Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:23]3[N:19]([N:20]=[C:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:22]=3)[CH:18]=[CH:17]2)[CH:10]=1)=[O:7])=O.[N:39]1(C(OC(C)(C)C)=O)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([CH2:1][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH:32]=[C:31]([S:33]([F:38])([F:36])([F:34])([F:37])[F:35])[CH:30]=2)=[CH:10][C:11]=1[N:16]1[C:23]2[N:19]([N:20]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=2)[CH:18]=[CH:17]1
Reactant: Cc1ccc(NC(=O)c2cc(C=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2cc(CN3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
90 mg (0.16 mmol) of the compound of Example 55A and 34 mg (0.18 mmol) of tert-butyl piperazine-1-carboxylate were dissolved in 3.2 ml of dichloromethane, 52 mg (0.25 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred at RT for 3 h. 3 ml of water were then added, and the mixture was extracted with 6 ml of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was then stirred in 2 ml of dichloromethane and 1 ml of trifluoroacetic acid at RT for 2 h. The reaction was then concentrated on a rotary evaporator and the residue was separated into its components by preparative HPLC (Method 24). The product-containing fractions were combined and concentrated under reduced pressure and the residue dried under high vacuum. This gave 11 mg (11% of theory) of the title compound.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([C@@H:17]1[CH2:21][CH2:20][C:19](=[O:22])[N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=O)[NH2:15].C(N(CC)CC)C>ClCCl.O>[C:14]([C@@H:17]1[CH2:21][CH2:20][C:19](=[O:22])[N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])#[N:15]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C#N
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Trifluoroacetic anhydride (178 gm, 0.845 mol) was added slowly to a stirred solution of (2S)-tert-butyl 2-carbamoyl-5-oxopyrrolidine-1-carboxylate (IV) (97 gm, 0.425 mol), containing triethylamine (TEA) (193 gm, 1.907 mol) in dichloromethane (DCM) (2900 ml) at 0° C. After 2 hours of stirring, reaction mixture was diluted with water (1450 ml) and stirred further for 10 minutes. The organic layer was separated and washed with aqueous saturated solution of sodium hydrogen carbonate solution (500 ml), followed by brine (500 ml). The organic layer was dried over anhydrous sodium sulphate, and the solvent evaporated under reduced pressure. To the residue was added diethyl ether (200 ml), stirred well and the separated solid was filtered under suction to obtain the product. The filtrate was concentrated under reduced pressure and the residue was chromatographed on a column of silica gel using mixtures of ethyl acetate and hexane. The evaporation of the combined fractions gave 64.5 gm of (S)-tert-butyl 2-cyano-5-oxopyrrolidine-1-carboxylate (V) as white solid in 72% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[S:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[C:20]=4[CH3:28])[CH2:14]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2].[CH:34](O)=O>C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:34])[CH:15]([C:19]4[S:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[C:20]=4[CH3:28])[CH2:14]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2]
Reactant: O=CO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sc5ccccc5c4C)C3)cc21
Agent: C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4sc5ccccc5c4C)C3)cc21

