Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([NH2:39])=[CH:33][C:32]=3[Cl:40])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]([C:43]1[N:44]=[CH:45][C:46]([NH:49][C:50](=O)[O:51]C2C=CC=CC=2)=[N:47][CH:48]=1)#[N:42]>CN(C=O)C.O>[C:25]([O:24][C:22]([N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([NH:39][C:50]([NH:49][C:46]2[CH:45]=[N:44][C:43]([C:41]#[N:42])=[CH:48][N:47]=2)=[O:51])=[CH:33][C:32]=1[Cl:40])=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1N
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A stirred solution of tert-butyl-4-(4-(((4-amino-2-chloro-5-methoxyphenethyl)(tert-butoxycarbonyl)amino)methyl)phenyl)piperazine-1-carboxylate (0.46 g, 0.800 mmol) and phenyl 5-cyanopyrazin-2-ylcarbamate (0.153 g, 0.64 mmol) in DMF (18 mL) was heated to 100° C. for 1.5 hours. The mixture was allowed to cool to room temperature, diluted with water (40 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (3×15 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified with column chromatography on neutral silica gel using 1.5% methanol in DCM to give the title compound (0.25 g, 43%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([C:13](OC)=[O:14])[N:10]=[CH:9][C:8]=2[N:17]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9][C:8]=2[N:17]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2sc(NC(C)C)nc2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc2cnc(CO)cc2s1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.3 %

Procedure:
To a solution of methyl 2-(isopropylamino)thiazolo[4,5-c]pyridine-6-carboxylate (0.1286 g, 0.51 mmol, 1.0 eq.) in THF (1.3 mL) under nitrogen at 0° C. was added LAH (1M, THF; 0.8 mL, 0.8 mmol, 1.6 eq.). After 1.25 h, ice and EtOAc were added, the cold bath was removed, and the solution was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (2-(isopropylamino)thiazolo[4,5-c]pyridin-6-yl)methanol as a light yellow solid (0.1063 g, 93% yield).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)#[C-:2].[O:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].N1CCNCC1>O1CCCC1>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:1]=[CH:2][O:22][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][CH:10]=1)#[N:9]
Reactant: [C-]#[N+]C(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=O
Agent: C1CNCCN1
Solvent: C1CCOC1
Product: CCOC(=O)c1ocnc1-c1ccc(C#N)cc1
Yield: 49 %

Procedure:
A solution of 4-(isocyano(tosyl)methyl)benzonitrile (1 g, 3.37 mmol, 1.00 equiv), ethyl 2-oxoacetate (1 g, 4.90 mmol, 1.45 equiv) and piperazine (500 mg, 5.80 mmol, 1.72 equiv) in tetrahydrofuran (20 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to afford 0.4 g (49%) of ethyl 4-(4-cyanophenyl)oxazole-5-carboxylate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 8.27-8.24 (m, 2H), 8.07 (s, 1H), 7.76-7.73 (m, 2H), 4.47-4.36 (m, 2H), 1.43-1.33 (m, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([CH:32]=[O:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[CH:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:3]=2)[CH2:27][CH2:26]1)=[O:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: O=CN1CCCNCC1
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCCN(C=O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 1,4-diazepane-1-carbaldehyde (116 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (127.7 mg, 50%). 1H NMR (METHANOL-d4) δ: 8.12 (s, 1H), 7.89-7.99 (m, 3H), 7.63-7.69 (m, 2H), 7.34 (s, 1H), 6.24-6.29 (m, 1H), 4.43 (t, J=5.8 Hz, 1H), 4.32-4.37 (m, 1H), 4.09 (t, J=6.2 Hz, 1H), 3.98-4.04 (m, 1H), 3.78 (t, J=5.9 Hz, 2H), 3.60-3.71 (m, 2H), 2.13-2.22 (m, 1H), 2.06 (t, 1H), 1.56 (s, 6H). ESI-MS: m/z 423.1 (M+H)+.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.Cl[CH2:12][CH2:13][CH2:14][C:15]#[N:16]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]2[CH2:14][CH2:13][CH2:12][N:16]=2)=[CH:5][CH:4]=1
Reactant: N#CCCCCl
Reactant: Fc1ccc(CBr)cc1
Agent: [Mg]
Solvent: CCOCC
Product: Fc1ccc(CC2=NCCC2)cc1
Reaction time: 2 h
Yield: 37.6 %

Procedure:
