Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[F:53][C:54]([F:65])([F:64])[O:55][C:56]1[CH:57]=[C:58]([NH2:63])[C:59]([NH2:62])=[CH:60][CH:61]=1>CN(C)C=O>[NH2:63][C:58]1[CH:57]=[C:56]([O:55][C:54]([F:53])([F:64])[F:65])[CH:61]=[CH:60][C:59]=1[NH:62][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:29]1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.2 g, 3.2 mmol) added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.25 g, 2.10 mmol) and N,N-Diisopropylethylamine (1.2 mL, 6.9 mmol) and 4-(trifluoromethoxy)benzene-1,2-diamine (0.48 g, 2.5 mmol) in N,N-Dimethylformamide (10 mL). The mixture was stirred overnight at RT, partially concentrated to ca. 2 rats and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to give the desired compound (2 g) as an oil.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].[C:18](#[N:20])[CH3:19]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]([OH:14])[CH2:19][C:18]#[N:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CC#N
Reactant: O=Cc1cccc(OCC2CC3CCC2C3)c1
Product: N#CCC(O)c1cccc(OCC2CC3CCC2C3)c1

Procedure:
Addition of acetonitrile to 3-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzaldehyde following the procedure given for Example 4 gave 3-(3-(bicyclo[2.2.1]heptan-2-ylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (1.09 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.19-7.24 (m, 1H), 6.90-6.97 (m, 2H), 6.77-6.83 (m, 1H), 5.88 (d, J=4.5 Hz, 1H), 4.80-4.85 (m, 1H), 3.91 (dd, J=7.0, 9.8 Hz, 1H), 3.78-3.84 (m, 1H), 3.54-3.61 (m, 1H), 2.74-2.89 (m, 2H), 2.15-2.28 (m, 3H), 1.68-1.75 (m, 1H), 1.40-1.51 (m, 2H), 1.24-1.38 (m, 3H), 0.70-0.75 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[CH2:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)=[CH:19][C:14]=2[CH2:13][CH2:12]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2ccc3c(c2)CCO3)cc1F
Yield: 76.7 %

Procedure:
The title compound (182 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and 2,3-dihydrobenzofuran-5-ylboronic acid (204 mg, 1.25 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.46 (s, 1H), 7.30 (dd, J 1.8, 8.3, 1H), 7.16 (dd, J 2.1, 8.2, 2H), 6.75 (d, J 8.3, 1H), 5.18 (s, 2H), 4.52 (t, J 8.7, 2H), 3.18 (t, J 8.5, 2H).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH2:35][CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:38]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>CC#N>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:38])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH2:35][CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CCC2)[nH]1
Agent: Cl
Solvent: CC#N
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile (compound 215) and using compound 11.2 HCl salt in place of compound 1.5. m/z (ES+) 502 [M+H]+, 543 [M+CH3CN+H]+. 1H-NMR (300 MHz, CD3OD): δ 7.73 (d, 2H), 7.64-7.58 (m, 2H), 7.39-7.26 (m, 2H), 4.89-4.82 (m, 1H), 4.35 (q, 2H), 4.10-3.95 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.27 (m, 1H), 2.75-2.65 (m, 2H), 2.22-1.86 (m, 10H), 1.41 (t, 3H), 1.35-1.20 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39]>>[CH3:37][S:38]([CH2:41][CH2:42][NH:43][CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)CCN
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CNCCS(C)(=O)=O)cc34)cc2C)cn1
Yield: 28.4 %

Procedure:
The procedure of Example 62 was repeated except for using 0.09 g of the compound obtained in Example 67 and 0.11 g of 2-methanesulfonyl-ethylamine instead of the compound obtained in Example 61 to obtain the title compound (0.03 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.Br[C:14]#[C:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:14]([O:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[N:3][C:2]=2[Cl:1])[C:15]#[C:16][CH3:17]
Reactant: Oc1cnc2c(Cl)nccc2c1
Reactant: CCC#CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#CCOc1cnc2c(Cl)nccc2c1
Temperature: 50 °C
Yield: 69.1 %

