Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:36])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:58][C:59]1[N:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:60]=1C(O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C>[Cl:58][C:59]1[N:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:60]=1[C:6]([NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)[CH3:11])=[O:36]
Reactant: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1ccnc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
(R)-(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.070 g, 0.14 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the resulting brown oil dried in vacuo (high vacuum system) for 2 h. The resulting amine, EDCI (0.030 g, 0.0.16 mmol) and HOBT (0.021 g, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (0.027 g, 0.16 mmol) followed by DIPEA (163 μL, 0.94 mmol) and the resulting mixture was stirred at 25° C. 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 (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 2-chloro-N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.027 g, 35%) as a white foam. 1H NMR (CDCl3) δ 0.94 (m, 1H), 1.00 (d, 3H, J=6.0 Hz), 1.20 (m, 1H), 1.53 (m, 1H), 1.77 (m, 3H), 2.14 (br t, 1H), 2.41 (s, 3H), 2.54 (br t, 1H), 2.80-2.96 (m, 3H), 3.33-3.47 (m, 2H), 3.71 (s, 3H), 3.88 (s+m, 3H), 6.61 (d, 2H, J=9.0 Hz), 6.72 (d, 2H, J=9.0 Hz), 7.16 (d, 1H, J=4.5 Hz), 7.43 (d, 1H, J=9.0 Hz), 7.54 (d, 1H, J=9.0 Hz), 7.67 (t, 1H, J=9.0 Hz), 8.14 (d, 1H, J=4.5 Hz), 8.77 (br s, 1H). ES-MS m/z 547 (M+H), 569 (M+Na). Anal. Calcd. for C30H35N6O2Cl.0.2 CH2Cl2: C, 64.30; H, 6.33; N, 14.90. Found: C, 64.10; H, 6.39; N, 14.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH2:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[N:18]([C:30]3[CH:31]=[CH:32][C:27]([CH2:26][O:25][CH2:23][CH3:24])=[CH:28][CH:29]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: CCOCc1ccc(I)cc1
Product: CCOCc1ccc(N2CCCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 158) from 9-(2-chloro-benzenesulfonyl)-2,9-diaza-spiro[5.5]undecan-1-one and 1-ethoxymethyl-4-iodo-benzene. White solid. MS (ESI): 477.4 (MH+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[I:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.O[NH:24][C:25](=[NH:27])[CH3:26].C[O-].[Na+].CO>CN(C)C=O.O.C(OCC)(=O)C>[I:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]2[O:20][N:27]=[C:25]([CH3:26])[N:24]=2)=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(=N)NO
Agent: C[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
1,1′-Carbonyldiimidazole (0.49 g, 3 mmol) was added to a solution of 4-iodobenzoic acid (0.5 g, 2 mmol) in dry dimethylformamide (4 ml) and stirred at room temperature for 30 minutes. N-hydroxy-acetamidine (0.224 g, 3 mmol) was added and stirring at room temperature continued for 16 hours. Sodium methoxide in methanol (25% wt solution; 1.1 ml, 5 mmol) was added and the mixture heated at 80° C. for 6 hours. Once cool, ethyl acetate (50 ml) and water (50 ml) were added. The organic layer was washed with water (50 ml), brine (50 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by silica SPE cartridge (5 g) (100% cyclohexane, 20:1 cyclohexane/ethyl acetate v:v to 10:1 cyclohexane/ethyl acetate v:v) to yield the desired product as a white solid (0.15 g, 0.52 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:27][C:21]=2[N:20]=1.Cl[C:35]1[N:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:41]([C:38]1[CH:37]=[N:36][C:35]([N:31]2[CH2:32][CH2:33][CH:28]([C:26]3[CH:25]=[CH:24][C:22]4[NH:23][C:19]([C:10]5[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:14][C:9]=5[F:8])=[N:20][C:21]=4[CH:27]=3)[CH2:29][CH2:30]2)=[N:40][CH:39]=1)[CH3:42]
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCNCC4)ccc3[nH]2)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(c3ccc4[nH]c(-c5ccc(S(C)(=O)=O)cc5F)nc4c3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 26.1 %

Procedure:
Example 57 (150 mg, 0.3 mmol) dissolved in DCM (12 ml) and added TFA (0.45 ml). This mixture stirred at rt for 3 h. After 3 h, DCM removed on rotavapour and co-distilled with DCM to obtain 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)-1H-benzo[d]imidazole 2,2,2-trifluoroacetate (150 mg). 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)-1H-benzo[d]imidazole 2,2,2-trifluoroacetate (150 mg, 0.4 mmol) and 2-chloro-5-ethylpyrimidine (60 mg, 0.4 mmol) were dissolved in propan-2-ol (10 ml) and added DiPEA (0.6 ml, 3.2 mmol). This mixture was refluxed at 90° C. for 12 h. After 12 h, propan-2-ol removed on rotavapor to obtain the residue. Residue was purified on combiflash using Ethyl acetate and Petether (1:1) as eluent to afford the titled compound (50 mg) as a white solid. M.P.: 220-223.5° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.69 (d, J 12.8, 1H), 8.49-8.45 (m, 1H), 8.24 (s, 2H), 8.00 (dd, J 1.5, 10.4, 1H), 7.91 (d, J 8.3, 1H), 7.67-7.56 (m, 1H), 7.55-7.40 (m, 1H), 7.22-7.12 (m, 1H), 4.80 (d, J 12.6, 2H), 3.33 (s, 3H), 2.97-2.91 (m, 3H), 2.43 (q, J 7.5, 2H), 1.89 (d, J 12.4, 2H), 1.69-1.54 (m, 2H), 1.13 (t, J 7.6, 3H).
