Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10](OCC)([O:14]CC)[O:11][CH2:12][CH3:13])[C:3]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CCO.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]([O:11][CH2:12][CH3:13])=[O:14])[C:3]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1(c2c(Cl)cccc2C#CC(OCC)(OCC)OCC)CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C#Cc1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
A mixture of ethyl 4-(2-chloro-6-(3,3,3-triethoxyprop-1-ynyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (2.42 g, 5.51 mmol) in 50 mL EtOH and 10 mL water was treated with 4-methylbenzenesulfonic acid hydrate (0.105 g, 0.551 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 100 mL EtOAc, washed with 20 mL saturated NaHCO3, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (20% EtOAc/hexane) to give 1.19 g pale yellow solid. MS m/e: (M+H)+ 365.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:21]([OH:22])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:5])[CH3:4].[CH2:23](Br)[CH:24]=[CH:25][CH3:26]>CN(C)C=O>[CH2:23]([O:22][C:21]1[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:8][C:9]2[O:19][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11][C:10]=2[CH:20]=1)[CH:24]=[CH:25][CH3:26]
Reactant: CC=CCBr
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Yield: 93 %

Procedure:
0.13 g of oily sodium hydride and 0.74 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-l′-cycloheptane synthesized in Example 7 were treated with 0.33 ml of crotyl bromide in dimethylformamide in the same manner as in Example 8-1) to give 0.82 g of a mixture of geometrical isomers of 5-(2-butenyloxy)-6-t-butyl-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10]Br)([O-:3])=[O:2].[CH3:15][N:16]1[C:21]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:19](=[O:28])[N:18]([CH3:29])[C:17]1=[O:30].C(N(CC)CC)C>O1CCOCC1>[CH3:15][N:16]1[C:21]([N:22]2[CH2:27][CH2:26][N:25]([CH2:10][CH2:9][CH2:8][O:7][C:6]3[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:24][CH2:23]2)=[CH:20][C:19](=[O:28])[N:18]([CH3:29])[C:17]1=[O:30]
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(N2CCN(CCCOc3cccc([N+](=O)[O-])c3)CC2)cc(=O)n(C)c1=O
Yield: 67 %

Procedure:
1.69 g of the above oily compound d, 1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound b) and 1 ml of triethylamine were heated under reflux in 20 ml of dioxane for 4 hours to carry out reaction. After completion of the reaction, insolubles were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Next, the resultant residue (concentrate) was dissolved in chloroform, and the resultant chloroform solution was washed with water. Afterward, the washed organic layer was dried over anhydrous magnesium sulfate and then treated with under reduced pressure to distill off the solvent. The residue was further purified through a silica gel column chromatography (chloroform/methanol=100/1 to 25/1 in volume ratio) and then recrystallized from ethanol. The resultant crystals were collected by filtration, washed, and then dried, thereby obtaining 1.35 g of 1,3-dimethyl-6-[4-(3-[3-nitrophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound c).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@H]2CCCC[C@@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)c(F)c2)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (40.5 mg, 0.0643 mmol) prepared in Example 171c, triethylsilane (0.055 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (6.0 mL) and 6 M hydrochloric acid (2.0 mL), to yield the title compound (28.0 mg, 99%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:25][CH2:24]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCCn2cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 2-methoxyphenyl piperazine (5.77 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 7.7 g compound (I-4) with a yield of 70.6%. ESI-MS [M+H]+: m/z 365.2.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH:14]([OH:17])[N:13]1[CH3:18])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH:14]([O:17][CH3:19])[N:13]1[CH3:18])=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(O)CC[C@H]1C(=O)NCCc1ccccc1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: COC1CC[C@@H](C(=O)NCCc2ccccc2)N1C
Reaction time: 1 h

Procedure:
Product 11B is dissolved hemi-aminal in 10 mL anhydrous methanol and 100 mg 10-camphorsulfonic acid is added. Methanolysis is complete in 1 hour. The resulting material is filtered and concentrated, then reconstituted with ethyl acetate and washed with saturated bicarb followed by drying over anhydrous sodium sulfate, filtered and concentrated. LCMS characterization ES+383.1 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:29]Br>O1CCOCC1.O>[Br:29][C:19]1[NH:20][C:21]2[C:17]([N:18]=1)=[C:16]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[N:15]=[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:22]=2
Reactant: BrBr
Reactant: COc1ccc(CCNc2nc(N3CCOCC3)c3nc[nH]c3n2)cc1OC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCNc2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl) amine (1.16 g, 3 mmol) in dioxane (75 mL) was added bromine (0.180 mL, 3.3 mmol) in dioxane (5 mL) dropwise over a period of 1 hour. The mixture was stirred at room temperature for additional 4 hours and diluted with water (25 mL) and extracted with EtOAc. The organic phase was washed with brine, water, dried over Na2SO4. The solvent was evaporated in vacuo and solid was washed with methanol to give (8-bromo-6-morpholin-4-yl-9H-purin-2-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine as a white solid (1.05 g, 75% yield).
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(O)(O)=O.COCCOC>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.CCO.O>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:4]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(O)O
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: c1ccc(Nc2ccc(Oc3ncccc3-c3cccnc3)cc2)nc1
Temperature: 145 °C

