Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([CH:12]=[O:13])=[CH:4]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([S:20]([N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[C:5]([CH:12]=[O:13])=[CH:4]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
Into a 100 ni 3-necked round bottom flask was placed tetrahydrofuran (50 mL). To the above was added NaH (2.19 g, 54.75 mmol) in several batches, while cooling to a temperature of 0° C. This was followed by the addition of a solution of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2 g, 13.70 mmol) in tetrahydrofuran (400 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at room temperature. This was followed by the addition of a solution of benzenesulfonyl chloride (3.63 g, 20.55 mmol) in tetrahydrofuran (50 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at room temperature. The reaction mixture was then quenched by the adding of H2O. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate. The resulting mixture was washed two times with 200 mL of brine and the organic layers combined. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with ethyl acetate/petroleum ether=1:40. This resulted in 3.4 g (82%) of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[CH:9]=[N:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[CH3:31][C:32](C)([O-])[CH3:33].[K+].C(Br)C#C>O1CCCC1.[Cl-].[NH4+]>[C:18]1([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:9]([CH2:33][C:32]#[CH:31])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[CH2:6][C:5]2[CH:28]=[CH:29][CH:30]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cccc(Cc2ccccc2C=NC(c2ccccc2)c2ccccc2)c1
Agent: C#CCBr
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCC(N=C(c1ccccc1)c1ccccc1)c1ccccc1Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 3.58 g of 2-(3-cyanobenzyl)benzaldehyde and 10.4 g of anhydrous magnesium sulfate was added 3.6 ml of diphenylmethanamine, and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give an oil that crystallised on addition of diethyl ether and cooling to 4° C., to give 4.11 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine, melting at 113-115° C. A stirred solution of 1.0 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine in 15 ml of tetrahydrofuran was cooled to -78° C. and 6.7 ml of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 20 min then 0.9 ml of propargyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction mixture was diluted with 25 ml of saturated aqueous ammonium chloride and extracted into dichloromethane. The combined organic extracts were dried over sodium sulfate the evaporated to give crude N-(diphenylmethylidene)-2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine which was not characterised due to instability. The crude product was dissolved in 20 ml of acetone and 5 ml of 1 M hydrochloric acid added. The solution was stirred at room temperature for 3 h then cooled to 4° C. overnight. The acetone was removed by evaporation and the crude product redissolved in 20 ml of dichloromethane. The solution was extracted with two 20 ml portions of 2N hydrochloric acid. The combined acid extracts were washed with 10 ml of dichloromethane and then basified with 4N sodium hydroxide solution. The basic extracts were combined and re-extracted with three 20 ml portions of dichloromethane, the combined organic extracts were dried over sodium sulfate and evaporated to give 120 mg of product. The product was dissolved in 1 ml of methanol and 57 mg of fumaric acid was added. The product was crystallised by trituation with ether and cooling to 4° C. to yield 120 mg of 2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine (E)-butenedioate, melting at 182-184° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Cl.[C:38]([O:42][C:43](=[O:47])[CH2:44][NH:45][CH3:46])([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:1][N:45]([CH3:46])[CH2:44][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:47])=[C:3]([Cl:10])[CH:4]=1)#[N:7]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: Cc1ccc(C#N)cc1Cl
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1Cl
Temperature: 100 °C
Yield: 37.2 %

Procedure:
A solution of 4-methyl-3-chlorobenzonitrile (4.69 g, 31 mmol), N-bromosuccinimide (6.04 g, 34.2 mmol) and benzoyl peroxide (0.750 g, 3.10 mmol) in ACN (20 mL) was heated under reflux for 18 hours. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of Na2CO3 and brine. The organic phase was dried (MgSO4) and concentrated under vacuum. A portion of the residue (1.0 g, 4.34 mmol) was treated with sarcosine tert-butyl ester hydrochloride (1.57 g, 8.69 mmol) and K2CO3 (2.39 g, 17.4 mmol) in dioxane (5 mL). The resulting mixture was heated at 100° C. for 2 hours, and then concentrated under vacuum. The residue was dissolved in a mixture of DCM and water, and then passed through a hydrophobic frit. The solvent was evaporated under vacuum to afford the title compound (0.952 g, 74%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C(O)COCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzyloxy)-ethanol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.Br[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[C:9]1[S:10][C:6]([C:13]2[S:12][C:11]([C:9]3[S:10][CH:6]=[CH:7][CH:8]=3)=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Brc1cccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1csc(-c2ccc(-c3ccc(-c4cccs4)s3)s2)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 141.4 %

