Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O)([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CO>[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1/[CH:36]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1)([O-:33])=[O:32]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (3.12 g, 6.00 mmol) was dissolved in methanol (50 mL) and the solution was added with o-nitrobenzaldehyde (1.00 g, 6.60 mmol) and potassium carbonate (2.82 g, 20.40 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water. The precipitated solid was collected by filtration and then dried. The obtained solid was triturated in methanol to obtain Compound 1 (1.05 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH2:30][NH2:31])[CH3:27]>>[CH2:26]([NH:28][CH2:29][CH2:30][NH:31][C:20]([C:14]1[C:15](=[O:19])[NH:16][C:17]2[C:12]([C:13]=1[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:21])[CH3:27]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CCNCCN
Product: CCNCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-ethylethylenediamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, br s), 10.68 (1H, br s), 8.17 (1H, s), 7.27 (3H, br s), 7.12 (2H, t, J=8.7 Hz), 4.00 (2H, s), 2.62-2.48 (6H, m), 0.99 (3H, t,J =7.1 Hz); HRMS calcd for C20H21FN4O3+H+: 385.1676. Found 385.1685.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7](C)[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13])N.[CH3:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=O.Cl.[CH2:26](O)C>>[CH3:13][C:4]1[C:3]2[N:1]=[C:16]3[C:17]4[C:22]([CH2:23][C:15]3([CH3:26])[C:14]=2[C:7]([CH3:8])=[C:6]([O:10][CH3:11])[C:5]=1[CH3:12])=[CH:21][CH:20]=[CH:19][CH:18]=4
Reactant: CC1Cc2ccccc2C1=O
Reactant: CCO
Reactant: COc1c(C)cc(NN)c(C)c1C
Agent: Cl
Product: COc1c(C)c(C)c2c(c1C)C1(C)Cc3ccccc3C1=N2

Procedure:
A mixture of 2.2 g (0.012 mol) of 4-hydrazino-2,3,6trimethylanisole, 1.9 g (0.013 mol) of 2-methyl-1-indanone and 2 ml of conc. aqueous HCl in 20 ml of ethanol was refluxed under argon for 1 hour. After cooling the solvent was removed by evaporation and the residue was partitioned in a mixture of water and methylene chloride. The aqueous phase was neutralized by addition of aqueous NaHCO3 and the phases separated. After drying (MgSO4) and evaporation of the organic phase, the remaining crude product was purified by chromatography on silica using methylene chloride as an eluant. This gave 1.1 g 31% of the product which was used directly in the next step.
Reaction SMILES: C([Li])CCC.CCCCCC.C(OP([CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[CH2:29]([O:31][C:32]1[C:33](/[C:46](/[CH2:51][CH3:52])=[C:47](/[F:50])\[CH:48]=O)=[CH:34][C:35]2[C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[C:40]=2[CH:41]=1)[CH3:30]>C1COCC1.CN1CCCN(C)C1=O>[CH2:29]([O:31][C:32]1[C:33](/[C:46](/[CH2:51][CH3:52])=[C:47](/[F:50])\[CH:48]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:34][C:35]2[C:36]([CH3:44])([CH3:45])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[C:40]=2[CH:41]=1)[CH3:30]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium and hexane (16.4 mL, 1.6 M, 26.2 mmol) was added over 20 minutes down the side of the flask into a stirring solution of ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate (6.92 g, 26.2 mmol referenced in text in THF (75 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.11 mL, available from Aldrich Chemical Co.) at −78° C. After 30 min, the mixture was treated with a solution of (E)-3-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enal (Intermediate 5, 3.55 g, 8.02 mmol) in THF (25 mL). The resulting solution was stirred for 2 h at 0° C. and then cooled again to −78° C. The reaction was quenched at −78° C. by adding saturated aqueous ammonium chloride. The solution was warmed to room temperature, and the products were extracted three times with ether. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound after purification by silica gel chromatography using a 94:6 mixture of hexane:ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:45])[C:14]3[N:15]([CH3:44])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26]([N:28]5[CH2:33][CH2:32][N:31](C(OCC6C=CC=CC=6)=O)[CH2:30][CH2:29]5)=[O:27])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].C1CCCCC=1>CO.[Pd]>[CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:45])[C:14]3[N:15]([CH3:44])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26]([N:28]5[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]5)=[O:27])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)N4CCN(C(=O)OCc5ccccc5)CC4)ccc3n(C)c12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)N4CCNCC4)ccc3n(C)c12
Yield: 78.4 %

