Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Br-]>C(OCC)(=O)C.CO.C(Cl)Cl.C(#N)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][S:8][CH2:7]2)[CH2:25][CH2:26]1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C1CSCN1CCCCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CSCN1CCCCN1CCN(c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 86 %

Procedure:
A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g), 1-(2-benzothiazolyl)piperazine (4.05 g), K2CO3 (7.01 g), NaI (250 mg) and acetonitrile (160 mL) was heated at 93° (bath temperature) under nitrogen. After 19 h, TLC analysis (silica gel, 5% methanol/methylene chloride) showed the absence of starting bromide and the presence of a major product, Rf =0.26. The reaction mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture filtered. The filtrate was concentrated in vacuo to a solid which was redissolved in ethyl acetate causing a white solid to precipitate. The mixture was filtered again and the filtrate concentrated in vacuo to 6.43 g of an off-white solid. Chromatography of the crude product by HPLC (Waters Prep 500, 1 silica gel column, 5% methanol/methylene chloride) yielded 5.44 g of an off-white solid. A sample of the solid (3.08 g) was recrystallized from methylene chloride (15 mL)/hexanes (85 mL) yielding 2.28 g of a crystalline solid, mp 111°-112° C.
Reaction SMILES: [CH:1]([C:3]1[C:14]2[O:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]=2[C:9]([CH:17]([C:36]2[C:46]3[O:47][C:48]([CH3:51])([CH3:50])[O:49][C:45]=3[C:44]([CH:52]=[O:53])=[C:38]3[O:39][C:40]([CH3:43])([CH3:42])[O:41][C:37]=23)[C:18]2[C:28]3[O:29][C:30]([CH3:33])([CH3:32])[O:31][C:27]=3[C:26]([CH:34]=[O:35])=[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=23)=[C:8]2[C:4]=1[O:5][C:6]([CH3:55])([CH3:54])[O:7]2)=[O:2].[S:56](=[O:59])([OH:58])[O-:57].OS([O-])=O.[Na+]>>[S:56](=[O:57])([OH:59])[OH:58].[CH:52]([C:44]1[C:38]2[O:39][C:40]([CH3:42])([CH3:43])[O:41][C:37]=2[C:36]([CH:17]([C:9]2[C:10]3[O:11][C:12]([CH3:16])([CH3:15])[O:13][C:14]=3[C:3]([CH:1]=[O:2])=[C:4]3[O:5][C:6]([CH3:54])([CH3:55])[O:7][C:8]=23)[C:18]2[C:28]3[O:29][C:30]([CH3:33])([CH3:32])[O:31][C:27]=3[C:26]([CH:34]=[O:35])=[C:20]3[O:21][C:22]([CH3:24])([CH3:25])[O:23][C:19]=23)=[C:46]2[C:45]=1[O:49][C:48]([CH3:51])([CH3:50])[O:47]2)=[O:53]
Reactant: O=S([O-])O
Agent: CC1(C)Oc2c(C=O)c3c(c(C(c4c5c(c(C=O)c6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(c(C=O)c6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Agent: [Na+]
Product: O=S(O)O

Procedure:
This reaction was performed with tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis-(1,3)dioxole-4-yl)methane (0.050 g, 0.066 mmol (Example 23)), and Na2S2O5 (0.285 g, 1.5 mmol) analogous to the formation of the bisulfite adduct of tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis-(1,3)dioxole-4-yl)methyl radical as detailed above in Example 88, yielding 0.140 g (the theoretical yield is 0.070 g) of crystals containing NaHSO3.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3OC)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:40]=[C:39](OC)[CH:38]=1>>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:42]=2)=[CH:9][CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCCCOc1cc(CCl)cc(OC)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3)cc2)c1

