Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CC[N:14]([CH:18]([CH3:20])[CH3:19])C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:9][C:4]2[CH:3]=[CH:2][CH:19]=[C:18]([NH2:14])[CH:20]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 126.3 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitro-benzene (1.14 ml, 9.25 mmol), benzene-1,3-diamiine (1.96 g, 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) in dry NMP (5 ml) was deoxygenated by evacuate/fill N2 (×3), then stirred and heated at 120° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and 0.5N HCl. The organic layer was washed with H2O (×1), brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/petrol) to give the title compound (1.8 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.28 (1H, s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7.07 (1H, t), 6.49 (1H, s), 6.48-6.39 (2H, m), 5.24 (2H, s).
Reaction SMILES: N1CCOCC1.BrC1SC(C=O)=CC=1.[N:15]1([C:21]2[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[S:25][C:21]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: O=Cc1ccc(N2CCOCC2)s1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)s1
Solvent: C1COCCN1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCOCC3)s2)cc1OC
Yield: 14.8 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from morpholine (523 mg) was introduced into 5-bromothiophene-2-carboxaldehyde (382 mg), to thereby yield 5-morpholin-4-yl-thiophene-2-carbaldehyde (yield: 176 mg, 45%). The produced 5-morpholin-4-yl-thiophene-2-carbaldehyde (172 mg) was condensed with 3,4-dimethoxybenzyl cyanide (154 mg) through Method A (production step 2), to thereby yield the target product (yield: 46 mg, 15%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][O:4]3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCC1CCCCO1
Product: Cc1nc(-n2ccc(OCC3CCCCO3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-(bromomethyl)tetrahydro-2H-pyran in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 66% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.77 (t, J=5.9 Hz, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.36-7.26 (m, 4H), 7.23-7.18 (m, 1H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.11 (d, J=2.6 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 4.03-3.94 (m, 2H), 3.86-3.82 (m, 1H), 3.62-3.55 (m, 1H), 3.38-3.31 (m, 1H), 2.53 (s, 3H), 1.76-1.69 (m, 1H), 1.59-1.20 (m, 5H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)O
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Ethyl 5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoate (Example 16; 1.6 mmol) was dissolved in a mixture of THF (6 ml), methanol (6 ml) and water (6 ml). Sodium hydroxide (5.0 mmol) was added and stirred for 2 h. The organic solvent was removed under vacuum, and the aqueous residue was acidified with 1 N HCl to pH=3. The mixture was extracted with ethyl acetate, and the organic phase was removed under vacuum to afford the title compound (0.55 gr) that was used as such in the next step (Example 5.1).
Reaction SMILES: [C:1]([CH:3]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Na+]>CO.O>[C:1]([CH:3]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)CCCCC(C#N)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CC(CCCCC(=O)O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
In 50 ml of methanol was dissolved 7.38 g (25 mmol) of ethyl 6-cyano-6-(1-naphthyl)hexanoate followed by addition of 50 ml of iN aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with 150 ml of pure water and washed with 150 ml of ethyl acetate. The aqueous layer was acidified with 100 ml of 1 N HCl and extracted with 200 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (hexane-ethyl acetate=1:4) to provide 6.66 g (yield 99.7%) of the title compound as colorless oil.
Reaction SMILES: C(N(C(=O)CC)CC[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)C.[H-].[Na+].C(O[CH2:23][CH3:24])(=O)C>O1CCCC1>[C:24]1([O:12][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH:23]=[CH:8][CH:7]=[CH:6][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CCC(=O)N(CC)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of N-ethyl,N-propionyl tyramine (2.84 g, 12.83 mmole) in tetrahydrofuran (32.1 ml) was added 60% sodium hydride dispersion (0.56 g, 14.11 mmole). After stirring for 10 minutes, the compound of Example 42(E) (4.70 g, 12.83 mmole) was added. The reaction was allowed to stir at room temperature for 5 hours, poured into ethyl acetate, and extracted with 10% sodium sulfate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a hexane-ethyl acetate gradient. Further chromatography on silica cgel using toluene-acetone gradients yielded the intermediate phenyl ether (2.10 g, 32%):
Reaction SMILES: [N:1]([C@H:4]1[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH2:7][CH2:6][CH2:5]1)[CH2:15][N:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]3)=[N+]=[N-]>CCOC(C)=O.CO.[Pd]>[CH2:18]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][C:8]3[CH2:7][CH2:6][CH2:5][C@@H:4]([NH2:1])[C:9]=3[CH:10]=2)[CH2:15]1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CN1CCc2cc3c(cc2C1)CCC[C@H]3N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CN1CCc2cc3c(cc2C1)CCC[C@H]3N
Reaction time: 8 h

