Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[CH2:11][CH3:12]>>[CH2:11]([C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1)[CH3:12]
Reactant: Nc1ccccn1
Reactant: CCC(=O)CBr
Product: CCc1cn2ccccc2n1

Procedure:
The title compound was prepared from 2-aminopyridine and 1-bromo-2-butanone, employing procedures analogous to those described in Procedure 27 Step A.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14]OS(C)(=O)=O)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:20]([C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O.CC(=O)OCC.O>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:25]3[CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:27]=[N:26]3)=[N:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC1(c2cnc(COS(C)(=O)=O)s2)OCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC1(c2cnc(Cn3cc([N+](=O)[O-])cn3)s2)OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl ester (520 mg, 1.86 mmol) in acetone (15.0 mL) was added to a solution of 4-nitro-1H-pyrazole (221 mg, 1.96 mmol) in acetone (15.0 mL). K2CO3 (1.300 g, 9.31 mmol) followed by TBA bromide (120 mg, 0.37 mmol) were added and the reaction mixture was stirred at rt overnight. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.15. LC-MS-conditions 01: tR=0.83 min, [M+H]+=296.90.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.S(=O)(=O)(O)O.B(OC)(OC)OC.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To 20 ml of sulfolane were added 1.41 g of 7-ACA, 1.96 g of ferric chloride, 0.29 ml of concentrated sulfuric acid and 1.22 ml of trimethyl borate. The mixture was heated at 30° C. for 3 hours to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 0° C. To the reaction mixture were added 30 ml of water, 10 ml of methanol and 3.04 g of sodium thiosulfate and the mixture was stirred for 1 hour while cooling with ice. The resultant precipitate was filtered off, and then washed with methanol. The filtrate was combined with the washings. The resultant mixture was adjusted to pH 3.5 with 36% hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 20 ml of cold methanol, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.05 g. The yield of the desired product was 83%.
Reaction SMILES: C([Li])CCC.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].CN(C)CCN(C)C.I[CH2:25][CH2:26][O:27][CH2:28][CH2:29]I>C1COCC1>[O:27]1[CH2:28][CH2:29][C:8]2([C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][C:7]2=[O:15])[CH2:25][CH2:26]1
Reactant: O=C1Cc2ccccc2N1
Reactant: ICCOCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to a solution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL). After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48 mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C. After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was added and the reaction warmed to ambient temperature. After 48 h the reaction was quenched with H2O (5 mL) and the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous solution was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[F:17].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([NH2:14])=[C:11]([F:13])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(Cl)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Tin (II) chloride dihydrate (15.5 g, 68.7 mmol) was dissolved in ethyl acetate (50 mL) and 1-chloro-2,5-difluoro-4-nitrobenzene (2.65 g, 13.7 mmol) was added dropwise. The reaction mixture was then stirred at 70° C. for 1 h. The reaction mixture was then carefully added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed several more times with water, dried, filtered, concentrated and purified by flash chromatography on silica gel (hexane/diethyl ether) to give the title compound as a white solid (1.65 g, 73.9% yield): 1H NMR (CDCl3) δ 7.02 (dd, 1H), 6.57 (dd, 1H), 3.81 (br s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:25][C:24]1[CH:23]=[C:22]([F:21])[C:29]([F:30])=[C:28]([F:31])[CH:27]=1)[N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(CBr)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cc(F)c(F)c(F)c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of N-(Diphenylmethylene)glycine ethyl ester (1.10 g, 4.1 mmol) and 3,4,5-trifluorobenzylbromide (0.91 g, 4.0 mmol) in dimethylformamide (10 mL) was treated with anhydrous potassium carbonate (2.83 g, 20.5 mmol) and stirred for 18 hrs at 25° C. The mixture was filtered and the filtrate was evaporated to dryness to give crude product. It was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give title compound (1.2 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[CH:40]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl.O>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:45]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:47])=[O:46])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=S(=O)(Cl)C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)C3CCCC3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (10.0 mL) was added cyclopentanesulfonyl chloride (62.5 μL, 0.474 mmol). The reaction mixture was stirred at 0° C. for 20 minutes, then it was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with water (25 mL). The resulting mixture was extracted with methylene chloride (2×30 mL). The organic phase was dried over MgSO4, filtered, and concentrated. Silica gel chromatography (33% ethyl acetate in hexanes) provided [4-(1-cyclopentanesulfonyl-piperidin-4-yl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (64.8 mg, 61%). MS cald. For C24H31FNO4S [(M+H)+]: 448, obsd. 448.2.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[CH:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 257.8 %

