Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]([O:18][C@@H:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C@H:21]2[CH3:33])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a mixture of 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (193 mg, 0.729 mmol), tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate (173 mg, 0.802 mmol) and triphenylphosphine (230 mg, 0.875 mmol) in THF (2.0 mL) was added DEAD (0.129 mL, 0.875 mmol). The resulting mixture was stirred at room temperature overnight and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield trans-tert-butyl 4-(5-chloro-1-(4-cyano-3-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)-3-methylpiperidine-1-carboxylate (183.5 mg, 50.1%) as an orange solid. 1H NMR (400 MHz, DMSO): 6 ppm 7.99-8.15 (m, 2H), 7.80 (dd, J=10.55, 1.76 Hz, 1H), 7.55 (dd, J=8.35, 1.76 Hz, 1H), 6.21 (s, 1H), 4.67-4.84 (m, 1H), 3.52 (app br s, 2H), 3.18 (app br s, 2H), 1.99 (app br s, 1H), 1.82 (app br s, 1H), 1.62-1.73 (m, 1H), 1.40 (s, 9H), 0.90 (d, J=7.03 Hz, 3H). MS (ESI) 406 (M−56+H).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[K+]>C(Cl)Cl>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:26][C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc3ccccc3c2)CC1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of piperazine-1-carboxylic acid phenylamide (103 mg) and 2-naphthaldehyde (94 mg) in DCM (2 mL) was treated with NaB(OAc)3H (148 mg). After 16 h, the resulting mixture was treated with 10% aq. KOH (2 mL). The aqueous phase was extracted with DCM (2×3 mL). The combined extracts were dried (MgSO4) and concentrated. Chromatography of the residue gave the title compound as a white foam (111 mg). 1H NMR (400 MHz, CDCl3): 7.85-7.80 (m, 3H), 7.74 (s, 1H), 7.52-7.45 (m, 3H), 7.35-7.25 (m, 4H), 7.05-7.00 (m, 1H), 6.37 (br s, 1H), 3.69 (s, 2H), 3.53-3.48 (m, 4H), 2.55-2.49 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.O.[OH-].OCC[N+](C)(C)C.Cl>CS(O)(=O)=O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)c(C)c1
Agent: CS(=O)(=O)O
Agent: C[N+](C)(C)CCO
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc(O)ccc1-n1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Temperature: 150 °C
Yield: 36.3 %

Procedure:
7-Chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (1.00 g, 2.61 mM) was stirred in methanesulfonic acid (10 mL) to give a brown solution. This solution was heated to 150° C. for 3 hours and cooled to room temperature. The cooled solution was added dropwise to water (50 mL) with stirring to give a grey suspension which was stirred for 20 hours and filtered. The collected solids were washed with water and then suspended in water (50 mL). To this suspension was added choline hydroxide solution (2 mL, 45 wt % in methanol) which dissolved the solids to give a brown solution. This solution was heated to reflux for 1 hour, additional choline hydroxide solution (2 mL) was added and the solution was heated to reflux for 3 hours. The solution was cooled to room temperature and acidified to pH=1 with 1N HCl to give a brown suspension. The suspension was filtered and the collected solids were washed with water to give a brown solid. Severalrecrystallizations from hot methanol gave the title compound as an off-white powder (0.35 g, 36%), mp 287 (decomp.); MS(CI): 370.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Mg]Cl)(C)(C)C.ClC1C=CC=CC=1>CC1(P(C(C)(C)C)C(C)(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1.O.C1COCC1>[C:10]1([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: c1ccc(-c2cc3ccccc3[nH]2)cc1
Temperature: 5 °C
Yield: 96 %

