Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[C:19]([NH:18][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[N:28][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)#[N:20]
Reactant: NC1CCCC1
Reactant: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Solvent: ClCCl
Product: N#CNC(=NC1CCCC1)Nc1cccc(C(F)(F)F)c1
Yield: 68 %

Procedure:
N-(3-Trifluoromethylphenyl)-N'-cyano-O-phenylisourea (1 mmol, 290 mg) was stirred for 19 h at 80° C. in cyclopentylamine (1 ml). After concentration of the cold reaction mixture, the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 3:1) to give the title compound (205 mg, 68%) as a syrup. Crystallisation from heptane:ethyl acetate 2:1 gave 147 mg (49%). Mp 111.5-113° C; 1H-NMR (CDCl3): δ 1.42 (m, 2H), 1.65 (m, 4H), 2.05 (m, 2H), 4.12 (sextet, 1H), 4.85 (br, 1H), 7.35 (br s,1H), 7.5 ppm (m, 4H); MA calc for C14H15F3N4 : C, 56.75%; H, 5.10%; N, 18.91%. Found: C, 56.48%; H, 5.08%; N, 18.65%.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]([N:19]2[CH2:23][C@@H:22]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C@H:21]([CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)[CH2:20]2)=[O:18])[CH:10]=[C:9]1C)=O)(C)(C)C.[Li+].[BH4-].C([O-])(O)=O.[Na+].[OH-].[Na+].C1C[O:56][CH2:55][CH2:54]1>CCOCC>[OH:56][CH2:55][CH2:54][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]([N:19]2[CH2:23][C@@H:22]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C@H:21]([CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:34][CH2:35]3)[CH2:20]2)=[O:18])[CH:10]=[CH:9]1
Reactant: Cc1cc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](c4ccsc4)C3)c2n1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(c1cccc2ccn(CCO)c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.07 g (0.115 mmol) of 1-(1-t-butoxycarbonyl methyl-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine and 0.23 mL (0.46 mmol) of LiBH4 (2M in THF) in 4 mL of THF was stirred at rt for 12 h. To the reaction mixture was slowly added 2 mL of sat. NaHCO3 solution and the mixture was stirred st rt for 3 h. To this mixture was then added 30 mL of ether and the pH was adjusted to pH=10-11 with 5N NaOH solution. The reaction mixture was extracted with CH2Cl2. The organic fraction was dried over Na2CO3, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, CH2Cl2: ethyl acetate: NH3 (2M in MeOH), 10:10:2) to give the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[NH:5][C:6]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[C:7]([F:12])[C:8](=[N:10][NH2:11])[N:9]=1.[CH:20]1([CH2:25][C@H:26]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:10][NH:11][C:27](=[O:28])[C@H:26]([CH2:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:30][N:31]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:39]=[O:40])[C:7]([F:12])=[C:6]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:5]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: NN=c1nc(Cl)[nH]c(NCc2nccs2)c1F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2nccs2)c1F)OC1CCCCO1
Reaction time: 8 h
Yield: 61.8 %

Procedure:
2-Chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone dihydrochloride (0.3052 g, 0.882 mmol) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.457 g, 1.059 mmol) were dissolved in DMF (8 mL). NMM (0.58 mL, 5.2753 mmol) was added, followed by HOAt (0.144 g, 1.059 mmol) and EDC (0.203 g, 1.059 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-2-yl methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a beige solid (0.3031 g, 62%). LCMS: (M+H)+=556.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC.C(OC(C)C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:23]2[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OC1CCSCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCSCC1
Yield: 60.6 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65 mmol) obtained in Example 5 and tetrahydrothiopyran-4-ol (400 mg, 3.38 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (800 mg, 3.31 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) was added. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with a hexane/diisopropyl ether mixture, whereby the title compound (404 mg, 1.00 mmol, 61%) was obtained as a white powder.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6]
Reactant: [H][H]
Reactant: CN(C)C=Nc1c(C(=O)CN=[N+]=[N-])ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Agent: [Pd]
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Yield: 89.2 %

Procedure:
The compound (23) (52 mg) obtained in item (12) above was dissolved in methanol (6 ml), and the solution was subjected to catalytic reduction by blowing hydrogen therein in the presence of palladium black as catalyst at room temperature for 30 minutes. The resulting reaction solution was filtered and the filtrate was concentrated to give a solid. The solid material thus obtained was washed with ethyl acetate to yield the titled compound (24) (43 mg) as an insoluble substance. Yield: 89%.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH:17][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)CCN
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzenesulfonyl chloride (500 mg, 2.83 mmol) in pyridine (10 mL) is added 3-amino-propionic acid ethyl ester (672 mg, 8.49 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using a gradient of 10-50% heptane/EtOAc to afford 3-benzenesulfonylaminopropionic acid ethyl ester. MS 258.3 (M+1); 1H-NMR (400 MHz, CDCl3); δ ppm 1.24 (t, 3H), 2.53 (t, 2H), 3.21 (q, 2H), 5.22 (m, 1H), 7.51-7.61 (m, 3H), 7.87 (d, J=7.20 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:49]=[CH:48][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C@H:38]([C:41]([O:43]C(C)(C)C)=[O:42])[CH2:39][OH:40])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]([CH2:21][C:22]1[CH:51]=[CH:50][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C@H:38]([C:41]([OH:43])=[O:42])[CH2:39][OH:40])=[O:36])=[CH:48][CH:49]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CO)C(=O)O)cc2)cc1

