Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH3:16][N:17]([CH3:29])[C:18]1([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(B)#N.[Na].CO.C(Cl)(Cl)Cl>CO.C(O)(=O)C>[CH3:16][N:17]([CH3:29])[C:18]1([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]([CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:20][CH2:19]1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CN(C)C1(c2cccs2)CCNCC1
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCN1CCC(c2cccs2)(N(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
6.4 g (1.3 eq) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 7.5 g (1 eq) N,N-dimethyl-4-(thiophen-2-yl)piperidin-4-amine bis hydrochloride in 75 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 4.9 g (3 eq) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 90 min at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was not yet complete, the pH of the reaction mixture was adjusted to 5-6 with acetic acid and the mixture was stirred for 12 h at room temperature. Once the conversion was complete, the methanol was distilled off, water was added, the mixture obtained was extracted with IPA/chloroform (2×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 8.5 g (84%) of product were obtained.
Reaction SMILES: CC(C)([O-:4])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](F)[C:9]=1[N+:15]([O-:17])=[O:16]>CS(C)=O.S(=O)(=O)(O)O>[F:7][C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([OH:4])[CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(O)cccc1F
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A solution of potassium tert-butoxide (1.23 g, 11 mmol) in 25 mL of anhydrous DMSO was stirred at room temperature for 30 minutes and treated with 1,3-difluoro-2-nitrobenzene (1.59 g, 10 mmol). After 18 hours, the mixture was diluted with 150 mL of 1 N aqueous sulfuric acid and extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 50 mL of trifluoroacetic acid. After 30 minutes at room temperature, the mixture was concentrated in vacuo, treated with 50 mL of 1 N aqueous sodium hydroxide, and extracted with three 30 mL portions of diethyl ether. The aqueous layer was acidified with 1 N aqueous sulfuric acid and extracted with two 50 mL portions of dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 g of 3-fluoro-2-nitrophenol as orange oil (61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].N1C=CC=CC=1.O1CCCC1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)=[O:8])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1)c1ccccc1
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Under argon atmosphere, a mixture of 5-amino-N-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxybenzamide (364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) and tetrahydrofuran (10 mL) was cooled on ice. Benzoyl chloride (155 mg, 1.1 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (121 mg, 25.7%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:23]1([C:29]2[C:30]3[C:35]([C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:37]4[C:42]=2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38]4)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.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.COCCOC>[C:23]1([C:29]2[C:30]3[C:35]([C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:37]4[C:42]=2[CH:41]=[C:40]([C:2]2[CH:3]=[CH:4][C:5]([N:8]5[C:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=6[N:10]=[C:9]5[C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:6][CH:7]=2)[CH:39]=[CH:38]4)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
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: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4ccc(-n5c(-c6ccccc6)nc6ccccc65)cc4)ccc23)cc1
Yield: 92.1 %

Procedure:
1.0 g (2.9 mmol) of 1-(4-bromophenyl)-2-phenyl-1H-benzimidazole, 1.2 g (3.2 mmol) of 9,10-diphenylanthracene-2-boronic acid, and 0.067 g (0.058 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 1.6 g of a greenish white solid (90% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 598 with respect to a molecular weight of 598.24.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].F[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C>>[CH2:1]([OH:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCF
Reactant: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCCCCCCO

Procedure:
93 mg (0.5 mmol) of dodecanol purified by distillation, 0.39 g (0.6 mmol, 1.2 equivalents) of N,N-diethyl-α,α-difluoro-[4-(1H,1H,2H,2H-perfluorodecyl)benzyl]amine (compound c) produced in Example 1, and 0.5 ml of heptane were put into a container formed of PFA (tetrafluoroethylene/perfluoroalkyl vinyl ether copolymer), and reacted in a nitrogen atmosphere at 100° C. for 3 hours. After the reaction, an aqueous saturated sodium hydrogencarbonate solution was added thereto for neutralization, and then the product was extracted out with dichloromethane. The solvent was evaporated away, followed by purification through silica gel column chromatography (solvent: dichloromethane/diethyl ether mixed solvent) to give a product. The main product was 1-fluorododecane, and its yield was 86%.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9](=S)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C:17]=3[CH:30]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:33][NH2:34].C(O)(=O)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C(O)C>[C:1]1([CH2:7][NH:8][C:9]2[NH:34][N:33]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C:17]=4[CH:30]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C(=O)CC(=S)NCc3ccccc3)cc2C1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cc(NCc4ccccc4)[nH]n3)cc2C1
Temperature: 78 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A mixture of 1,1-dimethylethyl 7-{3-[(phenylmethyl)amino]-3-thioxopropanoyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (155 mg, 0.35 mmol), hydrazine monohydrate (66 mg, 0.59 mmol), acetic acid and Lawesson's reagent (63 mg, 1.0 mmol) in ethanol (5 mL) was stirred at 78° C. for one hour. The reaction mixture was cooled, concentrated and the residue purified directly by silica gel chromatography (5% methanol in dichlomethane) to give 1,1-dimethylethyl 7-{5-[(phenylmethyl)amino]-1H-pyrazol-3-yl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (92 mg, 62% yield). MS (EI) for C24H28N4O3: 421 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Ic1ccc(NC2CN3CCC2CC3)cc1
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccc(NC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 35A (200 mg, 0.61 mmol) was treated with aniline (Aldrich, 93 mg, 1 mmol) according to the procedure of Example 17A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as an oil (120 mg, yield, 68%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.57 (m, 1H), 1.72–1.84 (m, 2H), 1.93–2.06 (m, 2H), 2.63 (ddd, J=12.9, 5.1, 2.7 Hz, 1H), 2.82–2.99 (m, 4H), 3.30–3.40 (m, 1H), 3.56–3.64 (m, 1H), 6.56–7.13 (m, 9H) ppm. MS (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](Cl)=[O:11]>CC(C)=O>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([N:3]=[C:2]=[S:1])=[O:11]
Reactant: O=C(Cl)c1cccs1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccs1
Yield: 53 %