Procedure:
A mixture of N-(4-(3-Bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (0.257 g, 0.68 mmol), 3-pyridineboronic acid (0.115 g, 0.94 mmol), sodium carbonate anhydrous (0.358 g, 3.4 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (0.045 g, 0.064 mmol) in 6:3:2 DME:H2O:EtOH was sealed under argon in a microwave tube and heated at 145° C. for 15 min in the microwave (Emrys by Personal Chemistry). The reaction was filtered and the filtrate was partitioned between EtOAc/brine. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography [Isco, (40 gram)] eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 341.1 [M+1]. IC50 (uM) 0.002612.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccc(C)cc1

Procedure:
methyl 2-(4,6-dichloro-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (1 eq), p-tolylboronic acid (1 eq), tetrakis(triphenylphosphine)palladium(0) (0.1 eq) are placed in a reaction tube and dissolved in a mixture of degassed DME and water (3/1 v/v; 5 mL/mmol). N,N-Diisopropylethylamine (4 eq) is added, the tube is sealed and irradiated in a microwave oven at 130° C. for 30 min. The reaction mixture is partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. Purification of the crude material is performed by flash chromatography on silica gel using a linear gradient of ethyl acetate in heptane.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=O)[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:39])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=S)OCc1ccccc1

Procedure:
1,3-Dihydro-5-cyclohexyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (M. Chambers, et. al. Biomed. Chem. Lett. 1993, in press) (1.09 g, 2.79 mmole) was mixed with 1.13 g (2.79 mmole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in 26 ml of toluene. The resulting suspension was heated to reflux for 1 hour. The reaction mixture was cooled, filtered, and concentrated in vacuo. The residue was flash chromatographed on silica gel (ethyl acetate-hexane, 1:3) and the product containing fractions were pooled and concentrated to give the title compound in approximately 85% purity. This material was recrystallized from hexane-ethyl acetate (1:1) to give 850 mg (75%) of the title compound in analytical form: m.p. 164°-165° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)(C)[CH2:8][OH:9])(=[O:4])=[O:3].C1C2C=CC3C(=CC(C=O)=C4C=3C=CC=C4)C=2C=CC=1.Cl.NC(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][CH:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cl
Agent: NC(CO)CO
Agent: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Product: CS(=O)(=O)OCC(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, chrysene-6-carbaldehyde (1A) and 2-amino-1,3-propanediol hydrochloride (Sigma) gave 2-((6-chrysenylmethyl)amino)-1,3-propanediol methanesulfonate mp 208°-209°, (CH3OH/Et2O), (C, H, N, S).
Reaction SMILES: [NH:1](C1N=NC=CC=1)[NH2:2].[Cl:9][C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1[CH3:16].O.[NH2:19][NH2:20]>>[Cl:9][C:10]1[N:11]=[N:12][C:13]([NH:1][NH2:2])=[CH:14][C:15]=1[CH3:16].[Cl:17][C:13]1[N:19]=[N:20][C:10]([NH:11][NH2:12])=[C:15]([CH3:16])[CH:14]=1
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: NN
Reactant: NNc1cccnn1
Solvent: O
Product: Cc1cc(Cl)nnc1NN
Product: Cc1cc(NN)nnc1Cl

Procedure:
The hydrazino pyridazine starting materials can be prepared by known procedures. For example, 3,6-dichloro-4-methylpyridazine heated at reflux with excess hydrazine hydrate (50 percent in water) for 0.3 to 1 hour produces 3-chloro-4-methyl-6-hydrazinopyridazine and 3-chloro-5-methyl-6-hydrazinopyridazine. The isomers can be separated by fractional crystallization using ethanol as a solvent. See, Takahayashi, Pharm. Bull., 5, 229 (1957); Chem. Abstr. 52:6359, Linholter et al., Acta Chem. Scand. 16, 2389 (1962); Chem. Abstr. 59:1632g, Steck et al., J. Amer. Chem. Soc., 76, 4454 (1954) and Horning et al., J. Org. Chem., 20, 707 (1955).
Reaction SMILES: [N:1]1([C:7]2[O:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].O>O1CCCC1>[N:1]1([C:7]2[O:11][C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[N:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1nnc(N2CCOCC2)o1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nnc(N2CCOCC2)o1)OCC(Cl)(Cl)Cl
Yield: 13.2 %

