Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([O:21][CH2:22][CH3:23])=[S:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:11]1[C:19]([O:21][CH2:22][CH3:23])=[S:20]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=S)c1[nH]c2ccccc2c1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=S)c1c(Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 6 h
Yield: 59.2 %

Procedure:
Powdered sodium hydroxide (3.2 g) was added in a single portion to a vigorously stirred solution of ethyl 3-benzylthioindole-2-carboxylate (2.48 g), 3,4-dichlorobenzyl chloride (1.71 g) and tetra-n-butylammonium hydrogensulphate (0.5 g) in dichloromethane (100 ml). The reaction was stirred for 6 hours then partitioned between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using iso-hexane:5% ethyl acetate as eluent to give the product as a white crystalline solid (2.26 g, 60%); NMR d (CD3SOCD3) 1.32 (t, 3H), 4.00 (s, 2H), 4.25 (q, 2H), 5.60 (s, 2H), 6.78 (d, 1H), 7.04 (m, 2H), 7.10-7.38 (m, 8H), 7.80 (d, 1H); M/z (+) 470 (M+), 426, 424.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[N:4]1[C:3]([CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cn2ccccc2n1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cn2ccccc2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
1.5 g (9 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were solubilised in 55 ml of dimethylformamide with magnetic stirring, 1.834 g (9.9 mmol) of potassium phthalimide were added portion wise and then the mixture was stirred at 60° C. for 2 h. The obtained solid was isolated by filtration, washed with 30 ml of diisopropyl ether and dried in a vacuum bell jar in order to obtain 1.81 g (yield=67%) of 2-(imidazo[1,2-a]pyridin-2-ylmethyl)isoindoline-1,3-dione as a white solid. LC-MS: m/z=278 (MH+); UV purity at 254 nm=93%. 1H NMR (300 MHz, DMSO) δ 8.45 (d, J=6.8 Hz, 1H), 7.96-7.67 (m, 5H), 7.45 (dd, J=9.1, 0.5 Hz, 1H), 7.33-7.14 (m, 1H), 6.84 (td, J=6.8, 1.1 Hz, 1H), 4.88 (s, 2H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[C:12]([C:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(C)[CH3:15])#N.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.C1COCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH3:15])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)N1CCCCC1
Reactant: Brc1ccc(Br)cc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
In a three necked round bottom flask fitted with a condenser and nitrogen stream, was placed a small quantity of ground glass and magnesium turnings (190 mg, 7.40 mmol). The mixture was stirred for 30 minutes under vacuum then placed under nitrogen and iodine added (one small crystal), followed by the rapid addition of 1,4-dibromobenzene (2.43 g, 10.3 mmol) in 15 ml of anhydrous diethyl ether. The reaction mixture was then heated under reflux for 5 minutes. After this time, a solution of 1-(1-cyano-1-methylethyl)-piperidine (1.0 g, 6.60 mmol) in anhydrous THF was added dropwise resulting in the formation of a white precipitate. The reaction mixture was heated under reflux for 1.5 h, before cooling to ambient temperature. The resultant mixture was treated with saturated aqueous potassium carbonate solution and extracted with DCM. The organic extract was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate in cyclohexane) to afford the title compound (200 mg, 95%) as a colourless oil. LCMS (Method B): RT=1.99 min, M+H+=282, 284.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CCC(Br)C(=O)OC
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Reaction time: 0.33 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (4.00 g, 10.7 mmol) in 45 mL of DMF was added a dispersion of 60% sodium hydride in mineral oil (1.71 g, 42.7 mmol) at 0° C. After being stirred for 20 min, methyl 2-bromobutanoate (6.15 mL, 53.4 mmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 12 h until completion of the reaction. Then sat. aq. NH4Cl solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 0 to 100% MTBE/hexanes, gradient elution), followed by separation of individual stereoisomers by chiral SFC (flowrate: 65 mL/min on a ChiralPak ®AD-H column (Diacel Inc., Fort Lee, N.J.) using 3:1 heptanes/IPA (0.1% DEA)/CO2 as the eluent) provided the title compound as the faster eluting isomer.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C)cc1)C2
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3nccn3C)C2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
1-Methyl-1H-imidazole (104 mg, 1.267 mmol) in dry ether (5 mL) was added to butyllithium (2.5M in hexanes) (519 μl, 1.298 mmol) in dry ether (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-methyl 1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (200 mg, 0.415 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 45 minutes at −78° C., then allowed to warm to room temperature over 2 hours. Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (3×20 mL), the combined organic phases were washed with brine (20 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-60% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone (22 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.52 min, m+H=532.0; 1H NMR (400 MHz, CDCl3): δ 7.61-7.58 (2H, m), 7.46-7.40 (2H, m), 7.31 (1H, s), 7.29-7.27 (2H, m), 7.18 (1H, d, J=0.9 Hz), 7.17-7.12 (2H, m), 6.99 (1H, br. s), 6.50 (1H, d, J=2.2 Hz), 5.53 (1H, dd, J=12.2, 2.2 Hz), 4.45 (1H, d, J=16.7 Hz), 3.88-3.84 (4H, m), 2.92-2.78 (2H, m), 2.60 (1H, d, J=12.2 Hz), 2.50-2.37 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl L-phenylalaninate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-phenylalaninate (oil), saponification of which and processing of the reaction product yields N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl-L-phenylalanine (M.P. 153° to 155°).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([NH2:16])[C:14]#[CH:15]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH2:13][C:14]#[CH:15])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C#CCN
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C#CCNc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (3-47 g) in acetonitrile (16 mL) a solution of propargylamine (1.76 g) in acetonitrile (16 mL) was added dropwise at 0° C., the mixture warmed to r.t. and stirred at r.t. for 48 h. The suspension was diluted with ethyl acetate, washed with brine, dried (Na2SO4), and evaporated. Purification by flash chromatography on silica using hexane/methyl tert-butyl ether gave the title compound (1.97 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].FC1C=C(C=CC=1[C:31]([F:34])([F:33])[F:32])C=O>>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])=[CH:3][C:2]=1[C:31]([F:34])([F:33])[F:32])(=[O:10])=[O:9]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1

