Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[S:14]([NH:17][C:18]1[N:26]=[C:25]2[N:20]([C:21]([O:29][CH3:30])=[N:22][CH:23]=[C:24]2[O:27][CH3:28])[N:19]=1)(=[O:16])=[O:15].[F:31][CH:32]([F:35])[CH2:33][OH:34].Cl>>[F:31][CH:32]([F:35])[CH2:33][O:34][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[S:14]([NH:17][C:18]1[N:26]=[C:25]2[N:20]([C:21]([O:29][CH3:30])=[N:22][CH:23]=[C:24]2[O:27][CH3:28])[N:19]=1)(=[O:16])=[O:15]
Reactant: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(F)cccc3C(F)(F)F)nc12
Reactant: OCC(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Temperature: 10 °C
Yield: 83 %

Procedure:
Sodium hydride (1.21 g, 30 mmol, as a 60% suspension in mineral oil) was charged into a round bottom flask equipped with magnetic stirring and a nitrogen blanket, washed twice with 10 mL hexanes, dried of residual hexanes under a nitrogen stream, and suspended in 1,2-dimethoxyethane (20 mL). After cooling in an ice bath to about 10° C., 2-fluoro-6-trifluoromethyl-N-(5, 8-di-methoxy[ 1,2,4]triazolo[1,5-c]pyrimidin-2-yl)benzenesulfonamide (4.21 g, about 98.5% purity, 10 mmol) was added over about 5 min, rinsing in with 1 mL 1,2-dimethoxyethane. A slight exotherm to about 13° C. occurred. Continued ice bath cooling lowered temperature to about 6° C. over about 10 min. To the off-white suspension was added 2,2-difluoroethanol (0.815 niL, 13 mmol) over about 5 min. A slight exotherm to about 13° C. occurred. The light tan suspension was stirred at about 5-10° C. for about 1 hr, then the ice bath was removed. The temperature peaked at about 28° C. (about 2° C. above room temperature) about 0.5 hr later. The tan suspension was stirred overnight (about 20 hr total reaction time), then worked up by addition of the reaction mixture over about 7 min into 5% hydrochloric acid (80 mL, 112 mmol) at about 5-10° C. with ice bath cooling. The suspension was stirred about 18 min at about 9° C., then filtered, washed twice with 15 mL water each, washed twice with 15 mL methanol each, air-dried for about 2 hr, and finally vacuum-dried at about 0.02 mm Hg for about 2 hr over phosphorus pentoxide to afford the product as a white powder (4.34 g, about 92.8% purity, 8.3 mmol, about 83% yield).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:6]=1[O:7][CH2:8][C@H:9]1[CH2:11][O:10]1)C=C.C(=O)(O)[O-].[Na+].[C:22]1(C)[CH:27]=C(C)C=C(C)[CH:23]=1>>[CH2:27]([C:15]1[C:5]2[O:4][C@@H:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[C:13]([Cl:16])[CH:14]=1)[CH:22]=[CH2:23]
Reactant: C=CCOc1ccc(Cl)cc1OC[C@H]1CO1
Reactant: Cc1cc(C)cc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCc1cc(Cl)cc2c1O[C@@H](CO)CO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-2-(2-Allyloxy-5-chlorophenoxymethyl)-oxirane (9.2 g, 38 mmole) was dissolved in 500 ml of mesitylene and refluxed under nitrogen for 48 hours. The solvent was then removed in vacuum and replaced with 500 ml of ethanol. Sodium bicarbonate (50 g, 0.60 mole) was added and the mixture stirred at room temperature under nitrogen for 24 hours. The mixture was then filtered and concentrated in vacuum. The solvent was replaced with 500 ml of methylene chloride and the solution was washed with water and with saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using chloroform as eluant to give 8.9 g of the title compound as a colorless oil. 1H (CDCl3) singlet, 6.80 δ(1 H); singlet, 6.73 δ(1 H); multiplet, 5.95 δ(1 H); doublet, 5.10 δ(1 H); doublet, 5.05 δ(1 H); multiplet, 4.25 δ(2 H); multiplet, 4.10 δ(1 H); multiplet, 3.85 δ(2 H); multiplet, 3.30 δ(2 H); broad singlet, 2.00 δ(1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)(=O)C>[N:12]1([C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCCC1
Reactant: [H][H]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCCC2)nc1

Procedure:
Crude 5-nitro-2-(piperidin-1-ylcarbonyl)pyridine was reduced by hydrogen under atmospheric pressure in the presence of 10% paladium on carbon (4 g) in acetic acid (500 mL). The catalyst was separated by filtration and the solvent evaporated in vacuum to give crude 6-(piperidin-1-ylcarbonyl)pyridin-3-amine, which was used for the next stage without additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](I)=[C:9]2[C:10](=[O:14])[NH:11][CH2:12][CH2:13][N:8]2[N:7]=1)=[O:5])[CH3:2].[CH3:17]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]([CH3:17])=[C:9]2[C:10](=[O:14])[NH:11][CH2:12][CH2:13][N:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CB(O)O
Reactant: CCOC(=O)c1nn2c(c1I)C(=O)NCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn2c(c1C)C(=O)NCC2
Temperature: 90 °C
Yield: 58.7 %

Procedure:
Palladium (II) acetate (38 mg, 0.17 mmol) was added to a solution of 3-iodo-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.56 g 1.68 mmol), methylboronic acid (0.75 g, 12.6 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triiso-propyl-1,1′-biphenyl (0.16 mg, 0.34 mmol) and potassium carbonate (0.69 g, 5.0 mmol) in toluene (15 mL) under nitrogen and the mixture was heated at 90° C. for 16 hours. Then the mixture was heated at 120° C. for 4 hours more. The mixture was diluted with a saturated Na2CO3 solution and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.22 g, 58% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C:65]1([F:79])[CH2:69][NH:68][C@@H:67]([C:70]2[CH:71]=[C:72]([CH:75]=[C:76]([F:78])[CH:77]=2)[C:73]#[N:74])[CH2:66]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:73]([C:72]1[CH:71]=[C:70]([C@H:67]2[CH2:66][C:65]([F:79])([F:64])[CH2:69][N:68]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[CH:3]=2)[CH:77]=[C:76]([F:78])[CH:75]=1)#[N:74]
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: N#Cc1cc(F)cc([C@H]2CC(F)(F)CN2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn2ccc(N3CC(F)(F)C[C@@H]3c3cc(F)cc(C#N)c3)cc12
Temperature: 140 °C

Procedure:
A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 0.37 mmol), palladium acetate (1.7 mg, 7 μmol), xantphos (7 mg, 11 μmol), cesium carbonate (170 mg, 0.52 mmol), 1,4-dioxane (0.5 mL) and (R)-3-(4,4-difluoropyrrolidin-2-yl)-5-fluorobenzonitrile (I-24) (84 mg, 0.37 mmol). The contents were heated to 140° C. for 1 hour under microwave irradiation. Upon cooling to room temperature the reaction was partitioned with EtOAc and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (R)-ethyl 5-(2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-8). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=7.6 Hz, 1 H), 8.24 (s, 1 H), 7.38 (s, 1 H), 7.33-7.29 (m, 1 H), 7.25-7.21 (m, 1 H), 6.93 (d, J=2.8 Hz, 1 H), 6.19 (dd, J=2.8, 7.6 Hz, 1 H), 5.14 (dd, J=4.4, 9.2 Hz, 1 H), 4.34-4.25 (m, 2 H), 4.25-4.16 (m, 1 H), 4.05-3.93 (m, 1 H), 3.14-2.98 (m, 1 H), 2.53-2.42 (m, 1 H), 1.34 (t, J=7.2 Hz, 3 H). MS m/z 415.1 (M+1)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.BrC[CH:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:56]=[C:55]([C:57]3[C:61]([CH2:62][CH2:63][CH3:64])=[C:60]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[O:59][N:58]=3)[O:54][N:53]=2)=[CH:48][CH:47]=1)[OH:45]>C(Cl)Cl>[OH:45][CH:44]([C:46]1[CH:47]=[CH:48][C:49]([C:52]2[N:56]=[C:55]([C:57]3[C:61]([CH2:62][CH2:63][CH3:64])=[C:60]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[O:59][N:58]=3)[O:54][N:53]=2)=[CH:50][CH:51]=1)[CH2:6][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@H]4CC(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (45.4 mg, 0.198 mmol) in DCM was added TFA. The reaction mixture was stirred for 1 hour followed by the removal of solvents in vacuo and drying of the solid material. Next, DMSO (2 mL) was added followed by the addition of tetrabutylammonium hydroxide (0.198 mL, 0.198 mmol) and then 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 30-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 9 mg of 2-((2S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)pyrrolidin-2-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.18 (4H, d, J=8.35 Hz), 7.77-7.84 (2H, m), 7.54-7.67 (5H, m), 5.92-6.01 (1H, m), 5.00-5.09 (2H, m), 4.26-4.42 (1H, m), 3.76-3.94 (1H, m), 3.00-3.11 (2H, m), 2.75-2.98 (2H, m), 2.18-2.34 (1H, m), 1.90-2.14 (2H, m), 1.60-1.85 (3H, t, J=7.25 Hz). MS (m+1)=503. HPLC Peak RT=3.50 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([O:3][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])[C:17]([CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[N:15]=1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Reactant: Cc1cc(O)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
At 0° C., NaH (60%, 125 mg, 3.06 mmol, 1.0 eq.) was added to 3-hydroxy-5-methyl-benzonitrile (408 mg, 3.06 mmol) in 10 mL of DMF solution. The reaction mixture was stirred at 0° C. for 5 minutes. 2,4,6-Trichloro-5-isopropyl-pyrimidine (691 mg, 3.06 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAc/hexane) to give a white solid (868 mg, 88%). LC-MS shows 322.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 3.60 (m, 1H), 2.42 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([O:22][C:23]2[C:35]([F:36])=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([F:37])[CH:24]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([O:22][C:23]2[C:35]([F:36])=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:37])[CH:24]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OC3CCOCC3)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(F)c(Oc2cnc(OC3CCOCC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-{[5-chloro-6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]oxy}-2,5-difluorobenzoate (Preparation 23, 0.28 g, 0.64 mmol) in DCM (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL), and extracted with DCM (3×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel chromatography eluting with EtOAc to afford an off white solid. The solid was triturated with 4:1, heptane: EtOAc to afford the title compound as a white solid (0.24 g):