Magnesium turnings (for Grignard, 6.4 g, 0.266 mol) are covered with a layer of 20 ml of a solution of 4-fluorobenzyl bromide (50 g, 0.265 mol) in abs. (absolute) diethyl ether (250 ml) in a 500 ml three-necked flask and the mixture is briefly heated until the reaction starts. The remaining volume of 4-fluorobenzyl bromide is added dropwise in the course of 30 min and at the same time the mixture is kept at a temperature of 40° C. for a further 2 h in an oil bath. A solution of 4-chlorobutyronitrile (13.6 g, 0.132 mol) in diethyl ether (50 ml) is added dropwise in the course of 30 min to the still warm, freshly prepared Gringnard solution. The largest part of the ether (200 ml) is distilled off over a bridge and replaced by abs. toluene (250 ml). Diethyl ether is driven off until a boiling temperature of 95° C. is achieved in the bottom. The mixture is stirred at this temperature for a further 2 h and then allowed to stand at RT overnight. The organic phase is transferred to a separating funnel and hydrolysed and extracted with 10% strength HCl (3×100 ml each). The toluene phase is discarded, and the HCl-acidic aqueous phase is again washed with toluene (100 ml) and then maintained at pH 10 using conc. NaOH (32% strength). The pyrroline base depositing is taken up with diethyl ether (100 ml) in the separating funnel. After separating the ether phase, the mixture is again extracted with ether (2×50 ml), and the combined ether phases are dried over K2CO3 sicc. and concentrated. 8.8 g of 2-(4-fluorobenzyl)-1-pyrroline (37.8% based on chloronitrile) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[NH4+].[Cl-].C(Cl)Cl>COCCOC.[Zn]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:10])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methanesulfonic acid (S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentyl ester (250 mg, 0.380 mmol) under nitrogen atmosphere in DME (4 mL) were added successively sodium iodide (569 mg, 3.80 mmol) and zinc powder (248 mg, 3.80 mmol). The dark mixture was stirred at RT overnight. After completion of the reaction a saturated aqueous solution of NH4Cl (3 mL) was slowly added, followed by CH2Cl2 (3 mL) and the resulting biphasic mixture was stirred at RT for 30 min. Few crystals of Na2S were added and the mixture was further stirred for 1 h. The mixture was filtered through a pad of celite, the organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated. The crude mixture was purified by flash chromatography on silica gel (c-hexane to c-hexane/EtOAc 8:2) the desired material as a white powder. TLC, Rf (c-hexane/EtOAc 1:1): 0.50; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 6.60 (d, 1H), 3.61 (m, 1H), 1.42 (dd, 1H), 1.38 (s, 9H), 1.15 (dd, 1H), 1.00 (d, 3H), 0.88 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[NH2:8][C:6]1[N:7]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(NC2CCCCC2)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(NC3CCCCC3)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N4-cyclohexyl-2,4-pyrimidinediamine (0.75 g, 3.31 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.546 g, 3.31 mmol) followed by 1,4-dioxane (13.2 mL) and saturated aqueous NaHCO3 (3.3 mL). The resulting mixture was degassed with nitrogen for 5 minutes. Pd(Ph3P)4 (0.19 g, 0.165 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 16 hours at 95° C. The reaction was cooled to room temperature, decanted, and concentrated. The resulting orange oil was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. To the resulting yellow solid was added CH3CN (5 mL), and the mixture was sonicated. Filtration of the solid and washing with minimal CH3CN afforded the title compound (387 mg, 36%) as a light tan solid. LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C:13](O)=[O:14])=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C:13]([Cl:3])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(O)C(Oc1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(Oc1ccc(F)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.45 