Procedure:
A 150 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-(3-methylbenzo[b]thien-2-yl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid was suspended in 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid was added. The mixture was heated on a steam bath for 2 hours, then cooled, evaporated and 5 ml of water added. The mixture was adjusted to pH 7 with 1N sodium hydroxide and the solid collected, washed with water and dried, giving 143 mg of the desired product, mp 253°-254° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([F:27])[C:17]=1[C:18]#[N:19]>C1COCC1.O>[F:27][C:20]1[C:17]([C:18]#[N:19])=[C:16]([NH:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1cncc(F)c1
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1cncc(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 5-Fluoropyridin-3-ylamine (1.22 g, 10.9 mmol) in THF (30 mL) at −0° C. was added potassium tert-butoxide (2.43 g, 21.7 mmol) and the reaction mixture stirred at 0° C. for 10 min. This solution was added via cannula to a solution of 2,6-difluoro-3-nitrobenzonitrile (2 g, 10.9 mmol) in THF (20 mL) at −78° C. and the dark purple reaction mixture stirred at −78° C. for 10 min. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane). The solid obtained was triturated with pentane to give the title compound as an orange solid (1.73 g, 58%). 1H NMR 400 MHz δ (CDCl3): 9.73 (1H, br s), 8.53 (1H, dd, J=9.5, 5.7 Hz), 8.47 (1H, d, J=2.5 Hz), 8.43-8.40 (1H, m), 7.33 (1H, dt, J=8.8, 2.2 Hz), 6.83 (1H, dd, J=9.5, 7.3 Hz).
Reaction SMILES: ClC1C=CC(N)=CC=1.N[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=1OC)[C:13]([NH:15]C1C=CC(F)=C(F)C=1)=[O:14]>>[C:13]([NH2:15])(=[O:14])[C:12]1[CH:24]=[CH:25][CH:26]=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: Nc1ccc(Cl)cc1
Product: NC(=O)c1ccccc1
Yield: 47.2 %

Procedure:
The title compound was synthesized as in Example 1 using 4-chloroaniline (1.0 g, 8.1 mmol), CSI (0.85 mL, 9.8 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.17 g, 4.2 mmol) to give 0.24 g of benzamide, 3-[[[[[(4-chlorophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-. Microanalysis: C21H17ClF2N4O5S; calculated: C=49.37; H=3.35; N=10.97. found: C=49.15; H=3.17; N=10.70. MS: M++1=511 Da. Mp 195-198° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:8]2[NH:9][C:10]3[C@:15]([CH2:18][C:19]([OH:21])=[O:20])([CH2:16][CH3:17])[O:14][CH2:13][CH2:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(O)(=O)C>CO>[CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]3[CH2:12][CH2:13][O:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])([CH2:16][CH3:17])[C:10]=3[NH:9][C:8]=12
Reactant: CCc1cccc2c3c([nH]c12)[C@@](CC)(CC(=O)O)OCC3
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Temperature: 25 °C
Yield: 60 %

Procedure:
(R)-Etodolac (1.0 g) is dissolved in methanol (20 ml) and treated with concentrated sulphuric acid (0.06 equiv). The mixture is heated under reflux for 3 days then cooled to ambient temperature. The racemic ester is deposited as a white crystalline solid and collected by filtration (60% yield). The racemic ester is treated with aqueous sodium hydroxide to effect hydrolysis, then acidified with acetic acid to pH 4 to give racemic etodolac as an off-white micro-crystalline powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:23])[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:22][CH2:11][C:10]([C:14]1[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=1[OH:12])([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH3:23]
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Yield: 83 %

Procedure:
Using 3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-1-benzofuran-2 (3H)-one synthesized in Reference Example 6, the title compound was synthesized in the same manner as in Reference Example 8. Yield 83%. Melting point: 116-117° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>O1CCCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=2[N:7]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: COC(=O)CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCCc1nc2cc(Br)ccc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-methylbenzothiazole (1000 mg) was dissolved in tetrahydrofuran (25 mL) and the mixture was cooled to −78° C. using an isopropanol/dry ice bath. Lithium diisopropylamide (1.5M in cyclohexane, 4.40 mL) was added, and the solution stirred for 30 minutes at −78° C. Methyl 3-bromopropionate (1.20 mL, 1836 mg) was added and the solution stirred at −78° C. for two hours. The reaction was quenched with 1M aqueous hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 10% ethyl acetate hexanes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].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+]>C1COCC1>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=[C:4]2[CH:10]=[N:9]1
Reactant: CC(C)(C)OC(N)=O
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cnc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc2c(cnn2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
Pd2(dibenzylidene acetone)3 (“Pd2dba3”; 0.031 g, 0.033 mmol) was added to a suspension of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.110 g, 0.335 mmol), tert-butyl carbamate (0.118 g, 1.00 mmol), Xantphos (0.039 g, 0.067 mmol), Cs2CO3 (0.163 g, 0.503 mmol) in THF (10 mL). The reaction mixture was purged with argon for 10 minutes and heated to reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give tert-butyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (0.100 g, 82%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[NH:17]1>>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([O:25][C@@H:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:1])([CH3:15])[C@H:3]2[OH:14])=[N:17]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: O=c1[nH]oc2ccccc12
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2noc3ccccc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and benzo[d]isoxazol-3-one as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[N:20]1([CH:26]([C:29]#[N:30])[C:27]#[N:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>[Au].C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:27]([NH2:28])[C:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[C:29]([NH2:30])[N:15]=2)=[N:6]1
Reactant: N#CC(C#N)N1CCOCC1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Agent: [Au]
Solvent: ClCCl
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1N1CCOCC1
Temperature: 105 °C

