Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][CH3:21])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-].[K+].[CH3:25][NH2:26]>CO>[CH2:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:26][CH3:25])[C:12]1=[O:22])[CH3:21]
Reactant: CCn1c(=O)n([C@H](CCCl)c2ccccc2)c2ccccc21
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: CCn1c(=O)n([C@H](CCNC)c2ccccc2)c2ccccc21
Temperature: 80 °C

Procedure:
To a mixture of 1-[(1R)-3-chloro-1-phenylpropyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (0.13 g, 0.4 mmol) and potassium iodide (0.2 g, 1.2 mmol) in methanol (5 mL) was added a solution of 33% methylamine in methanol (10 mL). The reaction solution was heated to 80° C. in a sealed tube for 3 hours and cooled to room temperature. The solvent was removed in vacuo and residue purified on a silica gel column (10-50% methanol in methylene chloride) to afford 1-ethyl-3-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one as an oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The solvent was removed in vacuo and the residue was triturated with ether/dichloromethane to give 1-ethyl-3-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one HCl salt as a yellowish amorphous solid (30 mg, 22%). MS (ES) m/z 309.8.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH3:33])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[C:12]([CH:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCCc2ccccc21
Product: CCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCCc3ccccc32)cc1
Yield: 19.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxamide (0.2 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH3:27])[C:23](=[O:26])[NH:24][CH2:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]([CH3:28])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH3:27])[C:23](=[O:26])[N:24]=[CH:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CN1C(=O)NCc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(Nc3ncc4cnc(=O)n(C)c4n3)cc2)CC1
Reaction time: 144 h
Yield: 64.9 %

Procedure:
Prepared from 170 mg (0.26 mmol) of 7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-1-methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 233 mg (2.07 mmol) of potassium tert-butoxide in 20 mL of tetrahydrofuran. The reaction mixture is stirred for 6 days, and the workup is done as described in the general procedure, including a back-extraction of the combined aqueous phase with chloroform. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated. The semi-solid is triturated in diethyl ether/hexane, and the powder is collected and dried to give 64 mg (60%) of the title compound: mp 198-202° C. (dec).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:31](=[O:33])[CH3:32])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCN(Cc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 45 °C
Reaction time: 50 h
Yield: 51.1 %

Procedure:
To N-cyclobutyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine (0.500 g, 1.218 mmol) in acetone (25 mL) and dioxane (25 mL) was added palladium, 10 wt % on activated carbon (0.052 g, 0.487 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.144 mL, 12.18 mmol) was added at 23° C. The mixture was stirred under hydrogen at 310 kPa for 50 hr at 45° C. The crude mixture was filtered through Celite™, rinsed with dioxane, and concentrated via rotary evaporation. The crude material was purified via medium pressure chromatography using a 10% to 100% gradient eluant of EtOAc in heptanes on an NH 60 μM size 60 column (Shoko Scientific Purif-Pack™) to give the title compound 1-(3-(cyclobutylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone (284 mg, 51.1%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.56-1.72 (m, 2H), 1.97-2.06 (m, 2H), 2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.18-2.27 (m, 2H), 2.52-2.66 (m, 4.9H), 2.69 (t, J=5.9 Hz, 1.1H), 2.99 (br s, 4H), 3.59 (s, 2H), 3.69 (dt, J=11.5, 6.0 Hz, 2H), 4.27-4.46 (m, 3H), 5.89 (d, J=7.3 Hz, 0.4H), 5.93 (d, J=7.8 Hz, 0.6H), 7.02-7.13 (m, 1H), 7.17-7.27 (m, 1H), 7.41-7.55 (m, 1H); ESI-MS m/z [M+H]+ 457.0.
Reaction SMILES: I.[CH:2]12[CH2:13][CH2:12][CH:5]([CH2:6][CH:7]1[C:8]([O:10]C)=[O:9])[CH2:4][NH:3]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([S:20]([N:3]2[CH2:4][C@H:5]3[CH2:12][CH2:13][C@@H:2]2[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6]3)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)C1CC2CCC1NC2
Agent: I
Product: O=C(O)[C@@H]1C[C@@H]2CC[C@H]1N(S(=O)(=O)c1ccccc1)C2

Procedure:
The title compound was synthesized as in Production Example 1, using methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide and benzenesulfonyl chloride as the raw material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[OH-].[NH4+:26]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5]([NH2:26])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(CNc2cccc(-c3cc(N)ncc3Cl)n2)C[C@H](C)O1
Temperature: 130 °C

