Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38](OS(C(F)(F)F)(=O)=O)[N:37]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:38]4[N:37]=[C:36]([CH3:35])[C:45]5[C:40]([CH:39]=4)=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)cc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (97.5 mg, 0.208 mmol), trifluoromethanesulfonic acid 1-methylisoquinolin-3-yl ester (62.3 mg, 0.214 mmol), and Pd(PPh3)4 (15 mg, 0.013 mmol) in 1,4-dioxane (3.2 mL, 41 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (135 mg, 0.413 mmol) in H2O (0.95 mL, 53 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried over MgSO4. The EtOAc extract was diluted with DCM (to give DCM:EtOAc≈1:1) and filtered through a plug of silica gel. The silica gel was then washed with DCM:EtOAc 1:2, DCM:EtOAc 1:5, and EtOAc until no more product eluted. Filtrate/washings that contained product were concentrated in vacuo. The crude material was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→DCM:EtOAc 2:1→DCM:EtOAc 1:1→DCM:EtOAc 1:2→EtOAc]. Mixed fractions were combined, concentrated in vacuo, and purified by prep. TLC [20×20 cm plates, 500 μm, eluting with 2% MeOH/DCM (1×) and 4% MeOH/DCM (3×)]. Clean material from prep. TLC was combined with pure fractions from the column chromatography and dried in vacuo, yielding the title compound as viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.0 Hz, 1H), 8.15 (dd, J=0.8, 8.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J=0.4 Hz, 1H), 7.72 (ddd, J=1.2, 7.2, 8.2 Hz, 1H), 7.66 (d, J=0.4 Hz, 1H), 7.62 (ddd, J=1.2, 6.8, 8.2 Hz, 1H), 6.49 (brs, 2H), 4.38-4.20 (m, 3H), 3.03 (s, 3H), 2.92 (brt, J=12.0 Hz, 2H), 2.19 (brd, J=12.0 Hz, 2H), 1.98 (dq, J=4.4, 12.2 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.18 (100) [MH+], 429.06 (39) [MH+-isobutene]. HPLC: tR=2.76 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2

Procedure:
A suspension of bicyclic olefin triazole 0.1 mmol, the title compound of Example 3257) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 3259.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[S:9][C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CO.[OH-]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[S:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnc(COc2ccc(Cl)cc2)s1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(COc2ccc(Cl)cc2)s1

Procedure:
A mixture of 10.9 of ethyl 2-(p-chlorophenoxymethyl)-thiazole-5-carboxylate, 165 ml of methanol, 10 ml of postassium hydroxide and 20 ml of water was refluxed for 30 minutes and was then cooled and extracted with ethyl acetate. The aqueous phase was acidified and 2-(p-chlorophenoxymethyl)-thiazole-5-carboxylic acid was extracted with ethyl acetate and then a mixture of chloroform-methanol. The combined extracts were dried and evaporated to dryness to obtain 7.9 g of a crystalline residue. The residue was crystallized from isopropanol to obtain 6.92 g of the desired acid and the latter in the form of its triethylamine salt was chromatographed over silica gel. Elution with first a 1-1 chloroform-ethyl acetate mixture and then a 90-10-1 methylene chloride-ethyl acetate-acetic acid mixture gave 6.7 g of raw product. The latter was purified by sublimation at 190° C under reduced pressure and was crystallized from isopropanol containing 10% water to obtain 5.23 g of 2-(p-chlorophenoxymethyl)-thiazole--carboxylic acid melting at 215° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Si:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]([N:6]2[C:22](=[O:23])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 2-nitro-4-(tert-butyldimethylsilyloxy)aniline (10.3 g, 38.5 mmol) and phthalic anhydride (6.50 g, 41.5 mmol) in toluene (30 mL) was refluxed for 18 h. A Dean-Stark apparatus was fitted to the flask, diisopropylethylamine (0.1 mL) was added and water was removed azeotropically over the next 24 h. About 20 mL of solvent was removed by distillation and the resultant solution allowed to cool to room temperature. The residue was diluted with methylene chloride and passed through a plug of silica gel eluting with methylene chloride. The desired fractions were combined and concentrated in vacuo. Recrystallization from methylene chloride-hexane provided 12.2 g (80%) of the title compound in two crops.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.I[CH:24]([CH3:26])[CH3:25].Cl>C1COCC1.O>[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][O:21][CH:24]([CH3:26])[CH3:25])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOC(C)C)cs1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 129 mg, 5.39 mmol) was added to a stirred solution of EXAMPLE 181A (359 mg, 1.08 mmol) in THF (10 mL) at room temperature. After stirring for 15 min, the mixture was treated with 2-iodopropane (917 mg, 5.39 mmol). After two days at 50° C., additional sodium hydride (26 mg, 1.08 mmol) and 2-iodopropane (366 mg, 2.16 mmol) were added. After stirring for 1 h the reaction mixture was acidified with 2M HCl and water was added. The product was extracted with DCM and dried (sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 4% acetone in DCM giving (15 mg, 4%) of an oil which solidified on standing: MS (Ionspray, [M+H]+) m/z 374.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[ClH:24]>O1CCOCC1>[ClH:24].[C:1]([C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccccc1OC1CCNC1
Yield: 83 %