Procedure:
The product from Example 258A was treated with 10% trifluoroacetic acid in dichloromethane (2 ml) for 5 hours at room temperature and concentrated in vacuo. Residue purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.04-12.95 (br.s, 1 H), 8.94 (s, 1 H), 8.00 (d, 1 H), 7.24 (m, 7 H), 6.88-7.09 (m, 7 H), 6.82 (d, 2 H), 4.29 (m, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 3.95 (t, 2 H), 3.65 (m, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.32 (m, 2 H), 1.94 (m, 2 H); MS (ESI+) m/z 662 (M+H)+.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.O>C1COCC1>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: BrBr
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc([N+](=O)[O-])cc1Br
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Bromine (62.6 mλ; 1.2 mole) was dropwise added to 2-amino-5-nitropyridine (154.1 g; 1.1 mole) in THF (300 mλ) at room temperature. The resulting mixture was stirred for one hour and then poured into water (3 λ). The crystals thus formed were recrystallized from acetonitrile (500 mλ) to give 2-amino-3-bromo-5-nitropyridine (A) (194.4 g; 80%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].Cl[Si:16]([C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:18])[CH3:17]>C(OCC)C>[C:1]1([Si:16]([C:19]2[CH2:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:17])[CH3:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: CCOCC
Product: C[Si](C)(C1=Cc2ccccc2C1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of lithium fluorene from Example 4 was slowly added dropwise at 0° C., by means of a septum and a syringe, to a solution of chloro-2-indenyl-dimethylsilane (2.85 g, 0.0136 mol.) according to Example 1 in 20 ml of diethyl ether. After 2 hours' stirring at 25° C., the resulting LiCl was filtered off. The solvent was removed from the filtrate and the beige-colored residue was dissolved in hot ether/petroleum ether and crystallized at −30° C. 3.45 g (75%) of fluorenyl-2-indenyldimethylsilane were obtained in the form of a colorless solid. M.p.: 125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][CH2:27][N:28]4[C:29](=[O:38])[C:30]5[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]4=[O:33])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (290 mg, 0.81 mmol), prepared as described in Example 1, N-(2-bromoethyl)phthalimide (215 mg, 0.84 mmol) and K2CO3 (337 mg, 2.44 mmol) in DMF (3 ml), was heated at 80° C. for 2.5 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified using silica gel column chromatography using an automated system eluting with a 1:1 mixture of ethyl acetate:hexane to give the title compound, 2-(2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)ethyl)isoindoline-1,3-dione as a yellow solid (290 mg, 68%). MS M+H=530.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(Cl)nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(Cl)ccc1C(=O)O

Procedure:
A solution of 10.1 g (0.05 mole) of methyl 2-methoxy-6-chloronicotinate in 20 ml of methanol is added dropwise at 70° C in the course of 30 minutes to 500 ml of 0.1 N aqueous sodium hydroxide solution. After completion of the addition, the mixture is refluxed for 1 hour. The clear solution is concentrated in vacuo to approx. 100 ml and acidified with 2 N hydrochloric acid to pH 3. The precipitate which has formed is collected by filtration, washed with a small amount of water and dried. The residue is recrystallized from benzene-petroleum ether to yield pure 2-methoxy-6-chloronicotinic acid with a melting point of 210°-215° C.
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19]>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([O:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[N:9][CH:10]=1
Reactant: CN(C)CCO
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Potassium t-butoxide was added to a DMF solution of 2,5-dibromopyridine and 2-(dimethylamino)ethanol, and the whole was stirred at an oil bath temperature of 100° C. for 3 hours to obtain N-{2-[(5-bromopyridin-2-yl)oxy]ethyl}—N,N-dimethylamine, which was further treated in a similar manner to Reference Examples 11 and 12 to obtain an objective compound.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C]=O.O=O.[C:17]([OH:20])(=[O:19])C>>[C:17]([C:5]12[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][C:3]([OH:11])([CH2:2]3)[CH2:4]1)[CH2:6]2)([OH:20])=[O:19]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: CC(=O)O
Agent: O=O
Agent: [C]=O
Product: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Yield: 80 %

