Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].[CH:6]1[N:7]=[CH:8][N:9]2[C@@H:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:13][CH2:12]C[C:10]=12.C(OO)(C)(C)C>C1CCNC(=O)CC1.C1CCNC(=O)CC1.C1CCNC(=O)CC1.C1CCNC(=O)CC1.[Rh].[Rh].ClCCCl>[O:4]=[C:1]1[CH2:12][CH2:13][C@H:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:9]2[CH:8]=[N:7][CH:6]=[C:10]12
Reactant: N#Cc1ccc([C@H]2CCCc3cncn32)cc1
Reactant: O=C([O-])O
Agent: [Rh]
Agent: CC(C)(C)OO
Agent: O=C1CCCCCN1
Solvent: ClCCCl
Product: N#Cc1ccc([C@H]2CCC(=O)c3cncn32)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added Rh2(cap)4 (80 mg, 0.09 mmol), NaHCO3 (38 mg, 0.45 mmol) and (R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile, CAS #102676-87-9, (200 mg, 0.99 mmol). To this crude was added DCE (10 mL). To this crude was added anhydrous tert-butyl hydroperoxide (1.5 mL, 9.0 mmol). The crude was stirred at 40° C. for overnight. The crude was cooled to room temperature and filtered through celite, and the filtrate was concentrated. The residue was purified via column chromatography using a gradient, CH2Cl2 to 10% (2M NH3 in MeOH)/CH2Cl2 to give 0.12 g of the entitled product. MS 238.0 (M+H), LCMS condition B, retention time 0.50 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.23-2.51 (m, 2H), 2.51-2.65 (m, 2H), 5.40-5.57 (m, 1H), 7.13 (d, 2H), 7.35 (s, 1H), 7.65 (d, 2H), 7.88 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]>CCO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[C:12]([C:20]([CH3:27])([CH3:28])[O:21][SiH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:11]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: COCOc1cc(C2=C(C(=O)OC)CCC2)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: COCOc1cc(C2CCCC2C(=O)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Yield: 84.4 %

Procedure:
Filter a solution of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2,5-bis-methoxymethoxy-phenyl]-cyclopent-1-enecarboxylic acid methyl ester (0.715 g, 1.53 mmol) in EtOH (40 mL) through a 1×6 cm pad of activated carbon. Add the filtrate to a Pair® bottle containing 10% Pd/C (50% wet, 0.15 g) and hydrogenate this mixture at 55-60 psi for 3 hours. Filter the reaction through Celite® and concentrate the filtrate to afford the subtitled product (0.605 g, 84%) as an oil that may be used without further purification. 1H NMR (CDCl3) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.94 (s, 9H), 1.60-1.67 (m, 1H), 1.91-2.04 (m, 4H), 2.11-2.18 (m, 1H), 3.22 (s, 3H), 3.17-3.24 (m, 1H), 3.45 (s, 3H), 3.58 (s, 3H), 3.65-3.72 (m, 1H), 4.79 (s, 2H), 4.95 (dd, J=5.8, 6.8 Hz, 2H), 5.10 (dd, J=6.6, 9.6 Hz, 2H), 6.74 (d, J=3.0 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30]1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[CH:29]1([N:32]2[CH2:37][CH2:36][N:35]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[CH:17][CH:16]=3)=[O:15])[CH2:34][CH2:33]2)[CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: C1CN(C2CC2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 22.5 °C