Procedure:
A stirred solution of tert-butyl 3-(2-tert-butylphenoxy)pyrrolidine-1-carboxylate (0.78 g, 2.44 mmol) and hydrochloric acid (7.0 mL of a 4.0 N solution in dioxane, 28.0 mmol) was reacted at room temperature for 16 h. Then, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate to provide 3-(2-tert-butylphenoxy)pyrrolidine hydrochloride as a colorless solid (0.52 g, 83%).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15].[CH2:16]([N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH2:17][C:18]#[CH:19]>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[I:15][C:10]1[CH:11]=[CH:12][C:13]([C:19]#[C:18][CH2:17][CH2:16][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[CH:14][CH:9]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Ic1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution containing triethylamine (250 mL), copper (I) iodide (1.72 g, 9.09 mmol) and diiodobenzene (56) (20.00 g, 60.60 mmol) dissolved in anhydrous tetrahydrofuran (250 mL) was stirred at room temperature. The reaction flask was evacuated and then purged with nitrogen three times. The solution was treated with bis(triphenylphosphine) palladium(II) dichloride (4.20 g, 6.06 mmol) and continued to stir at room temperature for 30 min. A solution containing triethylamine (250 mL) and 2-but-3-ynylisoindole-1,3-dione (12.06 g, 60.06 mmol) dissolved in anhydrous tetrahydrofuran (250 mL) was added dropwise through an addition funnel over 12 hours. The reaction was allowed to stir at room temperature for 48 h. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 57 (12.5 g, 51%) as a brown solid: 1H NMR (500 MHz, CD2Cl2) δ 7.85 (dd, 2H), 7.74 (dd, 2H), 7.60 (d, 2H), 7.04 (d, 2H), 3.92 (t, 2H), 2.79 (t, 2H); m/z (ESI) 402 [C18H12INO2+H]+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:13]([CH2:15]P(=O)(OCC)OCC)#[N:14].[H-].[Na+]>O1CCCC1>[C:13]([CH2:15][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1)#[N:14]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCc1ccc(S(N)(=O)=O)cc1

Procedure:
p-Aminosulphonylbenzaldehyde was reacted with diethyl cyanomethylphosphonate/sodium hydride in tetrahydrofuran to give 1-cyano-2-(4-aminosulphonylphenyl)-ethane which was hydrogenated in methanol with Raney-cobalt as the catalyst to give 3-(4-aminosulphonylphenyl)-propylamine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1.[C-:29]#[N:30].[Na+].O>CS(C)=O>[C:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)#[N:30]
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 3-[2-(5-bromopentyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.753 g) and sodium cyanide (0.37 g) in dimethyl sulfoxide (12.6 ml) was stirred at room temperature for 2 hours and then at 60° C. for 1 hour. To the mixture was added water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol as an eluent to afford 3-[2-(5-cyanopentyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.75 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]2[CH:17]=[CH:16][NH:15][C:10]=2[N:11]=[C:12](Cl)[N:13]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]2[CH:17]=[CH:16][NH:15][C:10]=2[N:11]=[C:12]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=2)[N:13]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: NCCCCCNc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NCCCCCN)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Yield: 7.6 %

