Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@@H:48]([NH2:51])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@@H:48]([NH:51][C:4](=[O:6])[CH:3]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:2]([CH3:1])[CH3:13])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Methyl-2-phenylbutanoic acid (1.049 mmol), 1-hydroxybenzotriazole hydrate (1.049 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (185 μL, 1.049 mmol) were combined in dichloromethane (4 mL). The mixture was stirred at room temperature for 10 minutes, then (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (1.049 mmol) from Step C was added in 2 mL of dichloromethane. The reaction was stirred at room temperature for 3.5 hours, and then quenched with 0.5 mL of water. The organic layer was separated and chromatographed using a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) eluting with 1-10% methanol(ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.08 (dd, J=7.2, 14.4, 1H), 7.64 (dd, J=7.5, 14.5, 1H), 7.56-7.52 (m, 1H), 7.43 (d, J=4.4, 2H), 7.42-7.40 (m, 1H), 7.38-7.22 (m, 5H), 4.40 (dt, J=7.2, 14.3, 0.5H), 4.35-4.28 (m, 0.5H), 3.55 (d, J=12.7, 0.5H), 3.40 (dd, J=4.5, 12.8, 1H), 3.26 (d, J=12.9, 0.5H), 3.15 (d, J=10.5, 0.5H), 3.05 (d, J=10.5, 0.5H), 2.83-2.74 (m, 1H), 2.70-2.55 (m, 1.5H), 2.43-2.26 (m, 3H), 2.23-2.13 (m, 1H), 1.94-1.83 (m, 1H), 1.74-1.57 (m, 1.5H), 1.50 (dt, J=7.1, 15.3, 0.5H), 1.37 (td, J=6.5, 12.1, 0.5H), 1.31-1.23 (m, 0.5H), 1.18 (d, J=6.5, 1.5H), 1.10 (dt, J=6.5, 11.5, 0.5H), 1.03 (d, J=6.5, 1.5H), 0.73 (dd, J=6.7, 10.7, 3H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]2[CH:9]=[CH:10][S:11][C:3]=12.[CH3:12][C@@H:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>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>[Cl:1][C:2]1[C:7]([C:15]#[C:14][C@H:13]([OH:16])[CH3:12])=[CH:6][N:5]=[C:4]2[CH:9]=[CH:10][S:11][C:3]=12
Reactant: C#C[C@@H](C)O
Reactant: Clc1c(I)cnc2ccsc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[C@@H](O)C#Cc1cnc2ccsc2c1Cl

Procedure:
A mixture of 7-chloro-6-iodothieno[3,2-b]pyridine (0.46 g, 1.6 mmol), bis(triphenylphosphine)palladium(II) chloride (0.11 g, 0.16 mmol) and copper(I) iodide (30 mg, 0.16 mmol) was purged with N2. (2R)-but-3-yn-2-ol (0.13 g, 1.9 mmol) and triethylamine (4.5 mL, 33 mmol) was added via syringe. The reaction mixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the resultant residue was purified on silica gel (eluting with 0-85% EtOAc/hexanes) to give the desired product. LCMS calculated for C11H9ClNOS (M+H)+: m/z=238.0. Found: 238.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.CN.[CH:37]([OH:39])=[O:38].ClC1C=[C:43]([N:47]2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:37]([OH:39])=[O:38].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][NH:47][CH3:43])[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN
Solvent: O=CO
Solvent: C1CCOC1
Product: CNCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and methylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 26 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18](NS(C4C(C)=NN(C)C=4Cl)(=O)=O)=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:33])[N:7]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2F)[C:6]1=[O:42])[CH2:2][CH2:3][CH3:4].C(Br)C1C=CC=CC=1.NCCC1C=CC([S:60]([NH2:63])(=[O:62])=[O:61])=CC=1>>[CH2:34]([N:7]1[C:8](=[O:33])[C:9]2[NH:10][C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:17][CH:16]=3)=[N:12][C:13]=2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)nn(C)c4Cl)cc3)nc21
Agent: BrCc1ccccc1
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(S(N)(=O)=O)cc3)nc21

