Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[N:13](C2CCCCO2)[N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:10]=1[C:24]1[NH:25][C:26]2[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]=3[NH:30][C:29]3[N:37]=[CH:38][CH:39]=[CH:40][C:28]=3[C:27]=2[N:41]=1.Cl>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[NH:13][N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:10]=1[C:24]1[NH:25][C:26]2[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]=3[NH:30][C:29]3[N:37]=[CH:38][CH:39]=[CH:40][C:28]=3[C:27]=2[N:41]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: Cc1c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(C(F)(F)F)nn1C1CCCCO1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1[nH]nc(C(F)(F)F)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b: 4′,3′-f]azepine trifluoroacetate (715 mg, 1.23 mmol) in methanol (16 mL) was added 1.25 mL concentrated HCl and the reaction was stirred at 50° C. for 3 h. The reaction was reduced in vacuo and then purified by preparative LCMS to obtain the desired product as a bis-TFA salt (548 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 8.60 (bs, 1H), 8.10 (d, 1H), 8.01 (s, 1H), 7.94 (dd, 1H), 7.61 (m, 2H), 6.88 (dd, 1H), 2.35 (s, 3H). 19F NMR (400 MHz, DMSO-d6): δ −59.476 (3F), −74.791 (6F). MS (EI) m/z=384. (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.[CH2:17](I)[CH3:18]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([CH2:17][CH3:18])[C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: O=c1[nH]ccc2ccc(OCCCCl)cc12
Reactant: CCI
Product: CCn1ccc2ccc(OCCCCl)cc2c1=O

Procedure:
By a similar method as in Reference Example 7,7-(3-chloropropoxy)-2-ethyl-2H-isoquinolin-1-one in the form of a colorless oil was prepared from 7-(3-chloropropoxy)-2H-isoquinolin-1-one using ethyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([NH:45][C:46](=[O:47])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:36][CH:37]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 62.7 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (148 mg, 0.3 mmol) in dichloromethane (4 mL) was added benzyl isocyanate (40 μL, 0.32 mmol) and the mixture was stirred at room temperature for 90 hours. After filtration, the reaction product was rinsed with diethyl ether to provide 118 mg (yield 63%) of the title compound. m.p. 169°-171° C.
Reaction SMILES: CC1CCCO1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][O:13][C:14]2=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1.[CH3:21][N:22]1[C:26]([CH:27]=O)=[N:25][CH:24]=[N:23]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>>[F:7][C:8]1[CH:16]=[C:15]2[C:11](/[C:12](=[CH:27]/[C:26]3[N:22]([CH3:21])[N:23]=[CH:24][N:25]=3)/[O:13][C:14]2=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1
Reactant: O=C1OCc2c1cc(F)cc2[N+](=O)[O-]
Reactant: Cn1ncnc1C=O
Solvent: CC1CCCO1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: Cn1ncnc1/C=C1\OC(=O)c2cc(F)cc([N+](=O)[O-])c21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a 80 L jacketed glass reactor equipped with a chiller, mechanical stirrer, thermocouple, and nitrogen inlet/outlet, at 15-25° C., anhydrous 2-methyl-tetrahydrofuran (22.7 kg), 6-fluoro-4-nitroisobenzofuran-1(3H)-one (2) (2.4 kg, 12.2 mol, 1.00 eq.), and 2-methyl-2H-1,2,4-triazole-3-carbaldehyde (49.6-52.6% concentration in dichloromethane by GC, 3.59-3.38 kg, 16.0 mol, 1.31 eq.) were charged consecutively. Triethylamine (1.50 kg, 14.8 mol, 1.21 eq.) was then charged into the above reaction mixture. The reaction mixture was stirred for another 10 minutes. Acetic anhydride (9.09-9.10 kg, 89.0-89.1 mol, 7.30 eq.) was charged into the above reaction mixture at room temperature for 20-30 minutes. The reaction mixture was heated from ambient to reflux temperatures (85-95° C.) for 80-90 minutes, and the mixture was refluxed for another 70-90 minutes. The reaction mixture was monitored by HPLC, indicating compound (2) was reduced to ≦5%. The resulting slurry was cooled down to 5-15° C. for 150-250 minutes. The slurry was aged at 5-15° C. for another 80-90 minutes. The slurry was filtered, and the wet cake was washed with ethyl acetate (2 L×3). The wet cake was dried under vacuum at 40-50° C. for 8 hours to give 2.65-2.76 kg of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroisobenzofuran-1(3H)-one (3) as a yellow solid (2.66 kg, yield: 75.3%, purity: 98.6-98.8% by HPLC). LC-MS (ESI) m/z: 291 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.94 (s, 3H), 7.15 (s, 1H), 8.10 (s, 1H), 8.40-8.42 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H), 8.58-8.61 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:29])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N.CO>N1C=CC=CC=1>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:13])[CH3:14])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: c1ccncc1
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a cold (˜0 C, ice/water bath) solution of 50 (2.65 g, 5.7 mmol) in 50 ml of anhydrous pyridine was added dropwise with stirring 1.0 ml (8.6 mmol) of benzoyl chloride (via a syringe). The reaction was allowed to warm up to room temperature, stirred for about 5 hrs until no starting material was found by HPLC analysis, and then treated with 10 ml of 6M NH3/MeOH. After being stirred for about 3 hrs and no more of the bis-benzoylated intermediate found by HPLC, the reaction was concentrated, re-suspended in dichloromethane (˜50 ml) and filtered to remove poorly insoluble benzamide. The filtrate was concentrated, washed with 10% citric acid, saturated NaCl, dried over Na2SO4 and concentrated again. The crude product was crystallized from 50% ethyl acetate/hexane (˜20 ml) to afford 2.4 g (74%) of 51 as white crystals. 1H NMR (DMSO-d6): δ 11.15 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 8.02 (d, J=7.2 Hz, 2H), 7.63 (m, 1H), 7.54 (t, J=7.8 Hz, 2H), 4.33 (m, 1H), 4.21 (m, 1H), 4.04 (m, 1H), 3.58 (m, 2H), 2.38 (m, 1H), 1.19 (d, J=6 Hz, 3H), 0.84 (s, 9H), 0.79 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H), −0.10 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>CN(C)C=O>[OH:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (70.3 g), triethylamine (105 cc) and 1-(4-hydroxyphenyl)piperazine dihydrobromide (85.2 g) in dimethylformamide (2100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 6 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and ethyl acetate (5-50 vol) as eluant, and recrystallization from boiling acetonitrile (1150 cc), 2-{3-[4-(4-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (20.5 g) is obtained, m.p. 185° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][C:14]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])[C:3]=12.Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][C:14]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:15]3=[O:23])[C:3]=12
Reactant: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Temperature: 90 °C
Yield: 56.9 %

