Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: ClCc1cccc(Cl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3-Dichlorobenzylchloride (5.0 g, 25.5 mmol) was dissolved in 100 ml DMSO. 9.2 g NaCN (188 mmol) were added and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product extracted with ether. The organic layers were washed with water (2×) and brine, then dried over magnesium sulfate, filtered and concentrated. The product was used as. Crude yield˜quantitative. An analytical sample was purified by column chromatography on silica, using a gradient from 10% to 75% dichloromethane in hexanes as eluent. The combined aqueous layers and wash liquids were treated with 100 ml bleach to oxidize the excess cyanide to less toxic materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:12]3)[C:8]1=[O:9])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClCC(OCC=[CH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:12]3)[C:8]1=[O:9])=[O:5])[CH:2]=[CH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(CCl)OCC=Cc1ccccc1
Reactant: CCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O)OCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A similar procedure (Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett. 1995, 36, 33, 5979-5982) to that described for the preparation of 207 was followed using NRB (0.49 g, 1.0 mmol) and potassium carbonate (0.33 g, 2.4 mmol) in dimethylformamide (5 mL), and cinnamyl chloroacetate (0.3 g, 1.4 mmol) in dimethylformamide (2 mL), and the mixture stirred at room temperature for 2 h. Purification by flash chromatography (hexane/ethyl acetate 3:2) afforded 371 as a white solid (0.63 g, 0.9 mmol, 90%). 1H NMR (400 MHz, CDCl3) δ 3.40-4.55 (8H, m, CH2CH═CH, NCH2, H-1, H-2, H-3, H-4), 5.48 (0.5H, s, OH), 5.52 (0.3H, m, V/H-6), 5.53 (0.5H, s, OH), 5.55 (0.4H, m, Y/H-6), 6.03 (0.1H, m, U/H-6), 6.05 (0.2H, m, W/H-6), 6.21-6.29 (1H, m, CH2CH═CH), 6.60-7.60 (22H, m, CH2CH═CH, Ar), 8.40-8.60 (2H, m, αPyr).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:11]2([OH:14])[CH2:12][CH2:13][O:9][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: O=C1CCOC1
Reactant: Brc1cncc(Br)c1
Solvent: C1CCOC1
Product: OC1(c2cncc(Br)c2)CCOC1
Reaction time: 16 h
Yield: 10.2 %

Procedure:
To a cooled (−15° C.) solution of 3,5-dibromopyridine (1.2 g, 5.0 mmol) in THF (12 mL) is added a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.7 M; 2.9 mL, 4.9 mmol). The resultant mixture is stirred at −15° C. for 30 min and dihydro-furan-3-one (517 mg, 6.0 mmol) is added. After stirring for 16 h, the reaction is quenched with saturated aqueous NH4Cl solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried and concentrated under reduced pressure. Purification by flash column chromatography provides 125 mg of 3-(5-bromo-pyridin-3-yl)-tetrahydro-furan-3-ol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:10])[C:7]([OH:9])=[O:8].[ClH:11].[CH2:12](O)[CH3:13]>>[ClH:11].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:10])[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: NCCCCC(O)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)CCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.1 mole of 6-amino-2-hydroxyhexanoic acid in 150 ml of anhydrous ethanol is saturated with dry hydrogen chloride gas and is stirred overnight at room temperature. The reaction mixture is then concentrated in vacuo to give ethyl 6-amino-2-hydroxyhexanoate hydrochloride.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=351 (M+ of free base). α[D]589 =-15.49 (c=0.86, methanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH2:11]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][CH3:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CO
Product: CNc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a cooled (0° C.) solution of 2,4,5-trichloropyrimidine (2.0 g, 11 mmol) in methanol (30 mL) was added dropwise a 2 M solution of methylamine in methanol (6.3 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and redissolved in DCM. The solution was washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-40% EtOAc in heptane) to give 2,5-dichloro-N-methylpyrimidin-4-amine (0.9 g, 50%). 1H-NMR (DMSO): δ 8.13 (s, 1H), 7.89 (s, 1H), 2.86 (d, J=4.5, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([CH:4]([C:3]([O:2][CH3:1])=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 12.3 g (66.0 mmol) of BOC-piperazine. The reaction mixture was refluxed for 3.5 hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography using chloroform as eluent and was concentrated to dryness to yield 7.73 g (100%) of the desired mixture of isomers as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH2:30][CH3:31])[CH2:24][O:23][C:22]3=[O:28])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 75.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (2.43 g) described in Preparation Example 163 and ethyl iodide (1.12 g), the title compound (1.97 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:34][CH3:35].[OH-].[Na+].CN(C)C=O>O>[CH2:34]([N:21]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[CH:20][CH:19]=1)[C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:26]=1)[CH3:35]
Reactant: CCBr
Reactant: COc1ccc(N2CCN(c3ccc(Nc4nc(-c5ccccc5)cs4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of 4.6 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-phenyl-2-thiazolamine, 2 parts of bromoethane, 1 part of sodium hydroxide and 94 parts of N,N-dimethylformamide was stirred for 16 hours at room temperature. Another portion of 2 parts of bromoethane and 1 part of sodium hydroxide was added and stirring was continued for 4 hours at 50° C. The reaction mixture was diluted with water. The precipitated product was filtered off and purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 4.0 parts (81.7%) of N-ethyl-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-phenyl-2-thiazolamine; mp. 223.6° C. (int. 3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:32]1([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCOCC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (92 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 4-(2-amino-ethyl)morpholine (36 uL), HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 521.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.52 (d, 1H), 7.36 (d, 1H), 3.85-3.48 (m, 7H), 2.89 (s, 2H), 2.73 (s, 2H), 2.51-2.48 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:28]([NH2:29])=[CH:27][C:26]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][OH:36])=[C:25]([Cl:37])[CH:24]=1.C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[NH:29][C:28]2[CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:35][OH:36])[C:25]([Cl:37])=[CH:24][C:23]=2[N:22]=1
Reactant: Nc1cc(Cl)c(N2CCC[C@@H]2CO)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC[C@@H]4CO)cc3[nH]2)c1)C1(C(F)(F)F)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide (85 mg, 0.3 mmol), (R)-1-(4,5-diamino-2-chloro-phenyl)-2-hydroxymethyl-pyrrolidine (62 mg, 0.3 mmol) and EDC (45 μL, 0.3 mmol) in MeCN (5 mL) in analogy with the method described in example 1 step (g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:29]O>C(OCC)(=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([O:24][CH3:29])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: -2.5 °C