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:22]N(C)CCO.C[Zn]C.C1(C)C=CC=CC=1>O1CCCC1>[CH3:22][C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(Br)ccc12
Reactant: CN(C)CCO
Agent: C[Zn]C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
A mixture of 6-bromo-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (Example 128) (0.1 g, 0.28 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (61.5 mg, 84.0 μmol) and N,N-dimethylethanolamine (14.1 μL, 140 μmol) in tetrahydrofuran (1.5 mL) under argon was treated with 1.2M dimethylzinc in toluene (280 μL, 0.33 mmol). The reaction mixture was stirred in a sealed vial at 50° C. overnight. At this time, the reaction was treated with additional dimethylzinc (0.14 mL). The reaction mixture was stirred at 50° C. over the weekend. At this time, the reaction mixture was cooled to room temperature, quenched with a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. Methanol (0.5 mL) was added, the mixture was filtered and the layers were separated. The organic layers were absorbed onto silica gel. Flash chromatography (12 g silica column, 0-40% ethyl acetate/hexanes) followed by trituration with methylene chloride afforded 6-methyl-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (14 mg, 17%) as white solid. 1H NMR (methanol-d4) δ ppm 7.76-7.86 (m, 4H), 7.69 (s, 1H), 7.28 (s, 1H), 6.95, (s, 1H), 2.28 (s, 3H). LC-MS calcd. for C15H12F3N2O [(M+H)+] 293, obsd. 293.1.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.ON1C(=O)CCC1=O.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1>[C:16]([O:20][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1O
Product: CC(C)(C)OC(=O)CCC(=O)O

Procedure:
Sodium 2,2-d2-4-hydroxybutyrate is prepared in the following manner: treatment of succinic anhydride with tert-butanol, N-hydroxysuccinimide, and 4-dimethylaminopyridine (4-DMAP) according to the procedure of Yao, Z-J., et al, J. Org. Chem. 2003, 68, 6679-6684 affords the succinic acid mono-tert-butyl ester. In accordance with Yao, reduction of the succinic acid with borane-dimethyl sulfide complex gives the 4-hydroxybutanoic acid tert-butyl ester. Subjecting the ester to hydrogen/deuterium exchange by treatment with potassium carbonate in d1-methanol affords the 2,2-d2-4-hydroxybutanoic acid tert-butyl ester. Finally, saponification of the tert-butyl ester with sodium hydroxide in d1-methanol in a manner analogous to the procedure of Goto, G., et al, Chem. Pharm. Bull. 1985, 33, 4422-4431 affords the desired sodium 2,2-d2-4-hydroxybutyrate.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:31]2[O:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)[CH:13]=[CH:14][C:15]=1[NH:16][C:17]([C:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:20]=1)=[O:18])#[N:9].[OH-].[Na+]>O.C(#N)C>[C:8]([C:10]1[CH:11]=[C:12]([CH:31]2[O:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH:13]=[CH:14][C:15]=1[NH:16][C:17]([C:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:20]=1)=[O:18])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)c3ccn(-c4ccc(F)cc4)n3)c(C#N)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2CNCCO2)ccc1NC(=O)c1ccn(-c2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a stirred solution of trifluoroacetic acid (84 μl) in water (4.5 ml) was added a solution of tert-butyl (RS)-2-(3-cyano-4-(1-(4-fluorophenyl)-1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (41 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2; gradient: 0% to 10% methanol in dichloromethane) to afford (RS)—N-(2-cyano-4-(morpholin-2-yl)phenyl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide (20 mg, 61%) as a white solid. MS (ISP): 392.2 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]3[C:20]([N:21]=[C:22]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]=24)=[CH:19][CH:18]=[N:17]3)=[CH:11][CH:10]=1)C1C=CC=CC=1.CCOC(C)=O>CO.[Pd]>[N:17]1[N:16]2[C:20]([N:21]=[C:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[C:15]2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCCCC4)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
10-(4-Benzyloxy-phenyl)-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (100 mg, 0.27 mmol) was dissolved in CH3OH (5 mL) and EtOAc (2 mL) followed by the addition of palladium (10% by weight on carbon, 5 mg). The resulting mixture was stirred under a hydrogen atmosphere (balloon) at room temperature overnight. The catalyst was filtered off and the filtrate concentrated to give 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol as a colorless solid (60 mg, 79% yield).
