Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:11][CH2:12][C:13]([C:15]1[CH:35]=[CH:34][C:18]2[O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)[O:21][C:17]=2[C:16]=1[O:36][CH3:37])=[O:14])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>Cl>[OH:21][C:17]1[C:16]([O:36][CH3:37])=[C:15]([C:13](=[O:14])[CH2:12][NH:11][C:2]([CH3:1])([CH3:10])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:35]=[CH:34][C:18]=1[OH:19]
Reactant: COc1c(C(=O)CNC(C)(C)Cc2ccccc2)ccc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Product: COc1c(C(=O)CNC(C)(C)Cc2ccccc2)ccc(O)c1O

Procedure:
34 g of the HCl salt of 2-(1,1-dimethyl-2-phenylethylamino)-1-(4-methoxy-2,2-diphenylbenzo[1,3]dioxol-5-yl)ethanone is refluxed in 340 mL of 15% methanolic hydrochloric acid for 2 hours. Then the solvent is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. The solid precipitated is suction filtered and washed with ethyl acetate and diethyl ether. Yield: 18 g (77%, hydrochloride); melting point: 192° C.-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:19][C:20]([NH2:22])=[S:21]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:19]=[C:20]([NH2:22])[S:21][CH:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)CBr)cn2)cc1
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(-c3csc(N)n3)cn2)cc1
Yield: 83.9 %

Procedure:
According to Scheme 6, Step 1: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (9.70 mmol, 3.00 g) and of thiourea (9.70 mmol, 739 mg) in acetone (20 mL) was stirred under reflux for 1 hour. After filtration and evaporation of the filtrate, the white solid was partitioned between EtOAc and a saturated solution of Na2CO3. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4, was filtered and was concentrated to yield 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine (8.14 mmol, 2.33 g) as an orange foam.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[N:12]([CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CNN>O1CCCC1>[CH:23]([O:22][CH2:21][CH2:20][N:12]([C:13]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])[NH2:3])([CH3:25])[CH3:24]
Reactant: CC(C)OCCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: C1CCOC1
Product: CC(C)OCCN(N)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a solution of tert-butyl 1,3-dioxoisoindolin-2-yl(2-isopropoxyethyl)carbamate (example 77B, 1.262 g, 3.62 mmol) in tetrahydrofuran (24.15 mL) at 0° C. was slowly added methylhydrazine (0.289 mL, 5.43 mmol). The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was filtered to remove the white precipitate and the filtrate was concentrated in vacuo. The semisolid was triturated with ethyl acetate (2×) and the triturant was concentrated in vacuo. This process was repeated to ultimately provide tert-butyl 1-(2-isopropoxyethyl)hydrazinecarboxylate (0.665 g, 84% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][C:17]=1[O:26][CH3:27])(=[O:11])=[O:10].C(Cl)CCl.C1C=C[C:44]2N(O)N=[N:47][C:45]=2C=1.C(N)C.C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[NH:47][CH2:45][CH3:44])=[CH:18][C:17]=1[O:26][CH3:27])[C:32]([NH:33][CH2:34][CH3:35])=[O:36])(=[O:11])=[O:10]
Reactant: CCNC(=O)c1ccc(Oc2ccc(CC(=O)O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCNC(=O)Cc1ccc(Oc2ccc(C(=O)NCC)cc2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
A mixture of acid (12) (63 mg, 0.114 mmol), EDC (44 mg, 0.228 mmol), HOBt (18 mg, 0.114 mmol), 114 μL of 2N ethylamine in THF (0.228 mmol) in 1 mL of methylene chloride was allowed to stir for 24 h at room temperature. Upon completion, the solvent was removed and 10 mL of 2N HCl aqueous solution was added and the resulting mixture was extracted with EtOAc (4×20 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on a silica gel column using 50% EtOAc/hexane and EtOAc sequentially as the eluents to give 53.0 mg of the title compound. 1H NMR (CDCl3): δ 7.96 (d, J=8.52 Hz, 1H), 7.87 (d, J=2.08 Hz, 1H), 7.83 (br s, 1H), 7.42 (obscured dd, J=8.52, 2.16 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=8.12, 2.20 Hz, 1H), 6.90 (d, J=1.72 Hz, 1H), 6.77 (d, J=8.20 Hz, 1H), 6.76 (s, 1H), 6.72 (d, J=8.08 Hz, 1H), 6.54 (d, J=8.52 Hz, 1H), 6.17 (br s, 1H), 5.62 (br s, 1H), 3.67 (s, 3H), 3.52 (s, 2H), 3.45 (m, 2H), 3.29 (m, 2H), 1.23 (dd, J=7.48, 7.48 Hz, 3H), 1.12 (dd, J=7.52, 7.52 Hz, 3H). LCMS (ESI−) 579 (M−1).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=1[F:26])[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(O)(=O)C.C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[C:19]([F:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=1[F:24])[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NNC(=O)C(CCCCl)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 199.8 %

