Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7]([C:9]1[S:13][C:12]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])=[CH:11][CH:10]=1)=O.[CH2:24]([NH2:27])[CH:25]=[CH2:26].C(O)(=O)C>C1COCC1>[CH2:24](/[N:27]=[CH:7]/[C:9]1[S:13][C:12]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])=[CH:11][CH:10]=1)[CH:25]=[CH2:26]
Reactant: C=CCN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC/N=C/c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous magnesium sulfate (94 mg; 0.78 mmol; 4.15 eq.) and N-[5-(5-formyl-2-thienyl)-4-methyl-1,3-thiazol-2-yl]acetamide, Compound (1), (50 mg; 0.19 mmol; 1 eq.), are added to a solution of allylamine (17 μl ; 0.23 mmol; 1.20 eq.) and acetic acid (16 μl; 0.28 mmol; 1.50 eq.) in dry THF (5 ml). The reaction is stirred at rt overnight. The mixture is filtered and rinsed with anhydrous THF and DCM, affording N-(5-{5-[(E)-(allylimino)methyl]-2-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide which is used in the next step without further purification (57.3 mg, quantitative).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.O.[NH:32]1[C:36]([NH2:37])=[N:35][N:34]=[N:33]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:37][C:36]2[NH:35][N:34]=[N:33][N:32]=2)=[O:28])=[CH:24][CH:23]=1)[CH:11]1[CH2:12][CH2:13][CH:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:15][CH2:16]1
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)c2nc3ccccc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 1 Step D (0.1 mmol, 41 mg), 1H-tetraazol-5-amine monohydrate (0.2 mmol, 21 mg), HOBt (0.25 mmol, 38 mg) and EDC (0.4 mmol, 77 mg) in 1 mL of DMF was added DIEA (0.5 mmol, 90 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/H2O, acidified with TFA, and purified by reverse-phase chromatography (Condition A). Lyophilization afforded the product as a white solid. MS (ESI): m/z 473 (M+H). HPLC A: 1.86 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:8][C:9]=2[S:11][CH3:12])[S:4][C:3]=1[C:21](=[O:23])[NH2:22].S([O-])(O[O-])(=O)=[O:25].[K+].[K+]>CO.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][S:14]([C:17]([F:19])([F:18])[F:20])(=[O:16])=[O:15])=[CH:8][C:9]=2[S:11]([CH3:12])=[O:25])[S:4][C:3]=1[C:21](=[O:23])[NH2:22]
Reactant: CSc1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonic acid 3-amino-2-carbamoyl-4-methylsulfanyl-thieno[2,3-b]pyridin-6-yl ester (500 mg, 1.29 mmol) was dissolved in MeOH (10 mL), chilled to 0° C., and potassium peroxymonosulfate (950 mg, 1.55 mmol) dissolved in water (15 mL) was added. The mixture was stirred for 18 h after which it was filtered to give the desired trifluoromethanesulfonic acid 3-amino-2-carbamoyl-4-methanesulfinyl-thieno[2,3-b]pyridin-6-yl ester in 86% yield.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[NH:32][C:31]=3[C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)=[CH:29][C:24]=2[O:23][CH2:22]1>C1COCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:34]=[C:33]([CH:35]4[CH2:36][CH2:37][N:38]([S:8]([CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])[CH2:39][CH2:40]4)[NH:32][C:31]=3[C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cc1cccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2[nH]c(C3CCN(S(=O)(=O)Cc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.9 %