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.122 g of 1-chloromethyl-3-methoxy-5-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=6.19.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[O:20][CH3:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(OC)c1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,4-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=0.93 min; [M+H]+=396.15.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C@H:28]([O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.42 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(1R)-1-(2-fluorophenyl)ethoxy]thiophene-2-carboxamide in 25 ml THF is cooled to 0° C. At 0° C., 0.98 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[N:37][NH:38]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:40]=[C:39]4[C:35]([CH:36]=[N:37][NH:38]4)=[CH:34][CH:33]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: c1cc(-c2c[nH]c3nc(Nc4ccc5cn[nH]c5c4)nc(NC4CC4)c23)ccn1
Temperature: 116 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (51 mg, 0.12 mmol), 6-aminoindazole (31 mg, 0.23 mmol) and TMSCl (0.040 mL, 0.32 mmol) in nBuOH (2 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 383.2 (M+H); UV 204.9, 250.9, 307.9 nm.
Reaction SMILES: CC1N=CN=C2C=1N=CN2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1[OH:13].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1.II>CN1CCCC1=O>[C:33]1([P:26](=[O:13])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O
Agent: II
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
Solid 1d (82 mg, 0.31 mmol), triphenylphosphine (274 mg, 1.03 mmol), and imidazole (140 mg, 2.05 mmol) are blended under argon by magnetic stirring before being dissolved in 1-methyl-2-pyrrolidinone (M-PYROL) (1.5 ml) at room temperature. Beads (1-3 mm) of iodine (261 mg, 1.03 mmol) are added over 5 min with slight heating observed. Further additions of triphenylphosphine, imidazole, and iodine (same quantities as above) are made in the order listed after 5 h, 24 h, and 56 h. More M-PYROL (0.5 ml) is added prior to the last addition. After 124 h, the reaction solution is partitioned between ethyl acetate (40 ml) and 10% sodium thiosulfate (15 ml). The aqueous layer is extracted with more ethyl acetate (3×15 ml). The combined organic layers are washed once with brine (15 ml), dried (MgSO4), and evaporated to a solid. A crop of triphenylphosphine oxide (Ph3PO) is obtained from a chilled ethyl acetate solution of this residue. More Ph3PO is removed by repeating this process with chloroform. Crude 1e is purified by preparative TLC (Analtech GF, 20×20 cm, 2,000 μ) using 9:1 CHCl3/MeOH as developing solvent. Pure 1e crystallized from 2-propanol as a white solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30]1[C:35](=[O:36])[N:34](COCC[Si](C)(C)C)[C:33]2[CH:45]=[CH:46][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:48][C:32]=2[S:31]1(=[O:59])=[O:58].C(O)(C(F)(F)F)=O>>[CH3:29][N:30]1[C:35](=[O:36])[NH:34][C:33]2[CH:45]=[CH:46][C:47]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:48][C:32]=2[S:31]1(=[O:59])=[O:58]
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CN1C(=O)N(COCC[Si](C)(C)C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)Nc2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2S1(=O)=O

Procedure:
Compound 2b was subjected to Suzuki coupling conditions using the methods described in Example 1, Step G, with compound 42c and the resulting product was deprotected with TFA using the methods described Example 37, Steps B and C to obtain the title compound 19. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.71 (s, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.96 (t, J=8.6 Hz, 2H), 7.83-7.90 (m, 2H), 7.75 (t, J=7.6 Hz, 1H), 7.64 (d, J=16.2 Hz, 1H), 7.53-7.60 (m, 1H), 7.43-7.51 (m, 2H), 4.31 (br. s., 4H), 3.82 (br. s., 4H), 3.25 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H25N7O4S: 568.2 (M+H). Found 568.5.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2([O:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:23][CH2:22]2)=[CH2:20])=[CH:15][CH:14]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:21]3([O:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH2:22][CH2:23]3)[CH2:20][O:9]2)=[CH:17][CH:18]=1
Reactant: C=C(c1ccc(Cl)cc1)C1(Oc2ccc(Cl)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccc(OC2(C3(c4ccc(Cl)cc4)CO3)CC2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 4.3 g=25 mmol of 80% strength m-chloroperbenzoic acid in 100 ml of chloroform was added dropwise at 20° C. with stirring to a solution of 6.1 g=20 mmol of 1-(4-chlorophenyl)-1-[1-(4-chlorophenoxy)-cyclopropan-1-yl]-ethene (compound from Example 12) in 20 ml of chloroform, and the mixture was stirred for 15 hours at 20° C. and 3 hours under reflux. For work-up, the mixture was shaken three times with 50 ml of 2N sodium hydroxide solution and once with 2N sodium bisulfite solution, washed with water and dried over sodium sulfate, and the solution was concentrated in a water-pump vacuum. The residue was dissolved in twice the volume of ether. After seeding using a crystal from Example 2a, 3.2 g of melting point 96°-97° C. crystallized.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(Cc2cccc(F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 60 °C
Yield: 100 %

Procedure:
A mixture of methyl 4-(3-fluorobenzyl)benzoate (0.574 g; 2.35 mmol) and lithium hydroxide (0.493 g; 11.75 mmol) in water (6 mL) and THF (6 mL) was heated at 60° C. for 3 hours and concentrated under reduced pressure. The resulting aqueous solution was acidified with a 6N solution of hydrochloric acid in water. The resulting precipitate was filtered off to give 0.541 g (quantitative) of 4-(3-fluorobenzyl)benzoic acid which was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCN(C)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and 1-methylpiperazine (0.16 mL, 1.44 mmol) in THF (20 mL) was refluxed for 5 hrs and then stirred at room temperature for 3 days. Additional 1-methylpiperazine (0.16 mL, 1.44 mmol) and 1,4-dioxane (20 mL) were added and the reaction mixture was refluxed for 20 hrs. The mixture was cooled to room temperature and the solvents were removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 95:5) followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (116 mg, 65%).
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[SH:34][CH2:35][CH2:36][OH:37]>>[CH2:25]([C@:23]1([OH:24])[C:13]2[CH:12]=[C:11]3[N:16]([C:15](=[O:19])[C:14]=2[CH2:20][O:21][C:22]1=[O:27])[CH2:17][C:18]1[C:6]([CH2:5][CH2:4][Si:3]([CH2:2][S:34][CH2:35][CH2:36][OH:37])([CH3:32])[CH3:33])=[C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]2=[N:9][C:10]3=1)[CH3:26]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Reactant: OCCS
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CSCCO