Procedure:
A suspension of 30 mg of Pd/C (10% w/w) in a solution of (R)-6-azido-2-isobutyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]isoquinoline (296 mg, 1 mmol) in 30 mL of EtOAc was stirred under H2 atmosphere overnight. The reaction mixture was then directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:15 to 100:25 to 100:35) to give (R)-2-isobutyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]isoquinolin-6-amine as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.CN.[CH:34]([N:37](CC)C(C)C)(C)C>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:24])[N:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]([C@@H:11]([NH:10][C:8]([C:3]1[C:2]([NH:37][CH3:34])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])[CH3:12])=[CH:22]2
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](NC(=O)c1nccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: CN
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nccnc1C(=O)N[C@@H](C)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide (12) (133 mg, 0.30 mmol) in anhydrous 1,4-dioxane (6 mL) in a sealed tube, methylamine hydrochloride (102 mg, 1.51 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.51 mmol) were added sequentially. The resulting mixture was stirred at 140° C. in a sealed tube for 14 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-8% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-3-(methylamino)pyrazine-2-carboxamide (compound 56). ESI-MS m/z: 434.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.[CH2:21](Br)[CH:22]=[CH2:23].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:23][CH:22]=[CH2:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1
Reactant: C=CCBr
Reactant: COC(=O)CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)OC)O2
Yield: 83.1 %

Procedure:
Using the procedure of Example 12, 1.42 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-acetic acid methyl ester was alkylated with allyl bromide (2.79 g) and sodium hydride (5.58 mmole) in anhydrous N,N-dimethylformamide. There was obtained 1.35 g (83.1%) of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(2-propenyloxy)-2H-1-benzopyran-2-acetic acid methyl ester as a yellow oil, after column chromatographic purification (silica gel, 9:1 hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.I[CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][OH:27])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Reactant: OCCI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccn(CCO)c(=O)c1