Procedure:
A solution of 4 N hydrochloric acid in acetic acid (3 mL) was added to a solution of tert-butyl N′-[5-chloro-2-(2,4,6-trifluorophenyl)pentanoyl]hydrazinecarboxylate (333 mg) in ethyl acetate (3 mL), and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure to obtain 277 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH2:42][CH3:43])[C:26]4[CH:27]=[CH:28][C:29]5[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=5[CH:41]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.FC(F)(F)C([O-])=O.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>CC#N>[CH2:42]([N:25]([C:26]1[CH:27]=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=2[CH:41]=1)[C:24]([C@H:22]1[CH2:21][C@@H:20]([NH:45][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:19][NH:18][CH2:23]1)=[O:44])[CH3:43]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(C(=O)[C@H]1C[C@@H](N)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccc2c(c1)N(CCCOC)C(=O)CO2
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: CCN(C(=O)[C@@H]1CNC[C@H](NC(=O)C(C)(C)C)C1)c1ccc2c(c1)N(CCCOC)C(=O)CO2

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{ethyl-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, trifluoroacetate and pivaloyl chloride. MS: 475.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.29 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:12][CH3:13])[CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21].O>C(Cl)Cl>[C:20]([O:23][CH2:24][C:25]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:12][CH3:13])[CH3:11])[C:3]=1[C:4]#[N:5])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCN(C)c1cccc(N)c1C#N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCN(C)c1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(N-ethyl-N-methylamino)-benzonitrile (4 g) in methylene chloride (200 ml) is added pyridine (2.4 ml), and thereto is added dropwise acetoxyacetyl chloride (3.3 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from hexane to give the title compound (4.2 g) having the following physical properties.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][N:23]([CH3:26])[C:21]=4[N:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>O1CCCC1.CO.O>[CH3:26][N:23]1[C:21]2[N:22]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:28])=[O:3])=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)[NH:18][C:19](=[O:27])[C:20]=2[CH:25]=[CH:24]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(ccn4C)c(=O)[nH]3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccc2c(=O)[nH]c(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.9 %

