Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:20](=[O:22])[CH3:21])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine (120 mg) in dichloromethane (2 ml) was added acetyl chloride (31.4 μL) and triethylamine (61.6 μL). The reaction mixture was stirred at room temperature for 3.5 hours, then diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude residue. This was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamide (110 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[S:28][C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:26][C:25]=3[CH2:35][N:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]3)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[S:28][C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:26][C:25]=3[CH2:35][N:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]3)[CH2:21][CH2:22]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(Cc3sc(-c4ccccn4)nc3CN3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc(N)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1nc(C(=O)NCC2CCN(Cc3sc(-c4ccccn4)nc3CN3CCNCC3)CC2)cc(N)c1C#N

Procedure:
A solution of the compound prepared in Example 159 (100 mg) in dichloromethane (1 mL)-trifluoroacetic acid (228 mL) was stirred for 30 minutes. The reaction was concentrated and the excess trifluoroacetic acid was removed via azeotropic distillation from toluene and hexane to obtain the title compound (110 mg) having the following physical data.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])=[O:11]>C1(C)C=CC=CC=1>[O:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](=[O:17])[O:16][CH2:9][C:10]1=[O:11]
Reactant: O=C(CBr)Oc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1COC(=O)c2ccccc2O1
Reaction time: 8 h

Procedure:
The triethylamine solution was added all at once to the refluxing solution of bromoacetylsalicylic acid. The addition took thirty seconds. Moments later, the byproduct Et3NHBr crystallized out of solution. The suspension was refluxed for one hour and then allowed to cool. The salt crystals were isolated by vacuum filtration, washed with 25 mL of acetone, air dried in the Bucher funnel, and finally vacuum dried at room temperature. 2.27 grams of triethylammonium bromide were collected. MP=249°-252° C. with decomposition. The filtrate was evaporated down, and a white solid was obtained which was then dissolved in 25 mL of boiling toluene. Everything did not dissolve. The hot toluene solution was gravity filtered into a 25 mL Erlenmeyer flask. A white solid started to crystallize after a few minutes. The insoluble material was soluble in water which strongly suggested that it was Et3NHBr. After standing overnight at room temperature, the crystals were isolated by suction filtration, washed with 20 mL of toluene, and vacuum dried at room temperature for five hours. 1.17 grams were collected (43% yield). MP-112°-114° C. at 3.5° C./minute. IR (KBr pellet) 1795, 1730, 1605, 1455, 1315, 1190, 1120, 1025, 930, 763 cm-1. 300 MHz 1H NMR (CDCl3): δ4.75 singlet (2H), δ7.30 doublet (1H). One of the lines overlapped with the chloroform signal. δ7.42 triplet (1H), δ7.70 triplet (1H), δ7.95 doublet (1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[C:30](=[O:31])[CH2:29][CH2:28][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH2:25]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCN(Cc2ccccc2)CCC1=O

Procedure:
3-Benzyl-7-chloro-2-[2-methyl-1-(7-oxo-[1 ,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one from Example 1e above, (133 mg, 0.30 mmol) was treated with benzyl bromide and Et3N in CH2Cl2 (10 mL) at room temperature overnight. The mixture was diluted with CH2Cl2 (10 mL), washed with H2, brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (20% EtOAc/hexane) gave the title compound as a white solid: MS (ES) m/e 529.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH:27][C@H:28]([C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[C:29]([OH:31])=[O:30]>>[OH:27][C@H:28]([C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[C:29]([OH:31])=[O:30].[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: C[C@H](N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 99 using 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB58) and (2R,3R)-2,3-dihydroxysuccinic acid and isolated as a white solid (0.70 g, 49%): mp 187-191° C.; 1H NMR 1H NMR (400 MHz, DMSO-d6) d 9.40 (s, 1H), 8.08 (dd, J=8.6, 3.6 Hz, 4H), 7.63 (dt, J=8.1, 1.0 Hz, 2H), 7.49 7.32 (m, 2H), 3.81 (s, 2H), 3.47 (dt, J=8.5, 6.2 Hz, 1H), 3.01 (dd, J=13.4, 5.5 Hz, 1H), 2.74 (dd, J=13.4, 8.7 Hz, 1H), 1.13 (d, J=6.4 Hz, 3H) (OH and NH2 not observed).
