Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ICI.[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]2[CH:10]=[C:9]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH3:28])=[O:26])=[CH2:18])[CH:8]=[CH:7][C:6]1=2.[CH2:30]([Zn]CC)C.CCCCCCC>ClCCl>[CH3:4][C:5]1([CH3:29])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]2[CH:10]=[C:9]([C:17]3([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([O:27][CH3:28])=[O:26])[CH2:30][CH2:18]3)[CH:8]=[CH:7][C:6]1=2
Reactant: CC[Zn]CC
Reactant: C=C(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC
Solvent: ClCCl
Solvent: ICI
Solvent: CCCCCCC
Product: COC(=O)c1ccccc1C1(c2ccc3c(c2)C(C)(C)CCC3(C)C)CC1
Reaction time: 4 h

Procedure:
Diiodomethane (230 μl, 2.85 mmol) is added dropwise, at 60° C., to a mixture of methyl 2-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (500 mg, 1.44 mmol) and a 1M solution of diethylzinc in heptane (2.9 ml, 2.9 mmol) in dichloromethane (10 ml). The heating is continued for 4 h. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed with 1N HCl solution and then with water, dried over anhydrous magnesium sulfate and concentrated. The same process is repeated once.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[S:9][CH:10]=1)C.[OH-].[K+].O>C(O)C>[CH3:32][C:30]1[CH:31]=[C:26]([S:23]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:12]([NH:11][C:8]4[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[N:7]=4)=[O:13])[CH:22]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])[CH:27]=[C:28]([CH3:33])[CH:29]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CC3)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)Nc4nc(CC(=O)O)cs4)cc32)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(2-{[1-(3,5-Dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester (0.10 g, 0.20 mmol) was suspended in ethanol (1.00 mL) and treated at room temperature with 3N KOH in water (0.20 mL, 0.60 mmol). The mixture was warmed to 50° C. and stirred for 18 hours, then cooled to room temperature and evaporated. The residue was dissolved in water (1.00 mL) and set to pH 1 with HCl 1N. The resulting suspension was filtered, washing with water and the filtrate dried under vacuum to yield (2-{[1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid as a white solid, 0.09 g (99%), MS (ISP): m/e=470.2 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:14]C(=O)CC)(=[O:13])[CH2:11][CH3:12].C([O-])(=O)CC.[K+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([CH3:12])[C:10]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc(O)cc1)C(=O)O
Reaction time: 30 h
Yield: 34.3 %

Procedure:
At 135° C., 122 g of 4-hydroxybenzaldehyde, 163 g of propionic anhydride and 112 g of potassium propionate were reacted with stirring for 30 hours, the reaction mixture was dropped into 1.5 l of distilled water, and sodium carbonate was added to form an aqueous alkaline solution. The unreacted 4-hydroxybenzaldehyde was removed and concentrated hydrochloric acid was added to render the solution acidic and precipitate the reaction product. The precipitate was recovered by filtration and washed with water to obtain 85 g of a crude product. The precipitate was dissolved in a solution comprising 150 g of water, 150 g of ethanol and 30 g of sodium hydroxide, and the solution was refluxed for 2 hours and dropped into a liquid comprising concentrated hydrochloric acid and ice to precipitate the reaction product. The precipitate was recovered by filtration, washed repeatedly with distilled water and dried to obtain 61 g of crude 4-hydroxy-α-methylcinnamic acid. A product (refined 4-hydroxy-α-methylcinnamic acid) obtained by recrystallizing this crude 4-hydroxy-αmethylcinnamic acid from hot water was used for the subsequent reaction.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2([CH:23]([CH3:28])[CH2:24][N:25]([CH3:27])[CH3:26])[OH:22])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([O:22][C:17]1([CH:23]([CH3:28])[CH2:24][N:25]([CH3:26])[CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:11][CH:12]=1)(=[O:37])[CH3:36]
Reactant: CC(CN(C)C)C1(O)CCCCC1c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1(C(C)CN(C)C)CCCCC1c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
2-(p-Benzyloxyphenyl)-1-(2-dimethylamino-1-methylethyl)cyclohexanol hydrochloride (11.3 g) is stirred with 140 ml chloroform and 26 g potassium carbonate. Acetyl chloride (6.5 ml) is added and the mixture is stirred overnight, washed with water, and the chloroform dried. The chloroform solution is stirred for 6 hours with 6.5 ml acetyl chloride and 26 g potassium carbonate, then washed with water, dried and concentrated to give 14 g crude product.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N>CC(N(C)C)=O.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: OC1CCNCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: OC1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 43.7 %

