Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([O:31][C:32]([F:49])([F:48])[C:33]([F:47])([F:46])[O:34][C:35]([F:45])([F:44])[C:36]([F:43])([F:42])[O:37][C:38]([F:41])([F:40])[F:39])([F:30])[F:29])=CC=2)=NC=1)CCCCCCC.[CH2:50]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[CH2:50]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([O:31][C:32]([F:48])([F:49])[C:33]([F:46])([F:47])[O:34][C:35]([F:44])([F:45])[C:36]([F:42])([F:43])[O:37][C:38]([F:40])([F:41])[F:39])([F:30])[F:29])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCOc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)1-bromobutane (6.1 g, 15.0 mmol, Example 25) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol). The resulting crude product was further purified by recrysallization from ethanol and subsequent Kugelrohr distillation (b.p. 200-210° C. at 0.3 torr; yield of 5.2 g).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCNCC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCC(C)CC2)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 4-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 206 mg of 4-(2-butynyloxy)-6-(4-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (18)).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: Nc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Product: Nc1ccccc1C(=O)Nc1ccccc1

Procedure:
Isatoic anhydride (130 g) and aniline (700 ml) were heated to 140°, cooled, poured into 20 liters of water and filtered. The solid was extracted with 4 liters of 1.25N HCl and filtered. The filtrate was washed with ether, made alkaline with 2.5N NaOH and filtered. The solid was treated with ether and water to give 120 g product.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:59][C:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:66][S:63]([C:60]6([CH3:59])[CH2:62][CH2:61]6)(=[O:65])=[O:64])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of carboxylic acid 46 (240 mg, 0.38 mmol) and carbonyldiimidazole (2 eq) in dry THF (5 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 eq) and DBU (2 eq) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 170 mg (58%) of the title compound 48 as an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven: m/z=764 (M+H)+. 1H NMR (acetone-d6): 0.86 (m, 2H), 1.15-1.78 (m, 19H), 1.87 (m, 2H), 2.13-2.54 (m, 3H), 2.57-2.71 (m, 4H), 2.96-3.25 (m, 4H), 3.54 (m, 2H), 4.02 (s, 3H), 4.58 (t, J=13 Hz, 1H), 5.04 (m, 1H), 5.46 (m, 1H), 5.62 (m, 1H), 7.31 (s, 1H), 7.43 (d, J=9 Hz, 1H), 7.58 (s, 1H), 8.07 (d, J=13 Hz, 1H), 8.19 (broad s, 1H), 11.44 (broad s, 1H).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)S(OC1C(F)=CC=CC=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]([C:31]2([NH:34][C:35]([C:37]3[CH:38]=[N:39][CH:40]=[N:41][CH:42]=3)=[O:36])[CH2:33][CH2:32]2)=[O:30])=[C:23]([F:43])[CH:22]=1)(=O)=O.[Cl-].[Br:47]C1C=CC(C[NH3+])=C(F)C=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Br:47][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]([C:31]2([NH:34][C:35]([C:37]3[CH:38]=[N:39][CH:40]=[N:41][CH:42]=3)=[O:36])[CH2:33][CH2:32]2)=[O:30])=[C:23]([F:43])[CH:22]=1
Reactant: [NH3+]Cc1ccc(Br)cc1F
Reactant: O=C(NC1(C(=O)NCc2ccc(-c3cccc(F)c3OS(=O)(=O)C(F)(F)F)cc2F)CC1)c1cncnc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1(C(=O)NCc2ccc(Br)cc2F)CC1)c1cncnc1
Reaction time: 1 h

Procedure:
Triethylamine (1.036 g, 10.24 mmol) was added to a stirred solution of the compound of reference Example 3 (2.556 g, 10.24 mmol), (4-bromo-2-fluorophenyl)methanaminium chloride (2.463 g, 10.24 mmol), EDC (1.963 g, 10.24 mmol), and HOAT (0.418 g, 3.072 mmol) in CH2Cl2 (25 mL). After 1 h, the reaction was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow solid. This solid was purified by silica gel chromatography, eluting with 5% methanol/CH2Cl2 to yield N-(1-{[(4-bromo-2-fluorobenzyl)amino]carbonyl}cyclopropyl)pyrimidine-5-carboxamide as a white solid. Low resolution MS: (M+H+)=393.03.
