Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:3]=1.[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:23]1([CH2:26][NH:1][C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]3[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(-c2cc(N)c(=O)n(C)c2)cc1NS(C)(=O)=O
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2cc(NCC3CC3)c(=O)n(C)c2)cc1NS(C)(=O)=O
Temperature: 30 °C
Yield: 13.2 %

Procedure:
To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30° C. NaBH3CN (24.5 mg, 0.4 mol) was added in portions at 30° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.61 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 3.05 (s, 2H), 2.95 (s, 3H), 1.21-1.14 (m, 1H), 0.64-0.56 (m, 2H), 0.35-0.28 (m, 2H). LCMS (M+H)+ 378.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCC(CCCN2CCCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCN3CCCCC3)C2)c2ccccc21
Yield: 14 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[3-[3-(piperidin-1-yl)propyl]-piperidin-1-yl]ethanamine in a yield of 14% of theory. Colourless amorphous substance, RF 0.13 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19](O)=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:22][C:23]1[C:32]([NH2:33])=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>>[NH2:22][C:23]1[C:32]([NH:33][C:19](=[O:20])[CH2:18][N:4]([CH:1]2[CH2:2][CH2:3]2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1cc(C)c(S(=O)(=O)N(CC(=O)O)C2CC2)c(C)c1
Reactant: COC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)c1N
Yield: 75 %

Procedure:
2-(N-Cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)acetic acid was reacted with methyl 2,3-diaminobenzoate (1.3 eq.) in the presence of EDCl (1 eq.), HOBT (1 eq.) and DIPEA (10 eq.) and the desired product thereby formed was employed directly in the next stage without further working up. Yield: 75%
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CC1C=C(Cl)C(S(C)(=O)=O)=CC=1C(O)=O.SC1C=CN=CC=1.O(C)[Na].O=S(Cl)Cl.[NH2:51][C:52]([NH2:54])=[NH:53]>COCCOC>[NH2:53][C:52]([NH2:54])=[N:51][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:18]([CH3:21])(=[O:20])=[O:19])[C:9]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: Cc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)Cl
Agent: CO[Na]
Agent: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: Sc1ccncc1
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: Cc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 3 h

Procedure:
1.8 g of 2-methyl-4-(4-pyridylthio)-5-methylsulfonylbenzoyl chloride [obtainable by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with 4-mercaptopyridine in the presence of NaOCH3 at 180° followed by chlorination with SOCl2 ] dissolved in 20 ml of ethylene glycol dimethyl ether are added dropwise at room temperature to a solution of 1.5 g of guanidine in 20 ml of ethylene glycol dimethyl ether, and the mixture is stirred at 25° for three hours. The mixture is then worked up in the customary manner and purified by chromatography on silica gel (ethyl acetate+15% methanol). N-Diaminomethylene-2-methyl-4-(4-pyridylthio)-5-methylsulfonylbenzamide is obtained in the form of a viscous oil, M+ +1(FAB)=365.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.[CH:10]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=CC1CCCC1
Reactant: NCc1cncc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1cncc(CNCC2CCCC2)c1
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A solution of (5-bromopyridin-3-yl)methanamine (LVIII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LIX) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C12H17BrN2 m/z 269 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][CH2:28][CH2:29]Cl)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>CN(C)C=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][CH2:28][CH2:29][N:32]([CH3:31])[CH2:33][CH2:34][OH:35])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Reactant: CNCCO
Solvent: CN(C)C=O
Product: CN(CCO)CCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Product: Cl
Temperature: 25 °C
Reaction time: 64 h
Yield: 197.9 %

Procedure:
A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (634 mg), 2-methylaminoethanol (534 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 64 hrs. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (55 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100). 4N Hydrogen chloride-ethyl acetate solution (10 mL) was added to the obtained amorphous solid and, after concentration under reduced pressure, the residue was recrystallized from ethanol-ethyl acetate to give the title compound (523 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>ClCCl>[OH:16][C:3]1([CH2:2][NH:1][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][C:26]=2[N+:35]([O-:37])=[O:36])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (78.4 mmol, prepared as described above) in dichloromethane (300 mL) was added triethylamine (11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). The mixture was stirred at rt for 1 h, then heated at reflux for 1 h. The solution was transferred to a separatory funnel and extracted with water (100 mL). The organic layer was isolated and upon standing a precipitate formed. The solid was isolated by filtration and washed with dichloromethane and water and dried. Additional solid precipitated from the mother liquor and was isolated. The two yellow solids were combined and dried to yield tert-butyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (20.23 g, 82%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11](Cl)=[N:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:17]=[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: C#CC(=O)OCC
Reactant: COc1ccc(C(Cl)=NO)cc1C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)no1
Temperature: 40 °C