Procedure:
A 50 mL round bottom flask was charged with 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.63 g, 2.0 mmol), 2-(bromomethyl)pyridine hydrobromide (0.51 g, 2.0 mmol), cesium carbonate (3.26 g, 10.0 mmol) and N,N-dimethylformamide (20 mL). The reaction mixture was heated at 90° C. for 1 h, allowed to cool to ambient temperature, filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 0% to 70% gradient of ethyl acetate in dichloromethane afforded 9-fluoro-1′-(pyridin-2-ylmethyl)-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.46 g, 57%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=4.3 Hz, 1H), 7.71-7.77 (m, 1H), 7.40-6.87 (m, 6H), 6.19 (d, J=1.8 Hz, 1H), 5.02 (ABq, 2H), 4.84 (ABq, 2H), 4.27-4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 155.6, 149.6, 143.1, 142.1, 142.0, 139.2, 139.2, 138.5, 137.5, 135.3, 133.9, 133.7, 131.5, 129.3, 124.1, 123.4, 123.2, 122.7, 122.7, 122.1, 109.9, 106.6, 106.6, 80.8, 64.7, 64.1, 58.0, 58.0, 45.2; MS (ES+) m/z 404.8 (M+1).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28]C>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)c(Cl)c1
Yield: 19.3 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 3-chloro-4-methoxyphenylboronic acid (0.67 g, 3.6 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.20 g, 36%, m.p. 234-36° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH:1]1([NH:7][CH2:8][CH:9]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(O)CNC1CCCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CNC1CCCCC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of N-cyclohexyl-N-(2-hydroxybutyl)amine (49.2 g) in tetrahydrofuran (1 liter) is added with stirring sodium hydride (60% oily dispersion, 12.6 g) in portions at 0° C. The mixture is stirred at the same temperature for one hour, and thereto is added dropwise benzyl bromide (34 ml). The mixture is stirred at room temperature overnight, and the mixture is concentrated under reduced pressure to remove the solvent. To the residue is added water, and the mixture is extracted with chloroform. The extract is dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol:aqueous ammonia=200:10:1) to give N-cyclohexyl-N-(2-benzyloxybutyl)amine (25.8 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:33]=[CH:34][C:35]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:36][CH:37]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide from Example 121 (115 mg) was reacted with 2-aminopyridine-5-boronic acid, pinacol ester via General Procedure A to yield 8.5 mg 124 following reverse phase HPLC purification. MS (Q1) 492.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:19])(=[O:18])[C:7]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:22])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:19])(=[O:18])[C:7]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc2c(c1)S(=O)(=O)c1ccccc1C(=O)N2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)S(=O)(=O)c1ccccc1C(=S)N2

