Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:24][CH:23]=[CH2:22])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenylacetic acid (12.0 g) of Formula XIII-A in 450 ml of anhydrous THF is cooled to 0° C. via an ice bath. The solution is treated with lithium bis(trimethylsilyl)amide (LiHMDS, 1.0M in THF, 112 ml) which initially results in a light yellow slurry which becomes an orange homogeneous solution. The solution is stirred at 0° C. for 2 hrs followed by warming to room temperature. The solution is recooled to 0° C. and is treated dropwise with allyl bromide (5.0 ml). The mixture is left to stir overnight with gradual warming to room temperature. After 18 hrs the mixture is cooled to 0° C. and quenched with 250 ml of 10% aqueous HCl. The mixture is poured into a separatory funnel and extracted with EtOAc (2×300 ml). The combined organic extracts are dried over anhydrous Na2SO4, filtered and concentrated to give a viscous oil. This material is distilled (0.5 mm Hg, collected 158°-161° C.) to give 10.1 g of the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3c(C)cccc3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.076 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.175 g, 0.40 mmol) and methylamine (0.12 g, 4.0 mmol). mp 170-172° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[NH:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH3:18]I>[OH-].[Na+].CO>[CH3:18][S:16][C:14]1[NH:13][C:12](=[O:17])[C:11](=[CH:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[N:15]=1
Reactant: CI
Reactant: O=C1NC(=S)NC1=Cc1c[nH]c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=NC(=Cc2c[nH]c3ncccc23)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxoimidazolidin-4-one (8 g, 32.8 mmol) in 12.6% aq. NaOH (12 mL) and methanol (80 mL), methyl iodide (2.25 mL, 36 mmol) was added and the reaction mixture stirred at RT for 4 h. Most of the solvent was distilled out and the precipitate was filtered and washed first with water, then with diethylether. The washings were concentrated and extracted with dichloromethane, dried over sodium sulphate and joined to the first solid crop. The whole crop was suspended in methanol, stirred 30′, filtered and dried to yield 2-(methylthio)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one as a yellow solid (8.15 g, 31.6 mmol, 96%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].O=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Reaction time: 0.67 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL, 15 mmol) was added dropwisely to a stirred solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol) in THF (50 mL) at 0° C. and stirred for 40 min at the same temperature. A solution of ethyl 4-oxocyclohexanecarboxylate (2.04 g, 12 mmol) in THF (20 mL) was added slowly at 0° C. and stirred for 2 h from 0° C. to room temperature. The reaction was quenched with saturated NH4Cl aq. and extracted with hexane. The collected organic layer was dried over MgSO4 and concentrated under reduced pressure. The solvent (100 mL, hexane/Et2O=5/1) was added to the residue and stirred for 30 min. The suspension was filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by silicagel chromatography (5% EtOAc/hexane as eluent) to provide compound A122-1 (1.478 g, 73%) as a colorless oil.
Reaction SMILES: C(OC(=O)[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:6][C:7](=[O:17])[CH2:8][NH:9][C:10](OC(C)(C)C)=[O:11])C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([C@@H:5]1[NH:6][C:7](=[O:17])[CH2:8][NH:9][C:10]1=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNC(=O)[C@H](Cc2ccccc2)N1
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of Boc-glycylphenylalanine ethyl ester (5.96 g) in dichloromethane (20 ml) was added trifluoroacetic acid (20 mL) at room temperature. After stirring 1.5 h, the resulting solution was concentrated in vacuo. The residue was dissolved in water, into which sodium bicarbonate was added until the pH was 9. After the solution was stirred for several hours, the resulting white crystals were collected and dried in vacuo to afford (S)-3-benzyl-2,5-dioxopiperazine (2.29 g, 70% in 2 steps) as a white powder.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: OCCCBr
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CCCO)CC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A suspension of 1-methylsulfonylpiperazine (1.58 g, 9.6 mmol), 3-bromo-1-propanol (1.13 ml, 12 mmol) and potassium carbonate (1.73 g, 12 mmol) in acetonitrile (10 ml) was stirred at 40° C. for 4 hours followed by 2 hours at 70° C. The mixture was cooled, filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 followed by 95/5) to give 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol (1.95 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][NH:32][C:33]([NH:35][OH:36])=[NH:34].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:31][NH:32][C:33](=[NH:34])[NH:35][OH:36])[CH2:8]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1cc(Cl)sc1Cl)C2
Temperature: 105 °C
Reaction time: 2 h
Yield: 121.7 %