Procedure:
Prepared by the same method as described for 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (example 34) except that in step 2 benzyl bromide was used in place of 2-fluorobenzyl bromide and in step 3 4-(2-amino-ethyl)-benzenesulfonamide was used in place of 2-(4-nitro-phenyl)-ethylamine hydrochloride salt. 4-(1-Benzyl-3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-benzenesulfonamide was obtained as a colorless solid; LRMS for C23H25N5O4S (M+H)+ at m/z=468.27.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[C:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reaction time: 96 h
Yield: 70.9 %

Procedure:
In pre-dried apparatus, held under a CaCl2 guard tube, 2,5-dibromopyridine (0.524 g), tert-butyl piperazine-1-carboxylate (0.824 g) and sodium carbonate (0.234 g) were combined in anhydrous 1-methyl-2-pyrrolidinone (10 ml) and heated in an oil bath held at 100° C. for 4 days. The mixture was then cooled, poured onto water (350 ml) and extracted with diethyl ether (3×50 ml). The combined organic extracts were washed with 2% citric acid solution (2×25 ml), water (2×25 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was then purified by silica gel column chromatography, with 30% diethyl ether/hexane as eluent, to provide the title compound as a white solid (0.537 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([SH:11])=[N:8][C:7]=2[CH:12]=1.[CH2:13](N(CC)CC)C.IC>C(O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11][CH3:13])=[N:8][C:7]=2[CH:12]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2sc(S)nc2c1
Solvent: CCO
Solvent: CC(C)O
Solvent: CI
Product: COc1ccc2sc(SC)nc2c1
Yield: 103.4 %

Procedure:
5-Methoxy-2-mercaptobenzothiazole (18.3 g, 0.1 mol) was dispersed in 125 ml 95% ethanol. Addition of 10.1 g (0.1 mol) triethylamine gave a brown solution. Addition of iodomethane (14.2 g, 0.1 mol) was slightly exothermic. Additional heating brought the mixture to reflux for 2 hours. After cooling, the residue was dispersed in isopropanol and filtered to remove triethylammonium iodide. The filtrate was mixed with water and the layers separated. The aqueous phase was extracted 3×50 ml methylene chloride. The organic portions were combined, washed and brine, and dried with Na2SO4. Filtration and rotary evaporation yielded 21.85 g brown liquid which was distilled at 158°-162° C. (0.125 mm) to give 16.73 g (85%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][CH:16]([P:20]([CH3:25])(=[O:24])[O:21][CH2:22][CH3:23])[O:17][CH2:18][CH3:19])[CH3:14].[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([CH2:32][N+:33]([O-:35])=[O:34])[CH2:25][P:20]([CH:16]([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])(=[O:24])[O:21][CH2:22][CH3:23])=[CH:36][CH:37]=1
Reactant: CCOC(OCC)P(C)(=O)OCC
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(Cl)cc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 1.16 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 7.2 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 2.0 g of ethyl (diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 1.75 g of 4-chloro-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-chlorophenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.2 and +41.8 ppm (CDCl3).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[CH:13]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)O)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[CH2:13][C:15]1[NH:19][CH:18]=[CH:17][N:16]=1)[CH3:2]
Reactant: CCc1cc(OC)cc(CC)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(OC)cc(CC)c1Cc1ncc[nH]1

Procedure:
2-(2,6-Diethyl-4-methoxy-benzyl)-1H-imidazole was prepared from rac-(2,6-diethyl-4-methoxy-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 245.4 ([M+H]+, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:28])[CH3:27]
Reactant: c1ccc(CNCCCSc2ccncc2)nc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCCSc1ccncc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 1.62 g (6.24 mmol) of 4-[3-(N-2-pyridylmethylamino)propylthio]pyridine and 1.10 ml (7.80 mmol) of triethylamine in 10 ml of methylene chloride, 0.51 ml (7.80 mmol) of acetyl chloride was added under ice-cooling with stinting. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain 1.61 g of the desired compound (yield: 85.6%, yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)Cl>[Br:17][C:16]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Fc1ccc(-c2cn3ccncc3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Fc1ccc(-c2nc3cnccn3c2Br)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine (Preparation #2, 0.176 g, 0.783 mmol) in DCM (3 mL) was added N-bromosuccinimide (0.153 g, 0.862 mmol) dropwise. After about 20 minutes, the mixture was concentrated under reduced pressure and purified by flash silica gel chromatography using EtOAc as the eluent to yield the title compound (0.130 g, 54%>: LC/MS (Table 1, Method a) Rt=2.0 min; MS m/z: 294.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.C[C:8]1[CH:9]=[N+:10]([O-])[CH:11]=CC=1[N+]([O-])=O>>[NH:1]1[C:6]2[C:5](=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Product: c1cc2[nH]ccc2cn1