Procedure:
The title compound, orange solid, MS: m/e=369.0, 371.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: Cl.CN.[CH3:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([OH:22])=O)[CH2:17][N:18]=1)=[CH:10]2.O[N:35]1[C:39]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[CH3:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([NH:35][CH3:39])=[O:22])[CH2:17][N:18]=1)=[CH:10]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(C)c3[nH]2)S1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a mixed solution of methylamine hydrochloride (120 mg), triethylamine (0.24 mL) and N,N-dimethylformamide (20 mL) were added [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (230 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 85:15, volume ratio), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (436 mg, yield 85%) as colorless crystals.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([NH2:14])[N:3]=1.[CH3:15]S(C)=O.[CH3:19][NH2:20]>CN(C)C(=O)C.CO>[CH3:19][NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([NH:14][CH3:15])[N:3]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(C)=O
Reactant: CN
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CNc1nc(NC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-diamino-3,5-dinitropyridine (25.0 g, 0.125 mole) and 225 ml dimethylsulfoxide in a 500 ml Parr bottle was added a solution of methylamine (20 g, 0.65 mole) in 75 ml N,N-dimethylacetamide (DMAc). The reaction was shaken for 4 hours at ambient temperatures and then heated 20 hours at 70°C. Upon cooling, the heterogeneous mixture was diluted with 100 ml methanol, filtered, washed with 200 ml DMAc-methanol (lv/lv), twice with methanol and dried. 2,6-Di(methylamino)-3,5-dinitropyridine, m.p. 323°-325°C (dec.) was obtained as a golden yellow solid (25.0 g, 93% yield). This product, unlike 2,6-diamino-3,5-dinitropyridine, is essentially insoluble in dimethylsulfoxide and 85% H3PO4. Anal. Calcd. for C7H9N5O4 : C, 37.0; H, 4.0; N, 30.8. Found: C, 37.2; H, 3.8; N, 31.0.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[4-(4-pyridinyl)-1-piperidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 31) (376 mg, 0.74 mmol) in dichloromethane (15 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred for 3 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×3) then dichloromethane. A saturated solution of sodium carbonate was added to the residue until a pH of 12 was achieved followed by dropwise addition of an aqueous citric acid solution solution (10% w/v) until the pH became 3.5. The solution was then diluted with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (310 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[SH2:14]>N1C=CC=CC=1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10](=[S:14])[NH2:11])=[CH:8][CH:7]=1
Reactant: S
Reactant: N#Cc1ccc(C2OCCO2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NC(=S)c1ccc(C2OCCO2)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 4-(1,3-dioxolan-2-yl)benzonitrile (2 g, 0.01 mol) in dry pyridine (50 mL) and TEA (5.75 g, 0.057 mol) was passed H2S gas (freshly generated) for 1 h with stirring at RT. The reaction mixture was diluted with water (100 mL), extracted with diethyl ether (100 mL), washed with brine (50 mL) and dried. The solvent was removed under vacuum and the crude product was purified by column chromatography over silica gel (PetEther/EtOAc, 3/7) to give 4-(1,3-dioxolan-2-yl)benzenecarbothioamide (1.9 g, 86%) as yellow solid. TLC (PetEther/EtOAc 3/7), Rf=0.35
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:21]#[C:22][Si](C)(C)C)[N:6]=1)=[O:4].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:21](=[O:27])[CH3:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C#C[Si](C)(C)C)c(Cl)c(F)c1Nc1ccccc1F
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-4-fluoro-3-(2-fluorophenylamino)-6-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), HgSO4 (1.00 equivalent), and conc. H2SO4 (2.00 equivalents) in acetone-water is refluxed with stirring for 3 hours. The reaction mixture is concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vauco to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCCCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. 1H NMR (400 MHz, CDCl3) δ 1.63 (br. s, 4H), 1.83 (br. s, 4H), 2.34 (s, 3H), 2.46-2.52 (m, 6H), 3.28 (s, 2H), 5.40 (s, 1H), 5.50 (s, 2H), 6.74 (d, J=8.3 Hz, 2H), 6.98 (s, 1H), 7.94 (br. s, 1H), 10.83 (br. s, 1H) ppm; MS (APCl, m/z): 468 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]34[CH2:31][CH2:30][CH2:29][C:27]5[C:28]3=[C:23]([CH:24]=[CH:25][CH:26]=5)[NH:22][C:21]4=[O:32])[CH2:14][CH2:15][C:6]2=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]34[CH2:31][CH2:30][CH2:29][C:27]5[C:28]3=[C:23]([CH:24]=[CH:25][CH:26]=5)[NH:22][C:21]4=[O:32])[CH2:14][CH2:15][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(CCCCC12CCCc4cccc(c41)NC2=O)C3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2c([nH]c4ccc(O)cc24)C1)CCC3
Temperature: 0 °C
Reaction time: 6 h
Yield: 30.1 %

Procedure:
A 1.3 ml portion of dichloromethane solution containing 68 mg (0.16 mmol) of 2a-[4-(6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-yl)butyl]-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one was cooled to 0° C. and mixed with 0.2 ml of dichloramethane solution containing 45 μl (0.48 mmol) of boron tribromide. After 6 hours of stirring at room temperature, the reaction solution was extracted with a solution of chloroform-methanol=5:1 and washed with sodium bicarbonate aqueous solution. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the residue was recrystallized from methanol-ethyl acetate to obtain 20 mg of the title compound (30% in yield).
Reaction SMILES: C(OC([NH:8][C:9]([NH:24]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[ClH:32].[CH3:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:24])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methylpyridin-2-yl)phenyl)guanidine (213 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-methylpyridin-2-yl)phenylguanidine dihydrochloride (119 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]2[F:19])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>O>[F:19][C@@H:12]1[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:23])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Temperature: 4 °C
Reaction time: 96 h

Procedure:
2,6-Diamino-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-9H-purine (0.20 g, 0.64 mmole), prepared as in Example 6, was dissolved in 15 ml of water. Calf intestinal adenosine deaminase (4 I.U., Boehringer Mannheim) was added and the solution incubated at 37° for 4 days. The solution was cooled to 4° C. After 3 hrs, the suspension was filtered to remove the first batch of product crystals. The volume of the filtrate was reduced under vacuum and the suspension cooled to 4° C. The suspension was filtered to remove the second batch of product crystals. The batches of product crystals were combined, suspended in water and lyophilized to obtain title compound that analyzed as a 1.3 hydrate.