Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CN1CCCC1=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[N:27][CH:28]=1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(Cl)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2,5-dichloro-pyridine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.43 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@@H:12]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:13]([CH2:29][CH2:30][C@H:31]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:14](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:15])[CH:2]=[CH2:3].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OC)(C)(C)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@H:12]1[N:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:14](=[O:15])[C@@H:13]1[CH2:29][CH2:30][C@H:31]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Br)ccc1[C@@H](Nc1ccccc1)[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Product: C=CCOc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
(4S)-3-[(2R,5S)-2-[(S)-[2-(Allyloxy)-4-bromophenyl](anilino)methyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-4-benzyl-1,3-oxazolidin-2-one (1.2 g, 1.5 mmol) was dissolved in anhydrous methyl tert-butyl ether (10 mL) and stirred at room temperature under nitrogen. N,O-bistrimethylsilylacetamide (1.1 mL, 4.5 mmol) was added followed by a catalytic amount (˜5 mg) of tetrabutylammonium fluoride trihydrate. The reaction was stirred at room temperature for 19 h, quenched at room temperature with glacial acetic acid (160 μL) and partitioned between ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (120 g silica gel, 1% to 85% ethyl acetate-hexane) to afford (3R,4S)-4-[2-(allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (816 mg, 87% yield); Rf 0.56 (1:4 ethyl acetate-hexane).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][C@@H:7](O)[CH2:6]1)=[N+:2]=[N-:3].C([O-])(=[S:13])C.[K+].C(#N)C>C(OCC)(=O)C.CCCCCC>[N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][C@H:7]([SH:13])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC([O-])=S
Reactant: [N-]=[N+]=NC[C@H]1C[C@H](O)CO1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: [N-]=[N+]=NC[C@H]1C[C@@H](S)CO1

Procedure:
The title compound is prepared by the procedure of Example 111 using 2.22 gof product from Example 116, 1.01 g of potassium thioacetate and 25 ml of acetonitrile to give 0.90 g of the desired product after chromatography (silica gel: 30% ethyl acetate/hexane). IR(neat): 2100 and 1692 cm-1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16].O>C(Cl)(Cl)(Cl)Cl>[C:2]1([C:1]([C:14]2[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccco1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)c2ccccc2)o1
Reaction time: 1 h
Yield: 61681.2 %

Procedure:
Anhydrous ferric chloride (0.42 g, 2.6 mmole) and benzoyl chloride (29.6 g, 0.21 mole), were dissolved in CCl4 (40 ml) and added dropwise over 10 min with methyl 2-furoate (25.2 g, 0.20 mmole). The reaction mixture was then heated under reflux for 36 hrs, and after cooling was added with water (120 ml). The mixture was stirred for 1 hr and then allowed to sit until it separated into two layers. The water layer and precipitate were extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent of the filtrate was removed under a reduced pressure; the residue was recrystallized from isopropanol to afford 28.4 g 5-methoxycarbonyl-2-furyl phenyl ketone in a yield of 65.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:26]2[CH2:27][CH2:28][C:23]([OH:22])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH2:24][CH2:25]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Yield: 28.4 %

Procedure:
A mixture of 4-benzyloxy-N-(3-chloro-propyl)-benzamide (0.5 g, 1.64 mmol), ), 4-hydroxy-4-(4-methyl-benzyl)-piperidine (0.34 g, 1.65 mmol), potassium carbonate (0.45 g, 3.29 mmol) and 2-butanone (10 ml) was stirred at 60° C. for 48 h. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[3-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-propyl]-benzamide (220 mg, 28%) as light yellow solid. MS: me/e =473 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17]([NH:19][NH2:20])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CS(C)=O>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[NH2:20]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: CC(C)(C)OC(=O)NN
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1N(N)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To 250 mg of 2-fluoro-3-methyl-nitrobenzene in 5 mL of DMSO are added 1.065 g of commercial tert-butoxycarbonylhydrazine (5 equivalents). The whole is brought to 100° C. for 10 min under microwave heating. The medium is hydrolyzed and then extracted with ethyl acetate several times. The organic phases are collected, dried on magnesium sulfate, filtered and evaporated under reduced pressure leading to a residue which is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). 342 mg of product corresponding to the expected product are obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH:5]([NH2:11])[CH2:6][C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH2:28][S:29][C:30]#[N:31])=[CH:23][CH:22]=1>C(O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([NH:11][CH:5]([CH2:6][C:7]([F:9])([F:8])[F:10])[C:4]([O:3][CH3:2])=[O:12])[S:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(N)CC(F)(F)F
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 55 °C
Yield: 56 %