Procedure:
To N-tert-butyl-3-[4-methyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonamide (example 297) (0.110 g, 0.19 mmol) was added TFA (6 mL) and the reaction mixture was stirred at 50° C. for 2 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.230 g, 98%). MS (ISP) 470.3 [(M+H)+]; mp 238° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH3:26])[C:20](=[O:27])[CH2:19][CH2:18]2.O1CCOCC1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I>[CH2:25]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:24][CH:23]=2)[CH2:18][CH2:19][C:20]1=[O:27])[CH3:26]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: CCN1C(=O)CCc2cc(Br)ccc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCN1C(=O)CCc2cc(N3CCN(c4cnccc4C)C3=O)ccc21
Yield: 32 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (215.15 mg, 0.847 mmol), 1,4-dioxane (0.03 mL, 0.254 mmol), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 95 mg of the product (31.99%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16]C(C)(C)C)=O)[C:11]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.F[C:29](F)(F)C(O)=O.CCN(CC)CC.C(OC(=O)C)(=O)C>>[C:14]([N:12]1[CH2:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:10][C:11]1([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:16])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1(C)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(c2cc(F)ccc2F)=CC1(C)c1ccccc1
Reaction time: 1 h

Procedure:
To a flame-dried flask equipped with stir bar under nitrogen was charged 20-9 (14 mg, 38 μmol) and anhydrous CH2CL2 (1 mL). The resulting solution was treated with trifluoroacetic acid (0.2 mL) and stirred 1 hour at 25° C. Upon completion, the reaction was concentrated, diluted with toluene (5 mL) and again concentrated. The TFA salt was then suspended in CH2CL2 at 25° C., and treated successively with Et3N (50 μL, 380 μmol) and acetic anhydride (25 μL, 20 μmol). After 1 hour, the reaction was complete. The reaction was concentrated and flash column chromatography (SiO2, 0-50% EtOAc/hex gradient) provided 20-10 as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 7.03 (m, 3H), 6.22 (m, 1H), 4.82 (m, 2H), 2.15 and 2.05 (s, 3H, rotamers), 1.98 and 1.74 (s, 3H, rotamers); LRMS m/z (M+H) 314.0 found, 314.2 required.
Reaction SMILES: [N:1]1([C:6]2[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[N:26]1([C:31](N)=[NH:32])C=CC=N1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:31]([NH2:32])=[NH:26])[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:23][CH:24]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (300 mg, 0.876 mmol), pyrazole-1-carboxamidine hydrochloride (0.128 g, 0.876 mmol.) and triethylamine (0.122 mL, 0.876 mmol) in DMF (2 mL) was stirred at rt for 3 hours. The precipitate was collected by filtration and washed with ether to afford the expected product. 1H NMR (DMSO-d6): δ 10.02 (1H, s), 7.93 (1H, s), 7.82 (2H, m), 7.70 (1H, s), 7.60(2H, br), 7.28 (2H, m), 5.20 (2H, s), 3.95 (2H, m), 3.38 (1H, m), 3.15 (2H, m), 2.09 (2H, m), 1.66 (2H, m).
Reaction SMILES: [C:1]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[S:27].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:18]=[C:31]3[S:25][C:26](=[S:27])[NH:28][C:29]3=[O:30])[CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cccc(OCc2ccc(C(=O)c3ccccc3)cc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cccc(OCc2ccc(C(=O)c3ccccc3)cc2)c1
Yield: 58.9 %

Procedure:
The 3-(4-benzoylbenzyloxy)benzaldehyde (2.0 g, 6.3 mmol) was coupled with rhodanine (1.06 g, 8.0 mmol) in the presence of sodium acetate (1.89 g, 22 mmol) and acetic acid (75 ml) essentially as previously described to yield 1.6 grams (59.0%) of the deisred title product. mp 212.5°-213.5° C. NMR. FDMS (M+) 431.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F-].[Na+].O>O1CCCC1>[N:8]1[N:5]2[CH2:6][CH2:7][CH2:2][NH:3][C:4]2=[CH:10][CH:9]=1
Reactant: O=C1CCn2nccc2N1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2n(n1)CCCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a suspension of 5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (0.5 g) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (0.277 g) at room temperature. The mixture was stirred at ambient temperature for 30 minutes. To the mixture was added sodium fluoride (1.22 g), and then water (0.394 g) was added dropwise thereto under ice-cooling. The mixture was stirred at 0°-5° C. for 30 minutes and filtered. The filtrate was evaporated to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (257 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.82 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.840 g, 4.20 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.40 g (93% yield) of tert-butyl (2S)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 394 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([O:25]C)=[O:24])[C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[CH:4][CH:3]=1.C1C=CC=CC=1.[OH-].[Na+].Cl>CCOCC.O.C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([OH:25])=[O:24])[C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccccc1N(Cc1ccc(C)cc1)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1ccc(CN(c2ccccc2CC(=O)O)c2c(Cl)cccc2Cl)cc1
Yield: 81.8 %