Procedure:
A brown solution of Intermediate 24b (855 mg, 4.98 mmol) and 4-hydroxypiperidine (2.02 g, 19.9 mmol) in DMA (15 mL) was irradiated to 175° C. in the microwave for 3 h. The cooled solution was concentrated in vacuo, then the residue diluted with water (20 mL) and brine (20 mL). The mixture was washed with diethyl ether (2×50 mL), then extracted with EtOAc (2×50 mL). The combined EtOAc layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a yellow oil. The aqueous was further extracted with DCM (3×50 mL). The combined DCM layers were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. The two oils were combined. FCC, using 4-5% [2M NH3 in MeOH] in DCM, gave the title compound as a yellow crystalline solid (514 mg, 44%). LCMS (Method 3): Rt 1.96 min, m/z 237 [MH+].
Reaction SMILES: [F:1][C:2]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([F:19])[C:3]([N:5]1[N:6]=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:8]=[CH:9]/[C:10]/1=[N:11]\[NH2:12])=O.COCC(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[F:1][C:2]([F:19])([C:3]1[N:5]2[N:6]=[C:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[CH:8]=[CH:9][C:10]2=[N:11][N:12]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: Cn1cc(-c2cc/c(=N\N)n(C(=O)C(F)(F)c3ccc4ncccc4c3)n2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCC(C)O
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
The crude 6-{1,1-difluoro-2-[(6E)-6-hydrazono-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-1(6H)-yl]-2-oxoethyl}quinoline from step 3 above (3.67 mmol) was brought in a reaction balloon under argon. 36 mL of 1-methoxy-2-propanol was added and the mixture was stirred at 105° C. for 1 h. Then the reaction mixture was brought to gentle reflux for one additional hour (108° C.). The reaction mixture was allowed to cool to room temperature and poured out in a solution of 10 g of sodium carbonate in 100 mL of water. 100 mL toluene was added and the layers were separated. The water layer was extracted with toluene (100 mL). The combined organic layers were washed with water and evaporated, yielding 700 mg of compound (I) (1.86 mmol; 51%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.CO.[Pd]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2[nH]cc(C3=CCNCC3)c2-c2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2[nH]cc(-c3ccncc3)c2-c2ccncc2)cc1
Yield: 52.9 %

Procedure:
450 mg (1.15 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrole dihydrochloride [prepared as described in Example 10 above] were suspended in a mixture of 25 ml of xylene and 2 ml of methanol and 450 mg of 10% palladium on carbon and 320 mg (2.30 mmol) of sodium carbonate were added to the suspension. The resulting mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was filtered and the resulting filtrate was concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 10:1:1 by volume mixture of ethyl acetate, methanol and isopropylamine as the eluant to give 192 mg (yield 53%) of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3([OH:21])[CH2:19][CH2:18][CH2:17][C:16]4[N:15]([CH3:20])[N:14]=[CH:13][C:12]3=4)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:10]1[N:9]=[C:8]([C:11]2([OH:21])[CH2:19][CH2:18][CH2:17][C:16]3[N:15]([CH3:20])[N:14]=[CH:13][C:12]2=3)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ncc2c1CCCC2(O)c1ncc2c(Cl)nccn12
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(Cl)nccn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (1 g, 3.3 mmol) in DMF (8 ml) was added NBS (584 mg, 3.3 mmol) portionwise at 0° C. After the addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to give 4-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (860 mg, 68%). MS-ESI (m/z): 382 (M+1)+ (Acq Method: 10-80AB_2 min; Rt: 1.01 min)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[K+].ClCCl>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(#N)C>[CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C(F)(F)F)c3)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Yield: 66.9 %