Procedure:
2.6 g of 1-[(2-dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-[(4-benzyloxycarbonyl-piperazino)carbonyloxy]-6H-pyrido[4,3-b]carbazole, 5 ml of cyclohexene and 1 g of 10% palladium-on-carbon in 260 ml of methanol are refluxed for 45 minutes. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is chromatographed on silica using a mixture of dichloromethane, methanol and ammonia (85:15:1) as eluant. The product obtained is washed with diethyl ether and ethanol to yield 1.6 g of the desired product, m.p.(cap): 230-234° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:20])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:22]Br>Cl>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:20])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[C:8]([Br:22])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)Nc1cccc2c1C(=O)c1cccc(O)c1C2=O
Agent: Cl
Product: CC(C)Nc1ccc(Br)c2c1C(=O)c1cccc(O)c1C2=O

Procedure:
If the 12.9 parts of 1-isopropylamino-5-hydroxy-anthraquinone obtained in Example 3 are dissolved in 130 parts of 30% strength hydrochloric acid, 9.5 parts of bromine are added dropwise at room temperature, and the mixture is further stirred at room temperature or at elevated temperature (up to 40°) until at most 5% of 1-isopropylamino-5-hydroxy-anthraquinone can still be detected chromatographically in a sample which has been withdrawn, then 15.95 parts of 1-isopropylamino-5-hydroxy-4-bromanthraquinone are obtained after pouring out into 300 parts of water and further working up as described in (a). The quality of this product is only slightly better than that of the product obtained according to Example 4a.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:6]1=[O:15].[NH3:17]>>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([NH2:17])=[O:2])[C:6](=[O:15])[C:7]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: N
Reactant: COC(=O)CN1CC(O)=C(C(=O)OC)C1=O
Product: COC(=O)C1=C(O)CN(CC(N)=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
23 g (0.1 mol) of the 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetic acid methyl ester described in Example 1 are dissolved in 200 ml of a concentrated aqueous ammonia solution and stirred at room temperature for 12 hours. The yellowish solution is then concentrated to dryness by evaporation under a water-jet vacuum. The resulting solid residue is dissolved in 200 ml of water, and a concentrated aqueous solution of hydrochloric acid is added until a strongly acidic reaction takes place. The resulting colourless precipitate is filtered off, washed with water and acetone and dried at 50° under reduced pressure. 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetamide is obtained in the form of white crystals having a melting point of 202° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(NC(C)C)(C)C.[Li].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]>C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:8])=[CH:5][CH:6]=1)[OH:21]
Reactant: Clc1cccc(Cl)n1
Reactant: O=Cc1ccccc1Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1ccc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
2,6-dichloropyridine (10.0 g, 67.6 mmol) was dissolved in 220 mL of dry THF and the reaction mixture was cooled to −78° C. under argon. Lithium diisopropylamine (60 mL, 118 mmol, 2M in heptanes) was added to the reaction mixture over 12 minutes via cannula, and the reaction mixture was stirred for 15 minutes at −78° C. 2-Chlorobenzaldehyde (16 mL, 141.96 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by addition of 80 mL saturated ammonium chloride and 200 mL of water, and the aqueous mixture was extracted once with 300 mL of EtOAc and a second time with 250 mL of EtOAc. The comnbined organic phase was washed with saturated brine and water and was dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified by FLASH column chromatography using 5%-20% EtOAc/Hexanes to yield 12.2 g of (2-chloro-phenyl)-(2,6-dichloro-pyridin-3-yl)-methanol as a yellow oil. Mass Spec. M+H=290.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)#[N:13].[C:22](#[N:26])[CH2:23][C:24]#[N:25]>>[NH2:26][C:22]1[O:1][C:2]2[C:10]([CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([C:12]#[N:13])[CH:15]=3)[C:23]=1[C:24]#[N:25])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: N#CCC#N
Reactant: N#Cc1cccc(C=O)c1
Reactant: Cn1ccc2c(O)cccc21
Product: Cn1ccc2c3c(ccc21)C(c1cccc(C#N)c1)C(C#N)=C(N)O3

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 3-cyanobenzaldehyde (36 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 87 mg (98%) of white solids. 1H NMR (CDCl3): 7.53-7.39 (m, 4H), 7.08-7.03 (m, 2H), 6.68 (d, J=8.4 Hz, 1H), 6.58 (d, J=3.3 Hz, 1H), 4.90 (s, 1H), 4.74 (brs, 2H), 3.79 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1nc(Br)cc(Br)c1OC

