Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[ClH:31]>ClCCl>[ClH:31].[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: Cl
Solvent: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 4-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazine-1-carboxylate (100 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (20 mL). Hydrogen chloride (g) was then introduced at 0-5° C. The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration to yield 3-(methylthio)-1-phenyl-6-(piperazin-1-yl)-1H-indazole hydrochloride as a yellow solid.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOC(C)=O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12][CH2:11][C:10]1[CH:9]=[C:8]([OH:7])[CH:22]=[CH:21][CH:20]=1
Reactant: COCCOCOc1cccc(COCc2ccccn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cccc(COCc2ccccn2)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[3-(2-methoxy-ethoxymethoxy)-benzyloxymethyl]-pyridine (171 mg, 0.56 mmol, example 73) in CH3OH (1.9 mL) is added p-toluenesulfonic acid monohydrate (148 mg, 0.78 mmol). The mixture is heated to 60° C. and stirred for 1.5 hrs, then cooled to room temperature and diluted with EtOAc. The organic layer is washed with sat NaHCO3, brine, then dried over MgSO4 and concentrated to give the title compound as a white crystalline solid. MS (ESI) 216 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:9]1[CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13][NH:8]1
Reactant: COc1ccccc1C1CC(OC)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1CC(OC)CCN1
Temperature: 20 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-(2-methoxyphenyl)-4-methoxypiperidine (864 mg, 2.67 mmol) in CH2Cl2 at 0° C. was added TFA (9.6 mL) and the resulting solution was stirred at 0-40° C. for 2 hours. TFA was removed in vacuo, and the residue was stirred with 40 mL of 1:1 mixture of CH2Cl2 and 1N NaOH for 20 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a light brown oil (565 mg). 1H NMR (CDCl3, 400 MHz) δ:3.82 (3H, s, OMe), 3.37 (3H, s, OMe).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[C:19]4[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]4)=[C:28]([C:41]([F:44])([F:43])[F:42])[CH:27]=3)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:45]NC1C2SC=C(C(O)=O)C=2N=CN=1>>[CH2:39]([N:36]1[CH2:35][CH2:34][N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:19]3[C:20]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[C:4]6[N:5]=[CH:6][N:7]=[C:2]([NH:1][CH3:45])[C:3]=6[S:10][CH:9]=5)=[O:12])[C:23]([CH3:24])=[CH:22][CH:21]=4)[CH:16]=[CH:17][N:18]=3)=[CH:27][C:28]=2[C:41]([F:43])([F:44])[F:42])[CH2:38][CH2:37]1)[CH3:40]
Reactant: CNc1ncnc2c(C(=O)O)csc12
Reactant: CCN1CCN(Cc2ccc(Nc3nccc4c(NC(=O)c5csc6c(N)ncnc56)c(C)ccc34)cc2C(F)(F)F)CC1
Product: CCN1CCN(Cc2ccc(Nc3nccc4c(NC(=O)c5csc6c(NC)ncnc56)c(C)ccc34)cc2C(F)(F)F)CC1
Yield: 12.6 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated in sequence, except for using N1-(4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl)-6-methyl-isoquinolin-1,5-diamine (0.020 g, 0.05 mmol) obtained in Example 7 and 4-methylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.05 mmol) to obtain the title compound (4 mg, 13%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][CH:8]=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:10]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nccc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccnn1CC(=O)NN
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (5-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 8 h. The mixture was cooled to rt and the precipitated product was filtered off, dried and crystallized from toluene. The title compound (95% purity, based on NMR) was obtained as a white solid (yield: 45%). 1H-NMR (300 MHz, DMSO): δ=2.24 (s, 3H), 4.29 (s, 2H), 4.65 (s, 2H), 6.00 (d, J=1 Hz, 1H), 7.55 (d, J=1 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH2:14]=[O:15]>C(O)C>[OH:15][CH2:14][N:5]1[C:4](=[O:13])[C:3]2[C:9](=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])[S:6]1(=[O:8])=[O:7]
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: C=O
Solvent: CCO
Product: Cc1cccc2c1C(=O)N(CO)S2(=O)=O
Temperature: 25 °C
Yield: 82 %

Procedure:
4-Methylsaccharin prepared in (b) (500 mg; 2.54 mmol) was dissolved in 2.53 ml of warm ethanol (steam bath). Once a homogeneous solution was achieved, formalin (37% in methanol; 1.76 ml excess) was added dropwise. The solution was allowed to cool to room temperature and then chilled to 0° C. for 4 days. The resulting solid was collected and air-dried to afford 476 mg (82%) of 2-hydroxymethyl-4-methylsaccharin, mp 196°-198° C. 1H nmr (300 MHz, CDCl3): 7.767 (1H, t, J=6.75 Hz); 7.732 (1H, d, J=7.72 Hz); 7.600 (1H, d, J=6.64 Hz); 5.361 (2H, d, J-8.00 Hz); 3.296 (1H, t, J=8.16 Hz); 2.793 (3H, s). IR (KBr, cm1): 3505 (s); 3070 (w); 1735 (s); 1580 (m).