Procedure:
A solution of 4-[4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-piperazin-1-yl]-benzoic acid ethyl ester (163 mg, 427 μmol) in tetrahydrofuran (1.6 mL) and methanol (0.8 mL) was treated with a 1N aqueous sodium hydroxide solution (748 μL, 748 μmol). The resulting yellow solution was stirred for 3 h at room temperature. At this point, another aliquot of a 1N aqueous sodium hydroxide solution (748 μL, 748 μmol) was added. At this time, the reaction was heated to 75° C. where it was stirred for 1.5 h. The reaction was then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was acidified to pH 2 with a 1N aqueous hydrochloric acid solution and further extracted with ethyl acetate (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL). Since product was not soluble in the organic layer, all of the layers were combined and concentrated in vacuo and dried to afford 4-(4-(7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)piperazin-1-yl)benzoic acid (193 mg, 128%) as a light grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.41 (br. s., 4H) 3.57 (s, 3H) 3.71 (br. s., 4H) 6.25 (d, J=3.39 Hz, 1H) 6.78 (d, J=3.39 Hz, 1H) 7.02 (d, J=9.23 Hz, 2H) 7.79 (d, J=8.85 Hz, 2H) 10.89 (s, 1H) 12.29 (s, 1H). LC-MS calcd. for C18H20N5O3 [(M+H)+] 354, obsd. 354.1.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3]>CN(C1C=CN=CC=1)C.ClCCl>[C:7]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
0.6 g of (R)-fenchol, 0.14 g of DMAP and 1.0 g of BOC-Ala-OH were dissolved in 30 mL of dichloromethane at 0° C. 2.0 g of EDIC were added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was extracted with dichloromethane versus water. The organic layer was washed with 1N HCl, NaHCO3 and brine, dried over MgSO4 and concentrated. The crude product was purified using column chromatography, to give 0.3 g of colorless oil (24%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[N:20]1([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][C:28]4[CH:29]=[CH:30][C:25]([N:20]5[CH:24]=[N:23][CH:22]=[N:21]5)=[CH:26][CH:27]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: O=C([C@H]1CC[C@@H](O)CC1)N1CCN(C2CCC2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C([C@H]1CC[C@H](Oc2ccc(-n3cncn3)cc2)CC1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 200 mg (0.75 mmol) of cis-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 133 mg (0.83 mmol) of 4-(1,2,4-triazole-1-yl)phenol, 241 mg (0.92 mmol) of triphenylphosphine in 1.5 ml of THF, a mixture of 212 mg (0.92 mmol) of di-tert-butyl azodicarboxylate in 1.5 ml of THF was added dropwise at 0° C., and stirred for 72 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel elating with CH2Cl2 and methanol=from 99:1 to 9:1. After that, the residue was purified by column chromatography on NH2-coating silica gel eluting % with CH2Cl2 and ethyl acetate=from 100:0 to 99:2. The combined product fractions were evaporated to dryness to yield 35 mg (11%) of the title compound. MS (m/e): 410.3 (MH+).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7]O.CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>C1(C)C=CC=CC=1>[CH2:16]([O:15][CH:5]([N:4]([CH3:10])[CH3:3])[CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN(C)CC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, dehydrated toluene (30 ml) and potassium hydroxide (1.8 g, 28.8 mmol) were added to a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.57 g, 4.78 mmol) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and refluxing was performed at 110° C. for 3 hours. The reaction was terminated because remaining linoleyl methane sulfonate became 4.8% (degree of conversion: 51.1%, integrated value of isomer: 0.142).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:12]=2[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=1>[Fe].O>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]([O:27][CH3:28])=[CH:13][CH:14]=[C:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1-c1cccc(Cl)c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2ccc(N)cc2)cc1-c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed iron powder (586 mg, 10.5 mmol), ethanol (12 mL) and water (3.8 mL). The mixture was heated to 85° C. in an oil bath and then I-270 (1.05 g, 3.00 mmol) was added and the reaction was continued at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. To the filtrate was added water (60 mL) and extractions were performed with ethyl acetate (2×60 mL). The organic portions were combined, washed with brine (60 mL), dried (MgSO4) and concentrated to produce 862 mg of I-271 as a pale orange viscous oil in 89% yield. MS (APCI+): 324.1 (M+1); LC-MS: 97%.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[NH4+].[Cl-]>CCO.[Fe]>[F:1][C:2]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1
Reactant: CN1CCN(Cc2cc([N+](=O)[O-])ccc2F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN(Cc2cc(N)ccc2F)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (0.577 g, 2.278 mmol) in EtOH (7 mL) was treated with satd. NH4Cl (4.75 mL, 22.78 mmol) followed by iron (powder) (1.272 g, 22.78 mmol) and the mixture heated at 55° C. overnight. The mixture was cooled to RT and gravity-filtered through filter paper, rinsing well with MeOH and DCM. The filtrate was concentrated to dryness. The residue was treated with EtOAc and water, then concentrated to dryness again. The resulting material was treated with THF (20 mL), sonicated for several hours and the solvent decanted from the solids. The solids were treated with additional THF (20 mL), sonicated again and the solvent decanted. The solids were treated with THF (20 mL) for a third time, stirred vigorously overnight, then the liquid was decanted. The combined decanted liquids were concentrated to dryness, treated with DCM, filtered to remove solids and concentrated to dryness to afford very hydroscopic 4-fluoro-3-((4-methylpiperazin-1-yl)methyl)aniline (382 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.81 (m, 1H), 6.49 (m, 2H), 4.99 (s, 2H), 3.44 (s, 2H), 3.32 (s, 8H), 2.69 (s, 3H); MS (ESI) m/z: 224.2 [M+H]+.
Reaction SMILES: [I-].[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([N:21]3[CH:25]=[CH:24][N+](C)=C3)=[O:20])=[CH:11][C:5]=2[O:4]1.[CH:28](N(C(C)C)CC)(C)C.CC(N)C>C(#N)C>[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([NH:21][CH:25]([CH3:28])[CH3:24])=[O:20])=[CH:11][C:5]=2[O:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC#N
Solvent: CC(C)N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)NC(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of (Z)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5 -methylthiazol-2(3H)-ylidenecarbamoyl)-3 -methyl-1H-imidazol-3-ium iodide (Example 40B, 48 mg, 0.09 mmol) dissolved in acetonitrile (0.5 mL) was added followed by the addition of diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile(0.5 mL). Then, to the solution was added propan-2-amine (5.9 mg, 0.10 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to supply the titled compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.07 (6H) 2.22 (3H) 3.65-3.83 (1H) 6.99 (1H) 7.32 (1H) 7.43 (1H) 7.61 (1H); MS (ESI) m/z 356 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[NH:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][S:7]1)=[O:5].[C:15](Cl)(=[O:17])[CH3:16].C(N(CC)CC)C>>[CH3:2][O:3][C:4]([CH:6]1[N:10]([C:15](=[O:17])[CH3:16])[CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: COC(=O)C1CSC(C(=O)OC)N1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CSC(C(=O)OC)N1C(C)=O

