Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14]([NH2:15])=[C:9]3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br.[OH-].[NH4+].C(O)(=O)C>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=4)=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([Br:22])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrBr
Reactant: Nc1nc(-c2ccncc2)nc2c1cnn2C1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccncc2)nc2c1c(Br)nn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 1-cyclopentyl-6-(4-pyridyl)-pyrazolo(3,4-d)pyrimidin-4-amine (3.0 g, 0.011 mole) in water 60 ml) at room temperature was added bromine (1.8 g, 0.011 mol). The reaction mixture was stirred at room temperature for 1 hour, then was heated on a steam bath for 2 hours. The solvent was removed in vacuo and the residue was suspended in water. Ammonium hydroxide was added followed by acetic acid until a pH of 4-5 was obtained. A solid was collected by filtration and washed with water. Water (60 ml) and bromine (0.3 ml, 0.006 mol) were added to the solid residue and the mixture was heated on a steam bath for 1 hour. The mixture was poured into ice-water and ammonium hydroxide, then acetic acid was added. A solid was collected by filtration, dissolved in ethyl acetate, dried over MgSO4 and concentrated in vacuo to afford 2.2 g (56%) of 1-cyclopentyl-3-bromo-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 189°-191° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[CH3:65][S:66](Cl)(=[O:68])=[O:67].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:37][N:38]([S:66]([CH3:65])(=[O:68])=[O:67])[CH2:39]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[NH:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)CN(S(C)(=O)=O)C2)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 24) (60 mg, 0.08 mmol) in anhydrous CH2Cl2 (1 mL) was added triethylamine (0.054 mL, 0.39 mmol) and the reaction was cooled to 0° C. Methanesulfonyl chloride (0.018 mL, 0.23 mmol) was added and the reaction stirred at 0° C. for 15 minutes. The solvent was removed in vacuo and the residue dissolved in methanol (1 mL) and potassium carbonate (80 mg, 0.58 mmol) was added and the reaction stirred at room temperature for 1.5 h. The reaction was partitioned between CH2Cl2 (10 mL) and water (10 mL) the organic layer was dried (MgSO4) and concentrated in vacuo to afford the title compound as a tan solid (57 mg, 86% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.50-7.86 (m, 10H) 7.33 (br. s., 2H) 5.06-5.21 (m, 1H) 4.04-4.26 (m, 2H) 3.75-4.05 (m, 6H) 3.56-3.72 (m, 6H) 3.38-3.55 (m, 2H) 2.84-3.04 (m, 3H) 2.70-2.86 (m, 1H) 2.40-2.64 (m, 1H) 2.10-2.40 (m, 3H) 1.83-2.09 (m, 2H) 1.20-1.37 (m, 2H) 1.07-1.20 (m, 2H) 0.81-1.07 (m, 12H). HRMS for C43H66N9O8S (M+H)+ calc: 858.3973, found: 858.3975. Purity (LC-MS): 86%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]4[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=[C:13]4[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:29][C:10]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]3[C:17]([C:20]([F:23])([F:21])[F:22])=[N:18][N:19]=[C:13]3[CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: FC(F)(F)c1nnc2n1CCN(c1ncc3c(Cl)nccn13)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCN(c1nc(Br)c3c(Cl)nccn13)C2
Yield: 89.6 %

Procedure:
To a 100 ml one neck round bottom flask was charged with 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (540 mg, 1.571 mmol) along with DMF (5 ml). The mixture was stirred and 1-bromopyrrolidine-2,5-dione (308 mg, 1.728 mmol) was added in on batch. The resulting reaction mixture was then stirred at room temperature for 18 hrs overnight. The mixture was diluted with ethyl acetate and washed with NaHCO3 (sat), water, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 50% to 100% ethyl acetate in hexanes, 18 CV) to afford light color solid product 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (595 mg, 1.408 mmol, 90% yield). LC-MS: C12H8BrClF3N7, 421. found 422.02 [M+H]+, RT=1.30 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:15][CH2:14]1.ClCCl>O1CCOCC1>[O:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([NH:25][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=Cc1cnn2ccc(Nc3cccc(OCCN4CCOCC4)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-(2-morpholinoethoxy)aniline (147 mg, 0.663 mmol). The mixture was heated in microwave at 120° C. Dichloromethane was added, and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 5-(3-(2-morpholinoethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The solid was used in the next step without further purification. LCMS (M+1=368)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[I:19])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:14]=[C:13]4[I:19])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C1=COCCC1
Reactant: Ic1n[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Ic1nn(C2CCCCO2)c2ccc(-c3cncc(C4CC4)n3)cc12
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indazole (192 mg, 0.53 mmol), 3,4-dihydro-2 h-pyran (96 μL, 1.06 mmol) and p-toluenesulfonic acid monohydrate (20 mg, 0.106 mmol) in THF (3 mL) was heated at reflux overnight (9 h). After cooling to RT, the mixture was concentrated to about 1 mL. The mixture was diluted with EtOAc and saturated NaHCO3 (aq.) and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-30% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (140 mg, 0.31 mmol, 59% yield) as a pale yellow foam. MS (ESI, pos. ion) m/z: 447.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH3:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([CH3:22])=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(C)ccc(Cl)c2s1
Product: Cc1ccc(Cl)c2sc(CCC#Cc3ccccn3)nc12
Yield: 7.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-but-3-ynyl-7-chloro-4-methyl-benzo[d]thiazole (30 mg, 0.13 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 2.9 mg (9.3 μmol, 7%) of 7-chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[O-])=[CH:10]/[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(C#N)c2)n(-c2cccc(Cl)c2)n1
Yield: 35 %