g (0.096 mol) of freshly distilled thionyl chloride are added to a suspension of 28.65 g (0.077 mol) of 2-(4-chloro-phenyl)-2-(4-fluoro-3-trifluoromethylphenoxy)-acetic acid in 35 ml of dry chloroform. The mixture is stirred for 30 minutes at ambient temperature and is then heated at the reflux temperature until all the acid has dissolved (about 6 hours). The solution is evaporated to dryness under reduced pressure and 2-(4-chlorophenyl)-2-(4-fluoro-3-trifluoromethyl-phenoxy)-acetyl chloride is obtained in the form of an oil, which is used without further purification for the next stage of the synthesis.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[NH:8]1[CH2:9][CH:10]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:11]1
Reactant: COc1ccccc1Oc1nccnc1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COc1ccccc1Oc1nccnc1C1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4 N HCl/MeOH (10 mL) was added compound (13) (80 mg, 0.22 mmol) at 0° C. The resulting mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to give (14) (65 mg, yield 100%), which was used for the next step without further purification. ESI-MS (M+1): 258 calc. for C14H15N3O2 257.
Reaction SMILES: Cl[CH2:2][C:3](=[N:13][NH:14][C:15]([NH2:17])=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[N:13][NH:14][C:15]([NH2:17])=[O:16])[CH2:2][P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COP(OC)OC
Reactant: NC(=O)NN=C(CCl)COc1ccc(Cl)cn1
Product: COP(=O)(CC(COc1ccc(Cl)cn1)=NNC(N)=O)OC
Reaction time: 2 h

Procedure:
1-Chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane (322 mg.) and trimethyl phosphite (720 mg.) were mixed and heated at 70°-100° C., with stirring, for 11/2 hours. The mixture was evaporated to dryness, finally under high vacuum, to give dimethyl 3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropylphosphonate, RF = 0.15 (5% v/v methanol in ethyl acetate), the required starting material. What we claim is:
Reaction SMILES: [C:1]1([C:7]2N=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([O:22][C:20]([C:19]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][O:10][CH:9]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: c1ccc(-c2cocn2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cocc1-c1ccccc1
Temperature: 220 °C
Yield: 78.4 %

Procedure:
Mix 4-Phenyl oxazole (3.33 g, 23.0 mmol) and ethyl phenylpropiolate (4.0 g, 23.0 mmol) in a sealed tube and heat at 220° C. for 20 hours. Perform flash-chromatography on silica gel eluting with 4:1 Hex/ethyl acetate to afford 3.9 g of 4-phenylfuran-3-carboxylic acid ethyl ester as a yellow oil. MS: m/e=217 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(=O)(=O)(O)O.[C:18]([O-])(O)=O.[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])O
Reactant: COc1cc(C(=O)O)ccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(OC)c1
Yield: 98 %

Procedure:
To a solution of 4-hydroxy-3-methoxybenzoic acid (0.1 g, 0.59 mmol) in 10 mL of methanol was added 0.3 mL of conc. sulfuric acid, and refluxed overnight. The pH of the solution was shifted into an alkaline zone by addition of 5% aqueous NaHCO3 solution. Following extraction with EtOAc, the extract was washed with a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford the compound 9 (0.107 g, 98%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:17]2[C:12](=[C:13]([C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=4)[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1.OB(O)[C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([OH:41])=[O:40]>COCCOC.C(O)C.O.