Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].II.[CH2:13]([C:16](=[CH2:21])[C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH3:15].C(N(CC)CC)C>O.ClCCl>[CH3:20][O:19][C:17](=[O:18])/[C:16](/[CH2:13][CH2:14][CH3:15])=[CH:21]/[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(CCC)C(=O)OC
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Sodium benzenesulfinate (11.21 g, 68.27 mmol) was dissolved in water (100 ml). This solution was shaken with iodine (17.33 g, 68.27 mmol) in dichloromethane (100 ml). The dichloromethane layer turned from deep pink to orange. The dichloromethane layer was dried over magnesium sulphate and filtered into a flask containing methy 2-propylacrylate (5.0 g, 39.01 mmol). The solution was stired overnight at room temperature and then cooled to 0° C. Triethylamine (11 ml, 78.01 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. The mixture was diluted with water and the organic layer was washed with 1N hydrochloric acid (75 ml), 10% aqueous sodium bisulfite (75 ml), and brine, then dried over magnesium sulfate, filtered and evaporated to give (E)-3-benzenesulfonyl-2-propylacrylic acid methyl ester (9.1 g, 87% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([F:44])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[F:44])[CH3:43]
Reactant: CCOc1ccc(OB([O-])[O-])cc1F
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-ethoxy-3-fluorophenyl borate (117 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 24 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:4) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-(4-ethoxy-3-fluorophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 50) (137 mg).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[CH3:7][C:8](=O)[CH2:9][C:10](=[O:12])[CH3:11].[CH2:14]=O>N1CCCCC1.C(O)C>[C:10]([C:9]1[CH2:14][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[NH:6][C:8]=1[CH3:7])(=[O:12])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: C/C(N)=C\C#N
Reactant: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)C1=C(C)NC(C)=C(C#N)C1
Yield: 59.1 %

Procedure:
A mixture of 3-aminocrotonitrile (2.0 g, 24 mmol), 2,4-pentanedione (4.9 g, 49 mmol), paraformaldehyde (1.5 g, 49 mmol) and piperidine (12 drops) in ethanol (100 mL) was heated to reflux for 4 hours, cooled and concentrated to dryness. The residue was treated with diethyl ether (150 mL). The solid was collected and washed with ether. The solid was triturated with dichloromethane (2×100 mL). The combined dichloromethane triturations were concentrated to provide 2.5 g of the title compound. 1H NMR (DMSO-d6) δ ppm 1.92 (t, J=1.02 Hz, 3 H), 2.09 (s, 3 H), 2.10 (s, 3 H), 3.20 (s, 2 H), 8.65 (s, 1 H). MS (DCl—NH3) [M+H]+ at 177.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc(Br)c1

Procedure:
3,5-Dibromopyridine 2.37 g is dissolved in methylene chloride 25 ml and thereto is added m-chloroperbenzoic acid 2.96 g at room temperature under stirring. After stirring for 5 hours at room temperature, additional m-chloroperbenzoic acid 246 mg is added thereto and the mixture is stirred. After 15 hours the solvent is removed in vacuo and the residue is purified by silica gel chromatography (solvent; n-hexane:ethyl acetate=1:1) to give 3,5-dibromopyridine N-oxide as colorless crystals, 2.26 g. mp 140–142° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9].C([O-])(O)=O.[Na+]>ClCCl>[NH2:27][CH2:26][CH2:25][CH2:24][N:21]1[CH2:20][CH:19]=[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C2=CCN(CCCN)CC2)c1
Temperature: 25 °C

Procedure:
A 1:1 solution of TFA:CH2Cl2 (5 mL) was added to tert-butyl N-(3-{4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinyl}propyl)carbamate in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 1–3 days, saturated NaHCO3 was added until pH>6, the organic layer was separated, and dried in vacuo, giving the desired product (45 mg): 1H NMR (CDCl3) δ 7.68 (br, 1H), 7.35 (dm, 1H, J=7.8 Hz), 7.25 (apparent t, 1H, J=7.8 Hz), 7.15 (dm, 1H, J=7.8 Hz), 6.12 (m, 1H), 3.22 (m, 2H), 3.03 (t, 2H, J=7.3 Hz), 2.78 (t, 2H, J=5.5 Hz), 2.70–2.50 (m, 4H), 2.10 (s, 3H), 1.87 (p, 2H, J=7.3 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:16])(=[O:15])[NH:13][CH3:14])[CH:6]=1)=[O:4].[CH2:17]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[S:21])[CH3:18]>C(OC(C)C)(C)C>[ClH:1].[CH2:23]([N:22]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:16])(=[O:15])[NH:13][CH3:14])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:19][CH2:17][CH3:18])[CH3:24]
Reactant: CNS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CCNC(=S)NCC
Solvent: CC(C)OC(C)C
Product: CCN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC)c2)N1CC
Product: Cl