Procedure:
[PdCl(π-allyl)]2 (15.6 mg, 0.1 mol %) and cBRIDP (60.2 mg, 0.4 mol %) were placed into a 50 mL, two-necked, round bottomed flask equipped a gas inlet, and the flask was evacuated and filled with nitrogen. Subsequently, to the mixture was added dehydrated THF (11 mL) to prepare a catalyst solution. A 200 mL, four-necked, round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, condenser, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. Indole (5.0 g, 42.7 mmol, 1.0 equivalent) and dehydrated toluene (55 mL) were charged into the flask, and the mixture was cooled to 5° C. using an ice bath. To the mixture was added a THF solution of tert-butylmagnesium chloride (tBuMgCl) (1.02 mol/L, 46.0 mL, 47.0 mmol, 1.1 equivalents) (containing 42.0 mL of THF) dropwise via the dropping funnel at such a rate that the temperature of the reaction solution was kept at 15° C. or lower. Subsequently, to the solution were added chlorobenzene (4.8 mL, 47.0 mmol, 1.1 equivalents) and the catalyst solution (11 mL) successively, and the solution was stirred for 15 minutes under reflux. After cooling the reaction mixture to room temperature, to the mixture were added water (30 mL) and the aqueous layer was separated off. The organic layer was concentrated under reduced pressure to give oily residue, which was purified by silica gel column chromatography (eluent: n-hexane/toluene) to afford 7.9 g of phenylindole as a viscous oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:6][CH:5]=1.[CH3:19][O:20][CH2:21]Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:19][O:20][CH2:21][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:9]=1
Reactant: OCCCCCCCCc1ccc(O)cc1
Reactant: COCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(CCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a suspension comprising 1.0 g of sodium hydride in 40 ml of dry tetrahydrofuran, 5.27 g of 8-(4-hydroxyphenyl)octanol dissolved in 50 ml of dry tetrahydrofuran was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 30 minutes and then cooled to 0° C. again. Subsequently, 2.1 ml of chloromethyl methyl ether was added dropwise thereto. After stirring at room temperature for 30 minutes, the mixture was cooled to 0° C. and ice and a saturated aqueous solution of sodium bicarbonate were added thereto. The resulting mixture was then extracted with ethyl acetate. The extract was concentrated and subjected to column chromatography (silica gel, ethyl acetate: hexane=1:3-1:2). As a result, 4.05 g of the desired compound was obtained (yield: 66%).
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:23][N:22]([CH3:24])[C:20]([C:19]1[C:18]([CH3:29])=[C:17]([N:16]=[C:1]=[O:2])[C:27]([CH3:28])=[CH:26][CH:25]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)N(C)C)c(C)c1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(C)C)c(C)c1N=C=O

Procedure:
A solution of di-tert-butyl dicarbonate (0.081 g) in methylene chloride (1.6 ml) and a solution of 3-amino-N,N,2,4-tetramethylbenzamide (J. Chem. Soc., Perkin Trans. I, 1973, 1-4; 0.072 g) in methylene chloride (1.0 ml) were added in turn to a solution of 4-dimethylaminopyridine (0.004 g) in methylene chloride (0.4 ml). The resultant mixture was stirred at ambient temperature for 20 minutes. There was thus obtained a solution of 3-(N,N-dimethylcarbamoyl)-2,6-dimethylphenylisocyanate which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=[O:23])[CH2:4][CH2:3]1.[C:25]([Si:27](C)([CH3:29])[CH3:28])#N>C1COCC1.[I-].[Zn+2].[I-]>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)=[CH:7][C:6]=2[C:5]([O:23][Si:27]([CH3:29])([CH3:28])[CH3:25])=[CH:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1(C)CC=C(O[Si](C)(C)C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cold solution (0° C.) of 50 mg (0.07 mmol) of zinc iodide (dried in vacuo over P2O5 for several hours) in 2 ml of dry THF (flushed with argon) was added a solution of 0.110 g (0.34 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) in 2 ml of THF followed by 0.14 ml (1.03 mmol) of cyanotrimethylsilane. The resulting mixture was stirred at 25° C. for 12 hours and purified by flash chromatography (silica, 50% EtOAc-hexane) to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (282 mg, 1.07 mmol) in DMSO (15 mL) was treated with Cs2CO3 (1.45 g, 4.45 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (376 mg, 2.21 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 0:1:1 to 1.49:50) gave the title compound (250 mg, 65%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.54 (dd, J=8.9, 1.7 Hz, 1H), 7.40 (d, J=8.9, 1H), 4.54 (t, J=7.1 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H), 2.56-2.54 (m, 4H), 1.79-1.75 (m, 4H); ESI MS m/z 362 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:22]1([NH:25][CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NC1CC1)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 1A (0.07 g, 0.3 mmol) and cyclopropylamine (0.33 mL, 4.8 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.016 g, 0.3 mmol) and acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 48 hours and concentrated. The residue was purified by chromatography on silica gel column with 0-10% dichloromethane/methanol/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 9.12 (s, 2H), 8.33 (d, J=8.3 Hz, 2H), 7.88 (d, J=7.4 Hz, 1H), 7.71-7.78 (m, 4H), 7.37 (t, J=7.8 Hz, 1H), 4.59 (m, 1H), 2.57 (s, 1Hz), 1.64 (d, J=6.6 Hz, 3H), 0.81-0.87 (m, 1H), 0.75-0.79 (m, 1H), 0.66-0.72 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1>>[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNc1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1