Procedure:
75 mg of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide 1-2-4 (0.29 mmol, 1.0 eq.) and 44 mg morpholin-4-ylmalononitrile [0.29 mmol, 1.0 eq.; for preparation see: H. Gold and O. Bayer, Chem. Ber. 94, 2594 (1961)] were suspended in a small amount of DCM and the resulting suspension was evaporated to dryness. The residue was heated for one h at 105° C. The crude product was purified by flash chromatography yielding 86 mg (0.21 mmol, 72%) of analytically pure target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([NH:22][CH2:23][CH:24](O)[CH2:25][CH3:26])[N:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:12]([N:22]2[CH2:23][CH:24]([CH2:25][CH3:26])[O:8][CH:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=1
Reactant: O=Cc1ccccn1
Reactant: CCC(O)CNc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1CN(c2cc(C(F)(F)F)c(C#N)c(Cl)n2)C(c2ccccn2)O1

Procedure:
Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-(2-hydroxybutylamino)-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg, 1.3 mmol) followed by a catalytic amount of para-toluene sulfonic acid (50 mg). The reactants were refluxed for 6 hours in a Dean-Stark apparatus, concentrated under reduced pressure, adsorbed onto silica and purified using a neutral alumina column, eluting with a mobile phase of 10% ethyl acetate in hexane. 2-Chloro-6-[5-ethyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile (Compound 17) was isolated as a solid in 37% yield. mp 115-118° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[C:11]([C:16]([OH:18])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=2)=O)=[C:6]([CH3:21])[CH:5]=1)[CH3:2].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.C(OC(=O)C)(=O)C>O>[CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]2([N:38]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=3)[C:35]3[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:33][CH:34]=3)[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[C:16](=[O:18])[O:17]2)=[C:6]([CH3:21])[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C(=O)c2nccnc2C(=O)O)c(C)c1
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(CC)CC)cc3C)OC(=O)c3nccnc32)cc1

