Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([Mg]Cl)([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C1COCC1.[Cu]I>[C:10]([C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(Cl)nc(Cl)n1
Temperature: -10 °C

Procedure:
Dissolved cyanuric chloride (4.2 g, 22.9 mmol) and CuI (0.22 g, 1.1 mmol) in anhydrous THF (12 mL) and cooled to −10° C. under N2. Added tert-butylmagnesium chloride (1.0M in THF, 25.4 mL) slowly over 20 min. Added saturated NH4Cl (5 mL) and warmed reaction to room temperature. Extracted mixture with CH2Cl2 (4×75 mL). Washed organic layer with water (35 mL) and saturated NaCl (35 mL) then dried (Na2SO4) and concentrated. Purified the product by filtration through a pad of silica gel eluting with CH2Cl2 to give the title compound (1.5 g) as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2.[CH3:16][S:17](Cl)(=[O:19])=[O:18].N1C=CC=CC=1.Cl>C(Cl)Cl.O>[CH3:16][S:17]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCc1ccc2sccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOCCc1ccc2sccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In 20 mL of methylene chloride is dissolved 2.10 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-ethanol. At an ice-cooled temperature, 1.63 g of methanesulfonyl chloride and 1.47 g of pyridine are added to the solution obtained above, and the mixture thus formed is stirred at the same temperature as above for 30 minutes and then at ambient temperature for 12 hours. Then, methylene chloride and water are added to the reaction mixture, pH is adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: n-hexane:ethyl acetate=4:1 to 2:1) to obtain 2.50 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-ethyl methanesulfonate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:5].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>ClCCl.O>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][O:1][CH2:2][CH2:3][N:4]([C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:5]
Reactant: CCOC(=O)C1=C(N(C)CCO)OCC1=O
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=C(N(C)CCOCOCCOC)OCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-[(2-hydroxyethyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.5 g, 2.18 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step in dichloromethane (6.0 mL) that cooled with ice bath, diisopropylethylamine (0.75 mL, 4.36 mmol) then 2-methoxyethoxymethyl chloride (0.5 mL, 4.36 mmol) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate for 3 times. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford ethyl 2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.31 g, y. 46%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1([CH3:45])[CH3:44])=O)(C)(C)C>>[CH3:44][C:39]1([CH3:45])[NH:38][CH2:43][CH2:42][N:41]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Product: CC1(C)CN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)CCN1

Procedure:
1-{2-[3-(3,3-Dimethyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,2-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=392.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](I)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[C:4]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[CH:3][C:2]([I:1])=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(I)cc(I)c2s1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(I)cc(-c3cccnc3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5,7-diiodo-benzothiazol-2-yl)-3-ethyl-urea (0.20 g, 0.42 mmol) in DMF (5 mL) was added pyridine 3-boronic acid (0.076 g, 0.63 mmol) and K3PO4 (0.133 g, 0.63 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.0044 g, 0.063 mmol). The reaction mixture was again degassed for half an hour and then heated at 120° C. for 1 h under nitrogen atmosphere. DMF was distilled off, added water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica (230-400 M) using DCM/Methanol (99:1) to provide 1-Ethyl-3-(5-iodo-7-pyridin-3-yl-benzothiazol-2-yl)-urea as an off white solid (0.025 g, 14%) and DCM/Methanol (98:2) to provide 1-Ethyl-3-(7-iodo-5-pyridin-3-yl-benzothiazol-2-yl)-urea as an off white solid (0.025 g, 14%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[NH:9][CH2:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(CCN)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)NCCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
2-(5-Methylfuran-2-yl)ethylamine (1.0 g) prepared in the step 2 and 2.2 mL of triethylamine were dissolved in 25 mL of methylene chloride, 0.87 g of ethyl chloroformate was slowly dropped thereinto under cooling with ice and the mixture was stirred at room temperature for 8 hours. To the reaction solution was added 200 mL of water followed by extracting with methylene chloride. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.61 g of the objective compound as yellow liquid.
Reaction SMILES: C(O)CCC.[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:20]([NH2:19])=[N:21][C:22]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([CH:7]4[O:6][CH2:10][CH2:9][CH2:8]4)=[O:12])[CH2:18][CH2:17]3)=[N:23][C:24]2=[CH:25][C:26]=1[O:32][CH3:33]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: O
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 111.7 %

