Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH:7]=[CH:8][C:9]([Cl:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=CC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=CC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-cyclohexyl-acrylic acid (5.0 g, 32.5 mmol) and oxalyl chloride (3.4 ml, 34.0 mmol) in anhydrous DCM (50 ml) was treated with one drop of dimethylformamide. The resulting solution was stirred at room temperature for 18 h, concentrated and used directly in the next step.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
In a 50 mL round-bottomed flask, 2-(methylsulfonyl)ethanol (1.24 g, 9.99 mmol, Eq: 1.00) was combined with DCM (5 mL). To the resulting solution was added diisopropylethylamine (2.1 mL, 12.0 mmol, Eq: 1.2) and methanesulfonyl chloride (1.37 g, 931 μL, 12.0 mmol, Eq: 1.2). The ice bath was removed and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 80% EtOAc in hexanes) to give 2-(methylsulfonyl)ethyl methanesulfonate (1.01 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[CH:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:42][CH3:43]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[C:29]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH2:42][CH3:43])[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
LiHMDS (20 mL, 0.020 mol) was added dropwise to a stirred solution of methyl 2-(4-(tert-butoxycarbonylamino)-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)acetate (4.32 g, 0.010 mol) in THF (80 mL) and HMPA (20 mL) at −78° C. The resulting mixture was stirred for another 1 h at −78° C. Iodoethane (2.3 g, 0.015 mol) was added to the above solution. The reaction mixture was warmed to −20° C. and stirred for 20 min. The mixture was quenched with sat. ammonium chloride and extracted with EA, washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=8:1) to afford the title compound. LC/MS m/z=405.1 [M-tBu+H]+.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]([NH-:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@H:30]1[CH2:32][C@@H:31]1[C:33](Cl)=[O:34]>ClCCl>[OH:2][CH2:3][C@H:4]([NH:17][C:33]([C@H:31]1[CH2:32][C@@H:30]1[C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Reactant: CC[C@H](C)COc1ccc([C@@H]([NH-])CO)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (1.08 g, 6.45 mmol) in dichloromethane (50 ml) in an ice-bath was added oxalyl chloride (6.50 ml, 64.4 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 250 ml round-bottom flask was charged with {(R)-2-hydroxy-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide HCl (6.47 mmol), dichloromethane (60 ml) and triethylamine (4.30 ml, 32.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×30 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (1.42 g, 58% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (d, J=8.6 Hz, 2H), 7.09 (m, 1H), 6.91 (m, 3H), 6.82 (d, J=3.5 Hz, 1H), 6.23 (d, J=6.1 Hz, 1H), 5.06 (td, J=6.3, 4.3 Hz, 1H), 3.91 (m, 2H), 3.78 (m, 2H), 2.75 (m, 2H), 1.88 (m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C21H28NO3S 374.5].
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:11]([C:14]1[O:18][C:17]([C:19](Cl)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[O:18][C:17]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: N=C(NO)c1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3ccccc3)no2)o1
Temperature: 25 °C

Procedure:
N-Hydroxy-benzamidine (0.3 g; 2.1 mmol) was dissolved in 10 ml of dry pyridine and added 0.5 g of 5-nitro-furan-2-carbonyl chloride (2.8 mmol). The reaction mixture was heated at reflux for 3 hours, cooled to room temperature and poured into 50 ml of ice/water, the product precipitated out of solution and was isolated by filtration. Yield 0.3 g (41%) of yellow solid. Mp. 164-166° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][NH:10][CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21].[Cl:23][CH2:24][CH2:25][CH2:26]Br.C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][N:10]([CH2:26][CH2:25][CH2:24][Cl:23])[CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21]
Reactant: ClCCCBr
Reactant: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CN(CCCCl)C3
Temperature: 60 °C

Procedure:
A mixture of 3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide hydrochloride (0.7 g, 2 mmol), 1-chloro-3-bromopropane (4 mmol), and triethylamine (2 ml) in 10 ml of anhydrous DMF was heated at 60° C. for 24 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column (chloroform/methanol, 40:1) to give pure compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.88 (d, J=5.1 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 7.27 (dd, J=3.6, 5.1 Hz, 1H), 7.22 (brs, 2H), 5.98 (brs, 2H), 4.00 (s, 2H), 3.77 (s, 2H), 3.67 (t, J=6.3 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H), 1.90 (m, 2H). ES MS m/z 393, 395 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15](OC)=[O:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11](=[CH:14][CH2:15][OH:16])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COC(=O)C=C1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCC(=CCO)CC2)ccc1Cl
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 101.6 %

