Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[F:1][C:2]1[CH:15]=[CH:14][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NCc1cccc(F)c1)C(F)(F)F
Product: O=C(NCc1cc(F)ccc1S(=O)(=O)Cl)C(F)(F)F
Temperature: 70 °C

Procedure:
3-Fluoro-N-trifluoroacetylbenzylamine (Intermediate 105, 1.11 g) was added portionwise to chlorosulfonic acid (5 mL), while stirring and cooling in an ice bath. On completion of the addition, the ice bath was removed and the mixture was allowed to come to room temperature then heated to 70° C. for 3 hours. After cooling, the mixture was slowly added to ice and the resultant suspension was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride (1.53 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccc(F)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccc(F)cc2c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.3 g (11 mmol) of 6-fluoro-3-nitro-quinolin-4-ol (Example 19b) in 12 ml POCl3 are heated kept at 130° C. for 4 h. The reaction mixture is cooled to 0° C. and poured into ice-water. A precipitate is formed, which is filtered off and washed with water. The solid material is dissolved in CH2Cl2 and washed with 0.1N NaOH and water. After drying the organic phase over MgSO4, the solvent is evaporated to dryness. The residue is dissolved in a few ml of CH2Cl2 and hexane is added. The title compound precipitates and is filtered off. Drying is done at 60° C. (high-vacuum) overnight. NMR (DMSO-d6): 9.38/s (1H), 8.32/d×d (1H), 8.18/d×d (1H) and 8.02/d×t (1H); HPLC: tret=11.82 min (Grad 1).
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]([CH3:19])([CH3:18])[C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=O.C(N(CC)CC)C>CC(C)=O>[Br:7][C:8]([C:9]1[O:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[N:11]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(Br)C(=O)NC(C)(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(Br)C1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of ethyl chloroformate (32.4 g, 0.30 mol) in 50 mL acetone was added dropwise to a stirring mixture of 2-(2-bromo-2-methyl propionylamino)-2-methylpropionic acid (67.9 g, 0.27 mol) and triethylamine (30.0 g, 0.30 mol) in 200 mL of acetone at −15° C. When addition was complete, the mixture was stirred at room temperature for 2 hours, and the white solid was filtered off and washed with 100 mL of ether. The combined filtrates were reduced in volume to about 200 mL at reduced pressure and cooled in a refrigerator at about 5° C. overnight. The small amount of white solid that had separated was removed by filtration, and the solvents were evaporated at reduced pressure. The residue was taken up in 300 mL of ether, filtered, and the solvent evaporated to leave the title compound (61.5 g, 98%) with IR and NMR spectra consistent with the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[C:13](=[O:19])[NH:14][C:15](=[S:18])[NH:16][CH:17]=2)=[CH:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=2)=[CH:23][C:22]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][S:18][C:15]3[NH:16][CH:17]=[C:12]([CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:2]([CH3:1])[CH:3]=4)[C:13](=[O:19])[N:14]=3)=[CH:32][CH:33]=2)=[CH:23][C:22]=1[C:36]([F:37])([F:38])[F:39]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c2ccccc21
Temperature: 80 °C
Yield: 25.8 %