Procedure:
A 100-L glass-lined reactor was charged with toluene (45.00 kg) and stirred at ˜20-25° C. To the stirring toluene was added 4-(4-morpholinylmethyl)benzoic acid hydrochloride (6.50 kg, 93.5%, 24.04 mol), 1-hydroxybenzotriazole monohydrate (2.32 kg, 15.13 mol), 1-cyclopropylpiperazine (3.50 kg, 27.07 mol) and acetonitrile (9.00 kg). The resulting off-white slurry was stirred under N2 at ˜20-25° C. for 40 minutes. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.50 kg, 27.07 mol) was added, followed by an acetonitrile (1.20 kg) rinse. After the addition, the reaction mixture was stirred at ˜20-25° C. overnight. Water (32.50 kg) and aqueous saturated sodium carbonate (19.50 L) were then added to the stirring suspension. The suspension was stirred for an additional 30 minutes. The resulting biphasic solution was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a 50% brine solution [water (19.50 L)/brine (19.50 L)]. To the stirred organic phase was then added anhydrous sodium sulfate (2.86 kg) and the resulting mixture was stirred at ˜20-25° C. for 1.5 hours. The solid sodium sulfate was filtered off and the filter cake was washed with acetonitrile (15.30 kg). The filtrate was transferred to a clean 100-L glass-lined reactor and stirred at ˜20-25° C. Water (0.47 kg) and 5/6N HCl in 2-propanol were added to precipitate the title compound as the corresponding bis-hydrochloride salt as a solid. The solid was filtered, washed with acetonitrile (10.2 kg) and dried (60 Torr, ˜40-45° C.) to a constant weight to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][NH2:18]>C1COCC1>[C:11]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]3[NH:17][NH:18][CH2:9][CH2:8][C:7]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: ClCCc1c(Cl)ncnc1-c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2ncnc3c2CCNN3)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 4-chloro-5-(2-chloroethyl)-6-phenylpyrimidine (150 mg) in dry THF (10 mL), hydrazine (5 mL, 1.0M in THF) was slowly added under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 60° C. for 5 hours and solvents were removed under reduced pressure. The resulting oil was purified by column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to afford 5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (45 mg) as colorless oily liquid. 1H NMR (DMSO-d6): δ 2.63-2.65 (t, 2H), 2.79-2.81 (t, 2H), 4.93-4.97 (t, 1H), 7.43-7.48 (m, 3H), 7.56-7.59 (m, 2H), 8.29 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].C(C12COC(C(SCCC#C)C)(OC1)OC2)CCC>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][S:5][CH2:1][CH2:2][C:3]#[CH:4])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CCCSCC(=O)O
Agent: C#CCCSC(C)C12OCC(CCCC)(CO1)CO2
Product: C#CCCSCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(but-3-ynylthiomethyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynylthio)acetic acid and 3-t-butyl-3-hydroxymethyloxetane using the methodology described in Example I. A small amount of 4-butyl-1-[1-(but-3-yn-1-ylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was also present.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[CH3:34][N:33]([CH3:35])[C:31]([C:30]1[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=1[NH:28][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1)=[O:32]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN(C)C(=O)c1ccccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N(C)C)n2)cc1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available 2-amino-N,N-dimethylbenzamide. MS (ES+): m/z 552.38 (100) [MH+]; HPLC: tR=0.96 min (UPLC, purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.Br[CH:25]([CH2:32]Br)[C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:25]([C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:32]1
Reactant: COc1ccc(CNCCNc2c(Cl)cccc2Cl)cc1OC
Reactant: C=CCNC(=O)C(Br)CBr
Product: C=CCNC(=O)C1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 23, react N-(2,6-dichlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromo-N-(2-propenyl)propanamide to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C:10](=[O:26])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]2=[O:25])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(O)(C(F)(F)F)=O>>[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C:10](=[O:26])[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:25])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)CN2CCNCC2=O)ccc(F)c1C#N

Procedure:
A flask charged with tert-Butyl 4-[2-{3-cyano-4-fluoro-2-methylphenyl}-2-oxoethyl]-3-oxopiperazine-1-carboxylate (0.030 g, 0.08 mmol) was treated with TFA (2.0 mL) for 20 minutes. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and crude was co-evaporated with dichloroethane (3×8 mL) to furnish the title product. LC/MS (IE, m/z): [M+1]+=276.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:52][OH:53])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reaction time: 2 h
Yield: 36 %

