Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:30]>C(O)C>[ClH:30].[C:22]1([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]2=[N:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCCC2c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2CCCCC2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The above ester (0.6 g, 1.6 mmol) was dissolved in ethanol (5 ml) and 4N sodium hydroxide (1.6 ml) was added. The mixture was stirred at ambient temperature for 20 h, placed on an ice-bath and excess concentrated hydrochloric acid was added. The mixture was concentrated in vacuo and dichloromethane (300 ml) was added. The phases were separated and the organic phase was washed with water (5 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 0.52 g of the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH2:21]([O:23][CH2:24][C:25]1O[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:22].CN>>[CH3:1][N:3]1[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:25]1[CH2:24][O:23][CH2:21][CH3:22]
Reactant: CCOCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: CN
Product: CCOCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 61.1 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1-ethoxymethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one 5.76 g (20 mmol, 1 eq.) and 4.65 g (60 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (3.68 g, 61.1%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (70 mg, 76%), MS (ISP) m/z=370.4 [(M+H)+], mp 274° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[OH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:21][CH2:20]1
Reactant: O=Cc1ccc2c(n1)COC2=O
Reactant: OCCOCCN1CCNCC1
Product: O=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Yield: 27.1 %

Procedure:
In a process similar to that described in Preparation 8, 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (150 mg, 0.92 mmol) and 1-[2-(2-hydroxyethoxy)ethyl]-piperazine (181 μL, 1.01 mmol) are reacted to provide the title compound as yellow oil (80 mg, 27%).
Reaction SMILES: Cl.[CH2:2]([O:4][C@@H:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)[CH2:6][OH:7])[CH3:3].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:40]=[C:41]=[O:42].O>C(Cl)Cl>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[NH:40][C:41](=[O:42])[N:17]([CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6][OH:7])=[CH:14][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCc1ccc(C[C@@H](CO)OCC)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCN(CCc1ccc(C[C@@H](CO)OCC)cc1)C(=O)Nc1ccc(F)cc1F
Reaction time: 8 h
Yield: 60.5 %

Procedure:
(2S)-2-Ethoxy-3-{4-[2-(heptylamino)ethyl]phenyl}propan-1-ol hydrochloride (21 mg, 0.059 mmol) and triethyl amine (0.009 ml, 0.065 mmol) were mixed in DCM. 2,4-Di fluorophenyl isocyanate (9.2 mg, 0.059 mmol) was added. The mixture was stirred overnight. Water was added. The organic phase was washed with brine and dried with magnesium sulfate. The solvent was evaporated in vacuum and an oil mixture was left. Chromatography of the oil mixture on a column (ISOLUTE, SI, 200 mg/1 ml) using DCM and MeOH/DCM (1:99) as eluant gave 17 mg desired product, yield 60%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:17]([NH:25][C:26]([NH:8][C:5]1[CH:4]=[C:3]([O:9][C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:2]([Br:1])=[CH:7][N:6]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ncccc1Oc1cc(N)ncc1Br
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1cc(NC(=S)NC(=O)c2ccccc2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
5-Bromo-4-(2-methylpyridin-3-yloxy)pyridin-2-amine (2.0 g, 7.14 mmol) and benzoyl isothiocyanate (1.0 ml, 7.5 mmol) were diluted in tetrahydrofuran (100 mL) and stirred at ambient temperature overnight. The solution was concentrated and charged with a mixture of ethyl acetate (10 mL) and hexanes (200 mL). The mixture was stirred for 10 minutes and filtered to give the title compound (2.8 g, 89% yield) as yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[N:6][CH:7]=1.[CH2:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][C:17]#[CH:18]>>[N:19]1([CH2:15][CH2:16][C:17]#[C:18][C:2]2[CH:3]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH:5]=[N:6][CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CCCN1CCCCC1
Reactant: Brc1cncc(CN2CCOCC2)c1
Product: C(#Cc1cncc(CN2CCOCC2)c1)CCN1CCCCC1