Procedure:
A mixture of N-(5-aminopentyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (79 mg, 0.31 mmol), N-(4-aminophenyl)-N-methylacetamide (100 mg, 0.61 mmol) and trimethylsilyl chloride (0.150 mL, 1.19 mmol) in nBuOH (2 mL) was heated at 116° C. for 4 h. The mixture was then purified by HPLC to give the titled compound (9 mg). MS 382.2 (M+H); UV 210.8, 267.5, 305.5 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+]>C(OC)(C)(C)C>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[CH:7][C:2]=1[F:1])=[O:15]
Reactant: CC(=O)c1ccc(-c2cscn2)cc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)cc1F
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a stirred solution of 1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (2.03 g, 9.18 mmol) in t-butylmethylether (60 ml) was added ethyl trifluoroacetate (1.56 g, 11.01 mmol), sodium methoxide (28 wt. % solution in methanol; 2.49 ml, 11.01 mmol) at 0° c., and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (2.92 g, 99% yield). The compound was used for next reaction without purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:17]([NH:20][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)[CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a stirred solution of 1.06 g (5.0 mmol, 1 eq.) of 4-phenylaminobenzoic acid, prepared by the method of Portnaya, et al., Zhur. Obshchei. Khim., 30: 2693 (1960), n-propylamine (0.82 mL, 10.0 mmol, 2 eq.) and 0.061 g (0.5 mmol, 0.1 eq.) of DMAP in THF at 0° C. was added 1.05 g (5.5 mmol, 1.1 eq.) of EDCl. The mixture was stirred overnight while the bath melted. The mixture was poured into 150 mL of ethyl acetate and extracted with 50 mL each of water, 1N aqueous HCl, water, and saturated aqueous NaHCO3 solution. The ethyl acetate layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on SiO2 eluting with 1:1 ethyl acetate-hexanes to give 0.51 g (40%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 10.57 (bs, 2H), 7.21-7.41 (m, 9H), 3.96 (s, 2H), 2.75 (m, 2H), 1.64 (hextet, 2H), 0.92 (t, 3H). MS (DCl) m/e 255 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH2:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[N:20][CH:21]=1)[CH3:33]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and ethanamine hydrochloride (17.4 mg, 0.213 mmol) were suspended in DMF (1.065 mL) and treated with DIPEA (0.186 mL, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)-N-ethyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (26.4 mg, 0.061 mmol, 28.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.09 (t, J=7.20 Hz, 3H) 1.82-2.02 (m, 3H) 2.18 (d, J=2.27 Hz, 1H) 2.41 (t, J=4.80 Hz, 5H) 3.20-3.29 (m, 2H) 3.34-3.44 (m, 3H) 3.51-3.63 (m, 5H) 3.95-4.03 (m, 1H) 6.82 (d, J=9.09 Hz, 1H) 6.99 (d, J=1.77 Hz, 1H) 7.61 (d, J=1.77 Hz, 1H) 7.93 (dd, J=9.09, 2.53 Hz, 1H) 8.23 (t, J=5.31 Hz, 1H) 8.57 (d, J=2.27 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C23H29N7O2, 422; found, 422.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH:28]1([CH2:31][N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:30][CH2:29]1.FC(F)(F)C(O)=O>O1CCOCC1>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[CH2:25][CH2:26]2)=[N:7][C:2]([NH:37][C:35]2[CH:34]=[N:33][N:32]([CH2:31][CH:28]3[CH2:30][CH2:29]3)[CH:36]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Nc1cnn(CC2CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl 9-[(2,5-dichloropyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxylate (500.5 mg, 1.21 mmol) and 1-(cyclopropylmethyl)-1H-pyrazol-4-amine (330.5 mg, 2.41 mmol) in 1,4-dioxane (50 mL) was added trifluoroacetic acid (686.5 mg, 6.02 mmol). The mixture was stirred at 100° C. overnight and concentrated in vacuo. The residue was purified with a silica gel column chromatography (PE/EtOAc (v/v)=1/1 to DCM/MeOH (v/v)=7/1) to give the product as a light yellow solid (550 mg, 88.45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[C:6]([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F-].[Cs+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:13])[C:5]=2[N:4]=1
Reactant: COc1cnc2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc2cccc(O)c2n1
Reaction time: 18 h
Yield: 113.5 %

Procedure:
A solution of (d) (6.95 g, 21 mmol) in tetrahydrofuran/methanol (280 ml/140 ml) was treated with caesium fluoride (4.73 g, 31.4 mmol) and stirred for 18 hours. The mixture was evaporated and the residue partitioned between diethyl ether and dilute aqueous hydrochloric acid. The aqueous phase was further extracted with diethyl ether and the combined extracts dried and evaporated to give an oil (4.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[CH:23][C:22]([C:36]([F:39])([F:38])[F:37])=[N:21]2)[CH:17]=[CH:18][CH:19]=1.O>C(#N)C.CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)=[CH:23][C:22]([C:36]([F:37])([F:38])[F:39])=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Oc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a solution of methyl 4-amino-2-fluorobenzoate (870 mg, 5.143 mmol) in acetonitrile was added DMAP (691 mg, 5.657 mmol) and phenyl (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (2036 mg, 5.143 mmol) at room temperature. The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was added water and extracted with EtOAC. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography to give pure methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (1.3 g, 54%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:14]Cl>O>[N:1]([CH2:14][C:13]1[CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=[C:11]([C:10]([F:9])([F:23])[F:24])[CH:12]=1)=[N+:2]=[N-:3]
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (74.3 g, 1.14 mol) is suspended in water (125 mL), then DMSO (625 mL) is added. After stirring for 30 minutes, a solution consisting of 3,5-Bis(trifluoromethyl)benzyl chloride (255.3 g, 0.97 moles) and DMSO (500 mL) is added over 30 minutes. (The 3,5-Bis(trifluoromethyl)benzyl chloride is heated to 35° C. to liquefy prior to dispensing (MP=30-32° C.)). The benzyl chloride feed vessel is rinsed with DMSO (50 mL) into the sodium azide solution, the mixture is heated to 40° C., and then maintained for an hour at 40° C., then cooled to 23° C.