Procedure:
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 12m (76 mg, 0.10 mmol) was dissolved in 10 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of o-dichlorobenzene (103 μL, 0.9 mmol) and Palladium/carbon (180 mg, 10%). The mixture was exchanged with H2 three times and stirred for 2 hours, then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 12 (17 mg, pale yellow solid), yield: 34.0%. MS m/z (ESI): 490.24 [M+18]; 1H NMR (400 MHz, CD3OD): δ 7.48-7.49 (m, 1H), 7.37-7.39 (m, 2H), 7.15-7.17 (d, 2H), 6.88-6.91 (d, 2H), 6.02-6.29 (ddt, 1H), 4.23-4.24 (d, 1H), 4.20-4.21 (d, 1H), 4.16-4.17 (d, 1H), 4.08 (s, 2H), 3.78-3.88 (m, 2H), 3.67-3.72 (m, 2H), 3.55-3.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[OH:25][CH2:26][C@H:27]1[O:32][CH2:31][CH2:30][N:29]([C:33]2[S:34][CH2:35][C:36](=[O:38])[N:37]=2)[CH2:28]1>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[C:35]3[S:34][C:33]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][OH:25])[CH2:28]4)=[N:37][C:36]3=[O:38])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:22])([F:23])[F:24])[N:3]=1
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Product: O=C1N=C(N2CCOC(CO)C2)SC1=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-(2-(S)-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following general procedure D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][N:30]([Si](C(C)(C)C)(C)C)[C:26]=3[N:27]=[CH:28][CH:29]=2)=[O:23])COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41].O.CO>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][CH:29]=2)=[O:23])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:40]([F:43])([F:41])[F:42]
Reactant: COCN(c1cc(Cl)ccc1C(=O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (20 mg, 0.029 mmol) in 4N HCl in dioxane (2 mL) and water (0.5 mL) was stirred at 70° C. for overnight. MeOH (0.5 mL) was added and further stirred at the same temperature for 30 min. Then reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by HPLC to afford 4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide in 60% yield. ESMS m/z (relative intensity): 514 (M+H)+ (100).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[C:22](Cl)(=[O:24])[CH3:23].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:22](=[O:24])[CH3:23])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), acetyl chloride (0.56 ml) and pyridine (0.64 ml) were added thereto, the mixture was refluxed for 2 hours. Water (100 ml) was added, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collectedly filtration, to thereby obtain 1.33 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si](C)(C)C#CC=C1CCNCC1.Br[C:34]1[CH:35]=[C:36]([CH2:40][C:41](=[O:43])[CH3:42])[CH:37]=[CH:38][CH:39]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[C:16][C:36]3([CH2:40][C:41](=[O:43])[CH3:42])[CH:35]=[CH:34][CH:39]=[CH:38][CH2:37]3)[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Agent: [F-]
Solvent: O
Product: CC(=O)CC1(C#CC=C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)C=CC=CC1
Yield: 41 %

Procedure:
The title Compound was prepared from Compound 274c following the procedure described for the compound of Example 274 using 3-bromophenylacetone instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 9:1 to 7:3 affording the title product. Orange oil. Yield: 41%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]3[CH2:22][NH:21][C:20]([CH3:24])([CH3:23])[C:12]=3[N:13](C(OCC)=O)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([C:66](O)=[O:67])[CH2:62][CH2:61]1.C(Cl)Cl.CO.[NH4+].[OH-]>ClCCl.CCOC(C)=O.CCCCCC>[CH3:23][C:20]1([CH3:24])[C:12]2=[N:13][NH:14][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:26][CH:25]=3)=[C:11]2[CH2:22][N:21]1[C:66]([CH:63]1[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]1)=[O:67]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)NC2
Reactant: CN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)N2Cc3c(n[nH]c3NC(=O)c3ccc(F)cc3)C2(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate hydrochloride (0.5 g, 1.3 mmol), in dichloromethane (25 ml), was treated with N,N-diisopropylethylamine (1.13 ml, 6.5 mmol, 5 eq) and TBTU (0.542 g, 1.69 mmol, 1.3 eq), at room temperature for 1 hour, and then 1-methyl-piperidine-4-carboxylic acid hydrochloride (0.29 g, 1.61 mmol, 1.2 eq) was added. The reaction was stirred overnight (TLC: CH2Cl2/MeOH 90/10). The solution was washed with saturated sodium hydrogencarbonate aqueous solution and brine, the organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in methanol (16 ml), treated with TEA (2 ml, 14.3 mmol, 11 eq) and stirred overnight at room temperature. (TLC: CH2Cl2/MeOH/NH4OH 90/10/1). After evaporation, the solid was purified by flash chromatography (eluent: CH2Cl2/MeOH/NH4OH 90/10/2). The solid was treated with diisopropylether and filtered to afford 0.36 g of the title compound in 69% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10].CO.O.[OH-].[Na+]>C1COCC1>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:23]1[CH:22]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[CH3:1])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3C)cc(OCc3ccccc3C)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1COc1cc(OCc2ccccc2C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 94.5 %