Procedure:
Thiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester hydrochloride (0.50 g, 2.07 mmol) was subjected to acylation with acetyl chloride (0.22 ml, 3.09 mmol) in the presence of triethylamine (0.58 ml, 4.17 mmol) to give N-acetylthiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester (with the ratio of two kinds of stereoisomers of about 49:51 as confirmed by NMR) as a pale-yellow oil (0.42 g, 83.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Cl[CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:19]=2)[O:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:19]=2)[O:16][CH:17]=1
Reactant: CC(=O)c1ccccc1Cl
Reactant: COc1ccc(-c2nc(CCl)co2)cc1OCC1CC1
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3Cl)co2)cc1OCC1CC1
Yield: 13.3 %

Procedure:
Using 0.31 g of 1-(2-chlorophenyl)ethanone and 0.59 g of 4-chloromethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazole obtained in Reference Example 11, 0.11 g of colorless oily 1-(2-chlorophenyl)-3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained in the same manner as in Example 177.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+].C([O-])(=O)C([O-])=O>CN(C)C=O.CC(C)=O>[CH3:30][N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:2](=[O:1])[CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:9][CH2:10]3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27]
Reactant: O=C1CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc2N1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])C(=O)[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CN1C(=O)CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 Grams of 6-[1-oxo-3-(4-phenyl-1-piperazinyl)-propyl]-3,4-dihydrocarbostyril and 0.24 g of of sodium hydride (50% in mineral oil) were mixed in 50 ml of dimethylformamide and stirred at a room temperature for 3 hours. Then 0.9 g of p-toluenesulfonic acid was added and stirred at a room temperature for 3 hours. The reaction mixture was poured into 150 ml of a saturated sodium chloride solution and was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduce pressure. The residue thus obtained was injected into preparative thin-layer chromatography to purify and separate the desired compound. The compound obtained was dissolved in acetone and converted into the oxalate by a method similar to that described in Example 27 and recrystallized from ethanol-water to obtain 1.5 g of 1-methyl-6-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril.monooxalate in colorless flake-like crystals.
Reaction SMILES: [C:1]([C:6]1[N:7]=[CH:8][NH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OCC)=[O:2].[OH-].[Na+].C=O>O>[OH:2][CH2:1][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nc[nH]c1-c1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCc1nc[nH]c1-c1ccccc1
Yield: 67.7 %

Procedure:
To a suspension of 2.16 g (0.01 mol) of 4-carbethoxy-5-phenylimidazole in 10 ml of water was added 0.8 g (0.02 mol) of sodium hydroxide. The mixture was heated to reflux for 2 hours. To this mixture was added 4 ml of ~ 37% aqueous formaldehyde solution, and the resultant mixture was heated at 60°-65° C. for 8 hours, with stirring. After completion of the reaction, the reaction mixture was cooled and the resultant solid was recovered by filtration, washed with water and recrystallized from ethyl acetate and filtered to give 1.18 g of 4-hydroxymethyl-5-phenylimidazole, m.p. 175°-176° C. Yield 68%.