Procedure:
In a microwave vial was placed ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester (100.0 mg, 0.154 mmol), 4,4,5,5-tetramethyl-2-(3-trifluoromethyl-phenyl)-1,3,2-dioxaborolane (209.7 mg, 0.77 mmol, 5.0 eq.), sodium carbonate (49.0 mg, 0.46 mmol, 3.0 eq.), potassium acetate (45.4 mg, 0.46 mmol, 3.0 eq.), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexed with dichloromethane (1:1) (25.2 mg, 0.03, mmol, 0.20 eq), ACN (9.0 mL), and water (1.9 mL). The reaction mixture was degassed with N2 for 10 minutes and then subjected to microwave irradiation at 100° C. for 40 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and then filtered through a pad of Celite. The filtrate was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 50 to 100% ethyl acetate/heptane to give 73.5 mg (66.8%) of desired product as an oil. MS (ESI) m/z: 714.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][C:41]=1[Cl:42])[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][C:41]=1[Cl:42])[O:32][CH:33]1[CH2:38][CH2:37][N:36]([C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])=[O:12])[CH2:35][CH2:34]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
To (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (1.13 g) in CH2Cl2 (5 ml) was added 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride (0.99 g) and left to stir for 5 mins. The product of Example 1, Step (b) (0.98 g) dissolved in CH2Cl2 (5 ml) was then and the reaction left to stir for 3 hrs. Aqueous NaHCO3 solution was added and the product extracted with ethyl acetate. The organic phase was dried, filtered and evaporated to give the sub-title compound (1.57 g).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:25]=[CH:26][C:27]=2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[CH:15][CH:14]=1.O.NN>CCO>[NH2:3][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:25]=[CH:26][C:27]=2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN)cc1

Procedure:
1,1-dimethylethyl {3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate (17 g, 31 mmol) and hydrazine hydrate (3.01 mL, 62.1 mmol) were stirred in refluxing EtOH (135 mL) for 5 hours. Room temperature was attained and the white precipitate removed by filtration and washed with EtOH. The filtrate was concentrated in vacuo and purified by MPLC (10% [MeOH+1% NH4OH]-DCM) to give 1,1-dimethylethyl [3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.86 (s, 1H), 8.77 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.62 (m, 3H), 7.49 (m, 3H), 7.44 (t, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 3.79 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=O)C.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[NH2:13][C:11]1[S:12][C:6]2[CH2:5][NH:4][CH2:9][CH2:8][C:7]=2[N:10]=1
Reactant: CC(=O)N1CCc2nc(N)sc2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2c(s1)CNCC2
Yield: 84.3 %

Procedure:
5-Acetyl-2-amino-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine (110 mg, 0.51 mmol) was dissolved in ethanol (1 ml) and treated with sodium hydroxide (15.4 mg, 0.38 mmol) in ethanol (1 ml). The solution was heated to 100° for 16 hours, then treated with additional sodium hydroxide (25.6 mg, 0.64 mmol) and heated to reflux for an additional 16 hours. Solid ammonium chloride was added, and the mixture was filtered and concentrated in vacuo. The residue was dissolved in chloroform, dried over sodium sulfate and solvent was removed, leaving the title product (67.4 mg, 0.43 mmol, 84% yield) as a yellow solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[CH2:14][C:10]4[S:11][CH:12]=[CH:13][C:9]=4[C:8]=3[NH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1cccc(Br)c1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
5-(3-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (30 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(3-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 2.5 mmol) as white solid in 30% yield.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:10]([F:32])[CH:9]=1.C1(C)C=CC(S([CH2:42][N+:43]#[C-])(=O)=O)=CC=1.Cl.CCOC(C)=O>CCOC(C)=O.C1COCC1.COCCOC>[ClH:7].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][CH:27]([C:42]#[N:43])[CH2:26][CH2:25]3)[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:10]([F:32])[CH:9]=1
Reactant: O=C1CCCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: N#CC1CCCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Reaction time: 1 h
Yield: 41.2 %