Procedure:
Methyl 6-[(3,5-di-(2-methylbenzyloxy)benzoyl)amino]-3-pyridinecarboxylate (61 mgs) was stirred at ambient temperature in a mixture of THF (4 ml), methanol (1 ml) and water (1 ml) with 2M sodium hydroxide (0.3 ml, xs). After four hours the solvent was removed, under reduced pressure, water (5 ml) added and the pH adjusted to neutral. This gave a white precipitate which was filtered off, washed with water, dried to give the title compound (56 mgs, 94%). MS [MH]+ 483
Reaction SMILES: [C:1]1(=[CH:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][Mg]Br.Cl>CCOCC>[C:1]1(=[CH:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: CC(=O)CCC=C1CCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(O)CCC=C1CCCC1
Temperature: 25 °C
Yield: 76 %

Procedure:
5-Cyclopentylidene-2-pentanone (13.4 g; 88 mmol) in ether (13 ml) was added dropwise during 30 minutes to a 3M solution of methylmagnesium bromide in ether (38 ml; 114 mmol). After addition of more ether (25 ml), the mixture was heated under reflux for 2 hours, then cooled down to room temperature, poured into ice (40 g), acidified with 5N HCl (50 ml) and extracted with MTBE (130 ml). The aqueous phase was separated and extracted with MTBE (2×130 ml). The combined organic phases were washed with saturated NaHCO3 (2×130 ml), water (130 ml), dried over MgSO4 and concentrated in vacuo. Distillation (52° C.-55° C./0.06 torr) yielded 11.24 g (76% yield) of 5-cyclopentylidene-2-methylpentan-2-ol.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]4[CH:26]=[C:25]([F:27])[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][C:22]=4[F:32])[C:15]3=[O:33])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:40]([Zn]CC)[CH3:41]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:32][C:22]1[CH:23]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[C:25]([F:27])=[CH:26][C:21]=1[NH:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[N:3][C:2]([CH2:40][CH3:41])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[C:15]1=[O:33]
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cc1F
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)cn1
Temperature: 60 °C
Yield: 54.3 %

Procedure:
(S)-1′-(5-chloropyrazin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (prepared according to the procedure of Example 45) (50 mg, 0.100 mmol) was dissolved in THF (2 mL) and K2CO3 (41.5 mg, 0.300 mmol) and PdCl2(dppf)*CH2Cl2 (8.17 mg, 0.0100 mmol) were added and purged with nitrogen. 1M diethylzinc (110 μL, 0.110 mmol) was added and the reaction was heated to 60° C. for 3 hours. The reaction was cooled to ambient temperature, concentrated in vacuo and purified over silica gel (70 to 90% EtOAc in hexanes) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1′-(5-ethylpyrazin-2-yl)-1,4′-bipiperidin-2-one (26.8 mg, 0.0543 mmol, 54.3% yield) as a tan solid. Mass spectrum (apci) m/z=494.3 (M+H).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cccc(F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: Fc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-fluorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-fluorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.