Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:3]3[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=3)=[S:9])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: S=C=Nc1cccnc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=S)Nc1cccnc1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of pyridine-3-isothiocyanate (0.136 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(3-pyridyl)thiourea as a white solid, m.p. 118–120° C. Mass spec M+1=468.3. Analysis: Calculated for C26H25N7S: % C, 66.79; % H, 5.39; % N, 20.97; Found: % C, 64.29; % H, 5.46; % N, 20.06.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[CH2:24]([C:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:30](=[O:39])[C:29]([C:40](O)=[O:41])=[CH:28][CH:27]=1)[CH3:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:29]5[C:30](=[O:39])[N:31]([C:32]6[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=6)[C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=5)=[O:41])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: CCc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)c(=O)n1-c1ccc(F)cc1
Yield: 74.4 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.324 mmol), 6-ethyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (101.5 mg, 0.389 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (111 μL, 0.648 mmol) and HATU (148 mg, 0.389 mmol) and in the same manner as in Example 57, the title compound (133 mg, 74%) was obtained as a white solid.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7](=S)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].COS(C(F)(F)F)(=O)=O.[CH3:28][O:29][CH2:30][CH2:31][C@H:32]1[CH2:37][NH:36][CH2:35][CH2:34][NH:33]1>ClCCl.N1C=CC=CC=1>[CH3:28][O:29][CH2:30][CH2:31][C@@H:32]1[NH:33][CH2:34][CH2:35][N:36]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:37]1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1NC2=S
Reactant: COCC[C@H]1CNCCN1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Combine 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (2.61 g, 9.48 mmoles) with trifluoromethanesulfonic acid methyl ester (1.61 mL, 14.2 mmoles) in dichloromethane (20 mL). Stir at room temperature for 2 h, then remove solvent in vacuo. Suspend residue in pyridine (20 mL) and add (S)-2-(2-methoxyethyl)piperazine (1.37 g, 9.48 mmoles). Heat at 115° C. for 8 h, then remove solvent in vacuo and apply residue to silica gel column. Elute column with dichloromethane followed by 5% 2N ammonia-methanol in dichloromethane to obtain the title compound (2.11 g, 58%) as a yellow oil: mass spectrum (APCI): m/z=386.2 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[CH3:18]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc—hexanes) afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 120 °C
Yield: 100 %

Procedure:
To a vial with tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (100 mg, 0.371 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (265 mg, 1.112 mmol) and cesium carbonate (362 mg, 1.112 mmol) under N2 is added DMSO (1.0 mL). The reaction is heated to 120° C. in an oil bath 1 h. The reaction was cooled to rt, added to H2O (5 mL), and extracted with Teac (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated to give tert-butyl 3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidine-1-carboxylate (175 mg) as a yellow oil which was carried on to the next step without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH2:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:15]3[CH:21]=2)=[C:8]([CH3:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:20][CH:18]1[CH2:17][CH2:16][N:15]2[CH:21]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:7][C:8]=3[CH3:22])[N:13]=[C:14]2[CH2:19]1
Reactant: C1CCNCC1
Reactant: Cc1cc(OCCCCl)ccc1-c1cn2c(n1)CC(C)CC2
Product: Cc1cc(OCCCN2CCCCC2)ccc1-c1cn2c(n1)CC(C)CC2
Temperature: 25 °C

Procedure:
The product of Step A (49 mg) and piperidine (1.0 mL) were heated at 100° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (2×10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (45 mg). 1H-NMR (CD3OD) δ 7.47 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.78 (m, 2H), 4.13 (m, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.98 (m, 1H), 2.99 (m, 1H), 2.89 (m, 6H), 2.41 (m, 4H), 2.10 (m, 4H), 1.75 (m, 5H), 1.60 (m, 2H), 1.18 (d, J=6.5 Hz, 3H)
Reaction SMILES: [S:1]1[C:5]([C:6]#[N:7])=[CH:4][N:3]=[CH:2]1.Cl.[NH2:9][OH:10].CCN(C(C)C)C(C)C>CCO>[S:1]1[C:5]([C:6](=[N:9][OH:10])[NH2:7])=[CH:4][N:3]=[CH:2]1
Reactant: NO
Reactant: N#Cc1cncs1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NO)c1cncs1
Yield: 72.3 %