Procedure:
A mixture of 5′-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine (60 mg, 0.17 mmol), and 3.0 ml 28% ammonium hydroxide aqueous solution was heated at about 130° C. in an oil bath for 17 hours. Formation of compound M was Reaction confirmed by LCMS/LC data. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, and brine, dried over sodium sulfate and concentrated to yield 50 mg of the desired product. LCMS (m/z): 347 (MH+), retention time=0.53 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47]O)[CH3:44]>>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH3:44]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CCN(CC)CCO
Product: CCN(CC)CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(diethylamino)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-diethylamino-ethyl ester. MS (ES+) m/z calcd. for C37H43Cl2F2N4O4: [(M+H)+]: 715. found: 715.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12](=O)[C:13](Cl)=[O:14])=[CH:5][N:6]2[CH3:11].Cl.C([O:21][C:22](=[NH:37])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[CH:30][CH:31]=2)[N:26]([CH3:36])[CH:25]=1)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12]1[C:13](=[O:14])[NH:37][C:22](=[O:21])[C:23]=1[C:24]1[C:32]3[C:27](=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[CH:30][CH:31]=3)[N:26]([CH3:36])[CH:25]=1)=[CH:5][N:6]2[CH3:11]
Reactant: Cn1cc(C(=O)C(=O)Cl)c2c(F)cccc21
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4cccc(F)c34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21

Procedure:
3-(4-Fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from (4-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-6-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[CH2:24]([NH:40][C:41]1[CH:42]=[C:43]([C:46](Cl)=[O:47])[S:44][CH:45]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CCOCC>[CH2:24]([NH:40][C:41]1[CH:42]=[C:43]([C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:47])[S:44][CH:45]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)Cl)c1
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)N2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-hexadecylamino-2-thiophenecarbonyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from ether to yield the product as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=O)=[C:5]([F:19])[CH:4]=1)[CH3:2]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]2[O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[C:5]([F:19])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)Nc2ccccc2O)c(F)c1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
4-Ethyl-2-fluoro-2'-hydroxybenzanilide (29.0 gm.) is heated for 40 minutes in a Wood's metal bath at 240° C. The reaction mixture is then cooled, taken up in chloroform and the chloroform solution treated with carbon, dried over magnesium sulfate and concentrated in vacuo to give 2-(4-ethyl-2-fluorophenyl)benzoxazole.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH3:14])[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH3:14])=[O:31])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1CC[C@H]([C@H](C)O)n1cnc(C(N)=O)c1
Solvent: ClCCl
Product: C[C@H](O)[C@@H](CCc1ccccc1S(C)=O)n1cnc(C(N)=O)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-(methylthio)phenyl)-3-pentyl]imidazole-4-carboxamide (7.1 mg) and m-chloroperbenzoic acid (75%; 5.12 mg) in dichloromethane (1 ml) was stirred at 5° C. for 2 hours. The mixture was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (5:1) to give a colorless oil of 1-[(2S,3R)-2-hydroxy-5-(2-(methylsulfinyl)phenyl)-3-pentyl]imidazole-4-carboxamide (3) (5.4 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:6]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].F[C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[N+:47]([O-:49])=[O:48])[C:42]#[N:43]>C(#N)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[CH2:6][C:5]3([CH2:20][CH2:21][CH2:22][C:3]([CH2:2][NH:1][C:44]4[CH:45]=[C:46]([N+:47]([O-:49])=[O:48])[CH:39]=[CH:40][C:41]=4[C:42]#[N:43])([CH2:23][O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:4]3)[O:9][C:8]2=[O:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(CN2CC3(CCCC(CN)(COCc4ccccc4)C3)OC2=O)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CN2CC3(CCCC(CNc4cc([N+](=O)[O-])ccc4C#N)(COCc4ccccc4)C3)OC2=O)cc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a light yellow solution of 7-(aminomethyl)-7-((benzyloxy)methyl)-3-(4-methoxybenzyl)-1-oxa-3-azaspiro[4.5]decan-2-one (4.27 g, 10.1 mmol) in acetonitrile (67.1 mL) was added potassium carbonate (2.78 g, 20.1 mmol) and 3-fluoro-4-nitrobenzonitrile (2.51 g, 15.1 mmol) and the reaction was stirred at RT. After stirring 15 h, the reaction was filtered through a frit. The collected inorganics were washed with DCM/EtOAc. The filtrate was concentrated onto florisil and purified on a 80 g silica gel column (20-55% EtOAc/hexanes, 30 min gradient; 55% EtOAc/hexanes, 5 min.; 60 mL/min elution; 254 nm detection) to provide 3-{[(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-ylmethyl]amino)-4-nitrobenzonitrile (5.02 g, 83% yield) as a reddish-orange oil. MS (m/z) 571.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:18]
Reactant: Nc1ccccc1F
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)Nc1ccccc1F

