Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1c(OCc2ccccc2)cccn1CS(=O)(=O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Cn3cccc(OCc4ccccc4)c3=O)cc2)cc1

Procedure:
The titled compound was prepared from 3-benzyloxy-1-(4-bromo-benzenesulfonylmethyl)-1H-pyridin-2-one (obtained from Example 65) and 4-methoxy-phenylboronic acid according to the procedure described in Example 52 Step A. MS: 462 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.O[C@H:15]([C@H:17]1[CH2:21][N:20]([C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:23])[C:19](=[O:32])[CH2:18]1)[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:13][C@@H:15]([C@@H:17]2[CH2:18][C:19](=[O:32])[N:20]([C@@H:22]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH3:23])[CH2:21]2)[CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: N#Cc1cnn2cc(Cl)nc(O)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
6-chloro-4-hydroxypyrazolo[1,5-a]pyrazine-3-carbonitrile (122 mg, 0.627 mmol) was dissolved in THF (1 mL). (R)-4-((8)-1-hydroxyethyl)-1-4R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.05 (255 mg, 0.97 mmol) and PPh3 (255 mg, 0.97 mmol) were added followed by diethyl azodicarboxylate (0.16 mL, 1.0 mmol). The resulting mixture was heated to 45° C. and was stirred for 45 min. The mixture was then cooled to r.t., let stand overnight, and concentrated onto 2 g silica gel. Purification by silica gel chromatography (25-100% EtOAc in hexanes) provided 6-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile (5.64). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClN5O3: 440.1; found: 439.8.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[CH:6]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)([OH:3])=O.Cl.[C:23]1([N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]1([N:29]([NH:30][C:1]([CH2:4]/[CH:5]=[C:6]2\[CH2:7][CH2:8][CH2:9][C:10]3[C:15]\2=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:3])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1CCCC2/C=C/C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1cccc2c1CCC/C2=C\CC(=O)NN(c1ccccc1)c1ccccc1
Yield: 70.8 %

Procedure:
A solution of the carboxylic acid (prepared in reference example 5, 150 mg), 2-chloro-N-methylpyridinum iodide (197 mg). 1,1-diphenylhydrazine hydrochloride (147 mg) and triethylamine (0.216 ml) in methylene chloride (6 ml) was stirred overnight at room temperature. The mixture was poured into 1N hydrochloric acid, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was crystallized from crystallized ethyl acetate to give the title compound (as pale yellow powder; 167 mg) having the following physical data.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[CH:13]2)=[CH:8][C:7]=1[Cl:21])C.[Li+].[OH-].Cl>C1COCC1>[Cl:21][C:7]1[CH:8]=[C:9]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[CH:13]2)[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.325 g (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid ethyl ester and 2 ml of 0.5 N aqueous solution of LiOH in 2 ml of THF is stirred for 1 hour at 40 C. The mixture obtained is allowed to cool to rt and an acidic pH is adjusted by addition of 0.5 N HCl aqueous solution. A precipitate forms and is collected by vacuum filtration. (2-Chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid is obtained in the form of a solid. ES-MS: 288.0 [M+H]+; single peak at tR=3.00 min (System 1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[CH:7][N:6]([C:9]3[CH:32]=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:33])[CH2:11][N:10]=3)=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][CH:16]=5)[N:5]=2)[CH2:3][CH2:2]1.Br[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([C:4]2[N:8]=[CH:7][N:6]([C:9]3[CH:32]=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:33])[CH2:11][N:10]=3)=[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)[CH:18]=[CH:17][CH:16]=5)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2cccc3c2CCN2C(=O)CN=C(n4cnc(C5CC5)n4)C=C32)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(-c4ccc(F)cn4)c3CCN12
Temperature: 80 °C
Yield: 21.8 %