Procedure:
To a freshly prepared solution of potassium thiocyanate (2.14 g, 22 mmol) in dry acetone (80 ml ), thiophene-2-carbonyl chloride (2.93 g, 20 mmol) was added dropwise at room temperature; the reaction mixture was then heated under a reflux for 15 min to give thiophene-2-carbonyl isothiocyanate in situ as a yellow suspension. The heating was stopped and 2-imidazolidinethione (2.04 g, 20 mmol) was added. The mixture was then heated under reflux for an additional 4 hours before being allowed to cool followed by stirring at room temperature overnight (15 hours). 50 ml of water was added and the mixture was further stirred at room temperature for a few minutes. The resulting precipitate was collected by filtration and washed with water, water/methanol (1:1) and methanol to give the compound ARE111 (2.865 g, yield=53%)
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:9](Cl)=[O:10].[N+:12](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-:13].CC1(C)CCCC(C)(C)N1.[Li]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[N+:12]=[N-:13])[C:9]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]=1[Cl:1])=[O:10])[CH3:19]
Reactant: O=C(Cl)C1=C(Cl)CCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C(=[N+]=[N-])C(=O)C1=C(Cl)CCCCC1
Reaction time: 1 h

Procedure:
To a solution of 2-chlorocyclohept-1-enecarbonyl chloride (4.6 g) and ethyl diazoacetate (2.8 ml) in THF (30 ml) cooled to −70C was added a solution of lithium 2,2,6,6-tetramethylpiperidine (1 equiv.) dropwise. On completion of the addition the reaction mixture was stirred for 1 h. The reaction mixture was quenched by pouring into 1M citric acid (100 ml), then extracted with ether (3×200 ml). The ether extracts were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using a gradient elution: hexane/ether (10:1) 500 ml, hexane/ether (9:1) 500 ml, hexane/ether (8:2) 500 ml. The appropriate fractions were combined and evaporated under reduced pressure to give a yellow oil. δH (360 MHz; CDCl3) 1.33 (3H, t, J=7 Hz, CH3), 1.74 (6H, m, CH2), 2.32 (2H, m, CH2), 2.64 (2H, m, CH2), 4.29 (2H, t, J=7 Hz, CH2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[CH:13](O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:12]=[CH:13][NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=CO
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)c2nc[nH]c2c1
Yield: 96.2 %

Procedure:
To a 100 mL round bottomed flask was added 3-bromo-5-nitrobenzene-1,2-diamine (5 g, 21.55 mmol) and formic acid (3.25 mL, 86 mmol) in Toluene (10 mL). The solution was heated to reflux overnight. The product precipitated and was triturated with toluene, diluted with water and adjusted to ph 9 with 6N NaOH. The solid was filtered, washed with water and placed in a vacuum oven overnight to yield 4-bromo-6-nitro-1H-benzo[d]imidazole (5.02 g, 20.74 mmol, 96% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H) 8.29 (d, J=2.02 Hz, 1H) 8.51 (d, J=2.02 Hz, 1H) 8.66 (s, 1H); LC/MS: MS (ES+) m/e 243 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C(N)=O)=[N:6][CH:7]=1.[CH2:11]([N:13](CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[C:11]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)#[N:13]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(N)=O)nc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cncc(C#N)c1
Yield: 100.9 %

Procedure:
To a suspension of 5-methylpyridinylcarboxamide from step 2 (10.5 g, 0.077 mol) in triethylamine (23.3 g, 0.23 mol) and 400 mL of methylene chloride was added trifluoroacetic anhydride (21.0 g, 0.100 mol) rapidly at 0° C. The reaction was completed after a few minutes. Water was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to give 9.18 g of 3-cyano-5-methylpyridine crude, which was used in the next step without purification.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[N+](=[CH2:44])=[N-]>>[CH3:44][O:30][C:29](=[O:31])[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:33])=[O:34]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: COC(=O)[C@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Yield: 68 %

