Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: BrCc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CSc2nnc(-c3ccccc3)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5-phenyl-[1,3,4]oxadiazole-2-thiol (3.1 g, 17.4 mmol; Aldrich) in ethanol (30 mL) was cooled to 0° C. and treated with diisopropylethylamine (3.1 mL, 17.4 mmol; Aldrich). The suspension cleared. Benzyl bromide (2.08 mL, 17.4 mmol; Aldrich) was then added, and the mixture was allowed to warm to room temperature. After 45 minutes, the resulting precipitate was collected by filtration and dried to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Product: COc1ccc(OCCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (ESI) m/z 433 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[CH2:13][NH2:14])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:13][NH:14][C:23]2=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCNC(CN)c2ccc(C)c(C)c2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCN2C(=O)NCC2c2ccc(C)c(C)c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of N1-[2-(4-methoxyphenyl)ethyl]-1-(3,4-dimethylphenyl)-1,2-ethanediamine (10.6 g, 0.0356 mol) in dry DMF (55 mL) is added 1,1′-carbonyldiimidazole (6.4 g, 0.0395 mol). The reaction is stirred at 50° C. for 30 minutes, cooled, diluted with ethyl acetate (300 mL), and washed with 0.5 N HCl and brine. The organic phase is dried (MgSO4), and concentrated. The residue is re-crystallized from ethyl acetate (70 mL) to afford 7.5 g (65% yield) of the desired compound. 1H NMR (CDCl3) δ 7.16 (d, J=7.8 Hz, 2H), 7.05 (m, 4H), 6.84 (d, J=7.8 Hz, 2H), 4.50 (t, J=8.1 Hz, 1H), 3.82 (s, 3H), 3.73-3.65 (m, 2H), 3.27 (t, J=8.4 Hz, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 2.68 (m, 1H), 2.30 (s, 6H). MS 325 (MH+). Anal. Calcd. For C20H24N2O2 ¼H2O: C, 73.03; H, 7.51; N, 8.52. Found: C, 73.29; H, 7.19; N, 8.32.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: Nc1cccc(O)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=O)[CH2:20]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:19]2[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COC(Cc1cc(Br)ccc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(Cc1cc(Br)ccc1NC1CC2CCC(C1)N2C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
Crude compound 67 (225.4 mg, 0.866 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (241.1 mg, 1.732 mmol) were stirred in acetic acid (10 mL) under argon in the presence of anhydrous sodium sulfate (1.230 g, 8.660 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (550.6 mg, 2.598 mmol) was then added and the mixture stirred for 24 hours at room temperature. After dilution with a mixture of 8:1 ethyl acetate:Hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95%) to yield a pale yellow residue, 83 (120 mg, 36.1%) as an 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.56-1.70 (m, 2H), 1.87-1.99 (m, 4H), 2.04-2.09 (m, 2H), 2.21 (s, 3H), 2.79 (d, 2H, J=5.3 Hz), 3.03-3.17 (m, 2H), 3.28 (s, 6H), 3.40-3.49 (m, 1H), 4.54 (t, 1H, J=5.3 Hz), 4.98 (s, 1H), 6.36 (d, 1H, J=9.3 Hz), 7.11-7.21 (m, 2H); ESI-MS (m/z, %): 383/385 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27]([NH:29][NH2:30])=[O:28])[CH2:24][C:23]([CH3:32])([CH3:31])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[C:33](O)(=O)C.C(N)=N.CC(O)=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([N:26]4[CH:33]=[N:30][NH:29][C:27]4=[O:28])[CH2:24][C:23]([CH3:32])([CH3:31])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC1(C)CC(NC(=O)NN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: N=CN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(n2cn[nH]c2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of Step B (0.14 mmol) and formamidine acetate (72 mg, 0.70 mmol) in 5.0 mL of DMF was allowed to stir at rt for 2 h. AcOH (40 μL, 0.70 mmol) was then added. The resulting mixture was stirred at 80° C. for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (20 mL) and washed with brine (3×20 mL). The organic phase was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridges using 1:99 v/v CH3OH/CH2Cl2 as the eluant afforded the title compound: 1H NMR δ 1.53 (s, 3H), 1.62 (s, 3H), 2.18 (t, J=12.7, 1H), 2.36 (dd, J=6.3, 13.1, 1H), 5.56 (m, 1H), 6.95 (d, J=8.3, 2H), 7.16-7.38 (m, 7H), 10.1 (br. s, 1H).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>Cl.CN1C(=O)CCC1>[CH2:13]([O:15][CH:16]([O:12][CH2:1][CH:2]([O:3][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:4]([O:5][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:6]([O:7][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:8]([O:9][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH2:10][O:11][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH3:17])[CH3:14]
Reactant: C=COCC
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOC(C)OCC(OC(C)OCC)C(OC(C)OCC)C(OC(C)OCC)C(COC(C)OCC)OC(C)OCC
Reaction time: 4.5 h