Procedure:
A solution of methyl 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-ylidene)acetate (275 mg, 0.930 mmol) in anhydrous THF (3 mL) was cooled to −78° C. and then treated with DIBAL-H (3.72 mL of a 1.0 M solution in toluene, 3.72 mmol). The reaction was stirred at −78° C. for 2.5 h and then quenched with EtOAc. After it warmed to 0° C., the mixture was treated with saturated potassium sodium tartrate solution and stirred vigorously for 20 min. The resulting mixture was extracted with EtOAc. The extract was dried (Na2SO4) and concentrated to give a yellow oil, which was purified by flash chromatography (4 g silica gel cartridge and gradient elution with EtOAc/hexanes) to give 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-ylidene)ethanol (253 mg, 0.945 mmol, 102% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 7.18 (1 H, d, J=8.79 Hz), 6.48 (1 H, d, J=16.92 Hz), 6.43 (1 H, s), 5.50 (1 H, t, J=7.03 Hz), 4.18 (2 H, d, J=7.03 Hz), 3.87 (3 H, s), 3.22 (4 H, dt, J=9.50, 5.68 Hz), 2.39-2.48 (2 H, m), 2.32-2.39 (2 H, m).
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].[Cl:10]CCl.C1(C)C=CC=CC=1>CN(C)C=O>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([Cl:10])=[O:4]
Reactant: ClCCl
Reactant: C=CCC(F)(F)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCC(F)(F)C(=O)Cl

Procedure:
For example, 2,2-difluoro-4-pentenoic acid 12c is contacted with about 1.0 to 1.5 molar equivalents of an appropriate chlorinating agent. The reaction is carried out in a suitable solvent, such as dichloromethane, toluene or dimethylformamide. The reaction is carried out at a temperature of from about 20° C. to about 35° C. and generally requires about 4 to 24 hours. The product, 2,2-difluoro-4-pentenoyl chloride 12a, can be isolated by fractional distillation and purified by techniques well known in the art, such as chromatography.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH3:27])[C:21]3=[O:26])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C1COCC1>C(O)C>[C:13]([C:11]1[CH:10]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH3:27])[CH:21]3[OH:26])[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1Cc2c(cccc2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1Cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cccc2C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
Sodium borohydride (2.35 g, 61.98 mmol, 1.5 equiv) was added in portions to a cold solution (0° C.) of compound 9 (13.8 g, 41.32 mmol, 1.0 equiv), THF (140 mL) and ethanol (140 mL). The reaction mixture was stirred at room temperature for 2 hours when LC/MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL). 1M HCL was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 10 (15 g, >99% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]1([C:13]2[O:17][C:16]([C:18]3[C:19]([NH2:30])=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:23]=3)=[N:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[N:23]=[C:18]([C:16]3[O:17][C:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:14][N:15]=3)[C:19]([NH2:30])=[N:20][CH:21]=2)[CH2:25][CH2:26]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethanesulfonyl chloride (37.51 mg, 27.64 μL, 0.2917 mmol) was added to a solution of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-piperazin-1-yl-pyrazin-2-amine (116 mg, 0.2652 mmol) and triethylamine (53.67 mg, 73.93 μL, 0.5304 mmol) in dichloromethane (5 mL) at 0° C. and the resulting solution stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane, washed with water and the aqueous layer extracted further with dichloromethane. The organics were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (3% MeOH/DCM) to afford the title compound still impure. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (25.2 mg, 18% Yield).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[F:13]C1C=CC(C(OC)=O)=CC=1>>[F:13][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: COc1ccc(C(C)(C)N)cc1
Product: CC(C)(N)c1ccc(F)cc1
Yield: 20 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 4-fluorobenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 20%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH:9]([C:17]([O:19]C(C)(C)C)=[O:18])[C:10]([O:12]C(C)(C)C)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH:9]([C:10]([OH:12])=[O:11])[C:17]([OH:19])=[O:18]
Reactant: COC(=O)/C=C/C=C/CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)/C=C/C=C/CC(C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a stirred solution of 40 (200 mg, 0.59 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL). The reaction was allowed to proceed overnight. Volatiles were removed under reduced pressure to leave 41 as a white solid (112 mg, 0.49 mmol, 83%). 1H-NMR (CD3OD, 400 MHz) δ 7.11 (dd, 1H), 6.33 (dd, 1H), 6.16 (m, 1H), 5.81 (d, 1H), 3.76 (s, 3H), 3.15 (t, 1H), 2.70 (t, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][NH:13][CH2:14]2)[CH2:10][CH2:9]1)=[O:6].C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>ClCCl>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][N:13]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=3)(=[O:40])=[O:39])[CH2:14]2)[CH2:10][CH2:9]1)=[O:6]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-4-Methyl-2-morpholino-N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)pentanamide (191 mg, 0.617 mmol), triethylamine (0.129 mL, 0.926 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.109 mL, 0.679 mmol) were combined in dichloromethane (0.5 mL). The reaction was stirred at room temperature for 3 hours. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=6.2, 1H), 8.38 (s, 1H), 8.19 (d, J=7.9, 1H), 7.92 (d, J=7.8, 1H), 7.72 (t, J=7.9, 1H), 4.27-4.20 (m, 1H), 3.90 (dd, J=2.3, 10.0, 1H), 3.76-3.67 (m, 4H), 3.20 (ddd, J=3.9, 9.4, 10.9, 3H), 2.97 (dd, J=7.1, 9.6, 1H), 2.78-2.72 (m, 2H), 2.72-2.67 (m, 2H), 2.62-2.53 (m, 2H), 1.94 (dt, J=6.2, 12.1, 1H), 1.89-1.77 (m, 3H), 1.64-1.54 (m, 2H), 1.30 (ddt, J=6.5, 9.3, 12.8, 1H), 0.92 (d, J=4.4, 3H), 0.91 (d, J=4.4, 3H); MS (ESI+) m/z 518(M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:36]([CH3:37])=[N:35][N:34]([CH3:38])[C:28]2=[N:29][C:30]=1[C:31](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:36]([CH3:37])=[N:35][N:34]([CH3:38])[C:28]2=[N:29][C:30]=1[C:31]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: Cc1nn(C)c2nc(C(=O)Cl)c(Cl)cc12
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2nc3c(cc2Cl)c(C)nn3C)n1
Temperature: 150 °C
Yield: 77.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 5-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6-carbonyl chloride (0.095 g, 0.389 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.061 g (77% yield) of pure product: MS (ES) m/z 513 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CC(C)NCC[C@@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 55.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.088 mmol) and [(3R)-3-aminobutyl](1-methylethyl)amine (78 mg, 0.60 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (26 mg, 56%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (21 mg, 90%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J=5.6 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m, 1H), 1.98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4.19 (m, 1H), 430 (m, 1H), 4.48 (s, 1H), 4.54-4.59 (m, 2H), 4.97 (m, 1H), 6.98 (m, 2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14](OC(F)(F)F)=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].BrC1C(O)=C(C=C(C(C)(C)C)C=1)C=O.[F:39][C:40]([F:51])([F:50])C1C=C(B(O)O)C=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:40]([F:51])([F:50])[F:39])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[N:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][CH2:6]2.C(Cl)Cl>CO.C(Cl)Cl>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc2ccccc2c1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc2ccccc2c1