Procedure:
The product from example 45 was treated with excess diazomethane, yielding the title compound in 68% yield.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18](SC)[N:17]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][N:42]([CH:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:18]2[N:17]=[C:16]([N:11]3[C:12]4[C:8](=[C:7]([CH2:6][O:5][CH2:4][CH2:3][S:2][CH3:1])[CH:15]=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[CH:21]=[CH:20][N:19]=2)[CH2:37][CH2:38]1)[S:43]([CH3:46])(=[O:44])=[O:45]
Reactant: CN(C1CCC(N)CC1)S(C)(=O)=O
Reactant: CSCCOCc1cccc2c1ccn2-c1ccnc(SC)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCCOCc1cccc2c1ccn2-c1ccnc(NC2CCC(N(C)S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
4-(2-Methylsulfanyl-ethoxymethyl)-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H indole (196 mg, 0.36 mmol) was dissolved in DCM, cooled on an ice bath, and MCPBA (635 mg, 2.83 mmol) was added and the mixture was stirred at RT overnight. The mixture was then diluted with DCM, washed with 5% NaHCO3, dried over sodium sulfate, filtered, concentrated in vacuo, and the residue dissolved in NMP and added to a suspension of N-(4-amino-cyclohexyl)-N-methyl-methanesulfonamide (409 mg, 1.98 mmol), 0.39 mL DIEA (2.27 mmol) and molecular sieves (previously stirred at RT for 1 h). The mixture was stirred at 120° C. for 1 h, cooled to RT, the mixture decanted into water, stirred for 30 min, filtered, and the precipitate purified by flash chromatography, eluting with DCM:MeOH 97:3. The product was then stirred in ether, filtered, and the solvent removed in vacuo overnight to yield N-methyl-N-(4-{4-[4-(2-methylsulfanyl-ethoxymethyl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:16]3[N:17]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:15]=3[CH:14]=[C:13]([C:37](=[NH:40])[NH:38][OH:39])[N:12]=2)[C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:16]3[N:17]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:15]=3[CH:14]=[C:13]([C:37]3[NH:40][C:41](=[O:42])[O:39][N:38]=3)[N:12]=2)[C:5]([N:8]([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)c1ncc(Cl)cc1-c1nc(C(=N)NO)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)c1ncc(Cl)cc1-c1nc(-c2noc(=O)[nH]2)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (racemic, 22 mg, 0.075 mmol) and 1,1′-carbonyldiimidazole (12 mg, 0.07 mmol) in acetonitrile (1 mL) was added 1,8-diazabicycloundec-7-ene (23 mg, 0.15 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with CH2Cl2 and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified on a silica gel column (0 to 10% MeOH/CH2Cl2) to afford 3-{4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic). NMR shows 8:2 mixture of rotamers, 1H NMR (400 MHz, CD3OD) (for major rotamer) δ 8.27 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 3.76-4.04 (m, 3H), 3.35-3.51 (m, 3H), 3.13 (m, 1H), 2.98 (m, 1H), 2.53 (s, 6H), 2.34 (m, 1H), 1.64-1.77 (m, 3H), 1.44-1.56 (m, 3H), 1.12-1.24 (m, 3H), 0.71-0.84 (m, 7H), 0.50-0.62 (m, 2H). MS ES calc'd. for C30H37ClN8O3 [M+H]+ 593. found 593
Reaction SMILES: CS(O[CH:6]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:7])(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH:6]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:7])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cc2ccccc2n1-c1cccc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To the crude 1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethyl methanesulfonate in N,N-dimethylformamide (5 mL) was added sodium azide (0.20 g, 3.0 mmol). The reaction was stirred at room temperature for 2 hr, quenched with water, and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-30% EtOAc in hexane) to give the desired product (0.14 g, 49%). LCMS calculated for C16H13FN(M-N3)+: m/z=238.1. Found: 238.1.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[CH3:20][C:19]([O:13][C:12](=[O:14])[C@H:10]([CH2:9][O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH2:11])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H](N)COCc1ccccc1
Temperature: 250 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a suspension of O-phenylmethyl-L-serine (50 g; 0.26 mol) in t-butyl acetate (1000 mL; 7.49 mol) 70% perchloric acid was added (50 mL; 0.58 mol). The solution was maintained under stirring for 72 h at 250° C. under inert atmosphere. The reaction mixture was diluted with Et2O (300 mL), then a 10% Na2CO3 aqueous solution was slowly added until pH 9 was reached. The organic layer was separated, dried over Na2SO4 and concentrated. The residual t-butyl acetate was distilled under reduced pressure (40° C.0.1 mm Hg). The desired product was obtained (54.2 g; 0.21 mol). Yield 83%.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1>>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: Cc1cccc(N)n1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: Cc1cccc(NC(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d)) and 2-amino-6-methylpyridine using the conditions described in Example 72. 1H-NMR (CDCl3-CD3OD; 400 MHz): δ 8.26 (dd, 1H, J=8.6, 2.0 Hz), 7.76 (s, 1H), 7.54-7.49 (m, 1H), 7.28-7.22 (m, 1H), 7.14 (d, 1H, J=2.2 Hz), 6.58 (d, 1H, J=7.3 Hz), 6.07 (m, 1H), 5.67 (m, 1H), 2.46 (s, 3H), 2.20-2.14 (m, 2H), 2.00 (m, 2H), 1.71 (s, 6H), 1.51-1.48 (m, 2H), 1.00 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H32N6O, 469.2 (M+H). found 469.1.