Procedure:
Into a 250 ml. flask, equi ped with static nitrogen head and magnetic stirrer, was charged 18.6 g. of mannitol, 100 ml. of N-methyl pyrrolidinone and 64.8 g. of ethyl vinyl ether. There was then added 10 drops of concentrated HCl and the mixture stirred at between 22° and 28° for 4.5 hours and allowed to stand overnight. The next day an infrared spectrum of an appropriately worked up sample showed the virtual absence of hydroxyl absorption and strong ether C--O--C bands. The reaction mixture was poured, with stirring, into 750 ml. of water containing excess NaOH and extracted twice with 150 ml. portions of hexane. Each extract was washed consecutively with two 750 ml. portions of water. The compbined oganic phases were dried over solid sodium carbonate-sodium sulfate and vacuum evaporated at about 10 mm. Hg to give 59 g. of crude oil. Distillation was performed on a short path micro still under the following conditions:
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=O)C.O.[OH-].[Li+]>CO.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@@H:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]2[OH:4])=[CH:13][CH:14]=1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate (2.047 g, 6.54 mmol) in methanol (12.2 mL) and water (0.32 mL) was cooled to 0° C. and treated with lithium hydroxide hydrate (95%, 1.73 g, 39.2 mmol). The reaction was stirred at 0° C. for 15 minutes, then allowed to warm and stir at room temperature for 18 hours. The methanol was removed under reduced pressure, and the aqueous residue was partitioned between ethyl acetate (200 mL) and water (100 mL). After extraction of the aqueous layer with ethyl acetate (100 mL), the combined organics were washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to provide (1R,2R)-2-(4-bromophenoxy)cyclohexanol as a yellow oil. Yield: 1.76 g, 6.49 mmol, 99%. 1H NMR (400 MHz, CDCl3) δ 1.26-1.46 (m, 4H), 1.74-1.79 (m, 2H), 2.08-2.14 (m, 2H), 3.72 (ddd, J=10.5, 8.4, 4.7 Hz, 1H), 3.96 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: Cl[C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)=[CH2:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C:2]([C:3]([O:5][CH3:6])=[O:4])=[N:7]2)=[CH:10][CH:11]=1
Reactant: C=Cc1ccco1
Reactant: COC(=O)C(Cl)=NNc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccco2)C1

Procedure:
The compound of Example 1 (2.0 g) was suspended in benzene (20 ml) and heated to reflux in the presence of 2-vinylfuran (2.5 ml). Triethylamine was added and the mixture was allowed to reflux for 1 hour longer. The mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated. Chromatography on silica gel (5:1 hexanes/ethyl acetate) gave the title compound (1.8 g). NMR (CDCl3) 7.3 to 6.9 (m, Ar-H, 5H); 6.2 (m, Furan-H, 2H); 5.5 (dd, CH, 1H); 3.9 (s, OCH3, 3H); 3.6 (m, CH, 1H); 3.4 (m, CH3, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29]>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: FC(F)(F)c1ccccc1I
Product: Cc1cc(SCC#Cc2ccccc2C(F)(F)F)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-iodo-2-trifluoromethyl-benzene gave the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C1(CN)CCCCC1.[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:47])=[CH:49][CH:50]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-(trifluoromethyl)aniline to replace cyclohexanemethylamine, and 4[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-[2-(trifluoromethyl)phenyl]benzamide was obtained (53%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.39 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.62 (dd, J=15.9, 7.9 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.31-7.14 (m, 4H), 7.04 (dd, J=7.6, 7.6, 0.7 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 5.02 (ABq, 2H), 4.85 (ABq, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 164.9, 161.9, 161.3, 142.6, 141.7, 140.4, 133.8, 133.1, 132.7, 128.8, 128.0, 127.7, 126.2, 124.6, 124.1 (2C), 123.7, 120.0, 118.8, 109.0, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0; MS (ES+) m/z 557.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:21][C:19](=[O:22])[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]5[CH2:25][CH2:24][CH2:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]1(=O)CCCCC1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:27][CH2:28][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:30][CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]5[CH2:25][CH2:24][CH2:23][CH2:39][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=C1CCCCC1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCCC6)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert cyclohexanone (310 μL, 3.00 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.8-8.6 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as an orange powder (0.022 g, 0.040 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 7.62 min; MS (MH)+ 544.