Procedure:
To a solution of n-butanol (316 ml), water (24 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 9 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 10-12 hours. The crystals were collected by filtration, washed with n-BuOH and dried in vacuo at 40-50° C. to yield 40.1 g (94%) of Terazosin.HCl dihydrate. The product of this example was characterized by XRD and DSC melting point as shown in FIGS. 1 and 2 and in Table I as Trial H. This procedure was repeated in n-butanol using the water volumes indicated in Table I and yielding the results indicated for Trials G, I and J.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 95 °C
Yield: 48.3 %

Procedure:
A mixture of intermediate 59 (5.0 g, 0.0136 mol), benzylamine (4.5 mL, 0.0407 mol) and MeOH (1 mL) is heated at 95° C. for 2 days. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-50:50) gives 2.81 g of the product 77. 1H NMR (CDCl3) δ 7.55-7.25 (m, 6 H), 7.10-6.85 (m, 8 H), 6.85-6.70 (m, 2 H), 5.50-5.30 (m, 2 H), 4.80-4.55 (m, 2 H), 1.14 (s, 9 H)
Reaction SMILES: [C:1](N1C=CN=C1)#[N:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:16]1=2.O>CN(C)C(=O)C>[F:41][C:9]([F:8])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:13][N:14]([C:1]#[N:2])[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:16]1=2
Reactant: N#Cn1ccnc1
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Temperature: 100 °C

Procedure:
Add a solution of 1-cyanoimidazole in N,N-dimethylacetamide to a solution of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in N,N-dimethylacetamide at room temperature under nitrogen and heat the mixture to 100° C. Pour the cooled mixture into water and extract with methylene chloride. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel to afford the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[N:20]([C:24]([NH2:26])=[O:25])[CH2:19][CH2:18][CH2:17]4)[CH:11]=[N:12][CH:13]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].CO>[O:27]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[N:20]([C:24]([NH2:26])=[O:25])[CH2:19][CH2:18][CH2:17]4)[CH:11]=[N:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C4=CCS(=O)(=O)CC4)c3)cnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC(=O)N1CCCc2cc(-c3cncc(C4CCS(=O)(=O)CC4)c3)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To the mixture of 6-[5-(1,1-dioxo-1,2,3,6-tetrahydro-1lambda6-thiopyran-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (56 mg, 0.15 mmol) and 10% Pd/C (17 mg) is added 2 mL of MeOH under Ar. Then ammonium formate (140 mg, 2.20 mmol) is added and the mixture is stirred for 1 hr at 80° C. The mixture is filtered, concentrated and purified via Preparative HPLC (10%-80% CH3CN/H2O) to give 30.2 mg of the titled product.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:13]([NH:14][C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)=[O:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>C1COCC1>[NH2:3][C:4]1[C:13]([NH:14][C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)=[O:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(NC(=O)c2cnccn2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(NC(=O)c2cnccn2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
A mixture of aq NaOH (20 mL, 88.2 mmol) and methyl 2-amino-3-(pyrazine-2-carboxamido)benzoate 15 (1.2 g, 4.41 mmol) in THF (20 mL) was stirred at room temperature for 4 h. The volatiles were evaporated and the pH adjusted to 4 using aq HCl. The resulting precipitate was collected by filtration, rinsed with H2O and dried under vacuum to give 16 (750 mg, 66% yield).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([NH:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[O:21])[C:15]([CH2:16][CH2:17][CH2:18]O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]4[C:15]([CH2:16][CH2:17][CH2:18][N:22]([O:23][CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[C:20]4=[O:21])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(NOC1CCCCO1)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ncc3c(ccn3Cc3ccc(F)cc3)c2CCCN1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide (149 mg, 0.35 mmol) in THF (4 mL), was added PPh3 (110 mg, 0.42 mmol) and DIAD (85 mg, 0.42 mmol). The resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated. Purification by flash chromatography (Biotage) over silica gel (100% ethyl acetate) afforded the title product as brown oil (18.5 mg, 13% yield). LC-MS (APCl, M+H+): 410.1. HPLC: 96% purity.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([O:22][CH3:23])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([O:22][CH3:23])[CH:14]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1cc(F)ccc1B(O)O
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: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(F)cc2OC)oc1C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 4-fluoro-2-methoxyphenylboronic acid (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 51%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reaction time: 90 h
Yield: 67.3 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (5.11 g, 17.9 mmol), 2-piperidin-4-ylpropan-2-ol (3.08 g, 21.5 mmol) and 4 Å powdered molecular sieves (9 g) in DCE (85 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (7.61 g, 35.9 mmol). The reaction mixture was stirred for 90 h then filtered through celite, washing the celite bed with DCM. The organic phase was washed with brine and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 0-100%) affording 2-[1-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol as an orange solid (4.96 g, 67%). LCMS (Method A): RT 2.77 min [M+H]+ 412.2
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:22][CH:23]=1
Reactant: Fc1cc(F)cc(Oc2ccc(OCCCBr)cc2)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(F)cc(Oc2ccc(OCCCn3cccn3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (30 ml) and sodium hydride (60% oil suspension; 0.70 g), pyrazole (1.19 g) was added, and the resultant mixture was stirred for 30 minutes. A solution of 3-[4-(3,5-difluorophenoxy)phenoxy]propyl bromide (5.00 g) in anhydrous N,N-dimethylformamide (20 ml) was dropwise added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with a saturated aqueous ammonium chloride solution two times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily substance thus obtained was subjected to column chromatography to give 4.20 g of 1-{3-[4-(3,5-difluorophenoxy)phenoxy]propyl}pyrazole as a colorless oil. nD23.5 1.5746.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:21]([NH:28][C:29]([NH:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 150 °C