Procedure:
To a solution of 8-chloro-1,7-naphthyridin-3-ol (618 mg, 3.42 mmol) in DMF (11 ml) were added bromobutyne (882 mg, 6.67 mmol), cesium carbonate (3233 mg, 9.92 mmol). The reaction mixture was heated at 50° C. for 0.5 h. It was quenched with water, and light brown precipitate was formed. It was then collected by Buchner funnel to yield 3-(but-2-yn-1-yloxy)-8-chloro-1,7-naphthyridine (550 mg, 74% yield) as light brown solid. MS m/z: 233.1 [M+H].
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>CO>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCc1ccncc1
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCc3ccncc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (220 mg, 0.528 mmol) obtained in Example 54 and 4-(2-aminoethyl)pyridine (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Water was added to the residue thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride=1:30 eluate was concentrated under reduced pressure to give the title compound (114 mg, 0.227 mmol, 43%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: CN(Cc1ccc(Cl)cc1C(=O)O)c1ccc(Cl)cn1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2CN(C)c2ccc(Cl)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-chloropyridin-2-yl)(methyl)amino]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])O>CS(C)=O>[CH3:34][O:35][C:36](=[O:40])[C@H:37]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:16])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)[CH3:39]
Reactant: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reactant: COC(=O)[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 24 g (0.1 mol) of 4-(5-chloro-3-fluoropyridin-2-yloxy)-phenol in 80 ml of dimethylsulfoxide is added dropwise to a stirred solution of 13.8 g (0.1 mol) of potassium carbonate in 50 ml of dimethylsulfoxide. When everything is added, the mixture is stirred for 2 hours at room temperature and then 25.8 g (0.1 mol) of (S)(-)-lactic acid-methylester tosylate is added dropwise over 30 minutes. The mixture is heated to 60° and stirred at that temperature for 20 hours, then poured onto ice/water and the organic material is extracted three times with ether. The ether-layer is washed with water and saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The residue is passed for purification through a silicagel column with a hexane/ethyl acetate 3:1 solvent. After distillation of the solvent, 26 g of a clear oil of the above ester is obtained ([α]D20 =+38.8±0.5° 2% in acetone).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:34]=[N:35][N:36]([CH:38]5[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]5)[CH:37]=4)=[CH:29][N:28]=3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:17]1.CCN(C(C)C)C(C)C.[O:53]1[CH2:56][C:55](=O)[CH2:54]1>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3[N:28]=[CH:29][C:30]([C:33]4[CH:34]=[N:35][N:36]([CH:38]5[CH2:43][CH2:42][N:41]([CH:55]6[CH2:56][O:53][CH2:54]6)[CH2:40][CH2:39]5)[CH:37]=4)=[CH:31][N:32]=3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:17]1
Reactant: O=C1COC1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C6COC6)CC5)c4)cn3)c2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Sodium triacetoxyborohydride (0.13 g; 0.62 mmol; 2.0 eq.) was slowly added to a solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidine (example 1,200 mg; 0.31 mmol; 1.0 eq.), DIEA (53 μl; 0.31 mmol; 1.0 eq.) and 3-oxetanone (39 μl; 0.62 mmol; 2.0 eq.) in DCE (4 mL). The reaction mixture was then stirred at 50° C. for 3 h. It was then quenched by addition of water. Aqueous phase was basified to pH 12 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige powder (100 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.59-8.50 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.18-8.11 (m, 1H), 7.96-7.89 (m, 1H), 7.77-7.66 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 4.23 (s, 1H), 3.90 (s, 3H), 3.51-3.40 (m, 1H), 2.87-2.73 (m, 2H), 2.17-1.90 (m, 6H). HPLC (Condition A): Rt 2.49 min (purity 97.2%). MS (ESI+): 442.5.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[O:19]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH2:30][CH:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1ccc(OC2CCNC2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(Oc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxypyrrolidine hydrochloride (28 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid was triturated in methanol, filtered, washed with methanol, acetone and diethyl ether then dried to give the title compound (30 mg, 68%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][NH:3]1.[H-].[Na+].[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH2:29]Br)=[N:26][C:25]=2[CH:31]=1.Cl>CN(C)C=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH2:29][N:3]3[C:2](=[O:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4]3)=[N:26][C:25]=2[CH:31]=1
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: BrCc1nc2cc(Br)ccc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(Cc2nc3cc(Br)ccc3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 4-oxo-3H-phthalazin-1-ylacetate (11.6 g.) and sodium hydride (288 g; 50% w/w dispersion in mineral oil) in dimethylformamide (150 ml) was added 5-bromo-2-bromomethylbenzothiazole (16.8 g) and the resulting mixture stirred at room temperature for 1 hour. This reaction mixture was poured over ice-water (500 ml.); sufficient 10% HCl was added to adjust the pH to about 4.0 and the precipitated crude solid was collected. This was chromatographed over silica gel to obtain the product (yield: 5.6 g; m.p. 160°-161° C.).
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.CCN(CC)CC.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][NH:29][CH2:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: C=C1Sc2ccccc2NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2SC1CNOCc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 2-methylene-4H-benzo[1,4]thiazin-3-one (5.14 mmol) in 10 mL of anhydrous DMF, Et3N (25.7 mmol) is added followed by O-benzylhydroxylamine hydrochloride (25.7 mmol). The mixture is stirred at 100° C. for 12 hours and then the solvent is evaporated. The crude is purified by column chromatography (hexane/EtOAc) to give 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one. Yield 58%. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.13 (m, 9H), 6.1 (bs, 1H), 4.64 (s, 2H), 3.86 (m, 1H), 3.3 (m, 1H), 2.9 (m, 1H). MS: (ES+): 301.2 [M+1].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:30])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28]C)=[O:27])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:30])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)N2CCC(C(=O)O)CC2)CC1
Yield: 95.6 %