Reaction SMILES: C([BH3-])#N.[Na+].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>CC(O)=O>[CH3:17][O:16][C:14]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][CH2:6][CH2:7]2)=[O:15]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
sodium cyanoborohydride (0.16 g, 2.57 mmol) was added to a solution of methyl indole-5-carboxylate (9) (0.30 g, 1.71 mmol) in AcOH (2 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h before it was quenched with water at 0° C. Concentrated NaOH was added to reach pH=10. The aqueous layer was extracted with CH2Cl2 (15 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:2) to afford 10 (0.28 g). 1H NMR (500 MHz, CDCl3): δ 3.06 (t, J=8.5 Hz, 2H), 3.65 (t, J=8.5 Hz, 2H), 3.84 (s, 3H), 6.53-6.55 (m, 1H), 7.75-7.76 (m, 2H).
Reaction SMILES: [K].CCSC(N(CC(C)C)CC(C)C)=O.[OH:16][C@@H:17]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C@H:19]([CH2:20][C:21](=[O:43])[C@@H:22]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[C@H:27]([CH3:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:18]1.[Na].C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=O>C(O)CCC>[CH3:33][C@@H:27]([C@@H:26]1[C@@:34]2([CH3:42])[CH2:35][CH2:36][C@@H:37]3[C@@:38]4([CH3:41])[CH2:39][CH2:40][C@@H:17]([OH:16])[CH2:18][C@H:19]4[CH2:20][C@H:21]([OH:43])[C@H:22]3[C@@H:23]2[CH2:24][CH2:25]1)[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K]
Solvent: CCCCO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of potassium ter.butylate (3.77 g, 33.6 mmols) and 3alpha-hydroxy-7-keto-5beta-cholanic acid (2.5 g, 6.36 mmols) in ter.butyl-alcohol (50 ml), kept at the reflux under nitrogen and under stirring, sodium metal (1.75 g, 0.76 gram-atoms) is added. The reaction mixture is maintained under stirring and reflux for 2 hours and then worked up as disclosed in example 1; 2.5 g of the residue consisting of the CDCA (7%) and the UDCA (93) are thus obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]#[C:20]Br>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:20]1=[NH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Product: N=C1N(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
The title compound was prepared in one step from N,N′-dibenzylethylenediamine and cyanogen bromide as described in Procedure A. The precipitated solid was filtered off the reaction mixture, washed with acetonitrile and recrystallized from MeOH to give the title compound as a hydrogen bromide salt. 1NMR (DMSO-d6) δ 3.48 (s, 4H), 4.61 (s, 4H), 7.32-7.46 (m, 10H), 8.51 (s, 2H). MS (ES+) m/z 266 ([M+1]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[C@H:14]([C:15](O)=[O:16])[CH:13]2[CH2:18][CH:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].C([N:25](C(C)C)CC)(C)C.[OH-].[NH4+]>C(#N)C.O>[C:15]([C@@H:14]1[CH:13]2[CH2:18][CH:10]([CH2:11][CH2:12]2)[N:9]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:19]([CH3:21])[CH3:20])(=[O:16])[NH2:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(=O)O)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(N)=O)C(C)C
Reaction time: 1 h

Procedure:
(3S)-2-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.78 g, 5.97 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (2.49 g, 5.56 mmol), and diisopropylethylamine (2.61 mL, 14.92 mmol) were dissolved in acetonitrile (30 mL) at ambient temperature and treated by dropwise addition with 28% ammonium hydroxide solution (2.49 g, 17.98 mmol). The resulting mixture was stirred for 1 hour and then diluted with water and extracted into dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give methyl (2S)-1-((3S)-3-carbamoyl-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a white waxy solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[C:27](C)=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]=3C)=[O:15])[CH:5]=[CH:4][C:3]1=2.OC1C(C)=CC(C(OCC)=O)=CC=1C>>[CH3:30][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1cc(C)c(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(C)c1
Agent: CCOC(=O)c1cc(C)c(O)c(C)c1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Ethyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)-3,5-dimethylbenzoate-Using ethyl 4-hydroxy-3,5-dimethylbenzoate, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.37 (6H, s), 1.39 (6H, s), 1.44 (3H, t, J~7.0 Hz), 1.77 (4H, s), 2.27 (6H, s), 4.41 (2H, q, J~7.0 Hz), 7.50 (1H, d, J~8.4 Hz), 7.86 (2H, s), 8.03 (1H, dd, J~8.4 Hz, 2.0 Hz), 8.23 (1H, d, J~2.0 Hz).
