Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16]([CH2:18][C@H:19]([NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:37])=[O:36])[C:20]([N:22]2[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24][CH:23]2[C:29]([O:31]CC)=[O:30])=[O:21])=[O:17])[CH2:9]1)(=[NH:7])[NH2:6].[OH-].[Na+]>>[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:17])[CH2:18][C@@H:19]([C:20]([N:22]2[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24][CH:23]2[C:29]([OH:31])=[O:30])=[O:21])[NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:37])=[O:36])[CH2:9]1)(=[NH:6])[NH2:7]
Reactant: CCOC(=O)C1C[C@H](C)CCN1C(=O)[C@H](CC(=O)NC[C@@H]1CCCN(C(=N)N)C1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[C@@H]1CCN(C(=O)[C@H](CC(=O)NC[C@@H]2CCCN(C(=N)N)C2)NS(=O)(=O)c2ccc3ccccc3c2)C(C(=O)O)C1

Procedure:
By treating the product from Example 68 with methanolic sodium hydroxide solution there is obtained (2RS,4R)-1-[N4 -[[(S)-1-amidino-3-piperidinyl]methyl]-N2 -(2-naphthylsulfonyl)-L-asparaginyl]-4-methyl-2-piperidinecarboxylic acid (epimers 1:1 ), FAB-MS: 587 (M+H)+.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12](C(=O)CCl)[C:11]=2[CH:25]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][NH2:27].[CH2:28]([OH:30])[CH3:29]>>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([C:28](=[O:30])[CH3:29])[C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([NH:27][CH3:26])[C:11]=2[CH:25]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CN
Reactant: CCOC(=O)Nc1ccc2c(c1)N(C(=O)CCl)c1ccccc1C=C2
Reactant: CCO
Product: CCOC(=O)Nc1cc(C(C)=O)c2c(c1)N(NC)c1ccccc1CC2
Reaction time: 5 h

Procedure:
12 g, 0.033 moles of 3-carbethoxyamino-5-chloroacetyl-5H-dibenz[b,f]azepine (hereafter referred to as "Startazepine 5") is suspended in 150 ml of ethanol. About 50 ml of an approximately 35% aqueous methylamine solution (about 0.5 moles of CH3NH2) are added and the mixture is stirred for 5 hours at 50° C. to 60° C., a clear, light yellow solution is formed. The reaction mixture is concentrated under vacuum to half the volume and then mixed with copious amounts of water. The oily precipitated base is extracted with chloroform (2×50 ml) and the organic phase is washed with water, dried over sodium sulfate and distilled to dryness under vacuum. A crystalline mass remains, which melts at 148° C. to 153° C., representing a yield of 7.2 g.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH-:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[C:18](=O)([O-])[O-:19].[K+].[K+].C=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:13][CH2:18][OH:19])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: [NH-]C(=O)c1cccc(Oc2ccccc2)c1
Agent: C=O
Agent: N
Agent: [K+]
Product: O=C(NCO)c1cccc(Oc2ccccc2)c1
Yield: 267.2 %

Procedure:
A flask was charged with 3-phenoxybenzoylamide (2.07 g, 9.8 mmol)(prepared from the corresponding acid chloride and concentrated ammonia), potassium carbonate (1.3 mL, 4% aqueous solution, 3.8 mmol), and aqueous formaldehyde (1.1 mL, 37% aqueous solution, 13.6 mmol). The resulting suspension was heated to reflux to give a two-phased solution. Addition of more aqueous formaldehyde (3 mL, 37 mmol) gave a homogeneous solution which was heated at reflux for 4 h. The reaction solution was cooled and partitioned between brine and ethyl acetate. The aqueous layer was dram off and extracted with ethyl acetate (2×). The combined organic layers were washed (2×, brine), dried (Na2SO4), and concentrated under vacuum to provide 2.47 gms of a viscous oil which solidified after vacuum drying. Recrystallization from cold ethyl acetate:hexanes provided the title compound as a colorless solid (1.38 g, 58%), mp 112.5-113° C.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[NH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:19]=O>>[P:1]([CH2:19][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CNCC(=O)O
Reactant: OP(O)O
Reactant: C=O
Agent: O=S(=O)(O)O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Yield: 95.9 %