Procedure:
N-Methyl-4-(4-nitroquinolin-2-yl)aniline T466P was prepared using general procedure A from 2-bromo-4-nitroquinoline (50 mg, 0.2 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (46 mg, 0.2 mmol). The product T466P was obtained as a brown solid (37 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 8.34 (m, 1H), 8.32 (s, 1H), 8.19 (m, 1H), 8.09 (m, 2H), 7.79 (m, 1H), 7.63 (m, 1H), 6.72 (m, 2H), 2.93 (s, 3H); MS (ESI): 280 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]>O1CCCC1.[Pd].CO>[NH2:11][C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1nc(C)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C)c(C)cc1N
Reaction time: 3 h
Yield: 98 %

Procedure:
5,6-Dimethyl-2-methoxy-3-nitropyridine (1-013-06) (2.56 g) was dissolved in tetrahydrofuran (41 mL), and to the reaction mixture was added a suspension of 5% palladium on carbon (450 mg) in methanol (41 mL), and then the catalytic reduction was carried out. After 3 h, catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-amino-5,6-dimethyl-2-methoxypyridine (1-013-07) (2.096 g, 97.9%, m.p.: 56-58° C.) as a blackish brown crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:27]([CH3:28])[CH3:29])[N:9]=2)=[CH:12][C:13]=1[O:25][CH3:26]
Reactant: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1N

Procedure:
A solution of tert-butyl 4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenylcarbamate (BA20) (20 mg, 0.05 mmol) in CH2Cl2, TFA, S(CH2)2, H2O (45:45:5:5) (1 mL) was stirred at room temperature for 15 minutes. NaHCO3 (2 mL) was added till reaction was alkaline. Reaction was extracted with H2O and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA20d.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:15]3[N:14]([CH:18]=[CH:17][N:16]=3)[CH2:2][CH2:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Product: Cc1ccc(C2=CCCn3ccnc32)cc1

Procedure:
Combine 100 g (0.51 mole) of 4-chloro-4'-methylbutyrophenone with 300 g (4.4 mole) of imidazole and heat to 175° C. under nitrogen for 24 hr. Purification from 1 kg of silica gel using methylene chloride as solvent, followed by crystallization from ether provides the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCCl.CO.C(Cl)Cl.C(O)(=O)C>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 20 mL 1,2-dichloroethane was treated with 1-methylpiperidin-4-one (2.76 mL, 23.8 mmol) followed by sodium triacetoxyborohydride (8.4 g, 39.7 mmol) then acetic acid (2.25 mL). The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C., quenched with 5 mL 1N NaOH and stirred for 20 minutes. The suspension was extracted with 100 mL CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated to give a light residue which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 then 5% 2M NH3 in MeOH/CH2Cl2. A yellow oil was obtained (440 mg, 24.1%). 1H-NMR (CDCl3) δ: 7.07-7.02 (m, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.55 (pseudo t, J=7.8 Hz, 1H), 3.65-3.55 (m, 1H), 3.20 (t, J=5.7 Hz, 2H), 2.99-2.95 (m, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 2.11-2.05 (m, 2H), 1.93-1.73 (m, 6H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CO.CCOCC>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[C:19]=1[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Cc1cccc(C)c1NC(=O)CCCn1ccnc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(C)c1NCCCCn1ccnc1