Procedure:
5.6 g of 2,4'-dichloro-3'-methylsulfamoylacetophenone and 2.7 g of 1,3-diethylthiourea were reacted as prescribed in Example 12. After the addition of 100 ml of diisopropyl ether and a dwelling period of 1 hour at 0° C., the solvent was decanted and the oily end product was crystallized under boiling diethyl ether. Colorless solid body, melting point: 168° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:10]1[C:9]2[N:8]=[C:7]([CH2:19][CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:23])=[O:22])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N(C)C

Procedure:
N,N-Dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (2.40 g, 7.73 mmol) was treated with mCPBA (3.11 g, 13.5 mmol), ammonium hydroxide (40 mL), and benzenesulfonyl chloride (1.92 mL, 15.1 mmol) according to the method described in Part D of Example 36. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol) to provide 0.097 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylpropanamide as a tan powder, mp 207-209° C.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.[C:18]([O:22][C:23](=[O:27])[C@H:24](Br)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23](=[O:27])[C@@H:24]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])[CH3:25])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@@H](Br)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1C1NCCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccccc1C1c2ccccc2CCN1[C@@H](C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Racemic 1-o-tolyl-3,4-dihydro-1H-isoquinoline (0.67 g, 3.00 mmol) is added to a solution of (R)-(+)-2-bromo-propionic acid tert-butyl ester (0.50 g, 2.39 mmol) in acetonitrile (10 mL) and the mixture was stirred at 85° C. for 16 hours. After cooling to room temperature the reaction is diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL) and the organic layer isolated, washed with water (2×100 mL), brine (1×100 mL), and dried over magnesium sulfate. Filtration and concentration are followed by flash chromatography on SiO2 using 40:1 hexane:ethyl ether to afford 2-(S)-(1-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid tert-butyl ester as a colorless syrup. C. 2-(S)-[1-(S)-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([O:34][CH3:35])=[O:33].C(OCC)(=O)C>CN(C=O)C.O>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:31]([C:32]([O:34][CH3:35])=[O:33])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:20][CH2:19]2)[CH:5]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: c1cc2[nH]cc(CCCC3CCNCC3)c2cc1-n1cnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccccc1)N1CCC(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl]piperidine (Description 2, 0.800 g, 0.0026 mol) was dissolved in anhydrous DMF (10 ml), under N2, and potassium carbonate (0.540 g, 0.0039 mol) added followed by (±)-methyl α-bromophenylacetate (Aldrich, 0.5 ml, 0.0031 mol). The reaction was stirred at 25° C. for 16 h, then poured into ethyl acetate (100 ml) and H2O (30 ml). The organic layer was collected, washed with H2O (3×30 ml), dried over MgSO4 and evaporated with 1-5% MeOH/CH2Cl2 to obtain the title compound as a colourless oil. 1H NMR 1.23-1.33 (6H, m), 1.66 (5H, m), 2.04 (1H, br m), 2.72 (2H, t, J=3 Hz), 2.96 (1H, bm), 3.69 (3H, s), 3.98 (1H, br s), 7.11 (1H, d, J=1 Hz), 7.14 (1H, d, J=2 Hz), 7.33 (3H, m), 7.43-7.48 (2H, m), 7.50 (1H, d, J=3 Hz), 7.51 (1H, d, J=1 Hz), 8.07 (br s, indole (NH)), 8.45 (2H, s, Ar (triazole)).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)=[O:9])=[CH:6][N:5]=[C:4]2[CH:36]=[CH:37][S:38][C:3]=12.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH2:44].C(N(C(C)C)CC)(C)C.O>CC(O)C>[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH:44][C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:12]2)=[O:9])=[CH:6][N:5]=[C:4]2[CH:36]=[CH:37][S:38][C:3]=12
Reactant: COCCCN
Reactant: CC(C)CN(C(=O)c1cnc2ccsc2c1Cl)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCCNc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cnc2ccsc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
tert-Butyl (3S,5R)-3-{[(7-chlorothieno[3,2-b]pyridin-6-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (120 mg), 3-methoxypropan-1-amine (113 mg) and diisopropylethylamine (0.22 ml) were dissolved in 2-propanol (5 ml), and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (90 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]=[N+]=[N-])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CO>C(OCC)(=O)C.[C].[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=3)=[N:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CN=[N+]=[N-])cc3)nc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CN)cc3)nc2)CC1
Yield: 68.4 %