Procedure:
Concentrated filtrates from Cycle 1 were charged to a 500 ml three neck flask fitted with thermometer, condenser, dropping funnel and stirrer. Phosphorous acid (40.8 g, 0.493 moles), iminodiacetic acid (63.6 g, 0.469 moles) and sulphuric acid (5.0 g, 0.050 moles) were added, with stirrring, to the flask (sulphuric acid was charged on the assumption that 10% of the sulphuric acid was lost in the wash and filter cake). The reaction mixture was then heated to 120° C. and formaldehyde (46.1 g at 36.1% strength, 0.555 moles) was then added over one hour. The temperature was maintained between 110° and 120° C. during addition. On complete addition the reaction mixture was allowed to cool to 25° C. over 90 minutes. The reaction mixture was filtered and the filter cake washed with water (57 ml). The product was dried in a vacuum oven to yield 102.2 g of N-phosphonomethyliminodiacetic acid at 95.4% strength equivalent to a cumulative isolated yield of 75.3%. The filtrates (99.3 g) and the water wash (76.8 g) were analysed at 7.5% and 3.7% N-phosphonomethyliminodiacetic acid respectively. This was equivalent to a total cumulative conversion yield of 81.7% N-phosphonomethyliminodiacetic acid.
Reaction SMILES: COC1C=CC(C([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC(OC)=CC=3)[C@H:32]([OH:33])[CH2:31]2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)(=O)C>[CH2:31]1[C@@H:30]([N:25]2[C:26]3[N:27]=[CH:28][N:29]=[C:21]([NH2:20])[C:22]=3[N:23]=[CH:24]2)[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]1[OH:33]
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1
Yield: 85.3 %

Procedure:
Compound 9 (0.44 g, 0.56 mmol) was treated with an aqueous solution of acetic acid 80% (17 mL) at room temperature for 5 h. The mixture was concentrated to dryness, the residue was dissolved in water (20 mL) and washed with diethyl ether (2×15 mL). The aqueous layer was concentrated and co-evaporated with toluene and methanol. The desired 2′-deoxy-β-L-adenosine (β-L-dA) (0.12 g, 83%) was obtained after purification by silica gel column chromatography (0-12% MeOH in dichloromethane) and filtration through a Millex HV-4 unit (0.45μ, Millipore): mp 193-194° C. (crystallized from water) (Lit. 184-185° C. for L-enantiomer [Ref: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J Org Chem 1970, 35, 636-639] and 187-189° C. for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, 183-187]; 1H NMR (DMSO-d6): δ 2.2-2.3 and 2.6-2.7 (2m, 2H, H-2′ and H-2″), 3.4-3.6 (2m, 2H, H-5′ and H-5″), 3.86 (pq, 1H, H-4′), 4.3-4.4 (m, 1H, H-3′), 5.24 (t, 1H, OH-5′, JH,OH=5.8 Hz), 5.30 (d, 1H, OH-3′, JH,OH=4.0 Hz), 6.32 (dd, 1H, H-1′, J1′,2′=6.2 Hz, J1′,2″=7.8 Hz), 7.3 (br s, 2H, NH2-6), 8.11 and 8.32 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 252 [M+H]+, 136 [BH2]+, (FAB−) m/z 250 [M−H]−, 134 [B]−, UV (95% ethanol): λmax 258 nm (ε 14300), λmin 226 nm (ε 2100); [α]D20=+25 (c 1.03, H2O), (Lit. [α]D20=+23 (c 1.0, H2O) for L-enantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J Org Chem, 1970, 35, 636-639] and [α]D20=−25 (c 0.47, H2O) for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, 183-187]). Anal. Calcd for C10H13N5O3+1.5H2O (M=278.28): C, 43.16; H, 5.80; N, 25.17. Found: C, 43.63; H, 5.45; N, 25.33.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C@H:3]([CH3:12])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)O.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:27][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:3]([N:2]([CH3:1])[CH2:13][C:14]#[CH:15])[CH3:12]
Reactant: C#CCN(C)[C@H](C)[C@@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN(C)[C@H](C)[C@H](Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2b (120 mg, 0.54 mmol) and triethyl amine (1.0 mmol), in THF (2 ml) was stirred at room temperature for 30 min. To the stirred mixture mesylchloride (0.60 mmol) was added drop wise at −7° C. and the reaction mixture was stirred at room temperature for additional 30 min. Saturated Na2CO3 solution (1 mL) was added and stirred for 30 more min. The organic layer was partitioned between CH2Cl2 (15 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO3 (10 ml) and brine (10 ml) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 3:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C(C(N)CN(C)[C:34](=O)[OH:35])(C)(C)C.[C:39]([N:46]([CH3:50])[CH2:47][CH2:48][NH2:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]([NH:49][CH2:48][CH2:47][N:46]([CH3:50])[C:39](=[O:40])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:35])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CN(CC(N)C(C)(C)C)C(=O)O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(CCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure of Example 13 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and N-Boc-N-methyl-ethylenediamine (tert-butyl 2-aminoethyl(methyl)carbamate) were reacted to give 139. MS: (ESI+) 470.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=O)[CH:6]=[N:7][CH:8]=1.[OH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[CH3:21].[C:22](#[N:26])[CH2:23][C:24]#[N:25].N1CCCCC1>>[NH2:26][C:22]1[O:11][C:12]2[C:20]([CH:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:23]=1[C:24]#[N:25])=[CH:19][CH:18]=[C:17]1[N:16]([CH3:21])[CH:15]=[CH:14][C:13]=21
Reactant: Cn1ccc2c(O)cccc21
Reactant: COc1cncc(C=O)c1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Product: COc1cncc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)c1