Procedure:
A mixture of 5-[(1-methyl-1H-indol-3-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (95 mg, 0.349 mmol), 1-chloro-4-(4-(chloromethyl)phenoxy)-2-(trifluoromethyl)benzene (112 mg, 0.349 mmol), and K2CO3 (90 mg, 0.651 mmol) in DMF (2 mL) was heated at 80° C. for 3 h. The reaction mixture was diluted with EA (10 mL) and filtered through a silica pad to remove the solid suspension. The clear filtrate was concentrated under reduced pressure and purification via MDAP then afforded the title compound (50 mg, 24.75% yield). LCMS: rt=4.79 min, [M+H+]=556
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:22])[CH2:14][C:15](=[O:21])[CH2:16][C:17](=O)[CH2:18][CH3:19])(C)(C)C>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:18]([C:17]1[O:16][C:15](=[O:21])[CH:14]=[C:13]([OH:12])[CH:22]=1)[CH3:19]
Reactant: CCC(=O)CC(=O)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1cc(O)cc(=O)o1
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 25% (v/v) trifluoroacetic acid (TFA) in trifluoroacetic anhydride (TFAA, 1117 mL) was placed in a 2 liter round bottom flask and cooled in an ice bath for 40 minutes. Crude compound U was loaded into an addition funnel and slowly added to the stirred mixture over 2 hours. The reaction was allowed to warm up to room temperature overnight. The TFA/TFAA solution was removed by rotary evaporation. Residual TFA could be removed azeotropically with toluene. The residue was then purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in dichloromethane. The appropriate fractions were collected and concentrated by rotary evaporation to yield compound V (63.15 g, 45%) as a yellow solid. 1H NMR CDCl3 δ: 11.08 (bs, 1H), 6.00 (s, 1H), 5.59 (s, 1H), 2.52 (q, 2H, J=8.0 Hz), 1.22 (t, 3H, J=8.0 Hz). ESMS m/z: 141.0 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>ClCCCl>[C:12]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CCCCC(=O)Cl
Reactant: CC(=O)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCC(=O)c1ccc2c(c1)CCN2C(C)=O
Temperature: 0 °C
Yield: 67.7 %

Procedure:
Pentanoyl chloride (10.8 g) was added dropwise to a mixture of anhydrous aluminium chloride (28.2 g) and 1-acetyl-2,3-dihydro-1H-indole (10 g) in 1,2-dichloroethane (100 mL) with mechanical stirring. The mixture was stirred at reflux for 16 hours, then cooled, then poured into ice-water. The mixture was extracted with dichloromethane. The extracts were washed with 1M aqueous sodium hydroxide, then dried over magnesium sulphate, then evaporated to give the title compound (10.3 g) as a dark gum.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](C(=O)OC)CC2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reaction time: 2 h

Procedure:
Hydrazine hydrate (0.152 mL) was added to a stirred solution of methyl trans-4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexanecarboxylate (913 mg) in EtOH (25 mL). The mixture was stirred for 2 hours. The precipitate was filtered off, washed with EtOH, and dried under vacuum to give the title compound (Intermediate 44, 277 mg) as a solid; 1HNMR δ 10.43 (1H, s), 7.67 (2H, d), 7.17 (2H, d), 4.52 (2H, s), 3.59 (3H, s), 2.53-2.33 (2H+DMSO, m), 1.97 (2H, m), 1.81 (2H, m), 1.46 (4H, m); MS m/e MH+ 320.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]Br)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCNC(C)(C)CO)cc1
Yield: 59.1 %

Procedure:
A mixture of 2-amino-2-methylpropanol (4.46 g), 4-methoxyphenethyl bromide (10.76 g), potassium carbonate (13.8 g) and potassium iodide (8.3 g) in acetonitrile (100 ml) was heated under reflux for 20 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was dried over sodium sulphate and evaporated. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (6.6 g, 60%), m.p. 114°-115°.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[C:9](Cl)(=[O:11])[CH3:10]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:9]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1)(=[O:11])[CH3:10]
Reactant: O=C(O)C1CC(O)C1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CC(C(=O)O)C1
Temperature: 0 °C