Procedure:
α-Toluenesulfonyl chloride (0.032 g, 0.17 mmol) and diisopropylethylamine (0.036 mL, 0.21 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine (0.050 g, 0.14 mmol; see Example 9) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.005 g (7%) of the title compound as a yellow solid. MS (ESP+) m/z 517.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.73 (t, 1H, J=7.7 Hz), 7.42 (m, 5H), 7.33 (d, 1H, J=7.3 Hz), 7.27 (d, 1H, J=7.3 Hz), 6.07 (s, 2H), 4.40 (s, 2H), 3.82 (m, 2H), 3.19 (m, 1H), 2.85 (m, 2H), 2.66 (s, 3H), 2.10 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[CH3:39]I>CN(C=O)C>[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[N:38]([CH3:39])[N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnnn4C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
The sodium salt (15.7 mg) obtained in Example 18 was dissolved in 0.3 mL of DMF, 0.009 mL of methyl iodide was added to it, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and saturated brine in order, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel chromatography (chloroform/methanol=10/1) to obtain 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 1-isomer) and 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(2-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 2-isomer) both as colorless powders. 1-Isomer: 1H-NMR (CDCl3) δ: 8.20 (1H, d, J=2.3 Hz), 8.05 (1H, dd, J=8.5, 2.3 Hz), 7.78 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4, 7.9 Hz), 7.25 (1H, d, J=8.5 Hz), 7.20 (1H, s), 7.09 (1H, d, J=7.9 Hz), 4.67-4.57 (1H, m), 4.29-4.18 (1H, m), 4.22 (3H, s), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.58 (1H, m), 3.46-3.33 (1H, m), 2.91 (1H, d, J=16.8 Hz), 2.84 (1H, d, J=16.8 Hz), 2.30-2.20 (1H, m), 2.16-1.88 (3H, m). MS [M+H]+=515. 2-Isomer: 1H-NMR (CDCl3) δ: 8.65 (1H, d, J=2.3 Hz), 8.29 (1H, dd, J=8.7, 2.3 Hz), 7.77 (1H, d, J=8.5 Hz), 7.47 (1H, dd, J=8.5, 7.6 Hz), 7.19 (1H, s), 7.15 (1H, d, J=8.7 Hz), 7.08 (1H, d, J=7.6 Hz), 4.65-4.54 (1H, m), 4.39 (3H, s), 4.23-4.13 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.69-3.57 (1H, m), 3.46-3.33 (1H, m), 2.88 (1H, d, J=16.7 Hz), 2.80 (1H, d, J=16.7 Hz), 2.28-2.19 (1H, m), 2.15-2.05 (1H, m), 2.01-1.85 (2H, m). MS [M+H]+=515.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:13][C:3]1[C:2]([S:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(Br)c1F
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CCOC(=O)c1cccc(SCc2ccc(OC)cc2)c1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound A2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound A3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [F:1][C:2]1([F:30])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:17]2=[O:29])[CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[F:30][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:17]2=[O:29])[CH2:3]1
Reactant: COc1ccc(C2CCN(C3CCN(Cc4ccc(C)cc4)C3=O)CC2(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CCC(c4ccc(O)cc4)C(F)(F)C3)C2=O)cc1
Temperature: -78 °C
Yield: 12.8 %

Procedure:
A mixture of 3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (230 mg, 0.55 mmol) and 4 mL DCM was cooled to −78° C., followed by the dropwise addition of boron tribromide (0.05 mL, 0.55 mmol). The mixture was then allowed to warm up to rt over 4 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate and extracted with 4×50 mL DCM. The combined organic fractions were dried over Na2SO4, filtered, and concentrated. The residue was subjected to preparative HPLC (method B) to afford 28.1 mg 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 4 diastereomers. LCMS (method N) RT 1.59 min, m/z 401 (M+H+).
Reaction SMILES: [Mg].Cl[CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].II.[CH:15](N1CCOCC1)=[O:16].Cl>O1CCCC1>[CH3:5][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH:15]=[O:16]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1ccccc1
Temperature: 0 °C
Yield: 62 %

Procedure:
A mixture of magnesium (4.48 g, 187 mmol), 1-chloro-2-methyl-2-phenylpropane (30.0 g, 179 mmol), a small amount of iodine and tetrahydrofuran (100 ml) was stirred at 70° C. for 2.5 hours. Then, the reaction mixture was cooled to 0° C., followed by adding dropwise thereto a solution of N-formylmorpholine (24.6 g, 214 mmol) in tetrahydrofuran (45 ml), and the resulting mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was re-cooled to 0° C. and 3N hydrochloric acid (180 ml) was added thereto, followed by stirring at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract solution was washed successively with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 18.0 g of 3,3-dimethyl-3-phenylpropionaldehyde.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21]>C(O)(=O)C>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:8]2[N:26]([CH2:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[CH:2]=[CH:6][CH:7]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(=O)CCC2OCCO2)cc1OC
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: COc1ccc(-c2cccn2CCNC(C)=O)cc1OC
Yield: 38.1 %

Procedure:
3-(1,3-Dioxolan-2-yl)-3',4'-dimethoxypropiophenone (6.3 g) was dissolved in 30 ml of acetic acid and added under argon and while stirring to a solution of 4.9 g of N-acetylethylenediamine in 50 ml of acetic acid. The reaction mixture was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 150 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 150 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted three times with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 7.3 g of dark brown oil, was chromatographed on 250 g of silica gel with ethyl acetate as the eluent. 2.6 g (38%) of N-[2-[2-(3,4-dimethoxyphenyl)pyrrol-1-yl]-ethyl]acetamide were isolated as a brown oil.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24].[ClH:31]>ClCCl.C(O)C>[ClH:31].[ClH:31].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17](=[O:19])[C:16]1[CH:21]=[CH:22][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:14][CH:15]=1)[CH3:24]
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 16 h