Procedure:
3-Cyano-N-hydroxy-4-methoxybenzenecaboximidoyl chloride, ethyl propiolate and triethylamine were dissolved in a THF solution, followed by stirring at 40° C. to obtain ethyl 3-(3-cyano-4-methoxyphenyl)-5-isoxazolecarboxylate. AP: 295.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CCCCCCCCO
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-octanol (651 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (2 mmHg, 82 to 92° C.) to give octyl pyruvate (762 g, yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:19]Cl)[C:8](=[O:18])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.N1C=[CH:24][N:23]=[N:22]1.[Na].[CH3:27][N:28](C=O)C>>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:6]=[C:7]([CH2:19][N:23]3[CH:24]=[N:28][CH:27]=[N:22]3)[C:8]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CCl)cc2ccc(Cl)cc2n1-c1ccccc1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: [Na]
Product: O=c1c(Cn2cncn2)cc2ccc(Cl)cc2n1-c1ccccc1

Procedure:
Following the procedure of example 22, react 7-chloro-1-phenyl-3-chloromethyl-2(1H)-quinolone with sodium triazole in DMF. Chromatograph to obtain the major product, 1-phenyl-7-chloro-3-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-quinolone.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=O)[CH3:18])=[O:14])=[CH:9][CH:8]=1)=[O:5].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:17]([CH3:18])=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(=O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(-c2ccc(NC(=O)c3ccccc3Cl)cc2)nc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
a solution of 2-chloro-N-(4-(((2-oxo-1-phenylpropyl)amino)carbonyl)phenyl)benzamide (90 mg, 221 μmol) and phosphoryl trichloride (1.5 mL, 16093 μmol) in 2 mL pyridine was heated in a 70° C. oil bath. After 2 hours the reaction was poured into 10 mL saturated aqueous sodium bicarbonate solution and stirred vigorously for 30 minutes. The aqueous mixture was extracted with 25 mL ethyl acetate. The organic extract was washed with 10 mL each water then brine. The organic layer was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow-green oil. TLC indicated a very complex mixture of products. The crude product was purified by reversed-phase preparative HPLC to afford a colorless film (4 mg, 5%). ESI+ m/z=389.0 [MH]+.
Reaction SMILES: O.[Sn](Cl)Cl.[CH2:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[CH:6]=[CH2:7].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH:6]=[CH2:7]
Reactant: C=CCOc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1cc(F)ccc1N
Reaction time: 4 h
Yield: 47.2 %

Procedure:
Tin (II) chloride hydrate (8.5 g, 38 mmol, 5 eq) was added to a solution of 2-allyloxy-4-fluoro-1-nitro-benzene (1.5 g, 7.6 mmol) in ethyl acetate (20 ml) at room temperature and the mixture was stirred for 4 hr. The reaction mixture was neutralized with triethylamine and then partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 2-allyloxy-4-fluoro-phenylamine (0.6 g, 50%). The crude compound was used in the next stage without purification.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=1[Br:6]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1Br
Temperature: 25 °C
Yield: 98 %

Procedure:
Concentrated sulfuric acid (5 mL) was added drop-wise to an ice-cold mixture of 2-bromo-4-chloro-benzoic acid (10.14 g, 0.0431 mol) and methanol (40 mL). The resulting mixture was heated at reflux for 17 hours. After this time, the reaction mixture was cooled to room temperature, and then poured into ice-cold water (150 mL), creating a white suspension. The suspension was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated aqueous NaHCO3 (100 mL), followed by saturated aqueous NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 98% yield) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@@H:29]([NH:32][C:14](=[O:16])[C@@H:9]([N:8]([CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH3:13])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: CCC[C@@H](C(=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step C of Example 14 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (501 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.44-7.45 (bs, 2H), 7.35-7.40 (m, 2H), 7.30-7.37 (m, 1H), 7.25-7.29 (m, 1H), 4.70-4.75 (bs, 1H), 4.37-4.43 (m, 1H), 3.56 (d, J=12.9 Hz, 1H), 3.52 (d, J=12.8 Hz, 1H), 2.95 (s, 3H), 2.71 (d, J=8.9 Hz, 1H), 2.62-2.68 (m, 1H), 2.44-2.48 (m, 2H), 2.25 (t, J=8.5 Hz, 1H), 2.14 (t, J=8.3 Hz, 1H), 1.91-1.99 (m, 1H), 1.66-1.80 (m, 3H), 1.56-1.63 (m, 1H), 1.50 (s, 9H), 1.26-1.38 (m, 3H), 0.88 (t, J=7.4 Hz, 3H); MS (ESI+) m/z 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[N:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:23]3[CH:24]=[CH:25][NH:21][N:22]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc[nH]n1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cc[nH]n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1H-pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 395.2 (M−H).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[N:16]1([CH2:22][CH2:23][C:24]2[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]3=[C:26]([C:33](Cl)=[O:34])[N:25]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:2]1([NH:1][C:33]([C:26]2[N:25]=[C:24]([CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: NN1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCCCC1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 1-aminopiperidine (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h. then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (55 mg, 34%). 1H NMR (DMSO-d6) δ 8.59 (1H), 8.35 (1H), 8.02 (1H), 7.08 (1H), 6.82 (1H), 3.57 (4H), 3.18 (2H), 2.80 (4H), 2.75 (2H), 2.44 (4H), 1.60 (4H), 1.38 (2H); m/z (M+H)=385.31.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:17][NH:18]C(=O)C[Cl:21].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[ClH:21].[NH2:18][CH2:17][C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[OH:15]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: O=C(CCl)NCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Product: Cl
Temperature: 25 °C