Procedure:
The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluoro-benzaldehyde with 3-fluoro-4-trifluoromethylbenzaldehyde.
Reaction SMILES: [CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4].C(O)(=O)C.Cl.[OH-].[Na+]>O.C(Cl)(Cl)Cl>[CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:4])=[O:5]
Reactant: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COS(=O)(=O)c1ccccc1N
Reaction time: 4 h

Procedure:
688 g of 2-nitrobenzenesulfonic acid methyl ester, 4.7 L of acetic acid, and 2.18 kg of SnCl.H2O are placed in a reaction container having a stirrer, a thermometer, and a nitrogen introducing pipe attached thereto, and cooled to a temperature of not more than 10° C. Hydrochloric acid gas is blown into the reaction mixture under stirring for 4 hours. Next, the reaction mixture is stirred at not more than 10° C. for 10 hours. 8.4 L of chloroform is added to the reaction mixture, and neutralized by a 20% NaOH aqueous solution while the temperature is kept at not more than 10° C. Further, 56 L of water is added, and the reaction mixture is separated. An aqueous phase is extracted by 4 L of chloroform, washed with a chloroform layer with 4 L of water twice, and separated. The separated product is dried by anhydrous magnesium sulfate, and filtered to obtain a chloroform solution of 2-aminobenzenesulfonic acid methyl ester. The obtained solution and 950 g of diethylaniline are placed in a reaction container having a stirrer, a thermometer, and a nitrogen introducing pipe attached thereto, and 287 g of acrylic acid chloride is dropped at a temperature of not more than 5° C. over 15 minutes. The temperature is kept at not more than 5° C., and the solution is stirred for 6 hours. 800 mL of concentrated hydrochloric acid and 12.8 L of water are added to the reaction mixture, and the reaction mixture is separated. An organic layer is washed with 6.4 L of 2% hydrochloric acid, 6.4 L of water, 6.4 L of a 3% sodium hydrogen carbonate aqueous solution, and 6.4 L of water in this order. The organic layer is dried with anhydrous magnesium sulfate, filtered, and dried under reduced pressure at 30° C. to obtain 796 g of crystals. The crystals are refined by column chromatography (5 kg of silica gel, mobile phase of hexane/ethyl acetate=2/1) to obtain 406 g of Monomer 6B represented by the formula (6B):
Reaction SMILES: [CH2:1]([P:5](Cl)([CH2:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]([CH3:4])[CH3:3].C(P(=O)CC(C)C)C(C)C.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O1CCCC1>[CH2:1]([P:5](=[O:6])([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CP(=O)(Cl)CC(C)C
Reactant: CCCCCCC[Mg]Br
Agent: CC(C)C[PH](=O)CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCP(=O)(CC(C)C)CC(C)C
Temperature: 25 °C

