Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH3:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:20]([CH3:27])[CH:21]=1)#[N:24]
Reactant: Cc1cc(C#N)ccc1CO
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixture of methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6, 112 mg, 0.51 mmol), 4-(hydroxymethyl)-3-methylbenzonitrile (83 mg, 0.56 mmol), PPh3 (268 mg, 1.02 mmol) and THF (6 mL) cooled in ice-water bath, DIAD (207 mg, 1.02 mmol) was added. The mixture was stirred overnight at room temperature. It was then concentrated and purified by flash column chromatograph to give 112 mg of the title compound (63%). [M+H] Calc'd for C19H16N4O3, 349; Found, 349.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(CO)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CO)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 45.3 %

Procedure:
1.29 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.451 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropanol were stirred at 190-200° C. for 90 minutes. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected; the residue was recrystallized from ethyl ether to yield 0.465 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[CH3:15]N>>[CH3:15][NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]#[N:7]
Reactant: CN
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CNc1cccc([N+](=O)[O-])c1C#N
Yield: 79 %

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and methylamine to give 2-methylamino-6-nitrobenzonitrile (0.42 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 2.85 (d, J=5.2 Hz, 3H), 6.75 (d, J=4.8 Hz, NH), 7.16 (d, J=8.4 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.64 (t, J=8.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[NH:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([CH:18]=[O:19])=[CH:3]1
Reactant: Brc1c[nH]c2ncccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1c[nH]c2ncccc12
Temperature: -60 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a suspension of 3-bromo-1H-pyrrolo[2,3-b]pyridine (9.85 g, 50.0 mmol) in THF (300 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (42 mL, 105.0 mmol, 2.1 equiv.) at −70° C. The temperature of the reaction mixture was raised to −60° C. during the addition and became a clear solution. The resulting brick red color solution was slowly allowed to warm to −10° C. during a period of 1 h and then stirred for 4 h at this temperature. Again, the mixture was cooled to −70° C. and a solution of dimethylformamide (8.5 mL, 110.0 mmol) in THF (30 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was dissolved in ethyl acetate (˜70 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with ethyl acetate. After drying in air, 6.05 g (83% yield) of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was isolated as an yellow solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480. found 146.0478.
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:14]=12)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][N:23]1[CH2:24][CH2:25][C:14]2=[C:13]([CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[C:21]3[C:16]([N:15]2[CH2:22]1)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: COC(=O)c1ccc(C(O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cc2c3n(c4ccccc24)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a solution of methyl 4-(hydroxy(2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)methyl)benzoate (80 mg) and Et3SiH (0.5 mL) in 5 mL of CH2Cl2 was added 0.1 mL of TFA. After stirring for 10 min at r.t., the reaction mixture was poured into 15 mL of saturated aqueous solution of NaHCO3 and the mixture was extracted with 2×20 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with up to 100% EtOAc/hexanes to give 70 mg of the title product as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31](O)=[O:32])=[C:25]([F:34])[CH:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37].C(N(CC)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>[CH3:35][N:36]([CH3:37])[C:31](=[O:32])[CH2:30][C:26]1[C:25]([F:34])=[CH:24][C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:28]([F:29])[CH:27]=1
Reactant: CNC
Reactant: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-((1S,2R)-2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}cyclopropyl)ethoxy]-2,5-difluorophenyl}acetic acid (313 mg, 0.661 mmol) in 2.5 ml anhydrous DMF at RT was added dimethylamine (2.0 M solution in THF, 0.661 ml, 1.32 mmol) and N, N-diisopropylethylamine (0.562 ml, 3.31 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (503 mg, 1.32 mmol) was then added to the solution and the mixture stirred at RT overnight. The reaction was quenched by addition of water (12 ml) and the mixture extracted with ethyl acetate (12 ml). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 25 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (800 ml) to afford the title compound. LC/MS (m/z): 501.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:8]2[CH2:11][C:12]([O:14]CC)=O)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:25])[N:7]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:8]2[CH2:11][C:12]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:14]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CC1c2cc(Cl)ccc2C(=O)N1c1ccc(OC)cc1
Solvent: O
Product: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)N2CCN(C)CC2)cc1
Yield: 86.9 %