Procedure:
The title compound was prepared from 5-methoxy-pyridine-3-carbaldehyde (70 mg, 0.51 mmol), 4-hydroxy-1-methylindole (75 mg, 0.51 mmol), malononitrile (34 mg, 0.51 mmol) and piperidine (0.05 ml, 0.5 mmol) similar to Example 1e to give 21 mg (12%) of white solids. 1H NMR (CDCl3): 8.19-8.15 (m, 2H), 7.07-6.99 (m, 3H), 6.73 (d, J=8.4 Hz, 1H), 6.57 (d, J=3.0 Hz, 1H), 4.89 (s, 1H), 4.75 (brs, 2H), 3.81-3.78 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1I>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:21]3[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=3[F:23])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Reactant: Fc1ccc(F)c(I)c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cc(F)ccc3F)cn2n1

Procedure:
The title compound, a white solid, MS: m/e=312.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 1,4-difluoro-2-iodobenzene.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: CCCc1nc(CC)n(-c2ccc(N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc(N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-1-(4-morpholin-4-ylphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.53 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl.CO>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH:41][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:25])=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)cn2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4cccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (prepared as described in Example 39 but using N-ethyl-piperazine in Step 39.2), and stirring the reaction mixture for 3 h at rt. Title compound: ESI-MS: 580.1 [M+H]+; tR=3.70 min (System 1); TLC: Rf=0.33 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CC(C)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CC(C)N1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 485.7 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-isopropylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.055 mL (0.046 mMol) 4-fluorobenzoyl chloride, 0.085 gm (58%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[OH-].[K+].I[CH2:15][CH2:16][CH2:17][CH3:18]>C(O)CCC>[CH2:15]([N:6]1[C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=[C:4]([O:10][CH3:11])[C:5]1=[O:9])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCI
Reactant: COc1cc(C)c(C)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCn1c(C)c(C)cc(OC)c1=O
Temperature: 85 °C
Reaction time: 24 h
Yield: 29.6 %

