CS(C)=O>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:10])[CH2:13][C:12]#[N:14]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(=O)CC#N
Temperature: 82 °C

Procedure:
In the reaction apparatus described in Example 4 were placed 40.5 g (0.75 mol) of sodium methoxide, 58.1 g (0.50 mol) of methyl pivalate, 30.8 g (0.75 mol) of acetonitrile, and 58.1 g of dimethyl sulfoxide (relative dielectric constant at 20° C.: 48.9) under nitrogen atmosphere. The mixture was heated under reflux at 82° C. for 6 hours. After the reaction was complete, 400 mL of toluene was added to the reaction mixture. To the mixture were added 56.7 mL (0.68 mol) of hydrochloric acid (12 mol/L) and 100 mL of water, keeping the temperature of the resulting mixture at 30° C. or lower. After the reaction mixture became to have pH 2.0, the mixture was extracted with 3 portions of 100 mL toluene. The toluene portions were combined and washed with 30 mL of an aqueous saturated sodium hydrogen carbonate solution and then dried over magnesium sulfate. The toluene solution was filtered and then analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that the following products were produced:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(Sc2ccnc(Cl)c2)cc1
Yield: 84.8 %

Procedure:
Using the method of Example 3, Step A, 4-chlorobenzenethiol (912 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(4-chlorophenylthio)pyridine (1.37 g, 85% yield) as an oil. 1H NMR (CDCl3) δ 8.14 (d, 1H), 7.48 (d, 2H), 7.46 (d, 2H), 6.90 (s, 1H), 6.85 (d, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17][CH:16]2[CH3:23])[C:10]=1[F:24].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17][CH:16]2[CH3:23])[C:10]=1[F:24])[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC1CCC(C)N(c2ncnc(Cl)c2F)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2CCC(C)CCC2C)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
0.07 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. The 0.5 ml of tetrahydrofuran solution of 0.12 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.34 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-2,5-dimethyl-hexahydro-1H-azepine at room temperature, and stirred for 8 hours at 60° C. After the reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-2,5-dimethyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (35)).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[C:3]1[CH3:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:52]([O:54][C:55](=[O:76])[C@H:56]([O:58][C:59]1[CH:64]=[C:63](Cl)[N:62]=[C:61]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:60]=1)[CH3:57])[CH3:53]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:61]1[N:60]=[C:59]([O:58][C@H:56]([CH3:57])[C:55]([O:54][CH2:52][CH3:53])=[O:76])[CH:64]=[C:63]([NH:10][S:7]([C:5]2[N:4]=[C:3]([CH3:11])[N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[N:62]=1
Reactant: Cc1nc(S(N)(=O)=O)cn1C
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2cn(C)c(C)n2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 1,2-Dimethyl-1H-imidazole-4-sulfonic acid amide (0.19 g), tris(dibenzylideneacetone)dipalladium (0) (56 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (41 mg), cesium carbonate (0.32 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 11 step i) (0.24 g) and dioxane (20 mL). Purification was by column chromatography on silica gel using DCM/MeOH (100:1 to 90:10 gradient) as eluent, to give the title compound as a pale yellow solid. Yield: 0.25 g
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][CH:7]=1.O=C1CCC(=O)N1[O:23][C:24](=O)[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:25][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:3]2[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cncnc1NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: Cc1cncnc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine (0.20 g, 0.97 mmol), in DMF (3 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.24 g, 0.97 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–10 (10% NH4OH in MeOH)/99–90 CH2Cl2) to give 4-[(5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:30])[C:14]([O:16][CH:17]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[CH3:18])=[O:15]>>[CH3:12][CH:13]([CH3:30])[C:14]([O:16][CH:17]([O:19][C:20]([CH:10]([NH2:11])[C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:21])[CH3:18])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)C
Product: CC(OC(=O)C(C)C)OC(=O)C(N)[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2-methylpropanoate were reacted to yield the title compound 13 (333 mg, 53% yield) as a colorless powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.058 (d, J=6.4 Hz, 3H), 1.062 (d, J=6.8 Hz, 3H), 1.17-1.36 (br. m, 3H), 1.38 (d, J=5.6 Hz, 3H), 1.65-1.73 (br. m, 2H), 1.83-1.91 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.49 (hept., J=6.8 Hz, 1H), 2.77-2.85 (br. m, 2H), 6.62 (q, 5.2 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.08 (M+Na)+; 314.01 (M−H)−.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:38]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[O:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:39]
Reactant: CC(C)[Si](O[C@@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)[Si](O[C@@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 60 °C
Yield: 27.9 %