Procedure:
2-Amino-4,4,4-trifluoro-butyric acid methyl ester hydrochloride (1.1 g, 5.3 mmol) was dissolved in 30 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate, prepared in step 1 of Example 1, (1.23 g, 4.8 mmol) was added followed by triethylamine (0.73 mL, 5.3 mmol). The mixture was heated to 55° C. for 18 h then cooled and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) afforded methyl 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutanoate (1.21 g, 56%) as a white solid. mp 113-114° C. HRMS: calcd for C14H12BrF3N2O2S+H+, 408.98277; found (ESI, [M+H]+), 408.9831. Analytical HPLC: retention time 11.5 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: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:12](/[C:17]#[N:18])\[C:13]([O:15][CH3:16])=[O:14].[N+:19]([CH3:22])([O-:21])=[O:20].N1CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:12]([C:17]#[N:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:22][N+:19]([O-:21])=[O:20]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(Cl)cc21
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C#N)C1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A suspension of methyl (2Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)(cyano)acetate, intermediate 1 (10.000 g; 38.1 mmol) in dry nitromethane (61 ml; 1.14 mol) was treated with piperidine (189 μl; 1.90 mmol). After stirring for 3 hours, the mixture was diluted with ethyl acetate and filtered through silica. Evaporation of the solvent gave methyl [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetate as an oil (9.1 g, 73.8%). This was a mixture of diastereomers which was sufficiently pure for subsequent reaction (HPLC purity 97%). MS (ESI+): 324.2; MS (ESI−): 322.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Br)ccc1C1(CO)CCC1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)c(OC)c3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a mixture of [1-(4-bromo-2-methoxyphenyl)cyclobutyl]methanol (180 mg, 0.660 mmol) in dioxane (10 mL) and water (4 mL) was added methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (213 mg, 0.660 mmol), Pd (dppf)Cl2 (48 mg, 0.070 mmol) and potassium carbonate (273 mg, 2.00 mmol). The reaction mixture was purged with nitrogen for 3 minutes and stirred at 80° C. for 2 hours. The mixture was extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (220 mg, 83%) as a brown solid. It was used for next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:21]([Mg]Cl)[CH:22]([CH3:24])[CH3:23].[Br:27]Br.C(N(CC)CC)C>C1COCC1.CCOCC>[Br:27][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:6][C:7]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)C[Mg]Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2cc(CC(C)C)c([N+](=O)[O-])cc2Br)cc1

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 2.18, from 10 g of N-(4-nitrophenyl)-4-methylbenzenesulphonamide in 100 ml of THF and 42.6 ml of a 2M solution of isobutylmagnesium chloride in ether, followed by 4.4 ml of bromine and 23.4 ml of triethylamine. 5.9 g of the expected product are obtained, m.p.=170° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]([CH2:25][CH2:24][O:23][CH3:22])[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (0.122 g, 0.48 mmol) in DMF (3 ml) was added NaH (19 mg, 0.48 mmol) and the suspension was stirred for 20 minutes under nitrogen. Methoxyethylbromide (45 μL, 0.48 mmol) was then added and the reaction mixture was heated to 100° C. under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was purified by radial chromatography (2 mm plate, eluting with EtOAc) to give the title compound as a clear oil (90 mg, 60%). 1H NMR (400 MHz, DICHLOROMETHANE-D2) δ ppm 8.54 (d, 2 H), 7.61 (d, 2 H), 7.18-7.24 (m, 2 H), 7.03 (t, 2 H), 6.32 (s, 1 H), 4.19 (t, 2 H), 4.05 (s, 2 H), 3.72 (t, 2 H), 3.28 (s, 3 H); m/z (APCI+) for C18H18N3FO 312.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10]1([S:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[S:25]([O-:28])(=[O:27])(=[O:26])[CH3:24].[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S+:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)O
Reactant: Cc1cc(C)cc(C)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CS(=O)(=O)[O-]
Product: Cc1cc(C)c([S+](c2ccccc2)c2ccccc2)c(C)c1
Temperature: 52.5 °C
Reaction time: 5 h