Reaction SMILES: C1C2N(C(=O)C[C@@H](CCC)C(O)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:24]([O:28][C:29](=[O:59])[CH2:30][CH:31]([NH:36][C:37](=[O:58])[CH:38]([CH2:42][C:43]([N:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[CH2:39][CH2:40][CH3:41])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:26])[CH3:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:24]([O:28][C:29](=[O:59])[CH2:30][CH:31]([NH:36][C:37](=[O:58])[CH:38]([CH2:42][C:43]([N:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[CH2:39][CH2:40][CH3:41])[C:32](=[O:35])[CH2:33][F:34])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Solvent: ClCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Reaction time: 3 h

Procedure:
A stirred solution of [3S/R, 4S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.51 g, 5.03 mmol) in anhydrous DCM (60 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.35 g, 5.53 mmol) at 0° C. The resulting mixture was kept at 0° C. for 3 h, diluted with DCM, and then washed sequentially with saturated aqueous sodium thiosulphate, NaHCO3 solution and brine. The organics were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (25% ethyl acetate in 40/60 hexanes) to afford the sub-title compound as an off white solid (1.437 g, 57%): IR (solid, cm−1) 1722, 1689, 1636, 1531, 1441, 1365, 1279, 1155; 1H NMR (400 MHz, CDCl3) δ 0.85-1.50 (3H, m), 1.35-1.54 (11H, m) 1.55-1.69 (1H, m), 1.78-1.95 (1H, m), 2.67-3.28 (4H, m), 3.60-3.79 (1H, m), 4.80-5.59 (3H, m), 6.89-7.04 (1H, m), 7.33-7.54 (4H, m), 7.98-8.04 (2H, m), 8.15-8.28 (2H, m); 13C (100 MHz, CDCl3) δ 14.12, 14.40, 14.47, 14.60, 20.78, 20.84, 21.47, 28.32, 28.42, 28.48, 29.77, 33.63, 34.58, 34.91, 40.05, 43.05, 43.26, 43.29, 52.60, 53.00, 53.64, 66.90, 66.99, 82.62, 82.69, 85.53, 116.88, 116.94, 120.28, 120.31, 124.27, 127.76, 127.86, 128.69, 128.77, 128.99, 138.80, 171.21, 171.29, 172.21, 172.25, 175.53, 176.03, 203.04, 203.20, 203.30, 203.46; 19F (376 MHz, CDCl3) δ −232.12, −233.24.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([N:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:10][CH:9]2[NH2:20])[CH:7]=1.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C@@H:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](Cl)=[O:40])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[CH2:26][CH2:25]1.[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([C@@H:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]5[N:10]=[C:11]([C:14]6[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=6)[CH:12]=[CH:13][N:20]=5)[CH:7]=4)=[O:40])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[CH2:28][CH2:29]1
Reactant: CN1CCN([C@H]2CCc3cc(C(=O)Cl)ccc32)CC1
Reactant: Cc1ccc(N)cc1N1C=CC(c2cccnc2)=NC1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CC[C@@H]3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (681 g, 2.46 mol, 1.1-fold) was dissolved in pyridine (3 L). (1S)-1-(4-Methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carbonyl chloride hydrochloride (1325 g, the actual maximum content of 626 g, equivalent to 2.235 mol, 1-fold) was added slowly within 30 minutes with stirring. The solution turned very hot since the reaction was severe but there was no need to have it cool down. After the solution was stirred overnight at room temperature, the reaction solution was added to 2 N aqueous solution of sodium hydroxide (2 L) with stirring, immediately followed by addition of methylene dichloride (2 L). After being stirred for a while, the solution was transferred to a 5 L separatory funnel and then methylene chloride layer was separated. The water phase was extracted with methylene chloride (2×500 mL). The extracts were pooled, dried over anhydrous magnesium sulfate, and then concentrated. The residue was dissolved in methylene dichloride and then purified by silica gel column chromatography using methylene chloride/5% methanol/1% triethylamine as eluent. The fractions containing the desired product were pooled, and concentrated under reduced pressure. The residue was dissolved in 1 L of warm ethyl acetate and crystals were precipitated after stirring. The solid was collected by filtration and dried in vacuum at 50° C. to obtain the title product (617 g, 53% total yield of the three steps). MS (M+1)=520.27.