Procedure:
A process according to claim 15, wherein the adduct used is obtained by reacting 6 mols of morpholine with 3 mols of methyl or ethyl orthoformate per mol of 3-methyl-4-nitro-pyridine-1-oxide.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Solvent: ClCCl
Product: CCC(c1nc2c(c(=O)n1Cc1ccccc1)CCC2)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-4, 0.070 g, 0.20 mmol) was dissolved in CH2Cl2 (1.0 mL) and treated successively with 4-bromo-benzoylchloride (0.052 g, 0.24 mmol) and TEA (0.08 mL, 0.59 mmol). The reaction was stirred at 25° C. for 1 hour. The reaction was diluted with CH2Cl2 (10 mL), washed with 5% NaHCO3 and dried over MgSO4. The organics were concentrated under reduced pressure and subjected to preparative thin layer chromatography (SiO2, 5% MeOH/CH2Cl2) to provide N-[1-(3-benzyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl) propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5). 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.2 Hz, 2H), 7.31 (m, 5H), 12 (d, J=8.0 Hz, 2H), 5.98 (d, J=15.6 Hz, 1H), 5.85 (m, 1H), 4.99 (d, J=15.8 Hz, 1H), 3.36 (m, 2H), 2.90 (m, 4H), 2.10 (m, 4 H), 1.87 (s, 6H), 1.80 (m, 1H), 1.63 (m, 1H), 0.62 (m, 3H); MS 537.2 found, 537.5 required.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][O:6][C:7]=1[N:8]=[CH:9]OCC)#[N:2].[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:1]1[C:3]2[N:4]=[CH:5][O:6][C:7]=2[N:8]=[CH:9][N:2]=1
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC=Nc1ocnc1C#N
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1ncnc3ocnc13)C2
Yield: 14.7 %

Procedure:
4-cyano-5-ethoxymethyleneaminooxazole (240 mg, 1.5 mmol) (see J. Am. Chem. Soc., 88, 3829 (1966), Bull. Chem. Soc. JAPAN, 43, 187 (1970), Bull. Chem. Soc. JAPAN, 43, 3909 (1970)) and 2-aminoindan (580 mg, 4.4 mmol) in dry ethanol (2 ml) were heated to reflux for 6.5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (methylene chloride:ethyl acetate=1:4) to obtain the title compound (56 mg, 0.22 mmol) having the following physical properties:
Reaction SMILES: O.NN.[OH-].[K+].[CH3:6][O:7][C:8]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH2:14][C:13](=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>C(O)CO>[CH3:6][O:7][C:8]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH2:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c1Sc1ccccc1CC2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1cccc2c1Sc1ccccc1CC2
Temperature: 175 °C

Procedure:
Hydrazine hydrate (4 ml) and potassium hydroxide (2.72 g, 48 mmol) was added to 6-methoxy-11H-dibenzo[b,f]thiepin-10-one (4.10 g, 16 mmol) in ethylene glycol (20 ml) and the reaction mixture was heated at 175° C. for 3 hours. The reaction mixture was cooled down to room temperature and water was added (100 ml). The white solution was extracted with ether (3×200 ml), the organics were combined, washed with water (100 ml), brine (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give an oil which solidify upon standing to give a brown solid which was used without any further purification (2.45 g, 63%).
Reaction SMILES: C([NH:11][CH2:12][C:13]([N:15]=[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[S:17]1)=[O:14])(OCC1C=CC=CC=1)=O.[BrH:26].C(OCC)C>C(O)(=O)C>[BrH:26].[NH2:11][CH2:12][C:13]([N:15]=[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([S:22]([NH2:25])(=[O:23])=[O:24])[S:17]1)=[O:14]
Reactant: Cn1nc(S(N)(=O)=O)sc1=NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cn1nc(S(N)(=O)=O)sc1=NC(=O)CN
Reaction time: 3 h