Procedure:
To a mixture of 2-fluoroaniline (2 mL) and potassium carbonate (4.3 g) in dichloromethane to (50 mL) was added bromoacetyl bromide (3.6 mL). The reaction mixture was stirred for 4h then water was added and the phases separated. The organic layer was concentrated, the residue treated with ether and evaporated again to give the sub-titled compound (4.98 g) as a cream solid that was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH2:18][NH:19][OH:20])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[O:23]([C:25]#[N:26])[K]>O.C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([OH:20])[C:25]([NH2:26])=[O:23])=[CH:21][CH:22]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CNO)cc1
Reactant: N#CO[K]
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CN(O)C(N)=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl hydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in a mixture of water (2 ml) and acetic acid (0,5 ml) was added a solution of KOCN (343 mg, 30 mmol) in water (1 ml) and stirred for 1 h at 30° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the compound (295 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH2:21].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Nc2ncccc2-c2ccncn2)ccc1F
Solvent: ClCCl
Product: O=C(Nc1cc(Nc2ncccc2-c2ccncn2)ccc1F)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-fluoro-N1-(3-(pyrimidin-4-yl)pyridin-2-yl)benzene-1,3-diamine (25 mg, 0.089 mmol) in CH2Cl2 (1.5 mL) was added 3-(trifluoromethyl)benzoyl chloride (21 mg, 0.098 mmol). The mixture was stirred overnight at RT. The crude material was purified by preparative TLC (100% EtOAc), which yielded the title compound as a yellow solid. MS m/z=454 [M+1]+. Calc'd for C23H15F4N5: 453.40.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[CH2:1]([NH:11][C:26]([C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 5.4 ml (0.027 mol) of decylamine and 5.6 ml (0.04 mol(of triethylamine in 20 ml of methylene chloride cooled in an ice bath was added dropwise a solution of 5.0 g (0.027 mol) of 4-nitrobenzoyl chloride in 40 ml of methylene chloride. The reaction mixture was stirred in the ice bath for 30 minutes, at room temperature for 15 minutes and kept at 0° for 18 hours. After dilution was methylene chloride, the mixture was washed with 0.5 N NaOH and the extract was dried and concentrated to a solid. Recrystallization from methylene chloride-hexane gave 8.1 g (98% yield, mp 89°-91°) of 4-[(decylamino)carbonyl]nitrobenzene. The nmr was consistent with the structure.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:7](=[N:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]([CH2:2][C:3]2[C:11]3[C:7](=[N:8][S:9][N:10]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: BrCc1cccc2nsnc12
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1cccc2nsnc12)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 91.4 %

Procedure:
4-Bromomethyl-benzo[2,1,3]thiadiazole (0.94 g, 4.12 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (1.01 g, 3.95 mmol), potassium carbonate (0.66 g, 4.76 mmol), sodium iodide (0.18 g, 1.21 mmol), and anhydrous dimethylformamide (15 ml). The reaction is heated to 85° C. under nitrogen for 3 h. The reaction is poured into saturated sodium bicarbonate (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield (1.46 g, 91%) of 4-{[(benzo[2,1,3]thiadiazol-4-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=405.2 (M+1): 1H NMR (CDCl3): δ=7.86 (1H, d), 7.76-7.74 (1H, m), 7.60-7.56 (1H, m), 4.19 (2H, s), 4.12 (2H, br s), 2.68-2.54 (3H, m), 2.35 (2H, d), 1.83-1.79 (2H, m), 1.71-1.61 (1H, m), 1.54-1.46 (2H, m), 1.44 (9H, s), 0.87 (6H, d).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH:11]1([C:17]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:23])[C:18](OCC)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:17]([C:24]#[C:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([OH:23])[C:18]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCCC1
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)C1CCCCC1
Yield: 27 %

Procedure:
3-Quinuclidinol (2.5 g., 0.020 mole) was dissolved in 50 ml. of toluene and a small piece of sodium (~0.05 g.) was added. The toluene was refluxed for about 40 minutes until all the sodium had reacted. Ethyl α-cyclohexyl-α-phenylethynylglycolate (4.3 g., 0.015 mole) was subsequently added as a solution in 35 ml. of toluene, over an hour period, to the refluxing reaction mixture. The reaction mixture was refluxed for an additional 20 hours. During the last four hours about 40 ml. of solvent was distilled over. The reaction mixture was then worked-up as described previously. The basic chloroform extract yielded 4.0 g. of an oil, which partially crystallized upon the addition of anhydrous ether. A total of 1.6 g. (27%) of crude product was obtained. Recrystallization from hexane gave analytically pure material, m.p. 171°-172°.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([C:15]([N:17]1[CH2:22][C@@H:21]2[CH2:23][C@H:18]1[CH2:19][N:20]2C(OC(C)(C)C)=O)=[O:16])[NH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C@H:18]12[CH2:23][C@H:21]([NH:20][CH2:19]1)[CH2:22][N:17]2[C:15]([C@@H:3]([NH:4][C:5](=[O:6])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]([CH3:31])([CH3:1])[CH3:32])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H]2C[C@H]1CN2
Yield: 94.7 %

Procedure:
A solution of 1,1-dimethylethyl (1S,4S)-5-(3-methyl-N-{[(phenylmethyl)oxy]carbonyl}-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g, 5.5 mmol) in 30 ml TFA/DCM (20%) was stirred at room temperature for 1 h. The reaction mixture was made basic by addition of sodium hydroxide, then extracted with DCM (3×50 mL). The DCM was dried over anhydrous Na2SO4 and concentrated to give the title compound (1.8 g) as a pale brown oil. LCMS (m/z): 346.1 (M+H).