Procedure:
To methyl 4,6-dibromo-3-hydroxypyridine-2-carboxylate 3.98 g (3.98 g, 12.81 mmol) in 40 mL of acetone was added K2CO3 (2.0 g, 14.47 mmol) and dimethyl sulfate (1.20 mL, 12.37 mmol). The reaction mixture was refluxed overnight and concentrated to dryness. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4) and concentrated to dryness. The residue was purified by chromatography (silica gel). Elution with 15% ethyl acetate/hexane gave 0.980 g, of a white solid. 1H NMR(CDCl3): δ 3.95 (s, 3H); 3.90 (s, 3H); 7.80 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:32])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[CH3:20])=[C:14]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO.C(=O)(O)[O-].[K+]>O>[C:1]1([S:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[C:19]([CH3:20])[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[F:31])[C:14]=3[CH:13]=2)=[O:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
N-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamide (0.370 g) is added to a mixture solvent of 10% hydrochloric acid (3.3 g), methanol (6 ml), and water (4 ml). Furthermore, 35% hydrochloric acid (0.5 g) is added and the solution is stirred for three hours at 60° C. After 20% potassium bicarbonate aqueous solution is added to turn the reaction solution into a basic, its acidity is adjusted to pH 5˜6 with 10% hydrochloric acid. Precipitated crystals are separated through filtration, dried and thus, 0.182 g of 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methyl-benzimidazole is obtained. 1H-NMR (DMSO-d6, δ): 2.53 (3H, s), 5.56 (2H, s), 6.95-7.01 (1H, m), 7.04 (1H, dt, J=8.7 and 1.4 Hz), 7.32 (1H, dt, J=10.7 and 2.1 Hz), 7.59-7.66 (3H, m), 7.68-7.74 (2H, m), 8.00 (2H, d, J=8.1 Hz), 8.13 (1H, s), 12.43 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:4]([C:5]4[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:6]=4)[CH2:3][CH2:2][O:1][S:44]([CH3:43])(=[O:46])=[O:45])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc([C@H](CCO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3-hydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (0.10 g, 0.21 mmol) and N,N-diisopropylethylamine (167 μL, 0.957 mmol) in dichloromethane (20 mL) was cooled in an ice water-brine bath. After 5 minutes, methanesulfonyl chloride (25 μL, 0.32 mmol) was added and the cold bath was removed until the mixture became homogeneous. The mixture was again cooled in an ice bath. After 30 minutes, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated to afford methanesulfonic acid (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propyl ester which was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:19][CH2:18][C:15]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:16]#[N:17])[CH2:14][CH2:13]1.S(=O)(=O)(O)[OH:28].[OH-].[NH4+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:19][CH2:18][C:15]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:16]([NH2:17])=[O:28])[CH2:14][CH2:13]1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Temperature: 70 °C

Procedure:
A mixture of 1-[(3,4-dihydro-2-naphthalenyl)methyl]-4-anilino isonipecotonitrile (5.0 g) and 90% sulfuric acid (60.0 g) is heated for 10 minutes at 70° C. The mixture is then stirred at room temperature for an additional hour. The reaction mixture is poured into ice-water, basified with ammonium hydroxide, and extracted with chloroform. Concentration of the dried chloroform solution followed by trituration with benzene yields the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][O:10][CH3:11])=[N+:6]([O-])[CH:7]=1.[CH2:12]([N:14](CC)CC)C.C[Si](C#N)(C)C.O>C(#N)C>[Br:1][C:2]1[C:7]([C:12]#[N:14])=[N:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCc1ccc(Br)c[n+]1[O-]
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: O
Solvent: CC#N
Product: COCc1ccc(Br)c(C#N)n1
Yield: 58.2 %