Procedure:
5,5′-bis(tributylstannyl)-2,2′-bithiophene (2.16 g, 2.90 mmol) was dissolved in dry DMF (45 mL) and transferred via cannula to Pd(PPh3)4 (0.101 g, 0.087 mmol) in a Schlenk flask. 2-bromothiophene (1.14 g, 6.96 mmol) was added via syringe and the solution was degassed with nitrogen. Reaction was then heated to 90° C. for 18 hours. Reaction was quenched with water, extracted with chloroform (3×), and the combined organics washed with brine. Organics were dried with magnesium sulfate and concentrated by rotary evaporator yielding crude material as a waxy orange solid. The solid was recrystallized from boiling toluene and collected by filtration. Filtered solid was then redissolved in boiling chloroform and stirred with activated charcoal for 15 minutes. The charcoal was removed by filtering through celite and the chloroform removed by rotary evaporator to yield product as a yellow solid (0.676 g, 2.05 mmol, 70%). Characterization data matches literature. Z. H. Li, et al., Org. Lett. 9:3659-3662 (2007).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[C:6]([OH:15])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].CN1CC=C(C2SC=CC=2)CC1>O>[F:8][C:7]([F:9])([F:10])[C:6]([C:11]([F:12])([F:14])[F:13])([OH:15])[CH2:5][OH:4]
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: CN1CC=C(c2cccs2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A glass 3-L four-neck flask was fitted with a mechanical stirrer, a Dimroth condenser, and a dropping funnel. Operating at room temperature, 1 L of pure water was introduced into the reactor followed by the introduction of 69 g (1.93 mol) sodium tetrahydroborate and dissolution. To this was added dropwise 515 g (2.28 mol) 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionic acid methyl ester (MTTHP). Suitable cooling was performed with ice water during this period so as to prevent the liquid temperature from exceeding 50° C. After the dropwise addition of all of the MTTHP, stirring was performed for 1 hour at room temperature and quenching was carried out by the dropwise addition of 300 mL 35% aqueous hydrochloric acid into the reaction solution on an ice bath. The quenched solution was subjected to suction filtration to remove the salts produced during the reaction and the residual salt was washed twice with 500 mL isopropyl ether (IPE). The obtained filtrate was separated and the organic layer was recovered and the aqueous layer was extracted twice with 700 mL IPE. The organic layer and the extracts were combined and dried over magnesium sulfate; suction filtration was performed and the filtrate was recovered; and the IPE was removed by condensation on an evaporator. Simple distillation of the resulting solution under reduced pressure yielded 217 g (isolated yield=48%, purity=98%) 3,3,3-trifluoro-2-trifluoromethylpropane-1,2-diol.
Reaction SMILES: [CH2:1]([CH:3]1[C:10](=[O:11])[N:9]2[CH:4]1S[S:6][C:7]([S:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([CH:3]1[C:10](=[O:11])[N:9]2[CH:4]1[S:6][C:7]([S:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(C)=O)SSC12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(C)=O)SC12
Reaction time: 0.17 h

Procedure:
To a solution of 0.90 g of 4-nitrobenzyl 7-ethyl-8-oxo-3-acetylthio-4,5-dithia-1-azabicyclo[4,2,0]oct-2-ene 2-carboxylate in 2 ml of dichloromethane was added, in one bath, a solution of 0.59 g of triphenylphosphine in 3 ml of dichloromethane. After 10 minutes, the reaction mixture was chromatographed directly on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title compound as a yellow crystalline solid. (Yield 0.25 g)
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:15]([C:17]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[N:18]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:15]([C:17]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[N:18]=2)=[O:16])=[CH:7][C:6]=1[O:5][CH3:4]
Reactant: COc1cccc(-c2nc(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n3ccccc23)c1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cccc(-c2nc(C(=O)c3ccc(N)c(OC)c3)n3ccccc23)c1
Temperature: 70 °C