Procedure:
Starting from 10 g (39.81 mmol) of lithium (1Z)-1-(3-cyanophenyl)-4-ethoxy-3,4-dioxobut-1-en-1-olate from example 10A and 9.7 g (54.15 mmol) of 3-chlorophenylhydrazine hydrochloride, 4.97 g (14 mmol, 35% yield of theory) of product are obtained according to the method described in example 4A.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>C(#N)C>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CCN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 38.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (300 mg, 0.919 mmol) in acetonitrile (10 mL) was added potassium carbonate (381 mg, 2.76 mmol) followed by tert-butyl 3-bromopropanoate (211 mg, 1.011 mmol) was heated in a seal tube at 80° C. for 4 hours. The reaction mixture was filtered, and the filtrate evaporated to dryness. The resulting oil was dissolved in 2 ml of EtOH and 2 ml of 1 M NaOH. The reaction mixture was stirred for 20 min. The solution injected on a preperatory HPLC (2 to 10% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. To each fraction was added 0.1 ml of 6 M HCl, and the fractions were evaporated to dryness. Acid was formed by deprotection of t-butyl during evaporation. 3-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoic acid (140 mg, 0.354 mmol, 38.5% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.37 (m, 2H), 7.11-7.29 (m, 3H), 3.65 (br. s., 2H), 3.45 (t, J=7.07 Hz, 2H), 3.23 (d, J=5.81 Hz, 2H), 3.11 (br. s., 2H), 3.04 (dt, J=4.01, 7.89 Hz, 1H), 2.90 (t, J=7.07 Hz, 2H), 2.62 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.04-2.29 (m, 3H), 1.70 (dd, 2H), 1.62 (ddd, J=4.42, 6.51, 10.55 Hz, 1H), 1.42 (q, J=6.91 Hz, 1H); LC-MS Rt=0.42 min; MS (ESI): 303.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN)cc3)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCNC(=O)c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-{4′-[4-(2-Amino-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.031 g, 0.08 mmol), benzoyl chloride (0.01 mL, 0.09 mmol), and triethylamine (0.03 mL, 0.24 mmol) were combined in CH2Cl2 (0.5 mL) and stirred at room temperature for 1 hour. After aqueous workup, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH3:26])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:48]([C:50]1[CH:58]=[C:57]([CH3:59])[C:53]([C:54](O)=[O:55])=[C:52]([CH3:60])[CH:51]=1)#[N:49].CCN(C(C)C)C(C)C>CN(C=O)C>[C:48]([C:50]1[CH:58]=[C:57]([CH3:59])[C:53]([C:54]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:25]=3[CH3:26])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)[CH3:5])=[O:55])=[C:52]([CH3:60])[CH:51]=1)#[N:49]
Reactant: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCN)CC1
Reactant: Cc1cc(C#N)cc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-phenyl-amine (200.0 mg, 0.57 mmol), EDCI (120.0 mg, 0.62 mmol) and HOBT (84.3 mg, 0.62 mmol) were combined in DMF (25 mL) to give a pale yellow solution. To this solution was added 4-cyano-2,6-dimethyl-benzoic acid (109.3 mg, 0.62 mmol) followed by DIPEA (119.0 μL, 0.68 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (97:2:1, CH2Cl2/MeOH/NH4OH) afforded 4-cyano-2,6-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-benzamide as an off-white foam (209.0 mg, 72%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz), 1.04 (m, 1H), 1.30 (m, 1H), 1.59 (m, 1H), 1.64 (s, 2H), 1.76 (m, 1H), 1.86 (m, 2H), 2.21 (t, 1H, J=11 Hz), 2.32 (s, 6H), 2.55 (t, 1H, J=11 Hz), 2.78 (m, 3H), 2.87 (s, 2H), 2.95 (s, 3H), 3.35 (m, 1H), 3.64 (m, 1H), 3.78 (sext, 1H, J=6 Hz), 4.07 (s, 2H), 6.59 (d, 2H, J=9 Hz), 6.73 (t, 1H, J=8 Hz), 7.14 (m, 3H), 7.50 (m, 1H), 8.01 (s, 1H), 8.28 (s, 1H), 8.35 (d, 1H, J=5 Hz).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([C:13]1[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:18][C:11]=1[NH:10][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH3:9])(=[O:25])[CH3:24]
Reactant: CC[C@H](NC(=O)Cc1ccccc1C(=O)O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1