Procedure:
A mixture containing 3.1 g. of 3-[4-(diethylamino)-2-methylbenzoyl]-2-pyrazinecarboxylic acid, 3.1 g. of 4,4'-dioctyldiphenylamine and 25 ml. of acetic anhydride was stirred in a warm water bath for 3 hours. The reaction mixture was poured into water and the resulting solid was collected and recrystallized from hexane to give 7-[4-(diethylamino)-2-methylphenyl]-7-[bis(4-octylphenyl)amino]furo[3,4-b]pyrazine-5(7H)-one as a light tan solid, m.p. 180°-187° C. A toluene solution of this product contacted with acidic clay or phenolic resin developed a violet image.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=3)[N:24]=2)[CH2:17][CH:18]=1)(=O)=O.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)O1>COCCOC.O.CCOC(C)=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>[F:29][C:28]([F:31])([F:30])[C:25]1[N:23]2[N:24]=[C:19]([N:16]3[CH2:17][CH:18]=[C:13]([C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)[CH2:14][CH2:15]3)[CH:20]=[CH:21][C:22]2=[N:27][N:26]=1
Reactant: O=S(=O)(OC1=CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1)C(F)(F)F
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nnc2ccc(N3CC=C(c4cccnc4)CC3)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
Sodium carbonate (114 mg, 1.08 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (150 mg, 0.36 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (81 mg, 0.40 mmol) in a mixture of DME (2 mL) and water (0.5 mL). The mixture was bubbled with nitrogen for 10 minutes then tetrakis(triphenylphosphine)palladium(0) (20.77 mg, 0.02 mmol) was added and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (3 mL) and water (2 mL). The organic layer was separated and dried, and the solvent was evaporated to give crude product. Purification by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM, gave 1′-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (100 mg, 80%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23]C(C6C(Cl)=NC=CC=6)=O)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:33]([NH2:35])=[O:34])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.N>C(O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:16]2[CH2:15][CH2:14][C:13]3[C:12]([C:33]([NH2:35])=[O:34])=[N:11][N:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[C:18]=3[C:17]=2[CH:19]=1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cccnc3Cl)cc1-2
Agent: N
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The title product of Step 3 was dissolved in anhydrous ethanol and then an approximately equal volume of liquid ammonia was added. The resulting mixture was sealed in a pressure vessel and then stirred overnight at 100° C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane—methanol and chromatographed over silica gel using ethyl acetate as eluent to give the title compound, 890 mg, as an oil which crystallized on standing. Anal. for C19H16N4O3.0.75 H2O (MW 361.87): Calc'd.: C, 63.06;, H, 4.46, N, 15.48. Found: C, 63.24; H, 4.70, N, 14.58.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH:21]=O)[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClC(Cl)C>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:21][CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=4[C:7]#[N:8])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4C#N)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 5-fluoro-2-[1-(2-oxo-ethyl)-1H-indazol-5-yloxy]-benzonitrile (0.307 g, 1.04 mmol) and triacetoxyborohydride (0.66 g, 3.1 mmol) in dichloroethane (10 mL) was added piperazine-1-carboxylic acid tert-butyl ester (0.65 g, 3.49 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with MeOH (2 mL) and diluted with ethyl acetate (100 mL). The solution was washed with aqueous NaHCO3, brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with ethyl acetate/hexanes (2:3, with 1% triethylamine) to afford 0.29 g of product (60% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:25]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38]([OH:40])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(C(C)C)C(C)C.[N+:50]([C:53]1[CH:58]=[C:57]([NH2:59])[CH:56]=[CH:55][C:54]=1[NH2:60])([O-:52])=[O:51]>CN(C=O)C>[NH2:60][C:54]1[CH:55]=[CH:56][C:57]([NH:59][C:38]([C@H:33]2[CH2:34][CH2:35][CH2:36][CH2:37][N:32]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:40])=[CH:58][C:53]=1[N+:50]([O-:52])=[O:51]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 4.96 g, 13.1 mmol) was added to a stirred solution of (R)—N-Boc-2-piperidinecarboxylic acid (3.00 g, 13.1 mmol) and DIPEA (9.0 mL, 51.2 mmol) in anhydrous DMF (50 mL). The mixture was stirred at room temperature for 5 min and then 2-nitro-1,4-phenylenediamine (3.00 g, 13.1 mmol) was added. The mixture was stirred for a further 18 hr, then the DMF was removed by evaporation. The residue was partitioned between water (200 mL) and EA (100 mL) and the phases separated. The aqueous phase was extracted with two further portions of EA (100 mL each) and the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each). The solution was dried over magnesium sulfate and concentrated to give (R)-tert-butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]-piperidine-1-carboxylate as a brown solid (4.80 g).
Reaction SMILES: N1C=CC=C(C(Cl)=O)C=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][CH:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:40]=[C:41]=[S:42])=[O:39])[CH:33]=1>C1(C)C=CC=CC=1.C(O)C>[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:40]=[C:41]=[S:42])=[O:39])[CH:33]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][CH:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:41]([NH:40][C:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[O:39])=[S:42])=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccnc1
Agent: O=C(N=C=S)c1cccnc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccnc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
3-Pyridinecarbonyl isothiocyanate was prepared using commercially available 3-pyridinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 64%).