Procedure:
A finely powdered mixture of 5.2 g (25 mmol) of 3,5-di-tert-butylphenol and 3.15 g (25 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 22.5 mL acetic acid and 2.5 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 16 hours. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15-30-50% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: C(Cl)(=O)C.[C:5]([OH:13])(=[O:12])[CH:6]([CH2:8][C:9]([OH:11])=[O:10])[OH:7]>>[C:9]([OH:11])(=[O:10])[CH3:8].[C:5]1(=[O:12])[O:13][C:9](=[O:11])[CH2:8][CH:6]1[OH:7]
Reactant: O=C(O)CC(O)C(=O)O
Solvent: CC(=O)Cl
Product: CC(=O)O
Product: O=C1CC(O)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three equivalents of acetyl chloride were added dropwise in a flask to one equivalent of malic acid while keeping the temperature below 0° C. After the acetyl chloride was added, the mixture was stirred at room temperature overnight. Excess acetyl chloride and acetic acid were then distilled under a water pump at room temperature to provide malic anhydride acetate.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1C=O)[CH3:5].[CH3:14][S:15]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22]P(=O)(OCC)OCC)=[CH:20][CH:19]=1)(=[O:17])=[O:16].[CH3:33]OCCOC>>[CH3:5][N:4]([CH3:3])[C:6]1[CH:7]=[CH:10][C:11]([CH:33]=[CH:22][C:21]2[CH:20]=[CH:19][C:18]([S:15]([CH3:14])(=[O:16])=[O:17])=[CH:32][CH:31]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1ccccc1C=O
Reactant: COCCOC
Reactant: CCOP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OCC
Agent: [H-]
Agent: [Na+]
Product: CN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Yield: 66 %

Procedure:
To a solution of 2.8 g (0.07 mol) of 60% sodium hydride dispersion, 7.46 g (0.05 mole) N,N-dimethylaminobenzaldehyde, and 100 mL of dry, freshly distilled 1,2-dimethoxyethane (DME) under nitrogen, at room temperature, was added 15.3 g (0.05 mole) diethyl 4-methylsulfonylbenzylphosphonate with vigorous stirring. The mixture immediately turned bright yellow. The mixture was heated at reflux for 2 hours. After cooling the very bright yellow solution was poured over 300 g of crushed ice under nitrogen blanket. The bright yellow solid was collected by filtration, washed with water, and air dried. Recrystallization from a 1:1 mixture of absolute ethanol and dry pyridine yielded 9.97 g (66%) of bright yellow crystals mp 242°-243° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8](N=C=S)=[CH:7][C:6]2[C:12]([O:14][C:15]3([C:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=4[O:23][C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]3=4)[C:5]=2[CH:4]=1)=[O:13]>O.CN(C)C=O>[CH:3]1[CH:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]([C:15]2[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[O:23][C:24]3[C:25]=2[CH:26]=[CH:27][C:28]([CH:29]=3)=[O:30])[CH:4]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 24 h

Procedure:
Bovine serum albumin (100 mg) was dissolved in distilled water (2.0 ml) and the mixture was adjusted to a pH of 9 with 1N NaOH. Fluorescein isothiocyanate (FITC, 100 mg) in dimethylformamide (1.0 ml) was added by drops with stirring while maintaining the pH at 9 by addition of 1N NaOH. After all of the FITC was added, the mixture was stirred at room temperature for two hours. The solution was then dialysed in a cellulose dialyzing tube (MW 12,000-14,000) against 10 mM phosphate buffer (1.0 liter, pH 7) for two hours. The dialyzing tube was then dialysed against two changes of 0.9% aqueous sodium chloride (4.0 liters), for 19 hours each time, and then against three changes of 10% dimethylsulfoxide in 0.9% aqueous sodium chloride, for 24 hours each time. The final solution showed no sign of fluorescein in the dialysis solution. The resulting immunogen solution was then removed from the dialyzing tube and lyophilized to yield an orange solid. The immunogen was used according to standard procedures to produce a rabbit anti-fluorescein antibody capture reagent. The antibody was purified according to the procedure described in Example 1.c. above.