Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[I-].[CH3:6][S+](C)(C)=O.[H-].[Na+].[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>O1CCCC1>[C:14]([C:15]1([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[CH2:6][O:16]1)([CH3:24])([CH3:23])[CH3:13]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)c1cncnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C1(c2cncnc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 10 ml of dimethyl sulphoxide are slowly added dropwise to 0.96 g (4.3 mmol) of trimethylsulphoxonium iodide and 0.17 g of sodium hydride (60%, 4.3 mmol). The reaction mixture is then stirred at room temperature for 15 min, and 0.65 g (3.9 mmol) of 2,2-dimethyl-1-(5-pyrimidinyl)-1-propanone, dissolved in 2 ml of tetrahydrofuran, is added. The reaction mixture is stirred at 50° C. for 90 min. The reaction mixture is then concentrated under reduced pressure, and saturated aqueous sodium chloride solution and ethyl acetate are added to the residue. The organic phase is separated off, dried over sodium sulphate, filtered and concentrated. This gives 0.70 g (99%) of the desired product, which is reacted without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([N:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]5)=[CH:8][C:6]=4[N:7]=3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4ccnc5cc(Cl)ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 42.8 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.150 g, 0.380 mmol), 7-chloroquinoline-4-boronic acid pinacol ester (0.132 g, 0.456 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.013 g, 0.02 mmol), 1 N aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20% methanol in dichloromethane) to give 104 (0.085 g, 43%) as a yellow solid. MS m/e 531 [M+H]+; 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.48-1.67 (m, 2 H) 1.82-1.96 (m, 2 H) 2.07-2.26 (m, 3 H) 2.30 (s, 6 H) 3.07 (d, J=11.7 Hz, 2 H) 3.82-3.91 (m, 6 H) 4.02-4.11 (m, 4 H) 7.36 (s, 1 H) 7.60 (dd, J=9.1, 2.3 Hz, 1 H) 7.95 (d, J=4.5 Hz, 1 H) 8.10 (d, J=2.3 Hz, 1 H) 8.67 (d, J=9.4 Hz, 1 H) 8.98 (d, J=4.9 Hz, 1 H)
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:58])([CH3:57])[C@H:7]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:8](=[O:48])[NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@H:13]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:17][C:18](=[O:21])[O:19][CH3:20])(=O)C.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[C:53]([O:52][C:50]([NH:49][C@@H:7]([C:6]([CH3:58])([CH3:57])[CH2:5][OH:4])[C:8]([NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@@H:13]([NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:25])([CH3:23])[CH3:24])[NH:17][C:18]([O:19][CH3:20])=[O:21])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:30][CH:29]=1)=[O:48])=[O:51])([CH3:54])([CH3:55])[CH3:56]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)CO)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product of Example 174F (0.020 g, 0.025 mmol) in a mixture of dioxane (0.250 mL) and water (0.100 mL) was added an aqueous solution of lithium hydroxide (0.028 mL, 1 N), and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate and washed with brine, dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH:22]CCN>>[CH2:1]([O:8][C:9]1([OH:22])[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][C:19]([OH:21])=[O:20])[CH:10]1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCO
Product: CC1N(CC(=O)O)C=CC(=O)C1(O)OCc1ccccc1

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with glycine under substantially similar conditions to those described under Example 11 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one, which is deprotected using the procedure described under Example 11 to give 1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one as white crystals, m.p >230° C.; νmax (nujol) 1625, 1645 cm-1 ; δ(d6DMSO) 1.9 (s, 3H), 4.3 (s. 2H), 5.9 (d, 1H), 7.35 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:47]([C:49]1[N:50]=[C:51]([C:62]([O-])=[O:63])[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=1)#[N:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:21])[CH:13]=[CH:12][C:11]=2[NH:14][C:62]([C:51]2[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=[C:49]([C:47]#[N:48])[N:50]=2)=[O:63])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Yield: 100.3 %

Procedure:
A solution of 365 mg (1.18 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 827 mg (1.78 mmol) of PyBroP, 398 mg (1.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 618 μL, (3.55 mmol) of DIEA at RT for 16.5 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-40% EtOAc-hexane afforded 660 mg (100%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C27H39N5O4SSi, 558.2 (M+H). found 557.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>C(O)C.O1CCCC1.ClCCl>[CH:16]1([CH2:15][CH:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)nc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (110 mg, 0.25 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL), was treated with an aqueous sodium hydroxide solution (10%, 1.5 mL) and stirred at 50° C. for 1 h. The mixture was acidified to pH 4-5 with a 2N aqueous hydrochloric acid solution, diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (100 mg, 94%) as a white solid which was used in the next step without further purification: LC/MS m/e calcd for C21H23N3O4S [M+H]+ 414.50, observed 414.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1