Reaction SMILES: [C:1]1([C:7]2([NH2:16])[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:27][CH2:28][C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:17]([NH:27][CH2:28][C:29]([NH:16][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15]1)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: NC1(c2ccccc2)Cc2ccccc2C1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)OCc1ccccc1)NC1(c2ccccc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a stirred solution of 2,3-dihydro-2-phenyl-1H-inden-2-amine (10.2 g, 0.049 mol) in chloroform (200 mL) were added N-CBZ-glycine (10.8 g. 0.052 mol) and then a solution of dicyclohexylcarbodiimide (11.1 g, 0.053 mol) in chloroform (70 mL). The mixture was stirred for 18 hours at ambient temperature. The mixture was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate (200 mL) and filtered again. The filtrate was washed with 1N hydrochloric acid (2×100 mL), 2N sodium carbonate (2×100 mL), brine (100 mL) and dried over magnesium sulfate. The solvent was then evaporated. The residue was recrystallized from ethyl acetate (75 mL) and cyclohexane (150 mL) to provide 17.1 g of 2-[(carbobenzoxy)amino]-N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)acetamide, mp 63°-70° C. To a solution of the latter (14.3 g, 0.037 mol) in methanol (200 mL), tetrahydrofuran (75 mL) and IN hydrochloric acid (70 mL), was added 10% palladium on carbon (1.4 g). The mixture was shaken on a Parr apparatus for 1.5 hours. The catalyst was removed by filtration, the solvents evaporated and the residue dissolved in chloroform (200 mL) and 2N sodium carbonate (200 mL). The aqueous layer was extracted with chloroform (2×100 mL). The combined chloroform extracts were washed with brine (100 mL), dried over magnesium sulfate, and the solvent evaporated. The residue was dissolved in methanol (50 mL) and 2-propanol (75 mL) and acidified with HCl gas. The solid which formed was collected by filtration and vacuum dried at 80° C. for 3 days to provide 7.3 g of 2-amino-N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)acetamide, mp 275°-276° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:15])[C@H:11]([CH2:13][OH:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH2:2]([O:9][C:10](=[O:15])[C@H:11]([CH2:13][OH:14])[NH:12][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: O=C(OCc1ccccc1)[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a mixture of L-serine-benzyl ester-HCl (2.3 g), benzaldehyde(1.05 eq.) and sodium acetate (1 eq.) in methanol was added sodium cyanoborohydride (1.0 eq.). The resulting mixture was stirred at ambient temperature for 15 hrs, then partitioned into ether and aqueous saturated sodium bicarbonate. The separated organic phase was extracted with 1M HCl (3×). Combined aqueous extracts were washed with ether, basified with aqueous 4.5M K2CO3 and extracted with ether. Combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to give 2.32 g of the desired compound (waxy solid, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: N#CC1(n2cc(Cl)cn2)CC1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (17.3 g, 103 mmol) in ethanol (50 mL) was added sodium ethoxide (prepared from 3.2 g, 139 mmol of sodium metal dissolved in 150 mL of ethanol). The reaction mixture was stirred at 70° C. for 2 h to afford ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate which was used for the next step without further purification. An aliquot of the solution was concentrated for analysis: 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.46 (q, 2H), 1.73 (q, 2H), 4.15 (q, 2H), 7.51 (s, 1H), 7.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:14](=[O:16])[O:13][C:12](=O)[C:11]=2[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[NH2:18]C(N)=O>>[CH3:1][O:2][C:3]1[C:15]2[C:14](=[O:16])[NH:18][C:12](=[O:13])[C:11]=2[CH:10]=[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: COc1c2c(cc3ccccc13)C(=O)OC2=O
Reactant: NC(N)=O
Product: COc1c2c(cc3ccccc13)C(=O)NC2=O

Procedure:
Prepared as described in Intermediate 33 from 4-methoxynaphtho[2,3-c]furan-1,3-dione (229 mg) and urea (120 mg). M.p. 216°-220°. NMR (DMSO-d6) δ 10.6 (1H, s), 7.52 (1H, d), 7.39 (1H, d), 7.34 (1H, s), 6.92 (2H, m), 3.43 (3H, s).