Procedure:
For example, in the preparation of non-radioactive diisobutyl-n-heptylphosphine oxide (Methods for preparing diisobutylphosphinyl chloride by chlorinating diisobutylphosphine oxide, described by R. H. Williams, L. A. Hamilton J. Am. Chem. Soc. (1952), 74, 5418), a solution of diisobutylphosphinyl chloride (3.9 gm) in tetrahydrofuran (50 ml.) was added dropwise to a refluxing solution of n-heptylmagnesium bromide (prepared from magnesium turnings (1.2 gm), n-heptyl bromide (9.0 gm) and tetrahydrofuran (100 ml.)). The mixture was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured onto ice and 2N HCl (300 ml.), and extracted with methylene dichloride. The combined extracts were washed with lithium hypochlorite solution, 2N NaOH solution and finally with water, then dried (MgSO4). The solvent was removed by distillation and the residual yellow oil (8 gm) was eluted with chloroform down a silica gel column. The product (R1=0.1 to 0.2 on silica t.l.c. (CHCl3)) was finally distilled to yield diisobutyl-n-heptyl-phosphine oxide (coded as WS148) as a colorless liquid, bp. 120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:34]=[CH:33][C:12]([O:13][C:14]3[C:15]([CH:20]4[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=[O:27])[CH2:22][CH2:21]4)=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl.C(N(C(C)C)CC)(C)C.[CH3:45][O:46][CH2:47]C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.O>[CH3:45][O:46][CH2:47][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([C:15]2[C:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[CH:34][CH:33]=3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: Cc1ccc(Nc2ccc(Oc3nccnc3C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(3-(4-(5-methylpyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate (0.220 g, 0.434 mmol) in DCM (5 mL) was added 4M HCl in dioxane (2 mL). After stirring for 2 h at RT, diisopropylethylamine (0.525 mL, 3.01 mmol), 2-methoxyacetic acid (0.077 mL, 1.004 mmol), and HATU (0.305 g, 0.803 mmol) was added and the reaction mixture was stirred at RT in 2 h. Water was added and the mixture was extracted with DCM (3×), dried over Na2SO4, concentrated. The crude material was purified by reverse phase HPLC, then neutralized with saturated NaHCO3, extracted with DCM (3×), dried over Na2SO4, concentrated to give the title compound. MS (ESI, pos. ion) m/z: 434.2 (M+1). IC50 (uM) 0.000058.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([NH2:22])=[C:18]([NH2:21])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:23]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15]([CH:16]=[C:17]4[N:22]=[N:23][N:21]=[C:18]4[CH:19]=3)=[CH:14][NH:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cnc(-n2[nH]cc3cc4nnnc4cc32)c(Cl)c1
Yield: 113.2 %