Procedure:
Hydroxylamine hydrochloride (3.07 g, 44 mmol) was added to a solution of 1,3-thiazole-5-carbaldehyde (5 g, 44 mmol) and pyridine (3.7 mL) in DCM (25 mL). The reaction mixture was stirred overnight at room temperature and then washed once with water. The product was recovered by filtration to give 5.23 g of 1,3-thiazole-5-carbaldehyde oxime (yield 92%). 1,3-thiazole-5-carbaldehyde oxime (2.5 g, 19.5 mmol, 1 equiv) was dissolved in 12 mL of dioxane and then TEA (6.8 mL, 2.5 equiv) was added. The reaction mixture was cooled to 0° C. and then trifluoroacetic anhydride (3.0 mL, 1.1 equiv) was added dropwise to the reaction. The solution was stirred overnight at room temperature and then 1.1 equivalent of trifluoroacetic anhydride was added to complete the reaction. The solution was stirred overnight at room temperature and then evaporated. The residue was dissolved in DCM and then washed five times with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 1.25 g of 1,3-thiazole-5-carbonitrile (Yield 58%). 1,3-thiazole-5-carbonitrile (1 g, 9.08 mmol, 1 equiv), hydroxylamine hydrochloride (0.95 g, 1.5 equiv) and DIEA (2.5 mL, 1.6 equiv) were mixed in absolute EtOH (30 mL). The reaction mixture was refluxed 5 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with water and once with brine. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 940 mg of 1,3-thiazole-5-amidoxime (yield 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]=[C:5]([CH3:14])[CH:4]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)(=O)C>[CH:14]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][N:6]=1)=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(C)ncc1CCC(C)C
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=Cc2ccccc2)ncc1CCC(C)C

Procedure:
The starting substance can be manufactured by dissolving 26 g of 4-methoxy-5-isoamyl-2-picoline in 78 ml of benzaldehyde and 86 ml of acetic anhydride and heating the reaction mixture for 16 hours under reflux. After cooling, the mixture is evaporated, treated with 2 N sodium hydroxide solution and extracted with ether. Distillation of the ether residue in a bulb tube in a high vacuum at a temperature of 180°-200° yields 2-styryl-4-methoxy-5-isoamyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:36]([C:33]2[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Product: CC(C)(C)CC1CN(S(=O)(=O)c2ccc(Cl)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 998.4 %

Procedure:
In a manner similar to the method described in Example 83, a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (82 mg, 0.0195 mmol) was reacted with 6-chloropyridine-3-sulfonyl chloride (66 mg, 0.311 mmol, Enamine) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(6-chloro-pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (116.6 mg, 97%) as a light yellow solid.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37](=[O:47])[C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[CH:35]=3)[N:30]([CH3:48])[C:29](=[O:49])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([OH:47])([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[CH:35]=3)[N:30]([CH3:48])[C:29](=[O:49])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1ccnc1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 0.25 h
Yield: 26.9 %

Procedure:
n BuLi (1.6M in hexane) (4.4 ml, 0.0071 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0071 mol) in THF (8 ml) under N2 flow. The mixture was stirred for 15 minutes. ClSiEt3 (0.0073 mol) was added dropwise at −70° C. The mixture was stirred for 15 minutes. BuLi (1.6M in hexane) (3.9 ml, 0.0062 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. A solution of 4-(3-chlorophenyl)-1-methyl-6-(4-nitrobenzoyl)-2(1H)-quinolinone (described in Example A3d) (0.0040 mol) in THF (15 ml) was added. The mixture was stirred at −70° C. for 15 minutes, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.54 g (27%) of (±)-4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methyl]-1-methyl-2(1H)-quinolinone, mp. 230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: CN
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: CNC(=O)c1sc(CCc2c(-c3ccc(F)cn3)noc2C)nc1C
Yield: 47 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using methylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (34 mg, 47%) which was obtained as an off white solid. MS: m/e=361.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@H:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]1[CH2:16][O:17][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1CO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC[C@@H]1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: -5 °C
Yield: 57.5 %