Procedure:
To 7-Methoxy-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one-5,5-dioxide (0.6 g, 2.07 mmol) in pyridine (5 ml) was added phosphorus pentasulphide (0.62 g, 0.675 equivalents) and the mixture was heated under reflux for 6 hours. On cooling, the pyridine was removed under reduced pressure, the residue obtained was washed with water, 3% HCl-brine and recrystallised from methanol to give the title compound (0.5 g, m.p. 250°-252°, Rf 0.5 [silica, cyclohexane/ethyl acetate (1:1, v/v)].
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([N:14]1[CH2:22][CH:21]2[CH:16]([C:17](=[O:24])[NH:18][C:19](=[O:23])[CH2:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([N:14]1[CH2:22][CH:21]2[CH:16]([C:17](=[O:24])[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19](=[O:23])[CH2:20]2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC2CN(Cc3ccccc3)CC2C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 111.4 %

Procedure:
To a mixture of 905 mg of K2CO3 and 400 mg of the compound from step 457b in 5 mL of DMF was added 308 mg of benzyl bromide, and the reaction mixture was stirred at room temperature under N2 for 6.5 hours. The mixture was diluted with ethyl acetate, which was washed With water and brine, dried and concentrated to give 610 mg of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:65])[NH:17][C@H:18]([C:58]([O:60]C(C)(C)C)=[O:59])[CH2:19][S:20][CH2:21][C@H:22]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:65])[NH:17][C@H:18]([C:58]([OH:60])=[O:59])[CH2:19][S:20][CH2:21][C@H:22]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCCCCCC

Procedure:
A solution of (5R,9R)-tert-butyl 1-(9H-fluoren-9-yl)-9-(hexadecyloxy)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hours). The reaction mixture was diluted in MTBE, washed three times with 1 M citric acid (pH 3), and once with 1:2 HCl (3 M)/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used in the next step without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Reactant: CSc1nccc(Cl)n1
Product: CSc1nccc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)n1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-chloro-2-methylthio-pyrimidine. Mass spectrum (ESI) 440.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N:8]([O-])=O.[Na+].[ClH:12]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[ClH:12].[ClH:12].[NH:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=N[O-]
Reactant: Nc1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: NNc1cccnc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of 3-aminopyridine (9.41 g, 100 mmol) and conc. hydrochloric acid (100 mL) was cooled to a temperature of lower than −5° C., a solution of sodium nitrite (7.20 g, 105 mmol) in water (60 mL) was added dropwise thereto. Subsequently, a solution of tin chloride (II) (56.9 g, 300 mmol) in conc. hydrochloric acid (50 mL) was added to the solution so that the temperature of the solution does not exceed −5° C., and the solution was stirred at a temperature of less than −5° C. for 3 hours, and the resulting crystals were collected by filtration. The crystals were washed with diethylether/methanol and air dried to give the title compound (15.6 g, 85% yield). The compound was used in the following process without further purification.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:13]=2[CH2:12][O:11]1)C1C=CC=CC=1>[Pd].CCO>[CH3:1][NH:8][CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=[CH:19][C:13]=2[CH2:12][O:11]1
Reactant: CN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 88 %

Procedure:
(+)-N-benzyl-N-methyl-1-[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, 1.06 mmol), palladium on carbon (10%, 45 mg) and EtOH (20 ml) was hydrogenated at 45 psi for 14 h. Purification by flash chromatography (EtOAc/MeOH 2:1) afforded the pure title compound (0.24 g, 89%, >95% e.e.). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 224° C. [α]DMeOH=+77°. 1H-NMR (400 MHz, MeOH): δ 7.48 (1h, dd, J1 8.0 Hz, J2 1.6 Hz), δ 7.43 (1H, d, J 2.0 Hz), δ 7.18 (1H, d, J 8.0 Hz), δ 5.19 (1H, t, J 4.8 Hz), δ 5.00 (2H, dd, J 50 Hz, J2 16 Hz), δ 3.03 (3H, s), δ 2.99 (2H, d, J 4.0 Hz), δ 2.53 (3H, s), δ 1.54 (1H, s).