Procedure:
To a solution of 5-morpholin-4-yl-1,3,4-oxadiazol-2-ylamine (1.00 g, 5.88 mmol) and pyridine (0.570 ml, 7.05 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.976 ml, 7.05 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to yield 269 mg (13.3%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#N)[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-:21].[K+].Cl.C[OH:25]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([OH:25])=[O:21])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: [OH-]
Reactant: N#CC1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Temperature: 2.5 °C

Procedure:
1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanenitrile (14.3 g, 0.047 mol) is dissolved in a mixture of methanol (143 ml) and water (71.5 ml), potassium hydroxide (35.1 g, 0.563 mol) is added portionwise, and the mixture is refluxed for 48 hours. The reaction mixture is cooled and poured into a solution of aqueous hydrogen chloride 36% (57 ml) in water (57 ml) at 20-25° C. The suspension is stirred and filtered; the solid is repeatedly washed with water and dried at 40° C. under vacuum. The crude product is dissolved in refluxing 2-propanol (178 ml), the solution is mixed with activated carbon (0.3 g), stirred at reflux and filtered, concentrated and mixed with n-heptane (116 ml). The hot solution is cooled to 0 to 5° C. and the crystallized solid is filtered, washed with 2-propanol and dried at 40° C. under vacuum. The compound 1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid is obtained as a white powder (10.3 g, 68% yield).
Reaction SMILES: C(OC([N:11]1[CH2:23][C:14]2[S:15][C:16]3[NH:17][CH2:18][N:19]=[C:20](Cl)[C:21]=3[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1CCC2C3C(Cl)=NC=NC=3SC=2C1)=O)(C)(C)C.[F:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:47]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50][C:20]2[C:21]3[C:13]4[CH2:12][NH:11][CH2:23][C:14]=4[S:15][C:16]=3[NH:17][CH2:18][N:19]=2)=[C:48]([O:53][CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:47]=1
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: O=C(OCc1ccccc1)N1Cc2sc3c(c2C1)C(Cl)=NCN3
Agent: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: Fc1ccc(NC2=NCNc3sc4c(c32)CNC4)c(OC2CCOCC2)c1
Temperature: 120 °C
Yield: 10 %

Procedure:
A solution of 4-chloro-5,7-dihydro-1H-pyrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester (prepared in an analogous fashion to 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester, WO2007/109279, 0.135 g, 0.39 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.090 g, 0.39 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated at 120° C. for 21 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH) to afford the title compound as white solid (0.015 g, 10%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:28]=1)[CH3:19]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-ethoxycarbonyl-phenylboronic acid to give 3-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzoic acid ethyl ester. LC-MS m/e 359(MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1.[C:20]([C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 26.4 %

Procedure:
To a solution of (4-(pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (510 mg, 1.84 mmol) described in Manufacturing Example 2-1-5 and 3-ethynyl-pyridin-2-ylamine (150 mg, 1.27 mmol) described in Manufacturing Example 1-2-3 in tetrahydrofuran (5 mL) was added triethylamine (708 μL, 5.08 mmol) at room temperature, which was stirred for 95 minutes at room temperature. Water was added at room temperature to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (120 mg, 26%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9](O)=[CH:10][CH:11]=2)[CH:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[O:18]1C[CH:19]1[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CN(C)[CH:31]=[O:32]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[O:32][CH2:31][C:24]2[C:23]([CH2:22][CH2:21][CH2:19][OH:18])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:13][CH:14]=1)[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCOc1ccc2ccc(O)cc2c1
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1ccc2cccc(OCc3ncccc3CCCO)c2c1

Procedure:
Prepared according to the method described in Example 5 from 2-(2-propenyloxy)-7-hydroxynaphthalene (1.27 g; J. Org. Chem., (1981) 46, 4988), sodium hydride (60% dispersion in oil; 0.25 g) and (±)-3-(2-oxiranylethyl)pyridine (1.0 g) in dimethylformamide (20 ml) at room temperature to yield the title compound as an oil (0.410 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].Cl.[CH3:16][O:17][C:18](=[O:24])[C@@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20].CO.C(N(CC)CC)C>>[CH3:22][CH:21]([CH3:23])[C@@H:19]([N:20]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:18]([O:17][CH3:16])=[O:24]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (5 g, 0.03 mol) and D-Valine methyl ester hydrochloride (5 g, 0.03 mol) were refluxed in methanol (40 mL, 1 mol) with triethylamine (5 g, 0.05 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g silica gel, 0-30% EtOAc/Hexane) and gave a brown oil. MS m/z 305.2 (M+H)+.