Procedure:
To a solution of 3-hydroxycyclobutanecarboxylic acid (100 mg, 0.86 mmol) in DCM (10 mL) was added DMAP (1.0 mg, 0.086 mmol). The solution was cooled to 0° C., followed by the addition of acetyl chloride (0.14 mL, 2.6 mmol). The reaction was heated at 45° C. for 4 hours, then cooled to rt and diluted with DCM (20 mL). The mixture was washed with water (10 mL), followed by washing with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtained the crude product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1)[CH3:2].S(Cl)([Cl:12])=O>>[CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([Cl:12])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(C(=O)O)C1
Reactant: O=S(Cl)Cl
Product: CCC1CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
A mixture of 3.3 g (0.027 mole) of 3-ethylcyclobutanecarboxylic acid (prepared in 1E) and 9.4 g (5.7 ml, 0.080 mole) of thionyl chloride was prepared and allowed to stir at room temperature for about 15 hr. Excess thionyl chloride was removed by distillation at atmospheric pressure. The residue was distilled at reduced pressure to yield 2.4 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[C:40](N1C=CN=C1)(=[O:48])[C:41](N1C=CN=C1)=[O:42]>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:21][CH2:22][N:23]([CH2:26][C:27]5[CH:28]=[C:29]6[C:30](=[CH:31][CH:32]=5)[NH:33][C:41](=[O:42])[C:40](=[O:48])[NH:34]6)[CH2:24][CH2:25]4)[C:13]=3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc(N)c(N)c5)CC4)cccc3[nH]2)cc1
Reactant: O=C(C(=O)n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc6[nH]c(=O)c(=O)[nH]c6c5)CC4)cccc3[nH]2)cc1
Yield: 24.4 %

Procedure:
In a round bottom flask under nitrogen was combined 4-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-benzene-1,2-diamine (0.17 g, 0.37 mMol), tetrahydrofuran (20 mL), and 1,1′-oxalyldiimidazole (0.284 g, 1.5 mMol) and the solution stirred overnight. Upon arrival the solution was diluted with ethyl acetate (100 mL) and washed with water (100 mL). A precipitate forms and was collected by filtration. The organic layer was concentrated to dryness on a rotary evaporator and combined with the precipitate. Purification by RP-HPLC (Method E) yielded 46 mg (24% yield) of 6-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-1,4-dihydro-quinoxaline-2,3-dione as an off-white solid. 1H NMR (DMSO-d6): δ=12.19 (s, 1H), 12.09 (s, 1H), 9.82 (br s, 1H), 8.07 (d, 2H, J=8.6 Hz), 7.58 (d, 2H, J=8.6 Hz), 7.27 (m, 2H), 7.22 (d ,1H, J=8.6 Hz), 7.13 (m, 2H), 6.64 (m, 1H), 4.48 (br s, 2H), 4.44 (s, 2H), 3.50 (br s, 2H), 3.38 (br s, 2H), 3.09 (m, 2H), 1.34 (s, 9H). HPLC: Xterra MS C18, 3.5 μm, 4.6×50 mm, flow=0.8 m/min, 5-95% ACN/PICB6 over 10 mins., rt=5.840 mins., 79% pure @ 210 nm, 77% pure @ 300 nm. LC/MS (Method A), rt=1.05 mins., purity=79.19%, calculated mass=508, [M+H]+=509, [M−H]−=507.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([O:18][C@@H:19]1[C@@H:23]([CH2:24][OH:25])[O:22][C@@H:21]([N:26]2[CH:33]=[C:32]([F:34])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:22][C@@H:21]([N:26]2[CH:33]=[C:32]([F:34])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1)c1cccnc1
Reaction time: 3 h
Yield: 69 %