Procedure:
A mixture of 2-[((S)-1-phenyl-propylcarbamoyl)-methyl]-benzoic acid (10 g), acetic anhydride (50 ml), and N,N-dimethylaminopyridine (100 mg) was heated at gentle reflux (Tmax=+124° C.) for 7 min and evaporated in vacuo at +50° C. to give the title compound as a yellow-brown solid (11.1 g, purity 98% by NMR). LC-MS (m/z) 322.3 (MH+); tR=1.72. 1H NMR (500 MHz, DMSO-d6): 0.89 (t, J=7.2 Hz, 3H), 1.86-1.97 (m, 2H), 2.56 (s, 3H), 4.95 (q, J=7.1 Hz, 1H, CH—NH), 7.26 (t, J=7.5 Hz, 1H), 7.29 (unres. m, 1H), 7.36-7.41 (unres m., 3H), 7.71 (t, J=7.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 11.53 (d, J=7.6 Hz, 1H, NH). 13C APT NMR (125 MHz, DMSO-d6, δ(DMSO-d6)=39.87 ppm): 10.68 (CH3), 30.0 (CH2), 31.57 (CH3), 57.01 (CH), 92.44 (C), 114.88 (C), 124.2 (CH), (CH), 124.26 (CH), 126.65 (CH), 127.8 (CH), 129.05 (CH), 129.93 (CH), 135.71 (CH), 138.68 (C), 141.86 (C), 158.51 (C), 160.55 (C), 194.82 (C, MeCO).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C(C)=CC=CC=1C.[I-].[Na+]>O>[C:16]1([NH:15][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CCC1(OC(=O)CCCCl)CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCC1(OC(=O)CCCNc2ccccc2)CCCC1
Temperature: 80 °C
Reaction time: 36 h
Yield: 74.1 %

Procedure:
In a nitrogen atmosphere, a mixture of 15 g of 1-ethylcyclopentyl 4-chlorobutyrate, 19 g of aniline, 7.3 g of 2,6-lutidine, and 1.5 g of sodium iodide was heated at 80° C. and stirred for 36 hours at the temperature. The reaction mixture was cooled, after which 15 g of water was added dropwise to quench the reaction. This was followed by ordinary aqueous work-up and vacuum distillation (135° C./13 Pa), recovering 14 g (yield 76%) of 1-ethylcyclopentyl 4-(phenylamino)butyrate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1.CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>>[OH:14][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]2[O:10][C:9]([CH2:11][N:12]([OH:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CN(O)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CN(O)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCSCc2ccc(CN(C)O)o2)o1
Yield: 45.5 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-hydroxy-N-methyl-2-furanmethanamine base (1.48 g) and 1,1-bis-(methylthio)-2-nitroethene (0.57 g) was heated at 98°-100° for 3 hr. The oily residue was chromatographed (silica/acetone) and the appropriate eluate evaporated to give the title compound (0.78 g) as an amber oil.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[CH3:8][N:7]([CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][S:12][C:11](=[NH:10])[NH2:13]
Reactant: CN(C)CCCCCl
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)CCCCSC(=N)N
Reaction time: 24 h
Yield: 84.4 %

Procedure:
A stirred mixture of 1-chloro-4-(dimethylamino)-butane hydrochloride (115 g), thiourea (51.9 g) and ethanol (500 ml) was heated under reflux for 24 hours then allowed to stand at 4° C. for 24 hours. The resulting solid was collected by filtration, washed with ether, and dried in vacuo at ambient temperature for 24 hours to give S-[4-(dimethylamino)butyl]isothiourea dihydrochloride as an off-white solid (140 g), m.p. 179°-182° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH2:33][CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C([CH:41]1CC[CH2:43][NH:42]1)CC>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[C:32]5[CH:41]=[N:42][CH:43]=[CH:34][CH:33]=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCC1CCCN1
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5cccnc5)c4)cc23)CC1
Yield: 22.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 3-(2-pyrrolidinyl)pyridine (148 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 13.0 mg of the title compound (22.5%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:35]([O:36][CH2:37][CH3:38])=[O:39])[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)OCC)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A mixture of the compound obtained in Example 5A (1.12 g), ethyl chlorocarbonate (0.35 g), potassium carbonate (0.47 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured over water and extracted with ethyl acetate; the ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-ethoxycarbonyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (0.89 g, 56%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 119 to 120° C. ##STR54##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH2:18][CH2:19]Br>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:19][CH2:18][O:17][CH3:16]
Reactant: Oc1ccc(F)cc1Br
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(F)cc1Br
Yield: 65.8 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (1.2 g, 6.28 mmol) in acetonitrile (10 ml) was added potassium carbonate (2.78 g, 20 mmol) and 2-bromoethyl methyl ether (0.85 ml, 9.5 mmol). The resultant solution was heated to reflux for 16 hours. The reaction mixture was cooled then concentrated in vacuo. tert-Butyl-dimethyl ether (20 ml) and sodium hydroxide (1M aqueous solution) (10 ml) were added and the layers were separated. The organic layer was washed with saturated brine solution (10 ml) then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo. Purification by column chromatography on silica gel eluting with heptane to heptane:ethyl acetate (9:1) afforded the title compound as a colourless oil (1.03 g, 66%).