Procedure:
In a 1 L, round bottom flask equipped with a reflux condenser was combined 1,3,5-trimethylbenzene (40 g, 0.333 mol), diphenylsulfoxide (67.3 g, 0.333 mol) and Eaton's Reagent (160 g). An exothermic reaction occurred. The reaction mixture was maintained at 50-55° C. with stirring for 5 hours. The reaction mixture was then added to deionized water (800 ml). This mixture was stirred for 30 minutes. The mixture was extracted two times with toluene (2×250 ml). The pH of the lower aqueous layer was adjusted to 8-8.5 by addition of a 25% aqueous solution of tetramethylammonium hydroxide (889.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Yield: 26.7 %

Procedure:
To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethyl amine (0.99 mL, 7.1 mmole). The contents were heated to 120 degrees in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20%) to afford 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg). 1H NMR (600 MHz, DMSO-d6) δ ppm 1.26-1.36 (m, 2H) 1.43 (m, 6H) 1.76 (m, 2H) 2.37 (m, 5H) 2.94 (t, J=12.74 Hz, 2H) 4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[N+:7]([O-:12])[C:6]([C:13]([NH2:15])=[O:14])=[C:5]([CH2:16]Br)[N+:4]=2[O-:18].[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[SH:25]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[N+:7]([O-:12])[C:6]([C:13]([NH2:15])=[O:14])=[C:5]([CH2:16][S:25][C:21]1[N:20]([CH3:19])[CH:24]=[CH:23][N:22]=1)[N+:4]=2[O-:18]
Reactant: Cc1cccc2c1[n+]([O-])c(CBr)c(C(N)=O)[n+]2[O-]
Reactant: Cn1ccnc1S
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1[n+]([O-])c(CSc1nccn1C)c(C(N)=O)[n+]2[O-]

Procedure:
Methyl 3-bromomethyl-2-quinoxalinecarboxamide-1,4-dioxide (0.24 moles) was suspended in 1 liter of chloroform with stirring and N-methyl-2-mercaptoimidazole (0.24 moles) was added as a solid. A complete solution resulted within 10 minutes. The solution was stirred overnight at room temperature during which time the desired product crystallized as the hydrobromide. The product was collected by filtration and dried. Yield, 96 grams (91%); m.p. 148°-52° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Cl)[CH:12]=2)[N:7]=1)=O)C.C(Cl)[Cl:29].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.CO>[CH:4]([C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[C:9]([Cl:29])[CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:3]
Reactant: ClCCl
Reactant: CCOC(=O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cccc(Cl)c2n1
Yield: 52 %

Procedure:
0.50 g (0.0013 mol) of 2-ethoxycarbonyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a solvent mixture comprising 20 ml of methylene chloride and 20 ml of tetrahydrofuran. 2.6 ml of a 1.0M solution of diisobutylaluminum hydride in toluene was dropped into the solution prepared above at -78° C. under stirring. The obtained mixture was stirred at -78° C. for several hours, followed by the addition of 20 ml of methanol. The obtained mixture was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate/n-hexane to give 0.23 g of the title compound as a pale-yellow crystal.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[N+:9]([C:12]1([N+:16]([O-:18])=[O:17])[CH2:15][NH2+:14][CH2:13]1)([O-:11])=[O:10].C(=O)(O)[O-].[Na+]>O>[N+:9]([C:12]1([N+:16]([O-:18])=[O:17])[CH2:15][NH:14][CH2:13]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])C1([N+](=O)[O-])C[NH2+]C1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Yield: 99.4 %