Procedure:
A 0.21 g quantity of nicotinoyl chloride hydrochloride was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at 80° C. for 3 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed twice with 20 ml of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.18 g of the title compound in a yield of 69%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17](=[CH2:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.C(OC(C)C)(C)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: C=C(C(=O)O)c1cccc(OC)c1
Reactant: Nc1ccccc1S
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COc1cccc(C(CSc2ccccc2N)C(=O)O)c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
7.6 ml of aminothiophenol were added to a solution of 8.9 g of the product of Step C and 130 ml of ethanol and the solution was stirred for 90 minutes at 95° C. and left to return to ambient temperature. The ethanol was eliminated under reduced pressure and 50 ml of isopropyl ether were added. Crystallization was started to obtain 7.2 of the expected product which was separated off and dried at 80° C. under reduced pressure. After chromatography of the mother liquors on silica (eluant: ethyl acetate-cyclohexane 1-1), 710 mg of pure product were obtained (Rf=0.16) which after crystallization from ether melted at 128° C.
Reaction SMILES: [N:1]1([C:7](=[S:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:8]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:11])[C:9]#[N:10])=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCC(=S)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-morpholin-4-yl-3-thioxopropanenitrile (0.122 g, 0.72 mmol) and p-anisaldehyde (0.1 mL, 0.86 mmol) in 10% piperidine/ethanol (5.5 mL) was allowed to stir at 50° C. under nitrogen for 3.5 h. The reaction mixture was concentrated and the residue was diluted with 10% citric acid solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile. The crude product was a mixture of stereoisomers and was used directly in the next step. LCMS: (AA) ES+ 289.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[CH3:33][N:32]([CH3:34])[C:30]([CH2:29][NH:28][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])=[O:31]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CN(C)C(=O)CN
Product: CN(C)C(=O)CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
30 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 was coupled to 2-amino-N,N-dimethylacetamide via General Procedure B. The product was purified via reverse phase HPLC to give 6.5 mg of 248. MS (Q1) 465.8 (M)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)nc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 2-chloro-4-methyl-quinoline (1.00 g, 5.63 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 6.76 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.88 g, 7.88 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.12 mg, 0.0056 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.26 mg, 0.0056 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 18 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.54 g (28%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.31-1.40 (m, 2H), 1.41 (s, 9H), 1.91-1.96 (m, 2H), 2.46 (s, 3H), 2.93-3.01 (m, 2H), 3.86-3.91 (m, 2H), 4.11-4.17 (m, 1H), 6.59 (s, 1H), 6.80 (d, J=7.7 Hz, 1H), 7.13-7.17 (m, 1H), 7.44-7.47 (m, 2H), 7.73 (d, J=7.7 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 18.16, 28.07, 31.57, 42.39, 46.37, 78.51, 112.89, 120.88, 123.12, 123.64, 125.96, 128.69, 143.28, 147.91, 153.91, 155.93. MS (ISP): 342.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:25]([NH:27][C:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:29])[CH3:26]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26 in 5.ml tetrahydrofuran was added 0.015 ml of ethyl isocyanate, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, to the reaction mixture was added with 1 ml of 5 N hydrochloric acid and the mixture was stirred for further 1 hour. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was sequentially washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. To the residue was added diisopropyl ether, and the mixture was filtered, to give 28 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:9]1[N:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][C:5]2=[N:11][CH:10]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cc2nccn2cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc2ncc(Br)n2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-trifluoromethylimidazo[1,2-c]pyrimidine (1.9239 g, 10.3 mmol) in acetic acid (40 ml) was added sodium acetate (1.265 g, 15.4 mmol), then a solution of bromine (0.529 ml, 10.3 mmol) in acetic acid (7.5 ml). The solution was stirred at room temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (1 l) and ethyl acetate (500 ml). The aqueous layer (pH 8) was further extracted with ethyl acetate (500 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20% EtOAc/isohexane) to afford 0.88 g (34% over 2 steps) of the title compound as a white solid: 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.93 (1H, s), 9.09 (1H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:29]=2)[C:24]([Cl:35])=[CH:23][N:22]=1>C(Cl)Cl>[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:31]([NH:1][C@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]3)(=[O:33])=[O:32])[CH:29]=2)[C:24]([Cl:35])=[CH:23][N:22]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl trans-4-aminocyclohexanecarboxylate (168 mg, 0.81 mmol), NEt3 (0.22 mL, 1.6 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (200 mg, 0.67 mmol) in CH2Cl2 (8 mL) was stirred at 0° C. for 1 h. The mixture was diluted with CH2Cl2 (100 mL), was washed with dilute HCl (50 mL, 1 M), water, dried (MgSO4) and evaporated in vacuo to give ethyl trans-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (232 mg, 0.54 mmol) as a white solid.