Procedure:
A solution of 27.27 g of N-(2,6-dimethylphenyl)-1H -imidazole-butanamide hydrobromide salt in 250 ml of dry tetrahydrofuran was added dropwise with stirring to 530 ml of 1 molar borane in tetrahydrofuran and the resulting solution was heated to reflux for 2 hours. After cooling, excess methanol was added to decompose the remaining borane and the solution was evaporated to dryness. The residue was acidified by the cautions addition of 285 ml of 2N hydrochloric acid and was warmed on the steam bath for 20 minutes. The resulting solution was cooled, made strongly basic with sodium hydroxide solution and was extracted with dichloromethane. The combined organic layers were dried with potassium carbonate and concentrated to give 25.1 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-butanamine as an oil which was dissolved in 200 ml of methanol, treated with 23.9 g of fumaric acid and diluted with 600 ml of ether. The resulting solid amounted to 37.0 g of N-(2,6-dimethylphenyl) -1H-imidazole-1-butanamide (E)-2-butenedioate(1:2 ) salt, mp 146°-147° C. Recrystallization from methanol-ether gave the analytical sample, mp 148°-149° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]1([F:17])[CH2:16][NH:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][C:13]([F:17])([F:12])[CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C2)nc1
Temperature: 120 °C

Procedure:
The 2-chloro-5-nitro-pyridine (317 mg, 2 mmol) and 3,3-difluoroazetidine hydrochloride (259 mg, 2 mmol) was mixed in 8 mL of THF. Diisopropylethylamine (1.4 mL) was added and the mixture was heated in a microwave at 120° C. for 20 minutes. After cooling to room temperature, the solid was filtered and the filtrate was distributed between ethyl acetate and water. The organic layers were evaporated and the solid material was triturated with methanol. The resulting solid was filtered to give 5-nitro-2-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd for C8H7F2N3O2 m/e 215.16, obsd 216.1 (ES, M+H). Hydrogenation of the nitro compound, as above, provided 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4ccc(F)cc4)CC3)cccc2n1
Yield: 41 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-fluorobenzene-sulfonyl chloride (79.8 mg; 0.41 mmol) to obtain 33.2 mg. (41% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.89 (m, 2H), 7.54 (t, J=8.5 Hz, 2H), 7.38 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.93 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.92 (br s, 2H), 3.73 (d, J=11.5 Hz, 2H), 3.11 (d, J=12.0 Hz, 2H), 2.85 (t, J=11.5 Hz, 1H), 2.59 (t, J=11.5 Hz, 2H). ESIMS+404.4.5 m/z
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH:14]=[N:22][OH:23])=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2Cl)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: ON=Cc1ccc(-c2ccc(Cl)cc2Cl)o1
Reaction time: 8 h

Procedure:
A mixture of 5-(2,4-dichlorophenyl)-2-furancarboxaldehyde (635 g, 2.63 moles), anhydrous sodium acetate (432 g, 5.26 moles), hydroxylamine hydrochloride (366 g, 5.26 moles), SDA #30 (9184 ml) and water (918 ml), was refluxed for 51/3 hours and allowed to stand overnight. The mixture was added to ice/H2O (42 liters), stirred 1 hour and filtered. The grayish-tan solid was washed with water (10 liters), filtered and dried at 65° to 660 g (98%).
Reaction SMILES: N1C=CC=NC=1.CS([C:11]1[N:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[C:19]1([CH2:18][O:17][C:14]2[CH:13]=[N:12][C:11]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:16][CH:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ncc(OCc2ccccc2)cn1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: c1cncnc1
Product: c1ccc(COc2cnc(N3CCNCC3)nc2)cc1
Yield: 42 %

Procedure:
A mixture of the pyrimidine prepared in (a) above (24.5 g, 0.09 mole), piperazine (77.5 g, 0.9 mole), and toluene (160 mL) was heated at 150° C. in a stainless steel omb for 22 hr. The reaction mixture was filtered, concentrated in vacuo, and the residue crystallized from Skelly B to give 10.15 g (42%) off-white solid, m.p. 94°-97° C.