Reaction SMILES: [CH3:1][O:2][Si:3](OC)(OC)[O:4][CH3:5].[CH2:10]([Si:13]([CH2:22][CH:23]=[CH2:24])([CH2:19][CH:20]=[CH2:21])[CH2:14][CH2:15][CH2:16][Mg]Br)[CH:11]=[CH2:12]>C(OCC)C>[CH2:19]([Si:13]([CH2:10][CH:11]=[CH2:12])([CH2:14][CH:15]=[CH2:16])[CH2:22][CH2:23][CH2:24][SiH:3]([O:4][CH3:5])[O:2][CH3:1])[CH:20]=[CH2:21]
Reactant: CO[Si](OC)(OC)OC
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Mg]Br
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCC[SiH](OC)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, tetramethoxysilane (5) (0.482 ml, 3.268 mmol) was cooled down to 0° C., then diethyl ether solution of 10 ml (7.2 mmol) of 0.72M 3-(triallylsilyl)propylmagnesium bromide (24) was added dropwise, then stirred at room temperature for 15 hours. The reacted mixture was cooled down to 0° C., quenched with water, then saturated ammonium chloride aqueous solution was added until the salt was completely dissolved. The obtained organic layer was separated, and the obtained water layer was extracted with diethyl ether, the collected organic layer was each washed with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, obtaining a crude product. The crude product was purified through short silica gel column chromatography (eluent: hexane/ethyl acetate=20/1), obtaining bis {(3-(triallylsilyl)propyl}dimethoxysilane (29′) represented by the following chemical reaction equation (yield: 1.04 g, yield (%): 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]#[N:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(Cl)cc23)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (300 mg, 1.61 mmol) in MeOH (4 mL) was added NH2NH2.H2O (5 mL). The resulting mixture was heated to reflux for 2 hours. The solvents were removed in vacuo to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ 406.1.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CCOCC>[CH:1]1([CH2:4][NH:29][CH2:28][CH2:27][C:21]2([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)[CH2:3][CH2:2]1
Reactant: COc1cccc(C2(CCN)C=CCCC2)c1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(C2(CCNCC3CC3)C=CCCC2)c1

Procedure:
3.45 g of cyclopropanecarboxylic acid chloride are placed in 50 ml of methylene chloride, whereafter 5.0 g of potassium carbonate are added, and then a solution of 7.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine in 10 ml of methylene chloride is added dropwise while stirring. The mixture is stirred at room temperature overnight and subsequently at reflux for 30 minutes and cooled. Then, the precipitate is removed by filtration under suction, the filtrate is evaporated, and the oil obtained is taken up in ether. The ethereal solution is washed with 1 N hydrochloric acid and subsequently with water, dried over magnesium sulfate and evaporated, and N-[2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]ethyl]-cyclopropanecarboxamide remains as the residue. 6.5 g of this compound, dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise to a dispersion of 6 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. The mixture is boiled at reflux for 3 hours, cooled and worked-up in the usual manner, and there is obtained N-(cyclopropylmethyl)-1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine, the hydrochloride of which melts at 141°-142° C.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1CCN2C(=NCCC2)CC1>O>[N:12]1([C:2]2[C:6]3[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Cc1ccc2onc(Cl)c2c1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2onc(N3CCNCC3)c2c1
Yield: 79.7 %

Procedure:
3-Chloro-5-methyl-1,2-benzisoxazole (2.17 g, 12.93 mmol) was stirred together with piperazine (10.0 g, 116.1 mmol) and DBU (diazabicycloundecene; 2.0 g 13.14 mmol) in a melt at 120° C. for 4 h, after which the reaction was complete according to TLC. After cooling, the mixture was added to water, and the aqueous phase was extracted 3 times with dichloromethane, and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. This resulted in 2.24 g of 3-piperazin-1-yl-5-methyl-1,2-benzisoxazole (yield: 80%) being obtained as a slightly impure solid product which was purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: C=CC(=O)O
Product: O=C(O)CCSc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
2,3-Dichlorothiophenol (4.94 g, 28 mmol) was placed in a flask with acrylic acid (2.11 g, 29 mmol) and stirred at 50° C. for 3 hours. The reaction mixture was poured into 10% Na2Cl3 and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(2,3-dichlorophenylthio)propanoic acid (3.88 g), contaminated with some acrylic acid, as a clear oil which was used without further purification in the next step.