Procedure:
The mixture of 4.3 g of methyl N-(p-methylbenzyl)-o-(2,6-dichloroanilino)phenylacetate, 8 ml of benzene, 5 ml of ethanol, 8 ml of water and 2.5 g of 98% sodium hydroxide was refluxed for 8 hours under thoroughly stirring. After cooling the reaction mixture, 10% HCl aq. sol. was added to adjust pH 2 to 3 and 30 ml of ether was added and the ether phase was separated. The ether solution was dried over anhydrous sodium sulfate and the solvent was distilled off and the residue was recrystallized from ether-hexane to obtain 3.4 g of N-(p-methylbenzyl)-o-(2,6-dichloroanilino)phenylacetic acid as colorless crystals. Yield: 85%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1)[CH:5]=O.[N+:19]([CH3:22])([O-:21])=[O:20].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C.CS(C)=O.C(OCC)(=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH2:5][CH2:22][N+:19]([O-:21])=[O:20])=[CH:3][C:2]=2[F:1])=[N:13][CH:14]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccc(F)cn2)c(F)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
To an acetic acid (8.00 mL) solution of 3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-benzaldehyde (629 mg, 2.52 mmol) described in Manufacturing Example 94-1-1 were added nitromethane (769 mg, 12.6 mmol) and ammonium acetate (388 mg, 5.04 mmol) under nitrogen atmosphere at room temperature, which was stirred for 6 hours at 100° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (736 mg). To a dimethyl sulfoxide (10.0 mL) solution of this crude product (736 mg) and acetic acid (700 μL) was added sodium borohydride (153 mg, 4.03 mmol) at room temperature while cooling appropriately, which was stirred for 30 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (341 mg, 46.0%).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=C(OC)C=CC=1C[N:21]1[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][C@@H:23]([N:30]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[S:31]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:33])=[O:32])[C:22]1=[O:49]>ClCCl>[F:29][C:25]1([F:28])[CH2:26][CH2:27][NH:21][C:22](=[O:49])[C@H:23]([N:30]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[S:31]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:33])=[O:32])[CH2:24]1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](N(Cc3ccc(OC)nc3)S(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)s2)cn1

Procedure:
A mixture containing trifluoroacetic acid/trifluoromethanesulfonic acid (5:2 v/v, 0.62 ml) was added to 5-chloro-thiophene-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-(6-methoxy-pyridin-3-ylmethyl)-amide (0.17 g, 0.19 mmol) in dichloromethane (10 ml). After 2 h the reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified over silica gel (heptane-ethylacetate, 9:1-0:1): white solid 69 mg (77%);
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[O:4][CH:5]1[CH2:10][C:9]([CH2:12][CH3:13])([CH3:11])[NH:8][C:7]([CH2:15][CH3:16])([CH3:14])[CH:6]1[CH3:17].[CH2:19]1[O:21][CH2:20]1>CO.Cl>[CH3:1][NH:2][C:3](=[O:18])[O:4][CH:5]1[CH2:10][C:9]([CH2:12][CH3:13])([CH3:11])[N:8]([CH2:19][CH2:20][OH:21])[C:7]([CH2:15][CH3:16])([CH3:14])[CH:6]1[CH3:17]
Reactant: C1CO1
Reactant: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1
Agent: Cl
Solvent: CO
Product: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1CCO
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a solution of 5.1 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidyl methylcarbamate (Compound 66 - prepared as described in Preparation 4) in 8 ml of methanol were added 1.74 g of ethylene oxide and 1 drop of concentrated hydrochloric acid. The mixture was heated overnight at 100° C. in a sealed tube. When the reaction was complete, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel using a 1 : 1 by volume mixture of benzene and ethyl acetate as eluent, giving 3.0 g of Compound 84. The compound showed a single spot on thin layer chromatography on silica gel (developing solvent: benzene/ethyl acetate, 1 : 1 by volume), Rf value 0.51.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([OH:23])=[O:22]>O>[C:7]1([C:4]2[N:3]=[C:2]([S:1][CH2:20][C:21]([OH:23])=[O:22])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1nc(-c2ccccc2)ns1
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CSc1nc(-c2ccccc2)ns1
Yield: 51 %

Procedure:
A mixture of 5-mercapto-3-phenyl-1,2,4-thiadiazole (76 parts), potassium carbonate (58 parts), chloroacetic acid (38 parts) and water (100 parts) was heated at reflux for 1 hour. The solution was filtered hot, cooled, acidified, and the solid separated to give (3-phenyl-1,2,4-thiadiazol-5-ylthio)acetic acid (50 parts, 51% yield), melting point 97° C.