Reaction SMILES: C(N(C(C)C)C(Cl)=O)(C)C.[CH:11]([N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1)[NH2:27].C1(C)C=CC=CC=1>C(O)C>[CH:11]([N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]([CH3:17])[CH3:16])([CH3:12])[CH3:13].[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:21]([NH:20][C:18]([N:14]([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:12])[CH3:13])=[O:19])=[S:22])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CC(C)N(C(=O)Cl)C(C)C
Agent: CC(C)N(C(=O)N=C=S)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(C(C)C)C(C)C)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(Diisopropylamino)methanoyl isothiocyanate was prepared using commercially available N,N-diisopropylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Diisopropylamino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][O:18]CC3C=CC(S(C)(=O)=O)=CC=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=NC(Cl)=NC=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][OH:18])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(Br)cn3)CC2)cc1
Agent: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC[C@@H]1C[C@@H]1C1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of step A (4.94 g, 19.6 mmol) was dissolved in DMF (40 mL), and Cs2CO3 (35 g, 107 mmol) and 5-bromo-2-chloropyrimidine (3.8 g, 19.6 mmol) were added. After stirring the mixture at RT for 5 hours, the mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layers were dried with Na2SO4 and concentrated in vacuo. The residue was purified via silica gel column chromatography (20/1, DCM/MeOH), yielding the title compound.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([OH:14])=[CH:12][C:11]=1[OH:17].Cl[CH2:19][CH2:20][C:21](O)=[O:22].[OH-].[Na+].Cl>>[Cl:9][C:10]1[CH:16]=[C:15]2[C:13](=[CH:12][C:11]=1[OH:17])[O:14][CH2:19][CH2:20][C:21]2=[O:22]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(Cl)c(O)c1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: O=C1CCOc2cc(O)c(Cl)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 208.7 %

Procedure:
A 50-liter reactor was charged with trifluoromethanesulfonic acid (8 kg) and the reactor cooled in an ice bath. To the reactor was added 4-chlororesorcinol (1.6 kg, 11.1 mol), in portions, at a rate such that the internal temperature did not exceed 10° C. To the reactor was then added 3-chloropropanoic acid (1.26 kg, 11.6 mol), and the resulting mixture was warmed to ambient temperature, then heated at 45-55° C. for 6 hours. The reaction mixture was then slowly added to ice-water (20 L). The resulting slurry was stirred for 2 hours, and the resulting precipitate was collected by filtration, washed with water (12 L), and air-dried. This material was added to a solution of sodium hydroxide (1.1 kg, 27.5 mol) in ice-water (24 L), at a rate such that the internal temperature did not exceed 20° C. The resulting solution was stirred below 20° C. for 1 hour, then cooled, and treated with concentrated hydrochloric acid (2.5 L), at a rate such that the temperature did not exceed 10° C. The resulting slurry was stirred below 10° C. for 1 hour, and the resulting precipitate was collected by filtration, washed with water (10 L), and partially air-dried. The crude solids from four such procedures were combined and added to a mixture of acetone (32 L) and water (40 L), and the resulting mixture was stirred and heated until a clear solution formed. This solution was then cooled to 5-10° C., and the resulting precipitate was collected by filtration, washed with water (12 L), and dried to afford 6-chloro-7-hydroxychroman-4-one as a white solid (4.6 kg, 52% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCBr)OCc1ccccc1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[Li+].[Cl-].C=O>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-5-Biphenyl-4-ylmethyl-3-isobutyryl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=t-butoxycarbonyl, R4=isopropyl) (2.5 g, 6.2 mmol) is dissolved in 10 mL of anhydrous tetrahydrofuran, add iPr2NEt (1.1 g, 8.2 mmol), anhydrous LiCl (140 mg, 3.2 mmol) and molecular sieves (0.5 g), the mixture is refluxed under nitrogen atmosphere for 30 min, then add paraformaldehyde (230 mg, 7.6 mmol) in one portion, reflux for 2 h, cool to room temperature, add 50 mL of toluene, filter, the filtration is washed with 10% HCl(aq), saturated Na2CO3 and brine, dry over anhydrous NaSO4, evaporate under vacuum, the residue is purified by column chromatography to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Stepectroscopic data as Example 23, Method 1.