Procedure:
To a solution of 1-acetyl-4-(6-{2-[4-(azidomethyl)phenyl]ethyl}pyridin-3-yl)piperazine (226.8 mg, 0.622 mmol) in ethyl acetate (10 ml) was added 10% palladium carbon (45.1 mg, 50% containing water), and the mixture was hydrogenated at room temperature, under atmospheric pressure. Methanol (10 ml) was added to the reaction mixture, and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was washed with a mixture of ethyl acetate/diisopropyl ether (1:1) and dried under reduced pressure to give 1-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanamine (144.0 mg, yield 68.2%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br.O>C(OCC)C>[Br:16][CH2:10][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: O=C(CBr)c1c(F)cccc1F
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (86 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-15° C. After stirring at room temperature for 2 hr, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:35][O:36][C@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:31](OC)=[O:32])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:35][O:36][C@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:31]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=4)=[O:32])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
Trimethylaluminium (0.334 mL, 0.67 mmol) was added to 5-methylpyridin-2-amine (69.1 mg, 0.64 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y8) (245 mg, 0.58 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 24 hours. The reaction mixture was allowed to cool and neutralised with citric acid (1M, aq) and then diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by preparative HPLC (Phenomenex Gemini C 18 110A (axia) column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (137 mg, 47.4%). 1H NMR (400 MHz, DMSO) δ 1.10 (d, 3H), 2.26 (s, 3H), 3.23-3.42 (m, 5H), 3.76-3.85 (m, 1H), 4.10-4.16 (m, 2H), 5.95-6.00 (m, 1H), 7.55-7.60 (m, 1H), 7.68-7.73 (m, 1H), 7.86 (d, 1H), 8.14-8.18 (m, 1H), 8.24-8.29 (m, 1H), 8.54 (s, 2H), 8.62-8.67 (m, 1H), 10.21 (s, 1H) m/z (ESI+) (M+H)+=498.16; HPLC tR=1.84 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1S[C:15]2[CH:21]=CC=C(Cl)[C:16]=2N=1.[OH-:23].[Na+].O>C(O)(C)C>[CH:15]([O:23][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)([CH3:21])[CH3:16]
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: [OH-]
Reactant: Clc1cccc2sc(Br)nc12
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1nc2c(Cl)cccc2s1
Yield: 95.9 %

Procedure:
A mixture (11.30 g, 0.05 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 94% sodium hydroxide (2.34 g, 0.055 mole) in isopropanol (100 c.c.) was heated under reflux for 1 hour. Water was added and the alcohol was distilled azeotropically together with water. The resulting oily substance was extracted with chloroform, and the chloroform layer was washed with water. The solvent was then removed under reducing pressure to obtain 10.92 g of 2-isopropoxy-4-chlorobenzothiazole as a yellow viscous liquid. Yield 95.9%, purity 97.7%, b.p. 95°-96° C./0.2 mmHg.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][C:31]=1C>CN(C=O)C>[F:29][C:30]1[CH:35]=[CH:34][C:1]([O:4][C:8]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:32]([CH3:33])[CH:31]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(OC(F)(F)F)ccc1F
Reactant: Cc1cc(O)ccc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1ccc(OC(F)(F)F)cc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Cs2CO3 (651.6 mg, 2 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide (63.2 mg, 0.2 mmol) and 4-fluoro-3-methylphenol (252.3 mg, 2 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide (40) (36.3 mg, 43%). ESI-MS m/z calc. 422.09. found 423.9 (M+1)+; Retention time: 1.64 minutes (3 minutes run).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34]3)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[CH2:34]4)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc5c(c4)CC(=O)N5)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (from Combi-Blocks) LCMS calculated for C24H23N4O3 (M+H)+: m/z=415.2. Found 415.3.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[N+:17]=1[CH2:18][CH3:19].C(N(CC)CC)C.[Cl:31][C:32]([Cl:37])([Cl:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:31][C:32]([Cl:37])([Cl:36])[C:33]([CH:12]=[C:13]1[N:17]([CH2:18][CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)=[O:34]
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1C(=CC(=O)C(Cl)(Cl)Cl)Sc2ccccc21
Reaction time: 3 h

Procedure:
10 g (28.6 mmol) of 2-methyl-3-ethyl-benzothiazolium p-toluenesulfonate are suspended in 150 ml of toluene, 6.8 g (67.2 mmol) of triethylamine are added and, at 5°-10° C. 6 g (33 mmol) of trichloroacetyl chloride, dissolved in a minor amount of toluene, are added dropwise. After three hours at room temperature, the ammonium salts are filtered off with suction, and the reaction solution is washed with water, dried over sodium sulfate and concentrated in vacuo. The product is caused to crystallize from the diisopropyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]([CH2:14][N:15]([CH3:17])[CH3:16])=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:24][CH3:25])[CH:10]=2)[C:5]1=[O:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(Cl)Cl>CCOCC>[CH3:16][N:15]([CH2:14][C:13]1[N:4]([CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:5](=[O:26])[C:6]2[C:11]([C:12]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:10][C:9]([O:24][CH3:25])=[CH:8][CH:7]=2)[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(=O)n(CCN)c(CN(C)C)c(-c3ccccc3)c2c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)n(CCNS(C)(=O)=O)c(CN(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.5 %

Procedure:
A solution of 116 (50 mg, 0.118 mmol), triethylamine (66 μL, 0.472 mmol), methanesulfonyl chloride (12 μL, 0.153 mmol) and methylene chloride (250 μL) were combined under Ar and stirred at room temperature 24 h. Added methylene chloride and washed the contents of the reaction flask with sat. sodium bicarbonate. Dried the organic layer with sodium sulfate (anh.), filtered then rotary evaporated the filtrate. Trituration of the resulting solid with ether gave 117 as a white solid (35 mg, 0.082 mmol, 69.1%).