Procedure:
A reactor was charged with 10 mmole of 1,3-adamantanediol, 1 mmole of NHPI, 0.005 mmole of Co(AA)2 and 25 mL of acetic acid, then equipped with a gas bag of mixed gas (a mixed gas of 2 L of carbon monoxide and 0.5 L of oxygen; pressure: 5 kg/cm). The resultant mixture was stirred for 6 hours at 60° C. to give 1-carboxy-3,5-adamantanediol (yield 80%). The conversion of 1,3-adamantanediol was 99%.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:13]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([O:9][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5 difluoro-2-nitrophenol(8.3 g), N,N-dimethylformamide(30 mL), potassium carbonate(10 g) and iodomethane(5 mL) was stirred vigorously at room temperature for 18 h. The mixture was diluted with water and extracted with ether. The extract was washed with brine, dried and evaporated to dryness to give the product(8.7 g) as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)S(=O)N=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(NS(=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.6 %

Procedure:
To a solution of (±)-N-((5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (770 mg, 1.91 mmol) in anhydrous THF (7.6 mL) was slowly added tBuLi (1.7 M solution in pentane, 3.34 mL, 5.74 mmol) at −78° C. After the reaction mixture was stirred at −78° C. for 3 h, the reaction was quenched with MeOH (2 mL) followed by addition of saturated NH4Cl solution (10 mL). Upon warming up to room temperature, the reaction mixture was stirred for 30 min and then extracted with EtOAc (50 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield (±)-N-(1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (340 mg, 38.6%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.64 (1H, m), 7.38-7.27 (4H, m), 7.27-7.21 (1H, m), 7.12-6.99 (2H, m), 4.24 (1H, m), 4.12 (2Hm), 3.92 (1H, m), 1.27 (9H, s), 0.95 (9H, s). LC/MS (uplc): MH+ 461.2, 1.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[O:11])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:11][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(Cl)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2cnc(-c3ccc(Cl)cc3)o2)cc1
Yield: 56.8 %

Procedure:
A mixture of ethyl 4-[2-(4-chlorobenzoylamino)-1-oxoethyl]benzoate (1.04 g), phosphorus oxychloride (0.92 g) and toluene (10 ml) was refluxed under heating for 1 hour. The reaction mixture was poured into water, and precipitated crystals of ethyl 4-[2-(4-chlorophenyl)-5-oxazolyl]benzoate (560 mg, yield: 57%) were collected by filtration. The product was recrystallized from ethyl acetate-hexane to obtain pale yellow prisms. Melting point: 137to 138° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:49]1([CH2:55][CH2:56][CH2:57]Br)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O>[CH:8]1([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:38][CH2:39][N:40]([CH2:57][CH2:56][CH2:55][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[CH2:41][CH2:42]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Clc1ccc(OCc2nc3c(OCC4CCCCC4)cccc3n2CCCC2CCNCC2)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCC4CCCCC4)cccc3n2CCCC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[CH3:9][C:10]1([CH3:24])[CH2:23][N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21](=[O:22])[C:13]2=[N:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C.ClCCCl>[CH3:9][C:10]1([CH3:24])[CH2:23][N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]([OH:22])([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7])[C:13]2=[N:12][CH2:11]1
Reactant: COCCCCBr
Reactant: CC1(C)CN=C2C(=O)c3ccccc3N2C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COCCCCC1(O)C2=NCC(C)(C)CN2c2ccccc21
Reaction time: 0.75 h

Procedure:
A solution of 1-bromo-4-methoxybutane (6.26 g) in diethyl ether (23 ml) was added dropwise to stirred magnesium turnings (0.9 g) under nitrogen, at a rate sufficient to maintain reflux. The mixture was stirred for a further 45 min., then a solution of 3,4-dihydro-3,3-dimethylpyrimido[1,2-a]indole-10(2H)-one (1.6 g) in 1,2-dichloroethane (75 ml) was added dropwise. The mixture was stirred for 30 min., then poured into aqueous ammonium chloride solution and extracted with chloroform (2×100 ml). The chloroform extracts were combined, dried (MgSO4) and evaporated under reduced pressure giving an orange solid. Trituration from ethyl acetate, followed by recrystallisation from ethyl acetate gave the title compound (1.2 g(. Addition of ethereal hydrogen chloride to a solution of the free base in methanol, followed by evaporation of the solvents and crystallisation of the resulting solid from propan-2-ol gave the hydrochloride salt (0.6 g), m.p. 188°-190°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[NH4+].[Cl-]>C(O)C.[Zn]>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 98.5 %

Procedure:
To a solution of 81 (0.75 g, 2 mmol) and NH4Cl (0.26 g, 4.85 mmol) in 86% aqueous ethanol (22 mL) was added zinc powder (0.52 g, 7.95 mmol). The resulting mixture was stirred vigorously at room temperature for 50 minutes. The mixture was filtered, and the solvent was washed with water (40 mL) and dried (MgSO4), and the solvent was removed with a rotary evaporator to obtain 0.71 g of 82 as a yellow oil which was condensed with aldehydes without further purification.