Procedure:
3,3-dinitroazetidinium trifluoromethanesulfonate (2.0 g, 0.0067 mole) was dissolved in 20 ml of water and neutralized with sodium bicarbonate (0.62 g, 0.0074 mole). The free base was extracted into chloroform (3×5 ml) and dried over sodium sulfate. The chloroform was removed under vacuum to quantitatively give the resultant product, 3,3-dinitroazetidine (0.98 g) as a colorless to light yellow oil.
Reaction SMILES: C(NC1C=C2C(CC(=O)N2)=CC=1)(=O)C.C1(C2C=C(C=CC=2OCCN2CCOCC2)C=O)CCCCC1.[CH:38]1([C:44]2[CH:45]=[C:46]([CH:62]=[CH:63][C:64]=2[O:65][CH2:66][CH2:67][N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:47]=[C:48]2[C:56]3[C:51](=[CH:52][C:53]([NH:57][C:58](=[O:60])[CH3:59])=[CH:54][CH:55]=3)[NH:50][C:49]2=[O:61])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([C:44]2[CH:45]=[C:46]([CH:62]=[CH:63][C:64]=2[O:65][CH2:66][CH2:67][N:68]2[CH2:69][CH2:70][O:71][CH2:72][CH2:73]2)[CH2:47][CH:48]2[C:56]3[C:51](=[CH:52][C:53]([NH:57][C:58](=[O:60])[CH3:59])=[CH:54][CH:55]=3)[NH:50][C:49]2=[O:61])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Agent: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Agent: O=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Yield: 80 %

Procedure:
6-Acetamido-2-oxindole was condensed with 3-cyclohexyl-4-morpholinoethoxybenzaldehyde using method B to give a mixture of isomers of N-{3-[3-cyclohexyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide as a mustard yellow solid which was reduced using method E to give 0.04 g (80%) of N-{3-[3-cyclohexyl-4-(2-morpholin-4-ylethoxy)-benzyl]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16](C3C=CC(CN4CCOCC4)=CC=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[N:62]1([CH2:68][C:69]2[CH:70]=[C:71]([CH:74]=[CH:75][CH:76]=2)C=O)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:71]3[CH:74]=[CH:75][CH:76]=[C:69]([CH2:68][N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)[CH:70]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(CN5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 77 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Morpholin-4-ylmethyl-benzaldehyde were reacted to produce the title compound (77%). 1H NMR (d-chloroform): 8.78 (d, J=8 Hz, 1H), 8.20 (m, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.63 (m, 2H), 6.42-6.50 (m, 2H), 6.01 (s, 1H), 5.61 (s, 1H), 5.38 (t, J=8 Hz, 1H), 4.37 (d, J=13 Hz, 1H), 4.27 (d, J=13 Hz, 1H), 3.99 (m, 4H), 3.53 (m, 2H), 3.18 (s, 1H), 3.05 (m, 1H), 3.04 (s, 1H), 2.70 (d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 1.68 (d, J=9 Hz, 1H). MS: 480.09 (M+H). HPLC retention time: 1.81 minutes (G Method).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([O:15]C)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BrH:17]>>[BrH:17].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cnnc(-c2ccc(F)c(Cl)c2)c1
Agent: Br
Product: Oc1cnnc(-c2ccc(F)c(Cl)c2)c1
Yield: 80 %

Procedure:
3-(3-Chloro-4-fluoro-phenyl)-5-methoxy-pyridazine (365 mg, 1.53 mmol) in aqueous HBr (48%, 3.6 ml) was heated at 100° C. for 19 hours under argon. The solvent was removed in vacuo and the resulting solid was dissolved in MeOH. The turbid solution was filtered though decalite and the filtrate was concentrated. The crude solid was stirred in MeCl2, filtered and dried to provide 6-(3-chloro-4-fluoro-phenyl)-pyridazin-4-ol hydrobromide (375 mg, 80%) as a beige solid, MS: m/e=225.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.C1(C(O)C)C=CC=CC=1>>[CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Agent: CC(O)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)OC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1 for Compound 1 but using racemic 1-phenylethyl alcohol in place of (R)-(+)-1-phenylethyl alcohol.