Procedure:
4-(3,4-Dichloro-phenyl)-6-methyl-1H-pyridin-2-one: The compound was prepared from the above described (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (26.7 g, 124 mmol), commercially available 1-ethoxycarbonylmethyl-pyridinium bromide [CAS-No. 17282-40-5] (33.6 g, 137 mmol) and ammonium acetate (47.8 g, 621 mmol) in EtOH (150 mL) according to general procedure Ib step 1. Obtained as a light brown solid (25.4 g, 81%). MS (ISP) 254.1 [(M+H)+], 256.2 [(M+2+H)+] and 258.0 [(M+4+H)+]0.3) The title compound was prepared from the above described 4-(3,4-dichloro-phenyl)-6-methyl-1H-pyridin-2-one (25.4 g, 100 mmol) and phosphoryl chloride (45.6 mL, 500 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (23.7 g, 87%). MS (ISP) 272.1 [(M+H)+], 274.0 [(M+2+H)+], 276.0 [(M+4+H)+] and 278.0 [(M+6+H)+].
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>CN(C)C=O>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH2:24])=[CH:21][CH:22]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1ccc(CC(C)C)cc1
Yield: 29 %

Procedure:
To a solution of chlorotrimethylsilane (16.3 g) and triethylamine (30.3 g) in N,N-dimethylformamide (50 ml) was added 4'-isobutylacetophenone (22.0 g). The yellow solid was immediately filtered off, and the filtrate was refluxed for 20 hours. The mixture was cooled, diluted with hexane, and washed with cooled aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 4-isobutyl-α-trimethylsilyloxystyrene (9.0 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24]CC)=O.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)[C:22](=[O:24])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: ClC(=Nc1ccccn1)c1ccccc1
Agent: Cl
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccn3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1, from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)2,6-dimethyl-3,5-pyridine dicarboxylate and N-(2-pyridyl)-benzimidoyl chloride HCl (2.5 g, 9.4%).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH:27]1([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]3[S:38][C:39]([C:43]([OH:45])=O)=[C:40]([CH3:42])[N:41]=3)[C:32]2=[O:46])[CH2:29][CH2:28]1.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=1>>[CH:27]1([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]3[S:38][C:39]([C:43]([NH:54][CH2:53][C:49]4[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=4)=[O:45])=[C:40]([CH3:42])[N:41]=3)[C:32]2=[O:46])[CH2:28][CH2:29]1
Reactant: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxotetrahydro pyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 22% yield: mp 142-145° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.52-8.51 (m, 1H), 7.68-7.65 (m, 1H), 7.28-7.23 (m, 1H), 6.07 (m, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 3.48 (t, J=5.9 Hz, 2H), 3.31 (d, J=7.0 Hz, 2H), 2.61 (s, 3H), 2.16-2.09 (m, 2H), 1.05-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.28-0.23 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.0, 159.2, 152.9, 152.7, 149.0, 148.6, 135.6, 133.9, 123.6, 117.6, 52.8, 45.6, 45.5, 41.2, 21.3, 17.3, 9.3, 3.4; MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Yield: 89 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (100 mg, 0.353 mmol) and 1-methylpiperazine (39.2 μL, 0.353 mmol) were combined and purified as per Preparation Hb to give 2-chloro-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (109 mg, 0.314 mmol, 89% yield). LC-MS (M+H)+=347.2.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].CC(C)=O>C(O)(C)C>[Cl:1][CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCl)Cc1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: OC(CCl)Cc1cccc(C(O)c2ccccc2)c1
Temperature: 50 °C
Yield: 105 %