Reaction SMILES: C1(C2C=CC(O)=C(Cl)C=2)C=CC=CC=1.C1(C2C=CC(OC)=C(Cl)C=2)C=CC=CC=1.[Cl-].C(O)CCCCCCC.[Cl-].[NH4+].[C:42]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([Cl:65])[CH:58]=2)=[CH:53][CH:52]=1)(=O)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(=S)=S>[CH2:42]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([Cl:65])[CH:58]=2)=[CH:53][CH:52]=1)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCC(=O)c1ccc(-c2ccc(OC)c(Cl)c2)cc1
Agent: COc1ccc(-c2ccccc2)cc1Cl
Agent: Oc1ccc(-c2ccccc2)cc1Cl
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCCCCCCCO
Product: CCCCCCCCc1ccc(-c2ccc(OC)c(Cl)c2)cc1
Yield: 75 %

Procedure:
4-phenyl-2-chlorophenol is methylated by means of well-known method steps and 4-phenyl-2-chloroanisole (hereinafter referred to as Material I) is extracted. 1/3 mole of Material I is dissolved into carbon disulfide 300cc and a Friedel Craft's reaction is effected in a MILO flask in which 1/3 mole of octanol chloride and 60 grams of anhydrous ammonium chloride are placed. As a result, 4-octanoyl-4'-methoxy-3'-chlorobiphenyl (hereinafter referred to as Compound 4) is extracted with a yield of 75%. As the result of reduction of said Compound 4, by the well-known Wolff-Kischner's reaction, 4-octyl-4'-methoxy-3'-chlorobiphenyl (hereinafter referred to as Compound 5) is extracted with a yield of 70 weight percent. 0.01 mole of 4-octyl-4'-hydroxy-3-chlorobiphenyl (hereinafter referred to as Material II), which is extracted from said Compound 5 by means of demethylation with HBr water, is dissolved into a mixed solution of 100cc pyridine and 50cc. of benzene. After this 0.012 mole of 4-octyloxy-benzoil chloride is added to the solution, this mixed solution is heated and stirred for 24 hours. Extraction is achieved by adding water (200cc) and benzene (100cc) to the solution. The resultant benzene layer is washed with a mixture of 1 mole of sodium hydroxide solution (50cc) and 1 mole of HCl liquid (100cc). The resultant compound in benzene layer is crystallized from ethyl alcohol (50cc). The result of the above method steps, 4-octyl-4'-(4"-octyloxy benzoil)-3'-chlorobiphenyl (Compound 1 in the above table), is extracted at the yield rate of 85%.