Procedure:
A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (23.5 g, 0.0636 mol) in methanol (235 ml, 10 vol) was stirred and cooled to 0 to −5° C. under nitrogen. Thionyl chloride (9.3 ml, 0.1272 mol, 0.40 vol) was charged dropwise over 20 minutes, maintaining the temperature −5 to +5° C. The resulting slurry was then heated and stirred at reflux under nitrogen for 16 h after which time LC analysis showed 1.4% by area of acid remaining. The solution was evaporated to dryness in vacuo at 40° C. to give a brown sludge. The sludge was dissolved in ethyl acetate (118 ml, 5 vol) and water (235 ml, 10 vol) and the layers separated. The aqueous layer was washed with ethyl acetate (118 ml, 5 vol) and basified to pH 11 with saturated aqueous potassium carbonate (118 ml, 5 vol). The product was extracted into dichloromethane (3×118 ml, 3×5 vol) and the combined extracts dried over magnesium sulfate (23 g, 1 wt) and concentrated in vacuo at 40° C. to yield title compound (21.7 g, 98% from the nitrile) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[O-].[Na+].CO[CH:15](OC)[CH2:16][NH2:17].C(O)(=O)C.Cl>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:17][CH:16]=[CH:15][N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1ccc(-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 20.4 %

Procedure:
To a solution of 4-bromobenzonitrile (80.0 g, 440 mmol) in MeOH (800 mL) was added NaOMe (20.1 mL, 87.9 mmol). The mixture was allowed to stir at ambient temperature for 5.5 hours. 2,2-Dimethoxyethanamine (61.6 mL, 571 mmol) was added followed by acetic acid (50.3 mL, 879 mmol). The reaction mixture was heated to 50° C. for 1 hour and then cooled to ambient temperature. MeOH (200 mL) and HCl (200 mL, 1200 mmol) were added, and the reaction mixture was heated to 65° C. for 18 hours. The reaction mixture was then concentrated, and washed with 1:1 H2O:Et2O (2000 mL). The pH of the aqueous layer was adjusted to pH=9 with 6 N NaOH. The resulting solid was filtered and dried to give 2-(4-bromophenyl)-1H-imidazole (20.0 g, 20%). LCMS (APCI+) m/z 223, 224 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O.[OH-].[Na+]>CC(N(C)C)=O>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ccnc2ccccc12
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 30.7 %

