Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[C@H:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 59.7 %

Procedure:
For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R)(-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([CH3:40])[N:27]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[C@H:26]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][C@H:25]2[O:24]1.[Li]CCCC>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[C@@H:18]([OH:19])[CH2:20][C@H:29]([C:28]([N:27]1[C@H:26]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][C@H:25]2[O:24][C:23]1([CH3:22])[CH3:40])=[O:32])[CH2:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Temperature: -78 °C

Procedure:
(1S,2S)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid tert-butyl ester (VI, 113 mg) and 1-((3aS,8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-butan-1-one (VII, 94 mg) were combined in dry THF (3 mL), and cooled to −78° C. To this solution was added BuLi (2.5 M in hexanes, 0.32 mL) over 5 min., whereupon the solution was allowed to warm to 0° C. for 1.5 h. The reaction mixture was partitioned between 0.5 N HCl (4 mL) and 1:1 EtOAc/hexanes (2×4 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20–30% EtOAc/hexanes) to give an oil: MH+559.1.
Reaction SMILES: Cl.[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:4]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[CH3:2][CH:3]1[N:8]([CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[C:4]1=[O:20]
Reactant: O=CCc1ccc([N+](=O)[O-])cc1
Reactant: CC1NCCN(CCc2ccc([N+](=O)[O-])cc2)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-Methyl-1-[2-(4-nitrophenyl)ethyl]piperazin-2-one hydrochloride (38 mg, 0.13 mmol) and (4-Nitrophenyl)acetaldehyde (31 mg, 0.19 mmol) was added_titanium(IV) isopropoxide (0.37 mL, 1.3 mmol). After stirring the mixture at RT for 15 minutes, ethanol (2 mL) and sodium cyanoborohydride (80 mg, 1.3 mmol) were added to the reaction. The mixture was allowed to stir at RT for 16 hours. The reaction was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give the crude title product. The title product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 413 [M+1]+.
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O-:15])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:20](#N)[CH3:21].C(N(CC)CC)C.C(OC(OCC)=O)(=O)OCC>C(OCC)(=O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2nc(C(=O)[O-])n(C)c2cc1C
Reactant: CC#N
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC(=O)c1cc2nc(C(=O)OCC)n(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate acid are introduced, in the course of 15 minutes, into a mixture of 150 ml of acetonitrile, 15 ml of triethylamine and 18.5 g of diethyl pyrocarbonate, while stirring at room temperature. The mixture is left to stand overnight, the acetonitrile is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, which is initially obtained as an oil but soon crystallises, is filtered off. When recrystallised from ethyl acetate/cyclohexane, it melts at 106°-108°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9].[C:14]([O:18][CH3:19])(=[O:17])[C:15]#[CH:16]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:6]([Sn:5]([CH2:4][CH2:3][CH2:2][CH3:1])([CH2:10][CH2:11][CH2:12][CH3:13])[C:15](=[CH2:16])[C:14]([O:18][CH3:19])=[O:17])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OC)[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41.8 %