Reaction SMILES: Cl[C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:6](Cl)[CH:7]=1.CCOCC>Cl>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([NH:19][C:3]3[CH:2]=[CH:7][CH:6]=[C:5]([NH:9][C@H:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH3:11])[N:4]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: C[C@H](Nc1cccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
tert-Butyl 5-cyclopropyl-3-[(6-{[(1S)-1-(4-fluorophenyl)ethyl]amino}pyridin-2-yl-amino]-1H-pyrazole-1-carboxylate (Method 21; 146 mg) was dissolved in a solution of hydrogen chloride in ether (2.0 M, 2 ml, 4 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed and semi-prep HPLC (Gilson) purification gave the title compound (37 mg, 25%). 1H NMR (CDCl3) δ 0.55 (m, 2H), 0.70 (m, 2H), 1.35 (m, 3H), 1.65 (m, 1H), 4.53 (m, 2H), 4.91 (br s, 1H), 6.10 (br s, 1H), 6.70 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [C:1]1(=O)[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCCCCC>C1C=CC=CC=1>[NH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: O=C1CCCCN1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: c1ccc(N2CCOCC2)c(N=C2CCCCN2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of delta-valerolactam (24 g) in dry benzene (100 ml) was cooled to 10° C. in ice-water and treated with freshly distilled phosphorus oxychloride (22.2 ml) under nitrogen over a period of 10-15 minutes. The initial white solid formed changed to a clear yellow oil over 3 hours. A solution of 4-(2-aminophenyl)morpholine (36 g) in dry benzene (150 ml) was added and the mixture heated at 65° C. with stirring for 32 hours. The benzene layer was decanted, the oil washed twice with benzene (2×40 ml), ether (100 ml) was added and the mixture cooled in ice treated with 10% aqueous sodium hydroxide solution to alkaline pH, with stirring. The aqueous layer was extracted with ether (2×100 ml) and the combined ether extracts washed with water, brine and dried. The solution was filtered and the solvent removed to give a thick oil which solidified on trituration with hexane. The crude solid was crystallised from hot hexane to yield 4-[ 2-(2-piperidinylideneamino)phenyl]morpholine (m.p. 89°-90° C.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCCBr)CC3)noc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55 mmol), K2CO3 (13 g) and 1,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) in acetonitrile (300 ml) was stirred at room temperature overnight. The inorganic material was filtered. The solution was concentrated to ~80 ml, when crystals crashed out. The product was filtered to yield 14.16 g (73%), m.p.=243°-245° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][CH:26]([OH:28])C.O>CC(C)=O>[CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C:20]3([O:23][CH2:25][CH2:26][O:28]3)[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(N2CC[C@H](O)C2=O)nc1Cc1ccccc1
Reactant: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: O=C1N(c2ccc(O)c(Cc3ccccc3)n2)CCC12OCCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.1 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 20 ml of acetone, and 1 ml of a Jone's reagent was added thereto, followed by stirring at room temperature for 1.5 hours. 2-Propanol and water were added thereto, followed by extracting with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The resulting residue was dissolved in 20 ml of toluene. 1 ml of ethylene glycol and 198 mg of p-toluenesulfonic acid were added thereto, followed by heating under reflux for 2 hours while removing water by use of Dean Stark apparatus. After cooling as it was, water was added thereto and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 30-40% ethyl acetate/hexane as an eluent for separation and purification, to give 398 mg of the target compound.
Reaction SMILES: CN1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:30])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[O:9])CC1.C(C/C(/C)=C/CC/C(/C)=C/CO)/C=C(/CCC=C(C)C)\C.[CH3:52][C:53]12[CH2:62]C3(N)[CH2:61][CH:55]([CH2:56][C:57](C)([CH2:59]3)[CH2:58]1)[CH2:54]2.C1N=CN(C(N2C=NC=C2)=O)C=1>>[CH3:52][C:53]12[CH2:58][CH:57]3[CH2:56][C:55]([CH3:61])([CH2:7][C:6]([NH:5][C:8](=[O:9])[O:10][CH2:11]/[CH:12]=[C:13](\[CH3:30])/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])([CH2:59]3)[CH2:62]1)[CH2:54]2
Reactant: CC12CC3CC(C)(C1)CC(N)(C3)C2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)N1CCN(C)CC1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=O)NC12CC3CC(C)(CC(C)(C3)C1)C2

Procedure:
Similar to the preparation of 40a, the reaction of alcohol 1 with memantine and CDI afforded the desired compound 41 as a viscous oil. Column (DCM/MeOH); TLC Rf: 0.70 (10% EtOAc/Hexanes).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[Cl:23])[CH3:12]>CCO.O1CCOCC1>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[Cl:23])[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (0.600 g, 3.80 mmol) (Aldrich) and (4-amino-2-chloro-phenyl)-acetic acid ethyl ester (see WO 97/21665) (0.800 g 3.80 mmol) in EtOH/dioxane (20 mL; 1:1, v/v) is stirred and refluxed for 72 h. The mixture is allowed to cool to rt and concentrated in vacuo. The crude material is purified by silica gel column chromatography (Hexane/EtOAc, 7/3) to afford a red solid, which upon trituration with Et2O provides the title compound as an orange solid: ES-MS: 336.0 [M+H]+; single peak at tR=5.59 min (System 1); Rf=0.39 (Hexane/EtOAc, 7:3).