Procedure:
To a solution of Intermediate A (123 mg, 0.755 mmol) in DMF (4 mL) was added NaH (60% in oil, 82 mg, 2.06 mmol) and the mixture stirred at RT for 20 min, before Intermediate 38b (260 mg, 0.687 mmol) was added. This mixture was heated at 60° C. in the microwave for 3 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH3 in MeOH] in DCM, gave the title compound as a viscous yellow oil (100 mg, 23%). LCMS (Method 1): Rt 2.90 min, m/z 522 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13](O)=[O:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1.B.C1COCC1>C1COCC1>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][OH:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCS2
Agent: B
Solvent: C1CCOC1
Product: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
0.32 g of (RS)-2-(4,4-dimethyl-thiochroman-6-yl)-heptanoic acid were dissolved in 5 ml THF and treated dropwise, at 0° C., with 5.23 ml of 1M BH3.THF in THF. The mixture was stirred at 0° C. for two hours and then was quenched at 0° C. with careful addition of one portion of 5 ml of 3N HCl. The mixture was stirred at room temperature for 30 min. then was extracted with three portion of 25 ml of ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), yielding 0.31 g of a colorless oil. 1H NMR (CDCl3): 7.10 (d, J=1.9 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.81 (dd, J=8.1, 1.9 Hz, 1H), 3.65 (dd, J=10.7, 5.9 Hz, 1H), 3.57 (dd, J=10.7, 8.4 Hz, 1H), 3.00-2.90 (m, 2H), 2.65-2.55 (m, 1H), 1.95-1.85 (m, 2H), 1.65-1.35 (m, 2H), 1.26 (s, 6H), 1.25-1.05 (m, 6H), 0.87 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:7]2[CH:6]=[C:5]([Cl:9])[N:4]=[N:3][C:2]=2[Cl:1])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3,4,6-Trichloropyridazin (10.5 g; 57.25 mmol) was dissolved in 10 ml of dry NMP. Afterwards were added DIPEA (28.4 ml; 171.73 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.04 g; 60.11 mmol) and all let stir at ambient temperature for 16 hours and 3 hours at 50° C. The reaction mixture was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][NH:21]4)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].I[CH2:32][CH2:33][F:34]>CN(C=O)C>[F:34][CH2:33][CH2:32][N:21]1[CH2:20][C@@H:19]2[CH2:24][C@H:22]1[CH2:23][N:18]2[CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1
Reactant: FCCI
Reactant: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4CCF)CC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To (1S,4S)-2-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2,5-diazabicyclo-[2.2.1]heptane (0.40 g, 1.2 mmol) and K2CO3 (0.38 g, 2.8 mmol) in DMF (10 mL) was added 1-iodo-2-fluoroethane (0.26 g, 1.5 mmol), and the reaction was stirred overnight. More 1-iodo-2-fluoroethane (50 mg, 0.29 mmol) was added, and the solution stirred an additional 4 h. The solvent was removed under vacuum, and the residue was taken up in DCM. Silica was added, and the solvent removed under vacuum. Silica gel chromatography provided the title compound of step C as a yellow oil (230 mg, 0.61 mmol, 49% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=9.3 Hz, 1H), 6.38 (dd, J=9.3, 2.4 Hz, 1H), 6.27 (d, J=2.4 Hz, 1H), 4.58-4.39 (m, 2H), 3.91 (s, 3H), 3.82-3.73 (m, 2H), 3.51 (br s, 1H), 3.34 (br s, 1H), 3.08-2.98 (m, 2H), 2.96-2.53 (m, 7H), 1.96-1.65 (m, 4H), 1.59-1.46 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([OH:14])[C:3]=1[C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([O:33][CH2:34][CH2:35][O:14][C:4]1[C:3]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[C:2]([NH2:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OCCBr
Reactant: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a stirred mixture of 5-amino-4-(1,3-benzodioxol-5-yl)-1-benzyl-1H-pyrazol-3-ol (30 g) (Preparation 59) and cesium carbonate (94.8 g) in anhydrous dimethylformamide (340 ml), under an atmosphere of nitrogen, 2-bromoethyl acetate (16.2 g) was added drop-wise over 10 minutes and the reaction was stirred overnight. The reaction was quenched by the addition of an aqueous solution of HCl (2N, 260 ml) then ethyl acetate (600 ml) and water (1000 ml) were added. The aqueous phase was extracted with ethyl acetate (3×500 ml) and the combined organic fractions were washed with brine (500 ml) and dried over Na2SO4. The dark oil was purified by flash chromatography (heptane/EtOAc; 1/1) (silica, 1000 g) yielding of the title compound as a dark oil (22.5 g).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1CCN2C(=NCCC2)CC1>CC#N>[C:5]([O:4][C:3](=[O:9])[NH:2][O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.8 %

Procedure:
Tert-butyl hydroxycarbamate (2.1 g, 15.77 mmol, 1 eq.) was dissolved in MeCN and bromopentane (2.73 g, 18.13 mmol, 1.15 eq.) was added followed by DBU (2.52 g, 16.56 mmol, 1.05 eq.). The reaction was stirred at room temperature for 12 h and quenched with 0.1N HCl, extracted with EtOAc, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel to give tert-butyl(pentyloxy)carbamate (3.23 g, 91% yield) as a clear oil.