Reaction SMILES: [CH3:1][C@@:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=O.[OH-].[Li+].Cl.CN1CCOCC1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:41][NH2:42]>C1COCC1.O.O>[CH3:1][C@@:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[N:11]1)[C:3]([NH:42][O:41][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][O:35]1)=[O:5]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2cnccn2)cn1)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: C[C@@](CCn1cc(-c2cnccn2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]butanoate (0.32 g, 0.908 mmol) in THF-H2O (20 mL:10 mL) was added lithium hydroxide (0.217 g, 9.08 mmol, 10 eq). The mixture was allowed to stir at room temperature overnight. The mixture was then acidified with 1M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The solid was taken up in 2-methyltetrahydrofuran (20 mL). N-methyl morpholine (0.185 g, 1.81 mmol, 1.4 eq) was added, followed by CDMT (0.273 g, 1.55 mmol, 1.2 eq). The reaction mixture was allowed to stir for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.182 g, 1.55 mmol, 1.2 eq) was added, and the reaction mixture was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash chromatography, eluting with 0-10% MeOH/EtOAC to give (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (182 mg, 33% yield). LC-MS M−H 424.1.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]4[C:25]([O:29][CH3:30])=[N:26][CH:27]=[CH:28][C:23]=4[N:22]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=4[F:38])[N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[F:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:38])[C:31]=1[N:22]1[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[C:24]=2[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[N:21]1
Reactant: COc1nccc2c1c(-c1ccc(C3=CCN(Cc4ccccc4)CC3)cc1)nn2-c1c(F)cccc1F
Agent: [Pd]
Solvent: CO
Product: COc1nccc2c1c(-c1ccc(C3CCNCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 3-(4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridine (670 mg) in methanol (10 mL) was added 10% palladium carbon (80 mg), and the mixture was stirred overnight at 50° C. under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (540 mg).
Reaction SMILES: [C:1]([C:3]([C:16]1[C:25]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[C:19]([O:26][CH3:27])=[CH:18][CH:17]=1)([CH2:10][CH2:11][C:12](OC)=[O:13])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[H-].[Na+].Cl>COCCOC>[C:1]([C:3]1([C:16]2[C:25]3[O:24][CH2:23][CH2:22][O:21][C:20]=3[C:19]([O:26][CH3:27])=[CH:18][CH:17]=2)[CH2:10][CH2:11][C:12](=[O:13])[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4]1)#[N:2]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2c1OCCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c3c2OCCO3)CCC1=O
Temperature: 0 °C
Yield: 85.2 %

Procedure:
To a solution of Compound 1b (6.4 g, 17 mmol) obtained in Step B in 1,2-dimethoxyethane (96 mL) was added 60% sodium hydride (2.0 g, 50 mmol). After refluxing for 3 hours, the mixture was allowed to cool, poured into ice water, acidified with 6 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 1c (5.0 g, 86%) as a white solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([OH:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH:12](=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC=O

Procedure:
32.3 g (150 mmol) of pyridinium chlorochromate are suspended in 200 ml of anhydrous methylene chloride at room temperature, with vigorous stirring, and a solution of 21.4 g (100 mmol) of tetradecanol in 20 ml of anhydrous methylene chloride is added. This results in the reaction mixture boiling. The reaction is complete after 11/2 hours. The solution is decanted off from the solid which is washed with about 200 ml of dry diethyl ether. After filtration and evaporation of the solvent, chromatography is carried out on silica gel using petroleum ether (boiling point 35°-80° C.)/ethyl acetate 9:1. Yield: 18 g (84%).