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C([Cl:33])C=C(C(OO)=O)C=1>ClCCl.C(OCC)(=O)C>[Cl:33][C:14]1[CH:13]=[CH:12][C:11]2[C:10]([S:7]([NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:9])=[O:8])=[CH:19][C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])=[CH:17][C:16]=2[N:15]=1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (272 mg, 0.73 mmol) and mCPBA (max 77% by weight, 364 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium sulfite solution followed by brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in POCl3 and heated at 80° C. for 1 hour. The reaction mixture was concentrated before being partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and purified on silica gel (rf=0.42 in 2:1 hexanes:ethyl acetate) to give 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([NH2:30])[CH:28]=2)[NH:23][C:22](=[O:32])[C:21]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](Cl)(Cl)=[O:42].C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([NH:30][C:41]([NH:52][C:53]3[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=3)=[O:42])[CH:28]=2)[NH:23][C:22](=[O:32])[C:21]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(NC(=O)Nc4ccncc4)c(Cl)cc3[nH]c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid benzyl ester (200 mg in 5 mL dry methylene chloride) at 0° C. was added phosgene (0.3 mL of a 1.93 M solution in toluene) followed by 0.111 mL of triethylamine and the mixture stirred for 1 hour at 0° C. At this time, 188 mg of 4-aminopyridine was added and the mixture allowed to warm to room temperature. After 20 hours, the mixture was diluted with ethyl acetate (200 mL) and the reaction quenched by the addition of 10% citric acid. The organic portion was concentrated in vacuo to provide the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:10]([CH2:16][CH2:17][NH:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:11]([C:13](O)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:10]3[CH2:16][CH2:17][N:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13](=[O:14])[C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1c2nc(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)c2CCN1C1CCCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylic acid I-5j (20 mg, 0.046 mmol), EDC (19 mg, 0.1 mmol), HOAt (13 mg, 0.1 mmol), and triethylamine (14 μl, 0.1 mmol) in 1,2-dichloroethane (20 ml) was stirred for 17 hours at room temperature. The reaction mixture was washed with sat'd aq NaHCO3 and the aqueous bicarbonate solution was back extracted once with CH2Cl2. The combined CH2Cl2 extracts were dried and concentrated in vacuo. The residue was dissolved in diethyl ether (1 ml) and several drops of 4M HCl in dioxane were added. The organic solution was decanted and additional ether was added. The mixture was stirred for several minutes and the solvent decanted again. The residue was dried under vacuum to give the desired produce 5A-1 as a colorless solid: +APCI MS (M+1) 426.3; 1H NMR (CDCl3): δ 7.62-7.57 (m, 1H), 7.53-7.47 (m, 1H), 7.44-7.39 (m, 1H), 7.37-7.33 (m, 2H), 7.32-7.28 (m, 1H), 7.24-7.19 (m, 2H), 5.16-5.06 (m, 1H), 3.56-3.50 (m, 2H), 3.26-3.17 (m, 2H), 2.71-2.56 (m, 2H), 1.92-1.83 (m, 2H), 1.76-1.46 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1I)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:18])[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)N(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-isopropyl-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless oil (85%). MS (ESI): m/z=347.15 [M+H]+.
Reaction SMILES: C(=O)([O-])O.[Na+].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.CN(C=O)C.Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH:28]=[C:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1>O>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:36]=[CH:35][C:27]([CH:28]=[C:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)=Cc1ccc(OCCCCl)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)=Cc1ccc(OCCCNc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Sodium hydrogen carbonate (3.5 g), 4-chloroaniline (10.45 g) and DMF (50 ml) were added to methyl 4-(3-chloropropoxy)-α-methylcinnamate (11 g), and the mixture was stirred at 100° C. overnight. After the reaction mixture was allowed to cool, water (200 ml) was added thereto, and further the mixture was stirred at room temperature for 30 minutes. The insoluble product was collected by filtration, washed well with water, and was added cold methanol (20ml) thereto, and the mixture was stirred. The resulting crystal was collected by filtration to give methyl 4-[3-[N-(4chlorophenyl)amino]propoxy]-α-methylcinnamate (8 g). mp. 62°-64° C.