Procedure:
A degassed solution of Bu3SnH (8.73 g, 30 mmol) in dry THF (40 ml) was added during 40 min to a degassed solution of methyl propynoate (2.52 g, 30 mmol) and Pd(PPh3)4 (0.693 g, 0.6 mmol) in THF (40 ml). The resulting mixture was stirred for 3.5 h at room temperature under nitrogen. THF was then removed under reduced pressure and the residue was diluted with hexane (200 ml). After 12 h, the mixture was filtered on celite and the filtrate was concentrated under reduced pressure. The residue was diluted with hexane (200 ml), filtered on celite and concentrated. The residue was purified by silica gel column using hexane/EtOAc (98/2) as eluant to give 4.7 g of 337B as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 6.89 (d, J=2.64 Hz, 1H), 5.92 (d, J=2.64 Hz, 1H), 3.74 (s, 3H), 1.60-1.20 (m, 12H), 0.97 (t, J=8.34 Hz, 6H), 0.89 (t, J=7.03 Hz, 9H)
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C@H:6]2[C:9]3[C:14]([CH2:15][CH2:16][C@H:5]2[CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.CC(C)([O-])C.[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][C@@H:5]2[CH2:16][CH2:15][C:14]3[C:9]([C@@H:6]2[CH2:7]1)=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a suspension of cis-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine (1.0 g, 4.65 mmol), from Step 3 of Example 75, in 20 mL of dry THF, was added potassium t-butoxide (0.78 g, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h and then cooled to 0° C. and benzyl bromide (0.8 mL, 6.7 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h and then poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was crystalized from ether/hexane to afford 1.1 g (79% yield) of the title compound, m.p. 114°-115° C.; MS DCl--NH3M/Z: 306 (M+H)+ ; 1H NMR (CDCl3) δ1.5-2.2 (5H, m), 2.42-2.54 (1H, m), 2.58-3.03 (5H, m), 3.79 (1H, dd, J=9.5, 13.6 Hz), 4.44 (1H, d, J=13.6 Hz), 4.95 (1H, d, J=13.6 Hz), 6.47-6.5 (1H, m), 6.97-7.45 (8H, m).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C:10]=2[NH:11][N:12]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:7][C:8]1[C:9]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C:10]=2[N:11]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(N)c2c1CN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in tetrahydrofuran (THF, 250 ml) was slowly added to a mixture of tert-butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (20 g, 89 mmol) and diisopropylethylamine (DIEA, 92 ml, 528 mmol) in THF (500 ml) at 0-5° C. The reaction was kept at the same temperature for two hours then allowed to reach room temperature and stirred overnight. The obtained mixture was evaporated to dryness under vacuum, and the resulting residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 g of the title compound as a white solid. [M+H]+ 297
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:22])[C:19]#[C:20][CH3:21].C(#N)CC.NC(=N)S>>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:22][CH2:18][C:19]#[C:20][CH3:21])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CC#CCN
Agent: N=C(N)S
Solvent: CCC#N
Product: CC#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (3.00 g. 0.0111 mole) and 2-butyne-1-amine (3.07 g., 0.0445 mole) in 60 ml. of propionitrile was stirred at reflux for 40 hours. TLC assay of an aliquot of the reaction mixture showed a trace of the isothiourea starting material, so the mixture was refluxed for an additional 6 hours and then stirred at room temperature for 64 hours. The solvent (along with excess amine) was removed at reduced pressure and the residual gum was placed on silica gel (100-200 mesh) and eluted with a mixture of methylene chloride (97 parts) and methanol (3 parts). The middle fractions were combined and evaporated to give 1.81 g. of yellow gum. The gum was dissolved in 20 ml. of ethyl acetate and crystallized at -15° C. The resulting pale yellow solid (1.2 g.) was dissolved in 11 ml. of hot acetonitrile and recrystallized at -15° C.; yield 1.072 g., m.p. 128°-130° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[N:17]1.Br[CH2:33][CH2:34][CH2:35][CH3:36]>CS(C)=O.CO>[CH2:33]([O:14][C:12]1[CH:11]=[CH:10][C:9]([CH2:15][N:16]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=3[F:29])=[N:17]2)=[C:8]([Cl:7])[CH:13]=1)[CH2:34][CH2:35][CH3:36]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CCCCOc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(Cl)c1
Reaction time: 0.08 h

Procedure:
Potassium t-butoxide (9.7 mg, 0.086 mmol, Aldrich) was added to a solution of N-{1-[(2-chloro-4-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Example 31)(29.4 mg, 0.081 mmol) in DMSO (0.5 ml). The reaction was stirred for 5 min before adding 1-bromobutane (10.42 μL, 0.097 mmo, Acros). The reaction was stirred for 56 h at ambient temperature. The reaction mixture was diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier. (Method B). The solvent was evaporated in vacuo to give the title compound as a yellow gum (14.5 mg); LCMS: (System 4) MH+=420, tRET=3.45 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]C(OC)=O)=[N:6][C:7]=1[O:8][CH3:9].C([O-])(O)=[O:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][OH:16])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)Cc1ccc(Br)c(OC)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1nc(CO)ccc1Br

Procedure:
step d—A solution of 357c (0.060 g), 5% aq. NaHCO3 (2 mL) and MeOH (2 mL) was heated at reflux for 2 h. The reaction mixture was partitioned between H2O and EtOAc and the combined EtOAc extracts were dried, filtered and evaporated in vacuo. The crude product was purified by SiO2 chromatography eluting with 25% EtOAc/hexane to afford 356a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:18])[CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:19]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:19][CH:16]([CH3:17])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(-c2ccccn2)c(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc(C(=O)C(C)Br)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one (120 mg, 0.5 mmol) in benzene (1 mL) and 30% HBr/Acetic acid (1 mL) was cooled to 0° C. and was treated with a solution of bromine (0.024 mL, 0.5 mmol) in benzene (0.5 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1csc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1cccs1

Procedure:
The title compound, white solid, m.p. 84° C. and MS: m/e=328.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-2-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][N:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2c1-c1ncccc1CNC2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1c[nH]c2c1-c1ncccc1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
A mixture of 130 mg (0.53 mmol) of 3,4,5,6-Tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid methyl ester and 0.6 mL (0.6 mmol of benzaldehyde is dissolved in 10 mL of dichloroethane. To this solution is added 270 mg (1.3 mmol) of sodium triacetoxyborohydride and the resulting mixture is stirred for 18 hours at room temperature. A 10 mL solution of saturated Na2HCO3 is added, and the reaction stirred for 60 minutes. The organic layer is separated from the aqueous layer, dried (Na2SO4) and evaporated. The residue is chromatographed on 10 grams of silica gel using 50/1 chloroform/methanol as the eluant. Appropriate fractions are combined to yield 118 mg of 5-benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid methyl ester. 1H NMR (CDCl3) δ10.1 (s, 1H), 8.6 (d, 1H), 7.55 (d, 1H), 7.3 (m, 6H), 7.1 (m, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 3.55 (s, 2H), 3.35 (s, 2H). Mass spectrum: m/e 334.3 (p +1). TLC (10/1 chloroform/methanol) Rf=0.15.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[Cl-].[NH4+]>C1COCC1>[S:25]([O:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]=1)([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -50 °C
Yield: 109.5 %