Procedure:
Example 133. A suspension of 2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (95 mg, 0.21 mmol), 2-bromo-5-fluoropyridine (79 mg, 0.45 mmol) and PdCl2(dppf)*CH2Cl2 (17 mg, 0.021 mmol) in DME (2.1 mL) was treated with a 2M aq. solution of Na2CO3 (0.5 mL, 1.06 mmol). The mixture was heated to 80° C. for 13 h, the allowed to cool to RT and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (Column: Silica 5 μm, 250×30 mm, Princeton; isocratic 5% MeOH/CO2 for 20 min; flow 100 mL/min) gave the title compound (19 mg). UPLC-MS: MS 415.2 (M+H+); UPLC rt 1.02 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.71-0.90 (m, 2H); 0.90-1.00 (m, 2H); 1.91-2.09 (m, 1H); 2.91-3.09 (m, 2H); 3.73 (t, J=6.24 Hz, 2H); 4.33 (s, 2H); 7.06 (s, 1H); 7.40-7.56 (m, 1H); 7.66 (d, J=7.70 Hz, 1H); 7.73 (dd, J=8.71, 4.68 Hz, 1H); 7.83-8.01 (m, 2H); 8.73 (d, J=2.75 Hz, 1H); 9.03 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][N:6]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:37])[F:38])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCN5CCNCC5)cc4)CC3)nn12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
A solution of methanesulfonyl chloride (0.034 mL, 0.44 mmol) in DCM (0.5 mL) was added dropwise to 6-[4-[4-(2-piperazin-1-ylethoxy)phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 727) (175 mg, 0.37 mmol) and triethylamine (0.103 mL, 0.74 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge then the organic layer evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[4-[2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (122 mg, 60%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NCc1ccc(F)cc1
Yield: 46.7 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-leucine methyl ester hydrochloride (2 gm, 11.0 mmol), THF (30 mL), MgSO4 (2.24 gm, 18.7 mmol), 4-fluorobenzaldehyde (2.37 mL, 22.0 mmol), Et3N (1.53 mL, 11.0 mmol), sodium borohydride (833 mg, 22.0 mmol), and methanol (40 mL) to give 11e (1.3 gm, 47%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.84 (3H, d, J=6.59 Hz), 0.9 (3H, d, J=6.59 Hz), 1.47-1.58 (2H, m), 1.76 (1H, heptet), 3.3 (1H, t, J=7.32 Hz), 3.63 (1H, d, J=12.93 Hz), 3.72 (3H, s), 3.81 (1H, d, J=12.93 Hz), 6.99 (2H, t, J=8.78 Hz), 7.32 (2H, dd, J=5.37, 8.3 Hz). ESI-MS: 276.2 (M+23).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)([CH:10]([CH3:12])[CH3:11])[C:6]([O:8][CH3:9])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:5]([C:6]([O:8][CH3:9])=[O:7])([CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)C(CCCCl)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C(=O)OC)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1e with 2c produced 3w. MS found M+H=500. The oxalate salt of 3w was recrystallized from ethyl acetate; mp 121-123° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]3[N:12]=[N:13][N:14]=[C:9]3[S:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1N2[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3CSC2=NN=1.CC1C2N3C=NN=C3SCC=2C=CC=1.CC1N2C3C=CC(C)=CC=3CSC2=NN=1.ClC1C2N3C=NN=C3SCC=2C=CC=1.CC1C2N3N=NN=C3SCC=2C=CC=1.ClC1C=CC2N3C(C)=NN=C3SC(C3C=CC=CC=3)C=2C=1.CC1N2C3C=CC=CC=3CSC2=NN=1>>[C:20]1([CH:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:11]=3[N:10]3[N:12]=[N:13][N:14]=[C:9]3[S:8]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:21]=1
Reactant: Clc1cccc2c1-n1nnnc1SC2
Reactant: c1ccc2c(c1)CSc1nnnn1-2
Agent: Cc1ccc2c(c1)CSc1nnc(C)n1-2
Agent: Cc1cccc2c1-n1cnnc1SC2
Agent: Cc1cccc2c1-n1nnnc1SC2
Product: c1ccc(C2Sc3nnnn3-c3ccccc32)cc1

Procedure:
The preferred compounds are 9-chloro-5H-tetrazolo-[1,5-a][3,1]benzothiazine, 5H-tetrazolo[1,5-a][3,1]benzothiazine, 9-methyl-5-H-s-triazolo[4,3-a][3,1]benzothiazine, 1,7-dimethyl-5H-s-triazolo[4,3-a][3,1]benzothiazine, 9-chloro-5H-s-triazolo[4,3-a][3,1]benzothiazine, 9-methyl-5H-tetrazolo[1,5-a][3,1]benzothiazine, 7-chloro-1-methyl-5-phenyl-5H-s-triazolo[4,3-a][3,1]benzothiazine and 1-methyl-5H-s-triazolo[4,3-a][3,1]benzothiazine.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:34])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:31][CH2:32][CH3:33])=[C:20]([S:23]([NH:26][C:27]([NH:29][CH3:30])=S)(=[O:25])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[OH:35]O>>[CH2:1]([C:3]1[C:4](=[O:34])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:31][CH2:32][CH3:33])=[C:20]([S:23]([NH:26][C:27]([NH:29][CH3:30])=[O:35])(=[O:25])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: OO