Procedure:
n-Butanol (13 mL) was added to a mixture of 5,6-dimethyl-3-methoxy-2-pyridone (1-004-06) (306 mg) and potassium hydroxide (157 mg). 1-Iodobutane (0.44 mL) was added to the suspension, and the reaction mixture was heated with stirring in an oil bath at 85° C. under nitrogen atmosphere. After 24 h, the reaction mixture was evaporated under reduced pressure, and the residue was dissolved in acetyl acetate and water. The reaction mixture was extracted twice with ethyl acetate, and once with water, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue (300 mg) was purified by silica gel column chromatography (Lobar column B, toluene/acetone (3/1)) to give 1-butyl-5,6-dimethyl-3-methoxy-2-pyridone (1-004-07) (124 mg, 29.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.C[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25][CH2:24]2.N1C2C(=CC=CC=2)CCC1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=3)[CH2:24][CH2:25][CH2:26]2)=[O:9])=[CH:10][C:11]([F:14])=[CH:12][N:13]=1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (Example 80, Step 1) and 6-methyl-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 417.0 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[CH:10]([C:13]([O:15]C)=[O:14])[CH2:11][O:12][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.O[Li].O>CO.C1COCC1.O>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[CH:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1COc2cc(-n3cnnn3)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1COc2cc(-n3cnnn3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(1H-tetrazol-1-yl)-2,3-dihydro-1-benzofuran-3-carboxylate (3.3 g, 13.6 mmol) in 100 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (2.84 g, 67.5 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 50 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized from DCM to give 6-(1H-tetrazol-1-yl)-2,3-dihydro-1-benzofuran-3-carboxylic acid. 1H-NMR (300 MHz, DMSO) δ ppm 7.58 (d, J=7.8 Hz, 1H), 7.32-7.50 (m, 2H), 4.71-4.92 (m, 2H), 4.45-4.55 (m, 1H); MS m/z 233 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:51]2[C:52]3[C:32]([CH2:33][C@@H:34]4[C:46]([C:47]=3[CH:48]=[CH:49][CH:50]=2)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:36][N:35]4[CH3:53])=[CH:31]1.C(N(CC)CC)C>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[C:51]4[C:52]5[C:32]([CH2:33][C@@H:34]6[C:46]([C:47]=5[CH:48]=[CH:49][CH:50]=4)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])[CH2:36][N:35]6[CH3:53])=[CH:31]3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCN)C[C@H]2N(C)C1
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCNC(=O)c3ccc(-c4ccc(C(=O)ON5C(=O)CCC5=O)cc4)cc3)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution of 850 mg (2.375 mmol) of 12 in 65 mL of dry THF under argon was cooled to 0° C. in an icebath, then treated with a solution of 900 mg (2.365 mmol) of 10 in 50 mL of dry THF and 0.6 mL (4.3 mmol) of triethylamine added dropwise over a 20 minute period. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature, with stirring, for 1 hour. The mixture was concentrated at reduced pressure and the residue was dissolved in 100 mL of methylene chloride. The solution was washed with 100 mL of H2O, 100 mL of saturated sodium bicarbonate solution, 100 mL of saturated brine solution, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a brown residue. This was chromatographed on a short column of 100 g of silica gel using first methylene chloride as eluent, then 9:1 methylene chloride-ether as eluent to elute front running impurities, then 14:1 methylene chloride-isopropyl alcohol as eluent to elute the product to yield 650 mg (39%) of 13 as a cream colored solid [α]D=+34.3° (c=0.45%; CHCl3).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([C@:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:22][S:21][C:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:19]3)[CH:15]=[CH:16][CH:17]=1)([O-])=O.O>C(O)C>[NH2:9][C:12]1[CH:13]=[C:14]([C@:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:22][S:21][C:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:19]3)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc([N+](=O)[O-])c3)CCCC[C@H]2CS1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N)c3)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
A saturated solution of sodium dithionite (879 mg) was added to a solution of tert-butyl (−)-[(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate (395 mg) in ethanol (20 mL) at room temperature. After stirring at room temperature for 10 minutes, ethanol (10 mL) was further added to the reaction solution. After stirring at room temperature for five minutes, water (10 mL) was further added. The reaction solution was warmed to 40° C. and stirred for 30 minutes. After confirming completion of the reaction, the reaction solution was cooled to room temperature. The excess of ethanol in the reaction solution was evaporated under reduced pressure and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (110 mg).