Procedure:
440 mg of potassium tert-butoxide was added to a mixture of 650 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-one, 380 mg of p-toluensulfonylmethyl isocyanide, 20 ml of 1,2-dimethoxyethane and 10 ml of THF and the resultant was stirred for one hour under ice cooling. After the reaction mixture was concentrated under reduced pressure, 50 ml of water was added to the obtained residue and extracted twice with 100 ml of EtOAc. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography chloroform-MeOH) and a foam-like substance was obtained. 50 ml of EtOAc and 0.5 ml of 4M HCl-EtOAc solution were added to the foam-like substance and the solvent was removed under reduced pressure to give a solid. The obtained solid was washed with ethyl acetate to give 150 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-carbonitrile hydrochloride.
Reaction SMILES: [C:1]([N:8]([CH3:28])[C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:30]1([C:36]2([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:25](=[O:26])[NH:41][CH2:40][C:36]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][CH2:38][CH2:39]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH3:28])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: NCC1(c2ccccc2)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of Boc-NMe-Tyr(OBn)-OH (0.90 g, 2.3 mmol) and C-(1-phenyl-cyclobutyl)-methylamine hydrochloride (synthesized according to the method in Bridges, A. J., Hamilton, H. W., Moos, W. H., Szotek, D. L., N6−substituted Adenosines, U.S. Pat. No. 4,755,594) (0.46 g, 2.3 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.97 g, 5.6 mmol) in methylene chloride (10 mL) was treated with DIEA (0.86 mL, 5.1 mmol). The suspension was stirred at room temperature overnight. The resulting solution was concentrated. The residue was taken up in ethyl acetate. The solution was washed with 0.5 M HCl, saturated NaHCO3, dried over MgSO4, filtered, and concentrated. The oil was chromatographed (CH2Cl2:CH3OH 50:1) to give the desired product (1.07 g, 2.02 mmol; 87% yield). MS-APCI 529 (m+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>CCCCC>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:15](=[O:17])[CH3:16])[CH2:23][CH2:22]1)=[O:25]
Reactant: COc1ccccc1OC
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1OC
Temperature: 100 °C

Procedure:
To a rapidly stirred slurry of aluminum chloride (1.1 g, 8.2 mmol) and 1,2-dimethoxybenzene (3.5 mL) at ambient temperature was added 1-acetylpiperidine-4-carbonyl chloride (0.8 g, 4.2 mmol). The reaction mixture was heated at reflux (100° C.) for 1.5 hours and then poured into 30 mL of ice water, the mixture was extracted with DCM (50 mL) and the organic layer was washed with water and dried over Na2SO4. The solvent was removed in vacuo to give an oil. Trituration of the oil with pentane gave the title product (0.88 g, 2.87 mmol) as a white solid. MS (ESI) m/z 292.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 0.86 min.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([NH2:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22](Br)=[O:23]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:21][C:22](=[O:23])[NH:13][C:8]=2[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Commercially available 4-ethylsulfonyl-2-aminophenol (4.02 g, 20 mmol) was dissolved in DMF (30 mL) and mixed with cesium carbonate (6.5 g, 20 mmol). The reaction mixture was cooled to 0° C. and bromoacetyl bromide (4.0 g, 20 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred overnight at room temperature. After aqueous work up, the product was purified by silica gel chromatography with methanol/dichloromethane to give the product as an orange solid, 1.7 g (35%).