Procedure:
1-[3-[(tert-Butoxycarbonyl)amino]phenyl]methanol (10 g, 44.8 mmoles) (Ref.: F. J. Brown, P. R. Bernstein, L. A. Cronk, D. L. Dosset, K. C. Hebbel. T. P. Maduskuie, Jr., H. S. Shapiro, E. P. Vacek, Y. K. Lee, A. K. Willard, R. D. Krell and D. W. Snyder, J. Med. Chem., 32, 1989, 807-826) and triethylamine (13 g, 17.9 mL, 138.4 mmoles) were dissolved in anhydrous THF (169 mL) and the solution was stirred and cooled to −50° C. Methanesulfonyl chloride (10.26 g, 7.02 mL, 89.6 mmoles) in anhydrous THF (85 mL) was added dropwise over a period of 20 min at −50° C. under an argon atmosphere. The mixture was stirred at −50° C. for an additional 20 min. A saturated aqueous solution of ammonium chloride (12.9 g) was added and the mixture was warmed to 25° C. The mixture was filtered and the filtrate was extracted twice with ethyl acetate. The ethyl acetate was washed with brine, water, dried (MgSO4), filtered and evaporated to dryness to give the title compound (14.78 g). The material was used without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:28]1[CH:29]=[CH:30][C:31]([O:48][CH3:49])=[C:32]([CH:47]=1)[CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([Cl:43])=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:44](O)=[O:45])([CH3:27])([CH3:26])[CH3:25].[NH2:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][OH:54]>C(Cl)Cl.O>[OH:54][CH2:53][C:52]([CH3:56])([CH3:55])[CH2:51][NH:50][C:44]([C:35]1[N:34]([CH2:33][C:32]2[CH:47]=[C:28]([C:24]([CH3:27])([CH3:25])[CH3:26])[CH:29]=[CH:30][C:31]=2[O:48][CH3:49])[C:42]2[C:37]([CH:36]=1)=[CH:38][C:39]([Cl:43])=[CH:40][CH:41]=2)=[O:45]
Reactant: CC(C)(CN)CO
Reactant: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)O)cc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)NCC(C)(C)CO)cc2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 36.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.57 mmol) followed by 1-hydroxybenzotriazole hydrate (0.08 g, 0.59 mmol) were added to a solution of 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid (0.20 g, 0.54 mmol) in DCM (10.0 ml) and after stirring for 10 min, 3-amino-2,2-dimethylpropan-1-ol (67 mg, 0.65 mmol) was added. After stirring for 17.5 h, water (10 ml) was added, the layers separated, the organic washed with water (3×15 ml) and dried with magnesium sulfate. Purification was achieved by chromatography on silica using DCM:methanol (3:1) as eluent. Crystallisation of the crude afforded the title compound as a white solid (90 mg, 36%).
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([CH3:27])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C.C(#N)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][CH2:28][N:11]4[C:12]=3[C:13]([CH3:27])=[N:14]2)=[CH:21][CH:22]=1
Reactant: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10-(benzyloxy)-2-(4-fluorobenzyl)-4,8-dimethyl-7,8-dihydropyrazino-[1′,2′:1,5]pyrrolo-[2,3-d]pyridazine-1,9(2H,6H)-dione (17 mg, 38 μmol) and Pearlman's catalyst (6.0 mg, 20% Pd(OH)2 on carbon) in ethanol (20 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 30 minutes. The reaction mixture was diluted with acetonitrile and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue triturated with a mixture of methanol and diethyl ether. A solid precipitate was obtained by filtration to provide the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:14][CH:15]([C:18]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:31])[C:21]2=[CH:32][CH:33]=[CH:34][N:20]2[N:19]=1)[CH2:16][CH3:17].[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][NH:14][CH:15]([C:18]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:22](=[O:31])[C:21]2=[CH:32][CH:33]=[CH:34][N:20]2[N:19]=1)[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC(NCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 258 %

Procedure:
(1,1-Dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (88.0 mg, 0.047 mmol) and 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 100 mg, 0.314 mmol) in CH3OH (20 mL) was stirred at 25° C. for 1 h and then treated with NaCNBH3 (29.5 mg, 0.47 mmol). The mixture was stirred for 0.5 h at which time a white precipitate had formed. The precipitate was collected, washed with cold CH3OH and air dried to afford the desired material (55 mg, 39%) as a white crystalline solid: 1H NMR (DMSO-d6, 400 MHz) δ 7.36 (s, 1H), 7.10 (m, 5H), 6.82 (s, 1H), 6.46 (s, 1H), 5.47 (s, 1H), 5.20 (m, 2H), 3.55 (s, 1H), 2.45 (s, 1H), 2.22 (s, 1H), 1.84 (s, 1H), 1.64 (m, 1H), 1.53 (m, 1H), 1.26 (s, 9H), 1.01 (s, 6H), 0.72 (m, 3H).