Procedure:
This compound was made in a similar way as described in Example 18, Step D, using 4-(5-bromo-pyridin-3-ylmethyl)-morpholine and 1-but-3-ynyl-piperidine (57%). MS (ESI): exact mass calcd. for C19H27N3O, 313.45; m/z found, 314.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49 (d, J=1.9,1H), 8.40 (d, J=1.6,1H), 7.66-7.64 (m, 1H), 3.68 (t, J=4.5, 4H), 3.45 (s, 2H), 2.67-2.58 (m, 4H), 2.49-2.38 (m, 8H), 1.62-1.52 (m, 4H), 1.46-1.40 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(CO)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(COS(C)(=O)=O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of 82 mg of 2-ethyl-4-hydroxymethylpyridine and 79 mg of triethylamine in dichloromethane (2 mL) was added 82 mg of methanesulfonyl chloride, followed by stirring at room temperature for 1 hour. It was purified by PLC (chloroform:methanol=10:1), dissolved in ethyl acetate, washed with an aqueous sodium bicarbonate solution and then with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 47 mg (yield 36%) of a title compound as a yellow oily substance.
Reaction SMILES: BrC1N2CCN(C)CC2=[C:4]([C:12]([NH:14][C@@H:15](C(C)(C)C)[C:16](NC)=[O:17])=O)N=1.[CH3:24][C:25]([CH3:53])([CH3:52])[C@H:26]([NH:31][C:32]([C:34]1[N:35]=[C:36]([C:44]#[C:45][C:46]2C=CC=CC=2)[N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][C:38]=12)=[O:33])[C:27]([NH:29][CH3:30])=[O:28].ClC/C=C/B(O)O.C([O-])([O-])=O.[K+].[K+].N1CCOCC1>O1CCOCC1.CCOC(C)=O.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.O>[CH3:24][C:25]([CH3:53])([CH3:52])[C@H:26]([NH:31][C:32]([C:34]1[N:35]=[C:36](/[CH:44]=[CH:45]/[CH2:46][N:14]2[CH2:12][CH2:4][O:17][CH2:16][CH2:15]2)[N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][C:38]=12)=[O:33])[C:27]([NH:29][CH3:30])=[O:28]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(C#Cc2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C)CC2)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)/C=C/CCl
Solvent: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](NC(=O)c1nc(/C=C/CN2CCOCC2)n2c1CN(C)CC2)C(C)(C)C
Yield: 34 %

Procedure:
(S)-3-bromo-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (Compound 203; 0.12 g, 0.31 mmol) was dissolved in dioxane (4 mL) and (E)-3-chloroprop-1-enylboronic acid (0.037 g, 0.31 mmol) was added, followed by K2CO3 (0.11 g. 0.82 mmol), morpholine (0.054 g, 0.66 mmol) and water (0.80 mL). The resulting mixture was degassed with nitrogen and Pd(PPh3)4 (0.019 g, 0.017 mmol) was added. The mixture was subjected to microwave irradiation at 160° C. for 20 min. The mixture was diluted with EtOAc, and filtered through celite. The organic layer was concentrated, washed with water, dried over anhydrous Na2SO4, filtered and concentrated again. The residue was purified by prep LC/MS using 5-95% gradient acetonitrile/water with 0.1% formic acid to provide Compound 286 (0.035 g, 34%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 1.07 (s, 9H), 2.52 (s, 3H), 2.81 (d, 3H), 2.89 (t, 2H), 2.97 (m, 3H), 3.28 (s, 1H), 3.58 (d, 1H), 3.99 (m, 8H), 4.35 (d, 1H), 6.11 (m, 1H), 6.68 (m, 2H), 7.71 (m, 1H); LCMS (+ESI) m/z 433.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[O:13][C:14](=[O:15])[C:6]3=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.[CH3:23][NH2:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](=[O:16])[NH:24][CH3:23])[C:6]([C:14]([OH:13])=[O:15])=[C:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(=O)c2c1nc1ccc(Cl)cc1c2-c1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-9-phenylfuro[3,4-b]quinoline-1,3-dione (100 mg, 0.32 mmol, 1 eq) in THF (2 ml) was added methyl amine (2M in THF, 807 μl, 1.61 mmol, 5 eq) and the reaction mixture was stirred overnight. The resultant precipitate was filtered and washed with ether. The solid was purified by flash column chromatography (10% AcOH in ethyl acetate) to give the title compound as a white solid. MS (ESI): 338.9 (M−H)−.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=2)[CH:15]=[CH:14][C:13]=1[CH3:28])=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=3)[CH:17]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-{2-methyl-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (2.5 g, 6.0 mmol), calcium chloride (1.75 g, 15 mmol) and reduced iron (4.03 g, 72 mmol) in ethanol (300 mL)/water (30 mL) was stirred with heating at 80° C. for 2 days. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethanol. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (300 mL×2), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (2.31 g, 99%) as a pale-yellow amorphous substance.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:19])=[O:3]
Reactant: OCCCCCO
Reactant: COc1ccccc1OC(=O)Cl
Product: COc1ccccc1OC(=O)OCCCCCO

Procedure:
The reaction of 2-methoxyphenol chloroformate with 1,5-pentanediol is conducted on a 0.01 mole scale using the same conditions as described in Example IV. A 1.4 g yield of the pure product is obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=CC=Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccccc1C=CC=CC(=O)O
Temperature: 0 °C
Yield: 85.5 %