Procedure:
The desired compound is prepared by subjecting 2-(N-carbobenzyloxy-glycylimino)-3-methyl-1,3,4-thiadiazoline-5-sulphonamide (0.5 gm) suspended in glacial acetic acid (5ml) to a solution of hydrogen bromide in glacial acetic acid (32% w/w. 8.0 ml) at room temperature for about 1 hour with stirring. Diethyl ether (50 ml) is then added and the mixture set aside for three hours at 0° C. The solid precipitate is collected, washed with diethyl ether, and dried to give the desired product, 2-(glycylimino)-3-methyl-1,3,4-thiadiazoline-5-sulphonamide hydrobromide, m.p. 209°-210° C. (0.4 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2OC)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 65 °C
Yield: 69 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-methoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.24 mmol), NaOH (20 mg, 0.48 mmol), H2O (3 mL) and THF (10 mL) was heated at 65° C. for 2 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated HCl solution. The precipitate was collected and dried to give the title compound as a white solid (100 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8](I)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[N:13][C:14]=3[NH2:15])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)[CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: Nc1ncnc2c1c(I)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)nn2C1CCCC1
Temperature: 85 °C
Yield: 12.3 %

Procedure:
To a mixture of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.631 mmol, 1 equiv) and 3-(benzyloxy)phenylboronic acid (0.110 g, 0.487 mmol, 1.0 equiv) in DME (6 mL) was added tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol, 0.07 equiv) and a solution of sodium carbonate monohydrate (0.187 g, 1.51 mmol, 2.4 equiv) in water (2 mL). The mixture was heated at 85° C. for 16 h, then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to afford an oily red-orange solid. Recrystallization from hot EtOAc afforded a red-orange solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford 3-[3-(benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.023 g, 0.060 mmol): 1H NMR (d6 CDCl3, 400 MHz): δH 8.34 (1H, s), 7.27-7.46 (8H, m), 7.07-7.10 (1H, m), 5.63 (2H, bs), 5.31 (1H, quint, J=7.6 Hz), 5.16 (2H, s), 2.15-2.20 (4H, m), 1.96-2.01 (2H, m), 1.72-1.75 (2H, m); RP-HPLC (Hypercil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 15 min, 1 mL/min) Rt 14.00 min. MS: MH+ 386.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15]CC)OCC)=[CH:7][CH:6]=1.[CH3:18][C:19]([S@@:22](/[N:24]=[CH:25]/[C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:23])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C@@H:25]([C:26]2[C:31]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:29]=[CH:28][N:27]=2)[NH:24][S@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])=[CH:10][CH:9]=1)=[O:15]
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C=O)cc1)c1ncccc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
Magnesium metal (0.200 g, 8.23 mmol) was activated using a crystal of iodine followed by the addition of THF (4 mL). 1-Bromo-4-(diethoxymethyl)-benzene (2.0 g, 7.72 mmol) was added and the mixture allowed to sit without stirring for 5 minutes. Gas evolution was observed and the colour of the iodine mostly disappeared. Stirring was then initiated and additional dry THF (20 mL) was added. After stirring for 2 hours, the mixture was allowed to settle. The supernatant was added to a solution of (S,E)-2-methyl-N-((3-(trifluoromethyl)-pyridin-2-yl)methylene)propane-2-sulfinamide (0.450 g, 1.617 mmol) in dry THF (10 mL). The resulting reaction mixture was stirred overnight. Saturated aqueous NH4Cl (10 mL) was added followed by H2O (80 mL) and EtOAc (100 mL). The phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. The acetal was further dried under high vacuum. The acetal was dissolved in EtOAc (50 mL) and treated with 50% TFA in H2O (50 mL). The solution was stirred vigorously for 20 minutes. Water (200 mL), EtOAc (100 mL), and Et2O (100 mL) were then added and the phases separated. The aqueous layer was removed, and the organic layer was washed with additional H2O (2×200 mL). The organic layer was then washed with saturated aqueous NaHCO3 (3×100 mL, strong gas evolution) followed by H2O (100 mL) and finally brine (100 mL). The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (S)—N—((S)-(4-formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide as an oil.