Reaction SMILES: BrC1C=CC=C(CC)C=1.[CH2:10]([C:14]([Sn])=[C:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18]C)CCC>CN(C)C=O>[CH2:22]([C:21]1[CH:20]=[C:15]([CH:14]=[CH2:10])[CH:16]=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: CCc1cccc(Br)c1
Solvent: CN(C)C=O
Product: C=Cc1cccc(CC)c1
Temperature: 75 °C
Yield: 65.4 %

Procedure:
To a solution of 1-bromo-3-ethylbenzene (2.0 g, 10.8 mmol) in deoxygenated N,N-dimethylformamide (50 ml) under nitrogen was added tributylvinyltin (5.0 g, 16.2 mmol) and tetrakistriphenylphosphine palladium (0) (500 mg, 4 mol %) and the reaction mixture was heated to 75° C. for 7 h. The cooled reaction mixture was poured onto water (400 ml) and extracted with diethyl ether (5×200 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. This was distilled under reduced pressure to afford a residue that was partitioned between water and hexane. The layers were separated and the aqueous layer was extracted with hexane. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (1.4 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.Br[CH2:39][CH2:40][F:41].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:39][CH2:40][F:41])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(C3CCN(CCF)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Yield: 81 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), 1-bromo-2-fluoroethane (47 ul, 0.629 mmol), Potassium carbonate (87 mg, 0.629 mmol) and Sodium iodide (10 mg, 0.066 mmol) were mixed in DMF (3 mL). The reaction mixture was heated at 80° C. overnight. The crude reaction mixture was purified by reverse phase preparative HPLC using acetonitrile/water (50 mM ammonium acetate buffer) as mobile phase to give N2-(4-{4-amino-1-[1-(2-fluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (221 mg, 81%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.26 (m, 4H), 2.66 (m, 1H), 2.73 (m, 1H), 3.05 (m, 2H), 3.97 (s, 3H), 4.04 (s, 3H), 4.61 (m, 1H), 4.61 (m, 1H), 4.64 (m, 1H), 7.15 (m, 1H), 7.33 (m, 4H), 7.58 (d, J=8.46 Hz, 1H), 7.70 (d, J=7.95 Hz, 1H), 8.11 (d, J=8.14 Hz, 1H), 8.25 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=2.17 min. MH+=543.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[C:11]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(Cl)(=O)C([Cl:39])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[C:11]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[C:13]([CH:17]=1)[C:14]([Cl:39])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)cc(OCc2ccccc2)c1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)Cl)cc(OCc2ccccc2)c1O[Si](C)(C)C(C)(C)C
Yield: 91.7 %

Procedure:
A solution of 5-benzyloxy-3,4-di-t-butyldimethylsiloxybenzoic acid (1 g, 2 mmol) in 46 mL of benzene was added to a solution of NaH (80 mg, 2 mmol) in 2 mL of benzene. The resulting solution was stirred with oxalyl chloride (0.9 mL, 10 mmol) under Ar for 20 h. Removal of solvent afforded 0.93 g (91%) of 5-benzyloxy-3,4-di-t-butyldimethylsiloxybenzoyl chloride as a yellow solid.