Procedure:
0.117 g of 10% Pd/C and then 0.27 ml (5.47 mmol) of hydrazine hydrate are added to 0.441 g (1 mmol) of (3-methoxy-4-nitrophenyl)[1-(3-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl]methanone obtained in example 34 in 10 ml of methanol. The mixture is heated at 70° C. for 3 hours. The reaction medium is filtered through talc and the catalyst is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is taken up in dichloromethane and washing is carried out with a saturated aqueous sodium chloride solution and then drying is carried out over sodium sulfate. After concentrating under reduced pressure, the residue is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.354 g of a yellow foam is collected. The product is salified by addition of 1N hydrochloric acid in ethyl ether. After addition of ethyl ether, the precipitate is filtered off, washed with ethyl ether and then dried. A yellow solid is collected in the hydrochloride form. Melting point: 210° C.; 1H NMR (d6-DMSO): 3.86 (3H, s), 3.92 (3H, s), 6.88 (1H, d), 6.99 (1H, d), 7.22 (1H, t), 7.40-7.60 (5H, m), 8.14-8.27 (3H, m), 9.75 (1H, d)
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:46][C:47]1[O:48][C:49]([CH3:52])=[N:50][N:51]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:46][C:47]3[O:48][C:49]([CH3:52])=[N:50][N:51]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: Cc1nnc(CCl)o1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nnc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as light-yellow gum. MS (m/e): 415.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][F:58])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][F:58])[CH2:54][CH2:55]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([NH:40][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=3)[C:20]([NH:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:41]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 11.6 %

Procedure:
In a 10 mL vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 5-chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (0.192 g, 0.520 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.203 g, 1.04 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.040 g, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.44 (br. s., 1H), 8.58 (s, 1H), 8.33 (s, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.78-7.95 (m, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.45-7.55 (m, 1H), 7.33-7.45 (m, 1H), 7.11-7.28 (m, 2H), 7.03 (t, J=7.0 Hz, 1H), 6.83 (s, 1H), 6.55 (d, J=5.3 Hz, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.84 (s, 3H), 3.08-3.51 (m, 2H), 2.09-2.92 (m, 13H), 1.72-2.00 (m, 2H), 1.41-1.72 (m, 2H). MS (M+H, ES+) 796.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:27][C:26]3[N:28]4[C:19](=[CH:20][N:21]=[C:22]4[CH:23]=[CH:24][CH:25]=3)[C:18]2=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:27][C:26]3[N:28]4[C:19](=[CH:20][N:21]=[C:22]4[CH:23]=[CH:24][CH:25]=3)[C:18]2=[O:29])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN2Cc3cccc4ncc(n34)C2=O)CC1
Agent: Cl
Solvent: CCO
Product: O=C1c2cnc3cccc(n23)CN1CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution prepared by dissolving 2.12 g (5.51 mM) of 4,5-dihydro-4-[3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one in 30 ml of ethanol was added 1.40 ml of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was added 5 ml of ethanol and 5 ml of ether and the resulting precipitate was recovered by filtration. The precipitate was rinsed with small amounts of ethanol and ether to provide 1.87 g (yield 91.2%) of the title compound as light-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([O:12][C:10]1[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccccc2)cc(C(=O)OCC)n1
Temperature: 82 °C
Yield: 96 %

Procedure:
To a solution of 4 (6.88 g, 28 mmol) in acetonitrile and K2CO3 (6.31 g, 45 mmol) was carefully added benzyl bromide (3.34 mL, 27 mmol). The resulting solution was stirred at 82° C. under reflux overnight. The reaction was stopped by filtration of K2CO3 and the solvent was removed under reduced pressure. The solid obtained was recrystallized from hot hexanes to yield 96% of the product as a white solid.
Reaction SMILES: ClCl.[CH3:3][S:4][CH2:5][C:6]#[N:7].[NH2:8][C:9]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][C:22]=1[CH:5]([S:4][CH3:3])[C:6]#[N:7]
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: CSCC#N
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccccc2)c(N)c(C(C#N)SC)c1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.0 ml (0.088 mole) of chlorine in 200 ml of methylene chloride cooled to -70° C. is added dropwise a solution of 7.65 g (0.088 mole) of methylthioacetonitrile in 1 liter of methylene chloride while maintaining the temperature below -65° C. After several minutes a solution containing 0.2 mole of 2-amino-5-methoxybenzophenone in 100 ml of methylene chloride is added dropwise over a 30 min period. The mixture is stirred at -70° C. for about 1.5 hr and 18 g (0.18 mole) of triethylamine is added. The mixture is stirred for about an hour at -70° C. and then allowed to warm to ambient temperature. The mixture is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from a suitable solvent, e.g., 2-propanol, to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1([CH2:37][C@@H:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[CH2:37][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC[C@H]1CN1CCCC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with (S)-2-(1-pyrrolidinylmethyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=583.96 (M+H+); retention time=0.58 minutes.