Reaction SMILES: CCN(CC)CC.[C:8]1([C:14]2[N:15]=[C:16]([C:19]3([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)#[N:28]>C(Cl)Cl>[C:27]([C:29]1[CH:30]=[C:31]([S:35]([NH:26][CH2:25][C:19]2([C:16]3[S:17][CH:18]=[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:15]=3)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)#[N:28]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
Et3N (0.15 mL, 1.43 mmol) was added dropwise to an ice cold solution of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (130 mg, 0.48 mmol) in dry CH2Cl2 (3 mL). The resulting reaction mixture was stirred at 0° C. for 5 min, then a solution of 3-cyanobenzene-1-sulfonyl chloride (105 mg, 0.52 mmol) in dry CH2Cl2 (2 mL) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford compound 3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide (0.13 g, yield 61%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.03-7.98 (m, 2H), 7.85-7.76 (m, 3H), 7.59-7.54 (m, 1H), 7.50-7.38 (m, 4H), 3.87-3.79 (m, 2H), 3.74-3.66 (m, 2H), 3.36 (s, 2H), 2.27-2.19 (ddd, J=13.5 Hz, 6.7 Hz, 3.5 Hz, 2H), 2.01-1.93 (ddd, J=13.8 Hz, 7.5 Hz, 3.7 Hz, 2H). MS (ESI) m/z: Calculated for C22H21N3O3S2: 439.10. found: 440.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[CH2:34]([N:36](CC)CC)[CH3:35].Cl.C(=N)(OCC)C>ClCCl.CO>[NH:36]=[C:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][CH:25]=2)=[CH:6][CH:5]=1)[CH3:35]
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=N)NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[4-(2-Aminoethyl)phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (100 mg) was dissolved in dichloromethane:methanol (2:5, 7.0 mL), treated with triethylamine (0.2 mL) and ethyl acetimidate hydrochloride (135 mg) sequentially and allowed to stir at ambient temperature for 4 h. The reaction mixture was concentrated and fractionated by column chromatography with NH4OH:MeOH:—EtOAc (10:20:70) to afford the title compound (51 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=O)=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:35](=[O:36])[NH:34][C:32]([C:31]2[CH:37]=[CH:38][C:28]([C:27]([F:40])([F:39])[F:26])=[CH:29][CH:30]=2)=[N:9]1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1F
Yield: 73.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.045 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=4.4 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.2 Hz, 2H), 8.17 (t, J=5.8 Hz, 1H), 12.9 (br s, 1H); MS (m/z): 471.10 (M+H+).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4]1.[OH:9][C:10]1[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]>C(O)C>[OH:9][C:10]1[C:17]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:16][C:13]([CH:14]=[N:2][N:3]2[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4]2)=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: Cc1cn(N)cn1
Agent: Cl
Solvent: CCO
Product: Cc1cn(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g of 1-amino-4-methylimidazole hydrochloride are dissolved in 200 ml of ethanol. 6.2 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde are added and the mixture is stirred at room temperature overnight. The solution obtained is then evaporated in a vacuum. The residue is treated with 150 ml of methylene chloride and 150 ml of water, stirred and saturated sodium bicarbonate solution is added up to a neutral reaction (pH=7). The methylene chloride phase is separated and the aqueous phase is extracted with 50 ml of methylene chloride. The methylene chloride phases are combined, washed once with 10% sodium chloride solution, dried and evaporated. The residue is triturated with cold ether. The solid is removed by filtration, washed with ether and n-hexane and dried at 70° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-4-methylimidazole of m.p. 150°-151°.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:35]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CN(C)CCCNc1ccccc1N
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.80 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.00 g) in chloroform (10 ml), and then tetradecanoyl chloride (1.42 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.3 ml) was added to a solution containing the residue (2.29 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.18 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (1.38 g) as pale brown wax.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>C(O)(=O)C.C(OCC)C>[BrH:11].[NH2:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([Br:11])=[CH:9][N:10]=1
Reactant: BrBr
Reactant: Nc1ncccc1C(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Br
Product: Nc1ncc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.6 g 2-amino-nicotinic acid in 450 mL of glacial acetic acid was treated with a solution of 4 mL of bromine in 50 mL of glacial acetic acid over 10-15 min. The resulting mixture was stirred at room temperature for 2 h, diluted with 2 L of diethyl ether, and the ensuing precipitate was filtered and dried to provide 6.1 g of the title compound of Step A as a solid melting at 280° C. (decompose) (lit1. m.p. 280° C., decomposed). 1H NMR (400 MHz, Me2SO-d6): δ 7.38 (br s,2H), 8.08 (s,1H), 8.25 (s,1H), 13.45 (br s,1H). (1U.S. Pat. No. 3,950,160)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.CCOCC.Cl.[N:16]([O-])=O.[Na+]>O>[N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)=[N+:9]=[N-:16]
Reactant: O=N[O-]
Reactant: NNc1cccc(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1cccc(Cl)n1
Reaction time: 2 h

Procedure:
To a 250 ml round-bottom flask equipped with a mechanical stirrer, a Claisen head and an addition funnel were added 2-chloro-6-hydrazinopyridine (4.00 g, 27.9 mmol), Et2O (20 mL) and concentrated hydrochloric acid (12 mL, 146 mmol). A solution of sodium nitrite (2.211 g, 32.0 mmol) in water (28 mL) was added dropwise to the cooled (0° C.) reaction mixture. The insoluble starting material gradually dissolved. After 2 h, the aqueous phase was extracted with ether (2×50 mL). The combined organic phase was dried over MgSO4, and concentrated in vacuo to provide the title compound as yellow crystals: LCMS m/z 155.14 [M+H]+.