Procedure:
The title compound was prepared by analogy to Example 48 except that 6-methoxy-1-naphthalen-2-yl-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: C(O)(C)C.C([O-])=O.[NH4+].Cl[C:10]1[N:11]=[C:12]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16](Cl)[C:14]=2[N:15]=1>O.[Pd]>[N:25]1([C:12]2[C:13]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=[CH:10][N:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc(Cl)c2nc(Cl)nc(N3CCCCC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2ncnc(N3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a round-bottom flask were added palladium (540 mg; 0.51 mmol; 0.05 eq.) isopropanol (90 mL). Ar was bubbled in this mixture. A degassed ammonium formate solution in water (2.56 g, 40.6 mmol, 4 eq., in 4 mL of water) was added, followed by methyl 2,8-dichloro-4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (Intermediate 1.4) (3.46 g; 10.5 mmol; 1 eq.) and degassed isopropanol (10 mL). After 30 min, a second batch of ammonium formate was added as solution in water (2.56 g, 40.6 mmol, 4 eq., in 4 mL of water). Finally, after additional 30 min, another 8 equivalents of ammonium formate in water were (5.12 g, 81.2 mmol, 8 eq., in 8 mL of water). The mixture was then stirred at rt. overnight and filtered through celite. The filtrate was evaporated. The crude product was dissolved in DCM and washed with water and brine. Organic phase was dried over magnesium sulfate, filtered and evaporated to give methyl 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (2.29 g; 83%) (Intermediate 1.5), as a yellow solid in 92.9% HPLC purity. This product was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[I:12]Cl.O>CC(O)=O>[I:12][C:9]1[CH:10]=[C:4]([O:3][CH:2]([F:11])[F:1])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OC(F)F)cc1I
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6 mL) was heated to 60° C. and iodine monochloride (1.07 g, 6.6 mmol) in AcOH (15 mL) was added dropwise. The reaction mixture was then heated to 85° C. and stirred for 1.5 h. The reaction mixture was cooled to r.t. and poured into cold water and the resulting suspension filtered. The filtrate was concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10-20% EtOAc/hexanes) gave the title compound (0.40 g, 22%) as a dark brown oil. δH (DMSO-d6) 7.38 (1H, d, J 2.7 Hz), 6.98-6.94 (1H, m), 6.97 (1H, t, J 74.8 Hz), 6.75 (1H, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)+, RT 3.28 minutes (Method 5).