Procedure:
4-Chloroquinoline (25 g, 0.153 mol) and anhydrous piperazine (59.2 g, 0.69 mol) were dissolved in dimethylacetamide (400 ml) and stirred at 130° C. for 4 hours. The mixture was allowed to reach room temperature, water (600 ml) and 2M NaOH (150 ml) were added and the mixture was extracted with dichloromethane (600 ml). The organic phase was dried over magnesium sulfate, the solvent was removed at reduced pressure and the residue crystallized with diisopropylether. The raw product was mixed with a mixture of dichloromethane, diisopropylether and ethyl acetate (1:1:1), and stirred overnight at room temperature. The mixture was filtered, the filtrate evaporated under reduced pressure and the residue crystallized with diisopropylether to yield 10.0 g of off-white crystals (0.047 mol, 31%). NMR (1H, CDCl3, 300 MHz): 8.74 (s, 1H), 8.04 (m, 2H), 7.65 (m, 1H), 7.48 (m, 1H), 6.85 (d, 1H), 3.19 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[S:30].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[NH:26][C:29](=[S:30])[O:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(Cc3cccc(-c4noc(=S)[nH]4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 101.2 %

Procedure:
Under an argon atmosphere, to a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamidoxime (174 mg) in acetonitrile (3.7 mL) were added 1,1′-thiocarbonyldiimidazole (125 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (0.278 mL), and this mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (196 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.33 (2H, s), 6.63 (1H, dd, J=2.3, 8.7 Hz), 6.88 (1H, d, J=2.3 Hz), 7.12 (1H, dd, J=2.3, 6.5 Hz), 7.28-7.39 (2H, m), 7.41-7.52 (2H, m), 7.68-7.79 (4H, m), 11.16 (1H, s). ESI-MS (m/z): 415 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:17][NH:18][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(CC)n[nH]c1CC
Yield: 72.9 %

Procedure:
A mixture of 4-oxo-3-propionyl-hexanoic acid ethyl ester (15 g, 70 mmol) and hydrazine hydrate (3.5 mL, 71 mmol) in absolute ethanol (150 mL) was refluxed for 16 h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (methanol in methylene chloride) to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester as yellow oil (11 g, 51 mmol).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27][CH3:28])(=[O:5])[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27]([CH3:28])=[O:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-(2-methylthioethoxy)quinoline (0.15 g, 0.38 mmol) was dissolved in methylene chloride (3 ml) and cooled to -20° C. A solution of 71% m-CPBA (0.089 g, 0.36 mmol) in 1 ml of methylene chloride was added dropwise. The temperature was allowed to rise to room temperature whereafter the solution was stirred for 15 min at room temperature. The reaction mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography with methylene chloride:methanol 10:1 as the eluent gave 0.064 g (41%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:19](Cl)=[O:20])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[C:26]([C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:24]=1[OH:25])[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
A suspension of 9.2g (0.061 mole) of p-aminophenylacetic acid in 150 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with water and chilled. The resulting precipitate was collected and recrystallized from a mixture of ethanol and water to give 1.32 g of yellow crystalline 4-(3,5-di-t-butyl-4-hydroxybenzamido)phenylacetic acid, m.p. 253°-254° C. Analysis: Calculated for C22H29NO4 : %C, 72.0; %H, 7.6; %N, 3.6; Found: %C, 72.0; %H, 7.7; %N, 3.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]OS(C)(=O)=O)=[CH:4][CH:3]=1.BrC1C=CC(CCO)=CC=1.CS(Cl)(=O)=O.[O-:30][S:31]([O-:33])=[O:32].[Na+:34].[Na+]>C(O)C.O>[Na+:34].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][S:31]([O-:33])(=[O:32])=[O:30])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1ccc(Br)cc1
Reactant: O=S([O-])[O-]
Agent: CS(=O)(=O)Cl
Agent: OCCc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCc1ccc(Br)cc1

Procedure:
Methanesulfonic acid 2-(4-bromo-phenyl)-ethyl ester (1.39 g) prepared from 2-(4-bromo-phenyl)-ethanol and methanesulfonyl chloride, and Na2SO3 (816 mg) were reacted in ethanol/water (1/1), to obtain a crude product of 2-(4-bromo-phenyl)-ethanesulfonic acid sodium salt as a colorless plate-like crystal. Then, thionyl chloride (3 ml) was left to react in the presence of DMF (500 μl), to obtain 2-(4-bromo-phenyl)-ethanesulfonyl chloride, and further N-methylpiperazine (73 μl) was left to react in dichloromethane (2 ml) in the presence of triethylamine (54 μl), to obtain 1-[2-(4-bromo-phenyl)-ethanesulfonyl]-4-methyl-piperazine as a yellow solid (94 mg, 24%).