Procedure:
Ethyl 6-chloro-3-oxo-2-(4-methoxyphenyl)isoindoline-1-acetate (1.0 g) and N-methylpiperazine (1.3 g) was heated at 110° C. for 4 hours in an nitrogen stream. After cooling, water (40 ml) was added to the reaction mixture and crystals separated were collected by filtration, washed with water and then dried. Recrystallization from ether gave 5-chloro-2-(4-methoxyphenyl)-3-(4-methylpiperazin-1-yl)carbonylmethylisoindolin-1-one (1.0 g). The product was identified with the compound No. 13 in Table 5 and melted at 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].[Na]>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: CCO
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccccn2)C1
Yield: 11.7 %

Procedure:
The title compound was prepared according to General Method 3. 8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 4) (220 mg, 1 mmol), 2-vinylpyridine (1 ml, 18 mmol), sodium (20 mg, 0.87 g atom) and CuSO4 (20 mg, catalytic) in ethanol (5 mL) at 150° C. for 16 h (overnight) to obtain 38 mg of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) followed by purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of pyridine-3-sulphonic acid (5.0 g), phosphorous pentachloride (8.0 g), phosphorous oxychloride (30 ml) and chloroform (30 ml) was stirred at 120° C. for 18 hours. The reaction mixture was cooled to room temperature then diluted with chloroform (30 ml) and then filtered. Hydrogen chloride gas was bubbled through the filtrate for 15 minutes and the resultant precipitate collected. This material was dried in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1ccc2ccccc2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ccc3ccccc3n2)CC1
Yield: 7.5 %

Procedure:
Using the procedure from Example 1A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloroquinoline (124 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (11 mg), a white solid, in 8% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.O>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (401 mg, 2.94 mmol), K2CO3 (570 mg, 4.12 mmol) and 6-chloronicotinonitrile (408 mg, 2.94 mmol) in DMF (6 ml), heat at 100° C. After 4 h cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Dry under vacuum at 45° C. overnight to get the title compound (680 mg, 97%). 1H-NMR (CDCl3, 400 MHz): 9.99 (s, 1H), 8.43 (d, 1H, J=2.5 Hz), 7.97 (dd, 1H, J=2.5 and 8.8 Hz), 7.84 (bs, 1H), 7.80 (dd, 1H, J=2.5 and 8.8 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([N:8](C)[C@H:9]([C:11]([C@:13]([CH3:23])([OH:22])[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:12])[CH3:10])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2].[C]>[CH3:1][NH:8][C@H:9]([C:11]([C@:13]([CH3:23])([OH:22])[C:14]([N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:15])=[O:12])[CH3:10]
Reactant: [H][H]
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)N1CCCCC1)N(C)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN[C@@H](C)C(=O)[C@](C)(O)C(=O)N1CCCCC1
Yield: 100 %

Procedure:
3.3 g (9.9 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are hydrogenated in 100 ml of ethanol in the presence of 0.35 g of Pd(OH)2-carbon [20% Pd content] until absorption of hydrogen is complete (about 4 hours). After filtering off the catalyst, the entire reaction solution is concentrated in vacuo. 2.4 g (100% of theory) of N-methyl-L-alanyl-D-lactic acid piperidide are obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].Cl>O1CCCC1>[C:1]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)[nH]c2ccccc21