Reactant: CCOc1cc2c(cc1S(=O)(=O)NC(=S)NC)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=O)NC)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminocarbonylaminosulfonyl)-7-ethoxychroman ##STR56## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminocarbonylaminosulfonyl)-7-ethoxychroman is prepared analogously to Example 18 by oxidation of 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman using hydrogen peroxide solution. Melting point: 187°-188° C.
Reaction SMILES: [N:1]1[NH:2][C:3](=O)[C:4](=O)[CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.P(Cl)(Cl)(Cl)=O.N1C(=O)N=C2C=CC=CC=12>>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=c1cc2ccccc2n[nH]c1=O
Agent: O=C1N=c2ccccc2=N1
Solvent: O=P(Cl)(Cl)Cl
Product: C1=Cc2ccccc2NN=C1

Procedure:
The title compound was prepared according to the procedures shown in the scheme below. Compound 5-chloroisatoic anhydride (A) was reacted with (R)-2-chlorophenylalanine to provide benzodiazepine-dione B based on procedures described in, for instance, Example 2. Reaction of benzodiazepine-dione B with para-methoxybenzyl chloride in the presence of base, according to procedures described in, for instance, Example 3, provided PMB-protected benzodiazepine-dione C. Conversion of benzodiazepine-dione C to imidoyl chloride D was accomplished using phosphorous oxychloride, based on procedures described in, for instance, Example 4. The benzimidazolone substituent was installed using Suzuki coupling, based on procedures described in, for instance, Example 7, to provide benzodiazepine E. Removal of the PMB protecting group was accomplished by reacting benzodiazepine E with AlCl3, based on procedures described in, for instance, Example 8, to provide benzodiazepine F.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][N:3]=1.NN>C(Cl)Cl.CCO>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[N:3][N:4]=1
Reactant: Cc1nnc(CN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2-[(3-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (2.00 g, 7.40 mmol) in DCM (10.0 mL) and EtOH (10.0 mL) was charged with hydrazine (0.58 mL, 18.5 mmol) and stirred at rt for 8 h, then heated to 45° C. for an additional 16 h. The reaction was charged with an additional 0.5 equiv of hydrazine (0.116 mL, 3.70 mmol) and heated to 45° C. for 4 h. The reaction mixture was allowed to cool to rt then filtered through a fritted funnel and the cake was washed with 2 portions of cold 1:1 EtOH/DCM (75 mL) and the filtrate was concentrated resulting in 622 mg of a pale yellow solid which was taken on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H), 3.72 (s, 2H); MS (ES+): m/z 141.06 [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:14]2[C:13](=[S:31])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=S)c12
Temperature: 25 °C
Yield: 145.1 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (13.94 g, 50.5 mmol) and Lawesson's Reagent (12.5 g, 30.9 mmol) in toluene (750 mL) was heated under reflux for 1 hour. The reaction solution was cooled to room temperature, and the resulting crude crystals were collected by filtration. The crystals were recrystallized from ethyl acetate to give the title compound (13.11 g, 89% yield).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[OH-].[K+].Br.Br[CH2:15][CH2:16][NH2:17]>C(O)C>[CH3:9][C:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][CH2:15][CH2:16][N:17]=1
Reactant: NCCBr
Reactant: CC(=O)c1ccccc1S
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1=NCCSc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