Procedure:
NaH (60% in oil, prewashed with hexane; 1.38 g, 34.5 mmol) was suspended in anhydrous THF (50 mL) under nitrogen, the reaction mixture cooled to −5° C. with stirring and a solution of (R)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (2.50 g, 11.5 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 30 min at 0 to 3° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 5.01 g, 14.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled with an ice bath and a 10% aq NaHCO3 solution (11 mL) was added. The solvents were removed in vacuo and the residue was partitioned between EtOAc (350 mL) and 10% aq NaHCO3 solution (100 mL)/water (200 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 70 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated once before drying in vacuo to give (3R)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (2.80 g) as a pale yellow gum.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:25][C:26]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCC1)C2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine 0.43 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.49 g, and stirred at 0° C. for 45 min. Cyclopentyl acetic acid 0.36 ml and WSC 0.59 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with 10% sodium hydroxide and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclopentylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.19 g and refluxed for 1.5 hours. The reaction mixture was cooled, then added ether, water and 10% aqueous sodium hydroxide thereto, and filtered the insoluble material. The filtrate was extracted with ether and dried by anhydrous sodium sulfate. After filtering the drying agent, a residue obtained by concentrating the filtrate in vacuo was purified by means of flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform-chloroform:acetone=20:1) to obtain the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][NH:17][C:18](=[O:32])[N:19]3[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)C>Cl.C(O)C>[CH2:25]([N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:23]([F:24])=[CH:22][CH:21]=2)[CH2:16][NH:17][C:18]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1NCc2c(ccc(F)c2N2CCNCC2)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
4-(1-Benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (141 mg) was dissolved in 4 mL 2 N HCl/ethanol and heated to 80° C. for 20 minutes, then cooled to room temperature. Diethyl ether was added, precipitating 115 mg: of 1-benzyl-6-fluoro-5-piperazin-1-yl-3,4dihydro-1H-quinazolin-2-one hydrochloride. MP: 285.6-290.0° C. MS: 341 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.C(N(CC)CC)C.[Cl:18][C:19]([Cl:23])([Cl:22])[S:20]Cl>C1C=CC=CC=1>[Cl:18][C:19]([Cl:23])([Cl:22])[S:20][NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: ClC(Cl)(Cl)SNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 23.9 %

Procedure:
To a 3-neck flask equipped with condenser, thermometer, and stirring bar was added 11.7 g (0.05 mole) 5-amino-3trichloromethyl-1,2,4-thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 16 hours and filtered hot. The filtrate was evaporatd under vacuum to give an orange paste which was triturated with acetonitrile, filered and washed with petroleum ether to obtain 4.4 g (24% yield) of product; mp=180° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].S(OCC)(O[CH2:14][CH3:15])(=O)=O.[OH-].[K+].C([Li])CCC.CCCCCC>>[C:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNC(C)(C)C
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: CCCCCC
Product: CCN(CC(C)C)C(C)(C)C
Temperature: 70 °C
Yield: 72 %

Procedure:
A mixture of tert-butylisobutylamine (25.84 g, 0.2 mol) and diethyl sulfate (46.26 g, 0.3 mol) was warmed to 70° C. with stirring. An exothermic reaction started and in a few minutes the temperature rose to 150° C. with vigorous boiling of the mixture. After cooling to ˜50° C., 5 M aqueous potassium hydroxide (100 ml, 0.5 mol) was added. The organic layer was separated and dried over anhydrous magnesium sulfate. Diethyl sulfate (10 ml) was added and the mixture was stirred at 100° C. for 1 h. Aqueous 5 M potassium hydroxide (100 ml) was added and the mixture was stirred at 80° C. for 1 h. The organic layer was separated and the aqueous layer was extracted with diethyl ether (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate and the product was isolated by distillation. A small amount (1-2%) of tert-butylisobutylamine which was removed by the addition of 2.5 M n-butyllithium in hexane (5.0 ml, 10 mmol) and the product distilled to yield 22.56 g, (72%) of product, bp 68-70° C./40 mm Hg; 1H NMR (CDCl3) δ0.85 (d, J=6.5 Hz, 6H, CH3), 0.98 (t, J=6.5 Hz, 3H, CH3), 1.01 (s, 9H, CH3), 1.66 (n, J=6.5 Hz, 1H, CH), 2.04 (d, J=6.57 Hz, 2H, CH2), 2.51 (q, J=6.5 Hz, 2H, CH2).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Br[CH2:17][CH3:18]>CN(C)C=O>[CH2:17]([N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=[C:2]1[CH3:1])[CH3:18]
Reactant: CCBr
Reactant: Cc1nc2cccc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc2c([N+](=O)[O-])cccc21
Temperature: 65 °C
Yield: 57 %

Procedure:
To a solution of 0.47 g (2.65 mmol) 2-methyl-4-nitrobenzimidazole, and 0.12 g (2.92 mmol) of sodium hydride in 10 mL of dry dimethylformamide was added 0.218 mL (2.92 mmol) bromoethane. The mixture was heated overnight at 65° C. The mixture was cooled to room temperature and the solvents were removed under reduced pressure. The resultant syrup was partitioned between water and ethyl acetate. The organic phase was evaporated to dryness and the syrup chromatographed on silica to yield 0.31 g (1.51 mmol, 52%) of a yellow syrup.