Procedure:
To a solution of tert-butyl-(2-nitrophenyl)-amine (1.27 g, 6.5 mmol), 5% palladium on carbon (0.5 g), and sodium borohydride (0.49 g, 13.1 mmol) in tetrahydrofuran (20 mL) was added methanol (10 mL) in a dropwise manner. Upon completion of the reaction, it was filtered through a pad of Celite and the filtrate was poured into a saturated aqueous solution of ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give N-tert-butyl-benzene-1,2-diamine which was used in the next step without further purification. A solution of N-t-butyl-benzene-1,2-diamine (1.1 g, 6.7 mmol) and carbonyldiimidazole (1.63 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at room temperature for 12 hours. Upon completion, the reaction was poured into a 1 N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 50% ethyl acetate in hexane) to give 1-tert-butyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS (ES) m/z 191.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH3:34][C:35]1([O:38][CH2:37]1)[CH3:36]>CO>[OH:38][C:35]([CH3:37])([CH3:36])[CH2:34][N:23]1[CH2:22][CH2:21][C:20]2([CH2:26][C:18]3([O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:27]3)[CH2:19]2)[CH2:25][CH2:24]1
Reactant: CC1(C)CO1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(O)CN1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 50 mg) and K2CO3 (17 mg) in methanol (4 mL) is stirred at room temperature for 15 min prior to the addition of isobutylene oxide (20 μL). The reaction vessel is sealed and the mixture is stirred at 60° C. overnight. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:4:1→0:9:1) to give the title compound. LC (method 1): tR=0.71 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2)=[O:2].[BH4-].[Na+].Cl>C(O)C.O>[CH2:17]([N:13]([CH2:14][CH2:15][CH3:16])[CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([CH2:1][OH:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1CCc2cccc(C=O)c2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C1CCc2cccc(CO)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-formyl-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (1 gm, 3.86 mMol) in ethanol (15 mL) was added sodium borohydride (500 mg, 13.2 mMol), and the solution was stirred for 18 hours at room temperature. The reaction mixture was then diluted with water and made acidic with 10% hydrochloric acid. The aqueous was extracted once with diethyl ether, and the organic phase was discarded. The remaining aqueous phase was made basic with concentrated ammonium hydroxide and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a colorless oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the title compound as a colorless, viscous oil (780 mg 77%). The fumarate salt was formed and crystallized (ethanol/diethyl ether) to give colorless crystals (m.p.=151°-152° C.).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH3:13]>CO.[Pd]>[NH2:13][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: N
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (3.0 g, 17.65 mmol) was dissolved in 150 mL methanol saturated with ammonia at 0° C., and to the solution was added wet 10% Pd/C catalyst (4.0 g). The mixture was stirred at room temperature under hydrogen (1 atm) for about 36 h. Then the catalyst was then removed by filtration and the filtrate was concentrated to give the crude product, which was purified by chromatography on silica gel to give 2.0 g of the desired product. MS (ESI): 172 (MH+).
Reaction SMILES: [C:1]1([CH:7]([CH:10]=O)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[CH:10]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:14]1
Reactant: O=CC(C=O)c1ccccc1
Reactant: CNN
Solvent: CCO
Product: Cn1cc(-c2ccccc2)cn1
Yield: 102.1 %

Procedure:
1 g of 2-phenylmalonaldehyde (6.75 mmol) were dissolved in 25 ml of ethanol. 0.36 ml of N-methyl-hydrazine (6.75 mmol) were added, the reaction mixture was stirred under reflux for 4 h, the solvent evaporated under reduced pressure to yield 1.09 g of the product.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:27]([C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:36](=[O:37])[CH:35]=[CH:34][C:33]1[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:40][CH:39]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1ccc([N+](=O)[O-])cc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 49 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 4-nitrocinnamic acid under the conditions described in example 86 to yield 49% of the desired product.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1>[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH:18]([OH:19])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: COc1cccnc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccnc1C(O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 2-bromo-3-methoxypyridine (564 mg, 3 mmol) under ice cooling. The reaction mixture was then stirred at room temperature for 60 minutes. To the resulting brown solution, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise under ice cooling. The temperature of the reaction mixture was gradually raised to room temperature. After addition of a saturated aqueous solution of ammonium chloride, the resulting mixture was extracted with ethyl acetate. After the solvent was dried, needle crystals obtained by concentration under reduced pressure were triturated with hexane to give the title compound (660 mg, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C:6](=[O:20])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]=1[CH3:9])#[N:2].Cl.[NH2:36][OH:37].CC([O-])=O.[Na+].C(O)C>O>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:5]2[C:6](=[O:20])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:8]([CH3:9])=[C:3]([C:1](=[NH:2])[NH:36][OH:37])[CH:4]=2)=[O:22])=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: NO
Reactant: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=N)NO)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 28 %

Procedure:
5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and a magnetic stirrer bar were placed in a vial. The mixture was heated (90° C.) overnight. LC-MS showed a 50:50 mixture of two components, one of which had the expected MW. The product was isolated by preparative HPLC giving 0.012 g (28%) of the intermediate N-hydroxyamidine.