Procedure:
To a solution of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5,6-diaminoindazole [Compound No. 81] (5.0 g) in acetic acid (20 g), a solution of sodium nitrite (0.9 g) in water (3 ml) was added dropwise at room temperature. After completion of the reaction, the reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 5-(3-chloro-5-trifluoromethylpyridin-2-yl)[1,2,3]triazolo[4,5-f]indazole (5.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:31][CH2:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CC(=O)c1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C(=O)CBr)cn1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a chloroform (28 mL) solution of 1-(5-methylpyrazin-2-yl)ethanone (1.9 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (2.7 mL) and trimethylsilyl trifluoromethanesulfonate (3.0 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (3.0 g) was added thereto, and the resultant was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resultant was stirred for 15 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→60/40) and then further purified by hexane/ethyl acetate-gradient elution (=90/10→80/20) to obtain the title compound (2.1 g) as a pale yellow solid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([CH2:17][N:18]4[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]4=[O:26])=[C:11]3[N:10]=[CH:9]2)=CC=1.C1(OC)C=CC=CC=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[N:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[CH2:17][N:18]2[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]2=[O:26])[NH:8][CH:9]=1
Reactant: CCCC1CC(=O)N(Cc2ccnc3c2ncn3Cc2ccc(OC)cc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2ccnc3[nH]cnc23)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution containing 1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x187 (0.6 g), anisole (0.4 ml) and concentrated H2SO4 (0.2 ml) in trifluoroacetic acid (4 ml) is stirred in a flow of argon at 20° C. for 2 h. The homogeneous reaction mixture is added dropwise at 0° C. to a mixture of a saturated aqueous solution of NaHCO3 (50 ml) and ethyl acetate (50 ml). The organic layer is separated. The aqueous one (pH ˜8) is subjected to additional extraction with chloroform containing 10% of tert-butanol. The combined organic layers are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel (chloroform/methanol) to afford 1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one 95 (0.34 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH2:6][CH:5]([C:8](OC)=[O:9])[CH2:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4]1)[CH3:2]
Reactant: CCC1CCC(C(=O)OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1CCC(CO)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-ethylcyclopentanecarboxylate (1.50 g, 9.61 mmol) in THF (10 mL) was added LAH (1 M in THF; 9.6 mL, 9.6 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with saturated Na2SO4, filtered through a pad of celite, washing with ethyl acetate, and the filtrate was concentrated to dryness to afford (3-ethylcyclopentyl)methanol (mixture of cis and trans isomers).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:46])([CH3:45])[O:6][C@H:7]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH2:36])=[O:35])[CH:29]=3)[CH:24]=2)[O:19]1)CC1C=CC=CC=1)([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:4][C:2]([Si:5]([CH3:46])([CH3:45])[O:6][C@H:7]([CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:8][NH:9][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH2:36])=[O:35])[CH:29]=3)[CH:24]=2)[O:19]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3ccnc(C(N)=O)c3)ccc2O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNC[C@H]1CCc2cc(-c3ccnc(C(N)=O)c3)ccc2O1)COc1ccccc1

Procedure:
4-((2R)-2-{[[(2S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-3-(phenyloxy)propyl](phenylmethyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)-2-pyridinecarboxamide (Example 89, 44 mg, 0.07 mmol) was added to a suspension of 10% Pd/C (44 mg) in methanol (3 mL). Ammonium formate (22 mg, 0.35 mmol, 5.0 eq.) was added, and the mixture was heated at reflux for 30 minutes. Solids were removed by filtration through Celite®, and the filtrate was concentrated in vacuo. The title compound was collected as a pale yellow oil (25 mg, 66%): 1H NMR (300 MHz, acetone-d6) δ8.58 (d, 1 H), 8.32 (d, 1 H), 7.96 (broad s, 1 H), 7.78 (dd, 1 H), 7.60-7.56 (m, 2 H), 7.30-7.24 (m, 2 H), 6.95-6.81 (m, 4 H), 6.80 (broad s, 1 H), 4.25-4.19 (m, 2 H), 4.15-4.07 (m, 1 H), 3.99-3.92 (m, 1 H), 2.99-2.86 (m, 6 H), 2.13-2.06 (m, 1 H), 1.90-1.80 (m, 1 H), 0.92 (s, 9 H), 0.16 (s, 3 H), 0.13 (s, 3 H); MS m/z 548.3 (MH+).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=O>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: COc1ccc(Br)cc1C=O
Product: COc1ccc(Br)cc1CN1CCN(c2cc(=O)[nH]cn2)CC1

Procedure:
6-[4-(5-Bromo-2-methoxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromo-2-methoxybenzaldehyde. Mass spectrum (ES) MH+=379.