Reaction SMILES: [C:1]([C:3](=[C:9]([S:12][CH3:13])SC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1>C(O)C>[C:1](/[C:3](=[C:9](/[NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)\[S:12][CH3:13])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C(\NCc1ccc(OC)cc1)SC
Yield: 121.3 %

Procedure:
Ethyl 2-cyano-3,3-bis(methylthio)acrylate (3.8 g, 17.49 mmol) was dissolved in 70 mL ethanol and (4-methoxyphenyl)methanamine (2.88 g, 20.99 mmol) was added. The reaction was stirred at reflux for 2 h. The solvent was evaporated to give 6.5 g (100% yield) of the title compound that was used in the next step without any further purification. Purity 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.ClC(Cl)(Cl)C(O[C:31]([CH3:34])([CH3:33])[CH3:32])=O>C1COCC1.C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([O:11][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(Cl)(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (2.2 g, 6 mmol) in dry THF (20 ml) under nitrogen, added the solution of tert-butyl 2,2,2-trichloroacetate (4.3 ml, 24 mmol) in dry DCM (10 ml), followed by BF3Et2O (0.1 ml, 0.72 mmol). The reaction was stirred at rt overnight. Quenched the reaction with sodium bicarbonate (sat. in water), diluted with EtOAc, washed with 1N HCl, water and brine, dried over anhydrous sodium sulfate. Concentrated, the result was purified by flash chromatography with EtOAc and hexane. Got 650 mg light yellow solid as product. MS calcd for (C19H23BN2O6S): 418.14. MS found (ESI negative): (M−H)−=417.0. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.83 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.09 (dd, J=8 Hz, 1H), 6.39 (d, J=6.8 Hz, 1H), 6.37 (s, 1H), 4.84 (s, 2H), 3.77 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:12](=[O:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([O:9]CC)=O.[H-].[Na+].[C:24]([O:33][CH2:34][CH3:35])(=[O:32])/[CH:25]=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:34]([O:33][C:24]([CH:25]1[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:7](=[O:9])[C:6](=[C:2]2[S:1][CH:5]=[CH:4][S:3]2)[C:12](=[O:21])[N:13]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)C(=C2SC=CS2)C(=O)N(Cc2ccccc2)C1C(=O)OCC
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (1.0 g) and dimethylformamide (25 ml) is added dropwise to a suspension of sodium hydride (63% dispersion in oil, 144 mg) in dimethylformamide (10 ml). Said addition is carried out under ice-cooling. The mixture is stirred at the same temperature for 30 minutes. A solution of diethyl maleate (0.6 ml) in dimethylformamide (10 ml) is added dropwise thereto. The mixture is stirred at room temperature overnight. The mixture is poured into water, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The mixture is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=1:2) to give 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-2,3-dicarboxylic acid diethyl ester (196 mg) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:11][O:10]1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[CH2:11][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1ccc(C2(Cn3ccnc3)CO2)c(F)c1
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(O)(Cn2ccnc2)c2ccc(F)cc2F)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A mixture containing 1-[[2-(2,4-difluorophenyl)-oxiranyl]-methyl]-1H-imidazole (P2) (0.5 g, 2.1 mmole), 4-hydroxy-benzaldehyde (0.31 g, 2.5 mmole) K2CO3 (0.41 g, 2.9 mmole), 18-C-6 (25 mg) in 5 ml of DMF is stirred for 6 hours, extracted with dichloromethane, washed with 2N sodium bicarbonate, dried over Na2SO4, filtered and evaporated under reduced pressure in order to obtain 0.957 g of crude product which is purified by chromatography eluting with a CH2Cl2/MeOH mixture 97/3 in order to obtain 0.557 mg of expected product. Rf=0.12 (CH2Cl2/MeOH 97/3).
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]Cl)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>O>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:3])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Yield: 30.2 %

Procedure:
The procedure described in Example 1(b) was followed, using 1.0 g of thiourea, 4.0 g of 1-[4-(4-chlorophenyl)butyl]-4-(3-chloropropyl)piperazine dihydrochloride and 50 ml of reagent ethanol. The hydrolysis was effected with 4.0 g of sodium hydroxide in 50 ml of water. Work-up of the free base, as described above, followed by purification on a silica gel column (methylene chloride:methanol, 97:3), precipitation as the hydrochloride salt and recrystallization from reagent ethanol, gave 0.6 g (16% of theory) of 3-{4-[4-(4-chlorophenyl)butyl]piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 254°-259° C.