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl]benzoate (2.2 g, Example 7) and N,N-diethylethylenediamine (7 ml) was boiled under reflux for 5 hours. The mixture was cooled and stood for 16 hours at ambient temperature. Petroleum ether, b.p. 60-80° C. (50 ml) was added and then decanted off to leave a gum which was further treated with petroleum ether as above and the residual gum dissolved in dichloromethane and purified by flash column chromatography on silica using dichloromethane/IMS/triethylamine (25:2:1) as the mobile phase to give a solid which was dissolved in ethanol (70 ml) and then dry hydrogen chloride gas was passed through the solution. The precipated solid was collected by filtration, washed with ethanol and dried to give N-(2-diethylaminoethyl)-4-(1,4-dihydroindeno[1,2-c]-pyrazol-3-yl)- benzamide dihydrochloride, m.p.230° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[I-:16].[Na+]>CC(C)=O>[CH2:9]([O:8][CH2:7][CH2:6][I:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOCc1ccccc1
Reaction time: 3 h
Yield: 90 %

Procedure:
2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 mL) and methanesulfonyl chloride (76.8 g) was added dropwise at from 0° C. to 10° C. The mixture was stirred for 3 hr. 10% Aqueous sodium bicarbonate (300 mL) was poured into the reaction mixture, the mixture was partitioned and combined with an extract of the aqueous layer with MTBE (300 mL), and the mixture was washed with 10% aqueous sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-benzyloxyethyl methanesulfonate (124.0 g). The 2-benzyloxyethyl methanesulfonate (124.0 g) was dissolved in acetone (500 mL), and sodium iodide (130.0 g) was added. The mixture was stirred at from 50° C. to 60° C. for 3 hr. The reaction mixture was filtered and the solvent was evaporated. Water (300 mL) was added, and the mixture was extracted twice with toluene (300 mL). The toluene layer was washed successively with aqueous sodium hydrogen sulfite solution, water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (127.0 g).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)CC1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11 mg, 44%), MS (ISP) m/z=444.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-(tetrahydrofuran-2-yl)acetic acid.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:43])[CH:11]([CH2:30][CH2:31][NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])C1C=CC=CC=1>CO>[OH:8][NH:9][C:10](=[O:43])[CH:11]([CH2:30][CH2:31][NH:32][S:33]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[C:12]1([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25]
Reactant: Cc1ccc(S(=O)(=O)NCCC(C(=O)NOCc2ccccc2)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NCCC(C(=O)NO)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Yield: 74 %

Procedure:
A mixture of N-benzyloxy-α-[2-[[(4-methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (133 mg, 0.220 mmol), MeOH (8.0 mL), and Pearlman's cat (25 mg) is hydrogenated (1 atm) for 8 h at room temperature. The mixture is filtered, the solids washed with MeOH (2×5 mL), CH2Cl2 (5 mL), and MeOH (5 mL). The combined filtrates are concentrated and the residue crystallized from EtOAc/hexane to give 84 mg (74%) of the title compound as a white solid (mp 166.5°-167° C.):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1)c1cc(Cl)ccc1O
Yield: 16 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-[4-(trifluoromethyl)phenyl]thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:14]([C:16]([CH3:18])=O)[CH3:15]>C(O)(=O)C>[S:1]1[C:5]2[C:6]([C:10]([NH:12][N:13]=[C:14]([CH3:15])[CH2:16][CH3:18])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CCC(C)=O
Reactant: NNC(=O)c1cccc2nnsc12
Solvent: CC(=O)O
Product: CCC(C)=NNC(=O)c1cccc2nnsc12

Procedure:
21.5 g of benzothiadiazole-7-carboxylic acid hydrazide and 150 ml of methyl ethyl ketone are heated to 70° C. over a period of 8 hours in 150 ml of glacial acetic acid. The reaction mixture is then concentrated by evaporation in vacuo, the residue is taken up in 1 l of dichloromethane and the solution is washed twice with 700 ml of ice/water. It is then dried over sodium sulfate, filtered and concentrated by evaporation and the residue is suspended in ethyl acetate, filtered and dried. The product indicated above melts at 159°-162° C.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21].C(NC(C)C)(C)C.O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:23][Si:22]([C:20]#[C:21][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:25])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a mixture of methyl 4-(4-bromobenzoyl)benzoate (1.20 g, 3.76 mmol), ethynyltrimethylsilane (554 mg, 5.66 mmol), (PPh3)2PdCl2(106 mg, 0.151 mmol), CuI (14.3 mg, 0.075 mmol) in THF (30 ml), diisopropyl amine (799 mg, 7.92 mmol) was added dropwise under argon atmosphere. The mixture was stirred at 50° C. for 4 h. Water was added to the mixture after cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give methyl 4-(4-trimethylsilylethynylbenzoyl)benzoate (83%).