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]>[Cl:33][C:25]1[CH:24]=[C:23]([C:21]2[O:20][N:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][N:9]=[C:8]4[C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([OH:41])=[O:40])[N:22]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)nccc34)no2)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(-c5cccc(C(=O)O)c5)nccc34)no2)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Sodium carbonate (85 mg) and PdCl2(dppf)2 (50 mg) were added sequentially to a suspension of 1-bromo-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D40; 180 mg) and 3-(dihydroxyboranyl)benzoic acid (Aldrich; 99 mg) in 1,2-dimethoxyethane (DME; 2 ml), ethanol (1 ml) and water (1 ml). The resulting suspension was heated to 80° C. and stirred for overnight. The solvent was evaporated in vacuo and the residue was purified by MDAP to give the title compound (20 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.90 (1H, m), 7.48 (1H, d), 7.73 (1H, t), 7.86 (1H, t), 7.95 (1H, dd), 8.19 (5H, m), 8.60 (1H, dd), 8.78 (2H, m), 13.17 (1H, br s).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([CH3:15])[CH:9]=[C:10]([CH2:11][C:12]([OH:14])=O)[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[C:24]([F:30])[CH:23]=[CH:22][C:21]=1[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.ClCCCl>[F:19][C:20]1[C:25]([C:26]([F:27])([F:28])[F:29])=[C:24]([F:30])[CH:23]=[CH:22][C:21]=1[C:31]1[N:32]=[C:33]([NH:36][C:12](=[O:14])[CH2:11][C:10]2[C:6]3[C:5](=[O:16])[N:4]([CH3:17])[C:3](=[O:18])[N:2]([CH3:1])[C:7]=3[N:8]([CH3:15])[CH:9]=2)[S:34][CH:35]=1
Reactant: Cn1c(=O)c2c(CC(=O)O)cn(C)c2n(C)c1=O
Reactant: Nc1nc(-c2ccc(F)c(C(F)(F)F)c2F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(F)c(C(F)(F)F)c4F)cs3)cn(C)c2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7 (100 mg, 0.398 mmol) with 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (111 mg, 0.398 mmol) in the presence of EDCI hydrochloride (91 mg, 0.475 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (4 mg, 0.032 mmol) in 1,2-dichloroethane (5 mL) to give 35 mg of the product as an off white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 3.21 (s, 3H), 3.73 (s, 3H), 3.81 (s, 3H), 3.95 (s, 2H), 6.35 (s, 1H), 7.51 (d, J=9.9 Hz, 1H), 8.32 (q, J=6.3 Hz, 1H), 12.61 (br s, 1H, exchangeable with D2O); ESI-MS (m/z) 514.09 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4](=O)[CH2:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)=O.O.[NH2:17][NH2:18]>C(O)C>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[NH:18][N:17]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:5]=1
Reactant: COC(OC)C(=O)CC(=O)c1nccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(OC)c1cc(-c2nccs2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred slurry of 4,4-dimethoxy-1-(1,3-thiazol-2-yl)butane-1,3-dione (8a) (1.55 g, 6.76 mmol) in ethanol (63 mL) was added dropwise hydrazine monohydrate (0.38 mL, 7.77 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo. A saturated solution of sodium hydrogenocarbonate (8 mL) was added to the residue and the aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid was triturated in diethyl ether and the precipitate was filtrated. The filtrate was concentrated and the treatment was repeated as much as necessary. The combined precipitates were dried in vacuo to provide 2-[5-(dimethoxymethyl)-1H-pyrazol-3-yl]-1,3-thiazole (8b) (714 mg, 3.17 mmol, 47%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([O:13]C)=[O:12].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([OH:13])=[O:12]
Reactant: C=C(Oc1ccccc1OC)C(=O)OC
Solvent: C1CCOC1
Solvent: O
Product: C=C(Oc1ccccc1OC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4 mmol) in tetrahydrofuran (30 mL) and water (30 mL was added lithium hydroxide monohydrate 0.17 g, 4.0 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of concentrated hydrochloric acid (final pH=2), and the product was extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.42 (ddd, 1H), 7.22 (dd, 1H), 7.10 (dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H), 4.51 (d, 1H), 3.64 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cnn(-c2ccc(C(=O)Cl)cc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
The 4-(4-methylpyrazol-1-yl)benzoyl chloride (0.72 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.60 g) and diisopropylethylamine (0.48 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.75 g), m.p. 179-181° C.; MS m/z: 369 (M+H)+.