Procedure:
A stirred mixture of 0.85 g (2.7 mmol) of methyl 5-[2-(tertbutoxycarbonylaminomethyl)phenyl]-2,4-pentadienoate, 1.17 g (11 mmol) of sodium carbinate, 15 ml of water and 15 ml of methanol was heated at reflux for 2 hours. After the produced methanol was distilled off, the solution was cooled to 0° C. and carefully acidified with 1N hydrochloric acid. The resulting mixture was extracted with methylene chloride and the extracts were washed with brine, dried (Na2SO4) and concentrated. Recrystallization of the residue from 1:3 methylene chloride:hexane gave 0.7 g (86%) of the product as crystals, mp 179°-182° C. (dec).
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=O)OCC(F)(F)F.N1C=C(C2(N)CC2)N=C1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH:39]1[CH:43]=[C:42]([CH:44]2[CH2:46][CH:45]2[CH:47]=O)[N:41]=[CH:40]1.Cl>O1CCCC1>[CH3:17][O:16][C:14](=[O:15])[CH:13]=[CH:47][C@@H:45]1[CH2:46][C@H:44]1[C:42]1[N:41]=[CH:40][NH:39][CH:43]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=CC1CC1c1c[nH]cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: NC1(c2c[nH]cn2)CC1
Solvent: C1CCOC1
Product: COC(=O)C=C[C@@H]1C[C@H]1c1c[nH]cn1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.648 g, 2.04 mmol, 1.2 eq) and 18 crown 6 (2.24 g, 8.5 mmol, 5.0 eq) in tetrahydrofuran (30 mL), was cooled to n78° C. To this at n78° C. was added potassium bis(trimethylsilyl)amide (4.08 mL, 2.04 mmol, 1.2 eq). The reaction mixture was stirred at n78° C. for 30 min and treated with a solution of 2-imidazole-4-ylcyclopropanecarbaldehyde (0.64 g, 1.7 mmol) in tetrahydrofuran (5 mL). The reaction mixture was again stirred at n78° C. for 1 hour, treated with aqueous satd. ammonium chloride solution and extracted with ether. The organic layer was separated, washed with water and dried over anhyd. Na2SO4. Crude product was purified by flash column eluted with ethyl acetate: hexane (1:3) to give trityl protected product (0.730 g). A small amount (150 mg) of this product was deprotected by treatment with 2 N HCl at 90° C. for 1 h to give final product (yield=62 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:26][N:25]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:20][NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[N:26][N:25]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: CNc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CNc1cc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyridin-2-amine (0.070 g, 0.24 mmol) and 1-chloro-4-phenylphthalazine (0.048 g, 0.20 mmol) was added tBuOH (1.0 mL). The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine as an off-white solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.58.
Reaction SMILES: CC1(C)[O:7][C@H:6]2[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][O:11][C@H:5]2[CH2:4][O:3]1.Cl>CO>[OH:3][CH2:4][C@H:5]1[C@@H:6]([OH:7])[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@@H]2OC[C@@H](O)[C@@H](O)[C@@H]2O1
Agent: Cl
Solvent: CO
Product: OC[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of (+)-(4aS,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (36 mg, 0.18 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1 H at ambient temperature and concentrated in vacuo.
Reaction SMILES: O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[N:20]=1)[C:13]([NH2:15])=[NH:14]>CO.O>[NH:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: N=C(N)Nc1nc(-c2ccccc2N)cs1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A solution of 57 gm of sodium sulfide octahydrate in 400 ml of methanol and 120 ml of water was added dropwise over a period of 300 minutes to a hot (60° C.) solution of 16.9 gm of 2-guanidino-4-(2-nitro-phenyl)-thiazole in 120 ml of methanol. After an additional 2 hours of heating at 60° C., the solution was filtered with charcoal and evaporated to dryness. The residual solid was suspended in water, filtered off and dried, yielding 12.4 gm of the title compound, m.p. 198°-200° C.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[CH2:10]([OH:12])[CH3:11]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:12][CH2:10][CH3:11])=[N:4][CH:5]=1
Reactant: CCO
Reactant: Brc1ccc(Br)nc1
Agent: [Na]
Product: CCOc1ccc(Br)cn1

Procedure:
Sodium metal (4.87 g, 0.212 mol) was added to ethanol (200 mL) and stirred until completely dissolved. To this solution was added 2,5-dibromopyridine 9-1 (10 g, 0.0424 mol) and the resulting mixture was stirred at reflux for 16 hr. The solvent was removed in vacuo and the residue partitioned between water and EtOAc. After extraction with EtOAc (2×), the organic layer was washed with brine, dried (MgSO4) and concentrated to give 9-2 as a red-brown solid which was used as such in the next step.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[NH:11][C:12]([C:21]#[N:22])=[C:13]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:14]=1)[CH2:8][CH3:9].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:7]([C:10]1[N:11]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:12]([C:21]#[N:22])=[C:13]([C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[N:14]=1)[CH2:8][CH3:9]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(=O)C(C)(C)C)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
1.08 g of potassium t-butoxide was added, whilst ice-cooling, to a solution of 2.00 g of 2-propyl-4-pivaloylimidazole-5-carbonitrile (prepared as described in Preparation 41) in 20 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at same temperature for 10 minutes. 6.10 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide were then added to the solution, and the resulting mixture was stirred at 50° C. for 4 hours. At the end of this time, ethyl acetate and water were added to the mixture, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The syrupy residue was purified by column chromatography through silica gel, using 1:3 and 1:2 by volume mixtures of ethyl acetate and hexane as the eluent, to give 5.44 g of the title compound as crystals, melting at 107°-110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 4-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1509 g, 0.823 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2291 g, 86.6%). EI-MS m/z 322 (M+H+) Rt (1.57 min).