Procedure:
A solution of 11.23 g of 3'(3'-chloro-2'-oxo-propyl)-benzophenone in 112 ml of isopropanol was added to 50 ml of isopropanol and 17 g of aluminum isopropylate heated to 50° C and the mixture was refluxed for 2 hours while slowly distilling isopropanol and the acetone formed while keeping the volume constant by adding 30 ml of isopropanol. The mixture was concentrated to 50 ml and after returning to room temperature, the mixture was added with stirring to a mixture of ice-water-hydrochloride acide. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 11.97 g of 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol which was used as is for the next step.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][NH:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:35][CH2:34][CH:33]([OH:40])[CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[C:11]=1[C:26]([NH2:27])=[O:28])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)NCC(O)CCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CNC(C)(C)C)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-amino-1-tert-butylamino-butan-2-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.8, 9.6 Hz), 7.04 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.66 (m, 1H), 3.34 (t, 2H, J=7.6 Hz), 2.58 (m, 2H), 2.25 (s, 3H), 1.69-1.60 (m, 2H), 1.12 (s, 9H) ppm; MS (APCI, m/z): 486 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[NH:5][C:6](=[O:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.O>C(O)(=O)C>[Br:1][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[NH:5][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c2ccccc2c1Br
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of bromine 491 mL, 9.58 mmol) in acetic acid (10 mL) is added to a stirred solution of 3-methyl-2H-isoquinolin-1-one (1.45 g, 9.12 mmol) in acetic acid (1 mL). After 3 hr, water (60 mL) is added and the resulting solids are collected by filtration to afford 4-bromo-3-methyl-2H-isoquinolin-1-one (1.90 g, 88% yield) as a white solid. LC/MS: MS m/e=238/240 (M+H); RT 2.97 min.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]#[N:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].[Br:26]N1C(=O)CCC1=O>ClCCCl>[Br:26][CH:21]([C:18]1[C:17]2[CH:24]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[N:2]([CH3:1])[C:3]3=[O:25])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)[C:22]#[N:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC#N)c3c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)C#N)c3c2)c1=O
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetonitrile (0.500 g, 0.00140 mol) in 1,2-dichloroethane is added N-bromosuccinimide (0.250 g, 0.00140 mol). The resultant mixture is irradiated with a UV lamp and stirred at reflux six hours. Additional N-bromosuccinimide (0.250 g, 0.00140 mol) is added and the resultant mixture is stirred 1.5 hours at reflux under a UV lamp. The mixture is cooled to room temperature and concentrated in vacuo. The resultant residue is taken up in methylene chloride, washed with water, treated with charcoal, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the title product as a red glass (0.350 g, 56.2%, mp 185-187° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:18]=[C:19]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[CH:21][CH:22]=2)=[CH:12][C:11]=1[Cl:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I>>[Cl:31][C:11]1[CH:12]=[C:13]([S:16][C:17]2[CH:18]=[C:19]([C:23]3([O:29][CH3:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][C:10]=1[N:9]([CH3:32])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(c2cccc(Sc3ccc(NC(=O)c4ccccc4)c(Cl)c3)c2)CCOCC1
Reactant: CI
Product: COC1(c2cccc(Sc3ccc(N(C)C(=O)c4ccccc4)c(Cl)c3)c2)CCOCC1
Yield: 86 %

Procedure:
Using a similar procedure to that described in Example 18, 4-[3-(4-benzamido-3-chlorophenylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give 4-[3-(3-chloro-4-(N-methylbenzamido)phenylthio)phenyl]-4-methoxytetrahydropyran in 86% yield as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])/[CH:12]=[CH:13]/[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].C.[H][H].[K+].[Br-]>C(O)C.C1COCC1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: CN(C)c1ccc(C(=O)/C=C/C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl
Agent: [Pt]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc(C(=O)CCC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl

Procedure:
A solution of 1.05 g (2.248 mmol) of (E)-3-{1-[4-(3-chloro-4-dimethylaminophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 104) in 110 ml of an ethanol-THF mixture (10/1 v/v) was hydrogenated at ambient temperature in the presence of 0.5 g of platinum on active charcoal until the uptake of hydrogen had ended. The mixture was freed from catalyst and solvent and purified by chromatography on silica gel using dichloromethane/methanol/conc. ammonia (95/5/0.3 v/v/v) as eluant. 0.36 g (34% of theoretical) of a colourless substance were obtained, Rf 0.31 (El A). IR (KBr): 1672, 1660 (C═O) MS: M+=468/470 (Cl)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(S(C)(=O)=O)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-methanesulfonyl-benzene as described in Example 49 and isolated as a white solid (0.058 mg, 45% yield). 1HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.57 (d, J=4 Hz, 1H), 7.91 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.26-7.32 (m, 1H), 6.89 (d, J=4 Hz, 1H), 6.03-6.12 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=4 Hz, 2H), 3.03 (s, 3H), 2.75 (s, 3H); MS (M+H)+=468.1; Rt=0.99 min; HRMS (M+H)+=468.12.