Reaction SMILES: Br[C:2]1([Cl:14])[CH2:7][CH:6]=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.CCCCCC.CON(C)[C:29]([C@@H:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)=[O:30]>C1COCC1>[C:40]([O:39][C:37]([N:33]1[CH2:34][CH2:35][CH2:36][C@@H:31]([C:29](=[O:30])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:14])[CH2:32]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ClC1(Br)CC=CC=C1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2-c2ccccc2Cl)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of 2-bromo-2-chloro-biphenyl (5.34 g, 20 mmol) in anhydrous THF (50 mL) cooled to −78° C. was added dropwise a solution of 1.6 M n-BuLi in hexane (12.5 mL, 20 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (5.44 g, 20 mmol) in anhydrous THF (50 mL) was added. The mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with satd aq NH4Cl (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by flash column chromatography to afford (3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 55%).
Reaction SMILES: [H-].[Na+].C(S)C.[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][N:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([C:19]#[N:20])[C:12]1=[O:21].Cl>CN(C=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][N:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:19]#[N:20])[C:12]1=[O:21]
Reactant: COc1ccn(Cc2cccc(F)c2)c(=O)c1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: N#Cc1c(O)ccn(Cc2cccc(F)c2)c1=O
Temperature: 100 °C
Yield: 92 %

Procedure:
To a solution of sodium hydride (92 mg of a 60% dispersion in mineral oil, 2.3 mmol) in DMF (7 mL) was added ethanethiol (0.14 g, 2.2 mmol), followed by a solution of 1-(3-fluorobenzyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.23 g, 0.89 mmol) in DMF (2 mL), and the reaction mixture was heated to 100° C. The reaction mixture was cooled to room temperature, acidified with 3 N HCl, and washed with EtOAc. The organic solution was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-(3-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile as an off-white solid (0.20 g, 91%): 1H NMR (300 MHz, MeOD) δ 8.00 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.40-7.30 (m, 1H), 7.15-7.00 (m, 2H), 6.13 (d, J=8 Hz, 1H), 5.11 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:37][C:36]1[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:3][C:2]=1[F:1])[CH3:44]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: CCN(CC)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 33.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.7 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:19]>>[NH2:19][C:11]1[CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: NC1=CC(=O)CC(c2ccccc2)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-phenylcyclohexan-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:12][CH:11]3[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]3)[CH2:6]2)[CH2:3][CH2:2]1.[NH2-].[Li+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25](Cl)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]2[CH2:8][CH:7]3[C:13]([CH3:15])([CH3:14])[CH:11]([CH2:12][N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6]3)[CH2:10]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Reactant: CC1(C)C2CNCC1CN(CC1CC1)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [NH2-]
Solvent: CN(C)C=O
Product: CC1(C)C2CN(CC3CC3)CC1CN(C(c1ccc(F)cc1)c1ccc(F)cc1)C2
Temperature: 60 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
3.5 g 3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane were dissolved in 25 ml dimethylformamide, and 0.8 g lithium amide were added to the solution. The reaction mixture was then maintained at a temperature of 60° C. for one hour and subsequently allowed to cool. After cooling, a solution of 8 g bis-(4-fluorophenyl)methyl chloride in 10 ml dimethylformamide was added in drops, and the reaction mixture was stirred for a further 4 hours at 40° C. Then aqueous citric acid solution was added to the reaction mixture, and the mixture was worked up as described in Example 1. 5.8 g 7-[bis-(4-fluorophenyl)methyl]-3-cyclopropylmethyl-9,9-dimethyl-3,7diazabicyclo[3,3,1]nonane were obtained as an oleaginous base.