Procedure:
Prepared according to Procedure F using Compound 4 and 2-mercaptoethanol, the crude product was purified on a silica gel column using 3% ethanol in dichloromethane to obtain the pure product in 83% yields.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(OC(=O)C)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH2:14]([C:15]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N:11]=1)[C:13]([CH3:12])=[O:17]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Cc1nc2cc(C)ccc2c(=O)o1
Yield: 47.1 %

Procedure:
A mixture of 4-methylanthranilic acid (25.0 g., 0.17 mole) and diketene (13.95 g., 0.17 mole) in CCl4 (250 ml.) was heated at reflux for 2.5 hours. Acetic anhydride (18.3 g., 0.18 mole) was added and the mixture was stirred under reflux for 16 hours. The mixture then was cooled and the product isolated by filtration; upon recrystallization there was obtained 2-acetonyl-7-methyl-4H-3,1-benzoxazin-4-one (17.4 g., 48 percent), mp 142°-144° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cccc(C)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)c1
Temperature: -70 °C

Procedure:
1 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][3-methylphenyl]methanone was dissolved in 29 mL of CH2Cl2 and cooled to -70° C. To the stirring solution was added 20 mL of 1M BBr3 in CH2Cl2 in small portions over a ten minute period. The reaction was allowed to proceed under a nitrogen atmosphere, slowly warming to ambient temperature. After sixteen hours, the reaction was quenched by adding 1N NaOH and extracted with 200 mL of EtOAc. The EtOAc layer was separated and washed with water, dried by filtration through anhydrous Na2 SO4, and evaporation to dryness, in vaccuo. The crude product was purified by chromatography on a silica gel column eluted with EtOAc-hexane (1:4)(v/v). The product was rechromatographed on a silica gel column eluted with EtOAc-hexane (1:3)(v/v). This yielded 190 mg of the title compound as a yellow amorphous powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:24])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[CH:22]=[O:23].[S]>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[NH:3][C:4](=[O:24])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH:22]=[O:23]
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2C=O)SCC(=O)N1
Agent: [S]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1=C(c2ccncc2C=O)SCC(=O)N1
Temperature: 160 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-formyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (0.5 g) and sulfur (2.5 g) was stirred at 160° C. for 3 hours. After cooling, the solid was ground and was extracted with methanol using Soxhlet extractor. Methanol was removed under reduced pressure. The residue was extracted with 40 ml of 2N hydrochloric acid. The insoluble matter was removed by filtration and the filtrate was washed with ether and the water phase was adjusted to pH 7.5 by 2N aqueous sodium hydroxide. The resulting precipitates were extracted with chloroform and were dried. Chloroform was removed under reduced pressure and the residue was purified by the preparative thin layer chromatography [TLC silica gel plate 60F254 (supplied by Merck & Co. Inc., U.S.A.), 20×20 cm, thickness 1 mm, chloroform-methanol=40:1] to give the titled compound (0.03 g, yield 10.6%) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11]([OH:22])=[N:10][C:8]=2[N:9]=1.I[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH3:26])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(O)nc2n1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a suspension of NaH (60% in mineral oil, 31 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one from Example 11 (205 mg, 0.67 mmol). The mixture was heated at 50° C. for 1 hour resulting in a clear solution. 1-Iodopropane (100 μL, 1.03 mmol) was added, and the solution was stirred at 50° C. for 10 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The residue was dried and purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate to provide 159 mg (68%) of 2-amino-6-(2,6-dichlorophenyl)-8-propyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 196-197° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:53]=[CH:52][C:38]([C:39]([NH:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][N:43]=3)=[O:40])=[CH:37][CH:36]=2)O1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:35]2[CH:53]=[CH:52][C:38]([C:39]([NH:41][C:42]3[CH:47]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:45]=[CH:44][N:43]=3)=[O:40])=[CH:37][CH:36]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Yield: 87 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (intermediate 10) to afford the title compound (163 mg, 87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:31][CH2:32][CH2:33][CH3:34])=[C:15]([C:17]2[NH:18][C:19](=[O:30])[C:20]3[C:25]([CH3:26])=[N:24][N:23]([CH2:27][CH2:28][CH3:29])[C:21]=3[N:22]=2)[CH:16]=1)(=[O:10])=[O:9]>>[CH3:26][C:25]1[C:20]2[C:19](=[O:30])[NH:18][C:17]([C:15]3[CH:16]=[C:11]([S:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:10])=[O:9])[CH:12]=[CH:13][C:14]=3[O:31][CH2:32][CH2:33][CH3:34])=[N:22][C:21]=2[N:23]([CH2:27][CH2:28][CH3:29])[N:24]=1
Reactant: C1COCCN1
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Product: CCCOc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from morpholine (0.451 g, 0.0052 mol) and 6-(5-chlorosulphonyl-2-n-propoxyphenyl)-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Preparation 8; 0.55 g, 0.0013 mol), according to the procedure of Example 14, and was obtained as colourless needles (0.403 g, 65%), m.p. 161-163° C., after crystallisation from ethyl acetate-hexane. Found: C,55.68; H,6.16; N,14.85. C22H29N5O5S requires C,55.56; H,6.15; N,14.73%.