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 88 μmol) and 4-dimethylaminopyridine (5 mg, 40 μmol) in pyridine (0.5 mL) was treated with benzyl isocyanate (29 mg, 0.2 mmol) and heated in the microwave at 150° C. for 20 min. The reaction mixture was concentrated and purified by preparative LCMS to give the intermediate N-benzyl-N′-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}urea. This material was diluted with ethanol (1.5 mL), treated with 2.0 M sodium hydroxide in water (0.3 mL), and stirred for 30 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (11 mg, 28%). LCMS for C17H15BrFN6O3 (M+H)+: m/z=448.9, 451.0.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[NH:8]2)=[CH:4][C:3]=1[F:14].[H-].[Na+].I[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:13])[C:7]([CH3:11])([CH3:12])[N:8]2[CH3:18])=[CH:4][C:3]=1[F:14]
Reactant: CI
Reactant: CC1(C)Nc2cc(Br)c(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cc(Br)c(F)cc2C(=O)C1(C)C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a stirred solution of 6-bromo-5-fluoro-2,2-dimethylindolin-3-one (D90) (240 mg, 0.930 mmol) in DMF (3 mL) at 0° C. was added sodium hydride (55.8 mg, 1.395 mmol). After stirring for 10 min, iodomethane (0.116 mL, 1.860 mmol) was added to the mixture and the mixture was stirred for 30 min at 0° C. The reaction was quenched with addition of saturated NH4Cl (1 mL) and the mixture was poured into water (60 mL). The mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound (247.7 mg). LCMS (A): m/z (M+H)+ 272/274, C11H11BrFNO requires 271/273 (acidic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19](=O)[O:20]C4C=CC([N+]([O-])=O)=CC=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ncc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)N3CCN(C)CC3)ncc2c1
Temperature: 90 °C
Yield: 3.8 %

Procedure:
4-nitrophenyl 7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylcarbamate (0.156 g, 0.374 mmol) was dissolved in N,N-dimethylformamide (2.0 mL, 26 mmol) and 1-methyl-piperazine (0.20 mL, 1.8 mmol) was added. The reaction mixture was heated at 90° C. for 1 hour. The reaction mixture was then diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-20% methanol in dichloromethane with 2% triethylamine) followed by reverse phase HPLC and lyophilization to yield 5.4 mg (4%) of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)-4-methylpiperazine-1-carboxamide. LCMS (ESI): RT (min)=4.017, M+H=379.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.12 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.38 (s, 1H), 7.16 (t, J=8.3 Hz, 2H), 3.52 (s, 4H), 2.33 (s, 4H), 2.25 (s, 3H), 2.21 (s, 3H).