To a solution of 1-(2-sulfanylphenyl)ethanone (6.40 g, 42.05 mmol) in ethanol (80 mL) was added an aqueous solution of potassium hydroxide (7.08 g, 126.14 mmol in 30 mL of water) and an aqueous solution of 2-bromoethanamine hydrobromide (9.48 g, 46.25 mmol in 30 mL of water). After being stirred at room temperature for 6 hours, the reaction mixture was concentrated in vacuo to remove most of ethanol and extracted with dichloromethane (60 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography to give 5.92 g of 5-methyl-2,3-dihydro-1,4-benzothiazepine.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:19]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCNC(=O)OC(C)(C)C)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCN)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A solution of tert-butyl 4-(2,6,7-trimethyl4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamate (6.70 g, 15.8 mmol) in dichloromethane (50 mL) was slowly added to a chilled (0° C.) mixture of trifluoroacetic acid (60 mL) and dichloromethane (100 mL). The reaction mixture was allowed to warm to ambient temperature and then left overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and the solution was made basic (pH 14) with 5% aqueous sodium hydroxide. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 4.50 g of 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylamine as a brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=2)[CH2:9]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[F:33][CH:31]([F:32])[O:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2ccccc2CCc2cccc(OC(F)F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)Oc1cccc(CCc2ccccc2OCC2CCCNC2)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
0.858 g of 1-t-butoxycarbonyl-3-{2-[2-(3-difluoromethoxyphenyl) ethyl]phenoxymethyl}piperidine [prepared as described in step (a) above] was dissolved in 8 ml of dioxane. 8 ml of a 4N solution of hydrogen chloride in dioxane was then added to the solution, whilst ice-cooling, and the solution was allowed to stand at room temperature for 1 hour. At the end of this time, it was concentrated by distillation under reduced pressure, and the resulting oil was dissolved in 50 ml of ethyl acetate. The solution was allowed to stand at room temperature, and the crystals which precipitated were collected by filtration and dried in vacuo, to give 0.680 g (yield 92%) of the title compound as colorless crystals, melting at 153°-154° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:8])=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:22]2[O:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:18][C:19]1[C:20]([C:2]2[S:6][C:5]([C:7]([NH:9][C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[F:17])=[O:8])=[CH:4][CH:3]=2)=[CH:21][C:22]2[O:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1
Reactant: O=C(Nc1c(F)cccc1F)c1ccc(Br)s1
Reactant: Cc1nc2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2cc(Cl)c(-c3ccc(C(=O)Nc4c(F)cccc4F)s3)cc2o1
Temperature: 110 °C
Yield: 69.2 %

Procedure:
A mixture of (5-bromo(2-thienyl))-N-(2,6-difluorophenyl)carboxamide (25 mg, 0.08 mmol), 2-(5-chloro-2-methylbenzoxazol-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) (29 mg, 0.1 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 12 mg) and sodium carbonate (32 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash column chromatography to furnish 22.4 mg of [5-(5-chloro-2-methylbenzoxazol-6-yl)(2-thienyl)]-N-(2,6-difluorophenyl)carboxamide (11) as yellow solid (yield: 55.3%; purity>95%). LC-MS: calcd. for C19H11ClF2N2O2S: 405 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([O:8][CH2:9][C:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:11]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=[C:10]([CH2:9][O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:31])=[O:3])[C:14]=2[CH3:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)OCc1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
To a solution of 735 mg of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 10 ml THF was added a solution of 51 mg of LiOH in 1 ml water at room temperature. After 16 h the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 677 mg.