Procedure:
A solution of 5-bromo-2-methoxymethyl-pyridine-1-oxide (5.0 g, 22.7 mmol), triethylamine (12.7 ml, 91 mmol) and trimethylsilyl cyanide (9.1 ml, 68.2 mmol) in acetonitrile (10 ml) was heated to 120° C. for 18 hours in a sealed tube. After completion of the reaction, water was added to the reaction mixture and acetonitrile was removed. The crude material was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 3.0 g (58%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5](CC2C=CC=CC=2)[CH2:4]1.[ClH:18]>CO.[Pd]>[ClH:18].[ClH:18].[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][CH2:4]1
Reactant: CN(C)C1CN(Cc2ccccc2)C(C)(C)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1CNC(C)(C)C1
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of the first eluting enantiomer of N,N,5,5-tetramethyl-1-(phenylmethyl)-3-pyrrolidinamine (1.0607 g, 4.569 mmol) in MeOH (40 mL) was added 1 N aq. HCl (9.1 mL, 9.1 mmol) and 10% Pd/C (50% water, 265 mg). The mixture was hydrogenated overnight and was then filtered through a 0.2 μm PTFE membrane. The solution was concentrated in vacuo, and the residue was azeotroped with MeOH (5×50 mL) to give crude N,N,5,5-tetramethyl-3-pyrrolidinamine dihydrochloride (1.0206 g, >100% crude yield) as a white foam. LCMS: (M+H)+: 143.1.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: COC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 81.8 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.55 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.41 g, 82%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][O:3]1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)c2[N+](=O)[O-])O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
Methyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoate (2.8 g, 9 mmol) was dissolved in 25 mL of methanol and 2 mL of water. To the above solution was added lithium hydroxide (1.13 g, 3 eq.). After stirring the reaction mixture at room temperature for 5 h, the volatile was removed under vacuo and the residue was partitioned between EtOAc and H2O. The aqueous layer was separated, cooled with an ice bath, and then acidified with 10% aq. HCl. The acidic aqueous layer was extracted with EtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na2SO4, and concentrated to give 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoic acid as a white solid (1.9 g).
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[O:8])=O.C(=O)(O)[O-].[Na+].O1CCCC1>O>[OH:3][CH2:4][CH2:5][N:6]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[O:8]
Reactant: O=COCCN(C=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CN(CCO)c1cccnc1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A mixture of 3-[N-(2-formyloxyethyl)formamido]-pyridine (7.01 g) and sodium bicarbonate (3.04 g) in a mixed solution of tetrahydrofuran (60 ml) and water (110 ml) was stirred for 8 hours at 45° to 46° C. The reaction mixture was extracted with a mixed solvent of chloroform and ethanol (1:1) and the extract was evaporated. The residue was dissolved in a mixed solvent of chloroform and ethanol (4:1) and subjected to column chromatography on silica gel (150 g). The elution was carried out with the same solvent and the fractions containing an object compound were collected and evaporated to give 3-[N-(2-hydroxyethyl)formamido]pyridine (4.60 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH:11]2[CH2:14][N:13]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C>C(O)C.O.[Fe]>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:13]1[CH2:14][CH:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:12]1
Reactant: O=[N+]([O-])c1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Temperature: 95 °C
Yield: 81.2 %

Procedure:
To a solution of 3-nitro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyridin-2-amine (1.05 g, 3.20 mmol) in ethanol (30 mL) and water (10 mL) was added iron (448 mg, 8.0 mmol) and acetic acid (240 mg, 4.0 mmol) slowly dropwise. The mixture was heated at 95° C. until TLC analysis confirmed the absence of starting materials. The reaction mixture was filtered through a plug of CELITE™ washing with methanol. The black filtrate was concentrated in vacuo, treated with brine (40 mL) and extracted with dichloromethane (3×60 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL) and then dried over sodium sulfate. The filtrate was evaporated in vacuo to give N2-(1-(quinolin-2-yl)azetidin-3-yl)pyridine-2,3-diamine (0.744 g, 2.6 mmol, yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]2=[C:11]([OH:13])[CH:12]=1.[N+](C1C=C(C=CC=1)O[CH2:21][C@@H:22]1[CH2:24][O:23]1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:23]1[CH2:24][C@H:22]1[CH2:21][O:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=12
Reactant: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Reactant: COc1cc(O)c2nc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(OC[C@@H]2CO2)c2nc(C)oc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A suspension of 6-methoxy-2-methyl-1,3-benzoxazol-4-ol (0.11 g, 0.60 mmol), (2S)-2-[(3-nitrophenoxy)methyl]oxirane (0.16 g, 0.79 mmol) and cesium carbonate (0.44 g, 1.37 mmol) in dry DMF (4 mL) was stirred at room temperature for 5 hours. After aqueous work-up the crude product was purified by flash chromatography (SiO2, toluene-ethyl acetate, 3:1) to afford the subtitle compound (0.118 g, 83.7%).