Procedure:
To a stirred solution of methyl 1-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}piperidine-4-carboxylate (Example 88, 0.159 g, 0.383 mmol) in THF (3 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (3 mL, 3 mmol). After 2 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide 1-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}piperidine-4-carboxylic acid (0.147 g, 96%) as a white amorphous.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl([O-])=[O:18].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)cc1OC1C=CCC1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1C=CCC1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) in t-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwise with an aqueous solution (150 mL) containing sodium chlorite (80% technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), and left to stand overnight. The resulting mixture is extracted with dichloromethane (2×250 mL), and the combined organic layers are dried over sodium sulfate, the solvent is removed under reduced pressure, and the resulting residue is recrystallized from ethyl acetate, to give 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of a colorless solid. m.p. 160-163° C. [Elemental analysis: C,66.4; H,6.0%; calculated: C,66.7; H,6.0%].
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[N:16][C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[S:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: S=c1c(Br)coc2ccccc12
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2nc[nH]n2)oc2ccccc12
Temperature: 0 °C
Yield: 80.5 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, 1,2,4-triazole (138 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and recrystallized from benzene/hexane to give the titled compound (92.6 mg; yield=80.8%) as white needle crystals. Melting point: 232° C. 1H-NMR(DMSO-d6, δ ppm): 7.70 (s, H3), 8.35 (dd, H5), 7.66 (t, H6), 7.80 (t, H7), 7.99 (d, H8), 8.40 (s, H3'), 9.63 (s, H5').
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.CCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncc(C(=O)O)c(O)c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCC
Product: COc1ccc2nccc(O)c2c1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
A suspension of 53.5 g of 4-hydroxy-6-methoxy-quinoline-3-carboxylic acid in 1000 cm3 of diphenyl ether was heated with stirring, at a temperature of between 250° C. and 260° C., for 2 hours 45 minutes. The reaction mixture was cooled to about 20° C. After stirring for 16 hours at this temperature, the mixture was poured with stirring into 1 liter of pentane and then filtered. The cake obtained was washed with 3 times 100 cm3 of pentane and then with 3 times 100 cm3 of diisopropyl ether. After drying in air, 37 g of 4-hydroxy-6-methoxyquinoline were obtained in the form of a beige-colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (0.8 g, 3.0 mmol), N-bromosuccinimide (1.6 g, 9.0 mmol) and azodiisobutyronitrile (16 mg, 0.09 mmol) in 1,2-dichloroethane (20 mL) was stirred at 90° C. for 16 hrs. The reaction was quenched with Na2SO3 (10 mL, 10%), extracted with 1,2-dichloroethane (20 mL×3), dried over anhydrous Na2SO4, concentrated and the residue was used in next step without further purification (1.1 g, crude). LCMS (ESI) m/z: 342.0 [M+H]+.