Procedure:
A mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (250 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (4 ml) was stirred at 105° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (40 ml), tetrahydrofuran (25 ml) and 0.2 N sodium hydroxide (25 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (15 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.8 ml), and the mixture was concentrated under reduced pressure. To the residue was added ethanol (4 ml), and the mixture was stirred at 90° C. (bath temperature) for 3 hours and cooled to give crystals, which were filtered, washed with ethanol and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 105) (205 mg) as colorless crystals.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH3:25]>>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH3:25])[N:13]([CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 118-133, 4-morpholinecarbonyl chloride was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 333.2025.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>C1COCC1.O>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([C:19]#[C:18][C:11]2[C:12]([CH2:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([Cl:27])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: CCc1nccc(-c2ccc(C(=O)OC)c(Cl)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nccc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 1.1 g (2.8 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoic acid methyl ester (A-39) using 134 mg (5.6 mmoL) LiOH in a mixture of 100 mL THF and 20 mL water. After completion of the reaction, THF is removed under reduced pressure, the aqueous solution is acidified with 1N HCl to pH ˜1 before the pH is adjusted to 6 with saturated aqueous NaHCO3 solution. The precipitated product is collected by filtration, washed with water and methanol. Yield: 760 mg (72%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:14]=[CH:13][C:12]=1[C:23]([OH:25])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]([CH2:58][N:59]([CH2:67][CH3:68])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([OH:57])[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[NH2:10][C:11]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N:14]=[CH:13][C:12]=1[C:23]([NH:50][CH2:51][C:52]([CH2:58][N:59]([CH2:67][CH3:68])[CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([OH:57])[C:53]([F:56])([F:55])[F:54])=[O:25]
Reactant: CCN(Cc1ccccc1)CC(O)(CN)C(F)(F)F
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 150.6 %

Procedure:
Diisopropylethylamine (0.175 ml, 1 mmol) was added to a mixture of 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (0.119 g, 0.54 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.205 g, 0.54 mmol) in dimethylformamide (1 ml). The resultant mixture was stirred at room temperature for 20 minutes, then a solution of 3-amino-2-{[ethyl(phenylmethyl)amino]methyl}-1,1,1-trifluoro-2-propanol (0.296 g, 1.07 mmol) in dimethylformamide (1 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml) and the separated organic phase washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica (10 g) using 0-100% ethyl acetate in cyclohexane gradient over 15 minutes to give the title compound (0.39 g).
Reaction SMILES: Cl.NCCC(NN[C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=O.S1C=CC=C1S(Cl)(=O)=[O:33]>>[Cl:26][C:24]1[CH:23]=[CH:22][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH2:17][N:11]([C:9]([OH:10])=[O:33])[C:12]=2[CH:25]=1
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Product: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-[(2-thienylsulfonyl)amino]propyl hydrazide (30) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and 2-thiophenesulfonyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.48 g (50%) of product. Analysis calculated for C21H19N4O5ClS2 (M.W. 506.99): C, 49.26; H, 4.36; N, 12.77; Cl, 6.99; S, 12.65. Found: C, 49.05; H, 4.40: N, 12.66; Cl, 7.13; S, 12.88.
Reaction SMILES: [CH3:1][C:2]1([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.CS(O)(=O)=O.[H][H]>[Pt].CCOCC>[CH3:1][C:2]1([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([OH:10])[CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)CC(=O)CC(C)(OOC(C)(C)C)C1
Agent: [Pt]
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CC1(C)CC(O)CC(C)(OOC(C)(C)C)C1
Reaction time: 18 h

Procedure:
The catalytic hydrogenation of 3,5,5-trimethyl-3-(t-butylperoxy)-cyclohexanone, 10.0 g. (0.045 mole), was carried out in a Parr Hydrogenation Apparatus using 1.0 g. 5% Platinum on carbon catalyst and in the presence of 50 ml. of 10% methanesulfonic acid solution. The hydrogenation at 60 p.s.i.g. hydrogen pressure was started at 0° C. and the temperature allowed to rise to 21° C. After 2 1/2 hours, the reaction was stopped, the product taken up in ether, the etheral solution washed to neutrality with water, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure. Examination of the IR spectrum of the product showed that some of the desired product had been obtained as evidenced by the hydroxyl absorption band while some unreduced carbonyl was still present. Further catalytic hydrogenation at 35° C. for 18 hours caused a further increase in hydroxyl absorption band and reduction of the carbonyl absorption band.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][OH:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:1][C:2]1[C:20]([F:21])=[CH:19][C:18]([I:22])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][O:16][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(=CNCCO)C(=O)c1cc(I)cc(F)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate (2.0 g, 4.7 mmol) obtained in Step 2 was dissolved in DMF (10 ml), imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49 g, 9.9 mmol) were added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give the object product (2.3 g, yield 91%) as a white solid.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([NH2:5])=[O:4].C(=O)=O.[NH2:13][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15]>CO>[NH2:18][C:17]1[N:16]=[C:14]([NH2:13])[N:15]=[C:1]([CH2:2][C:3](=[O:4])[NH2:5])[N:19]=1
Reactant: N=C(N)NC(=N)N
Reactant: CCOC(=O)CC(N)=O
Agent: O=C=O
Solvent: CO
Product: NC(=O)Cc1nc(N)nc(N)n1
Temperature: 15 °C

Procedure:
Ethyl malonamate (34.7 g, 0.26 mole) and methanol (100 ml) were placed in a flash equipped with a dropping funnel, a stirrer, and a soda lime trap (to exclude CO2). The flask was cooled to about 15° C. in an ice-water bath. Freshly prepared biguanide (26.3 g, 0.26 mole, in 250 ml methanol) was added, with stirring, over 35 ml at 15°-20° C. A white precipitate began to form within 8-9 min. The mixture was allowed to stir overnight at room temperature. It was then cooled to 15° C., and the white precipitate was filtered, washed with cold water to remove sodium sulfate, and finally washed with cold methanol. A crude yield of 32.7 g (76%) was obtained. A pure sample recrystallized from water had a mp of 295°-96° C. (dec.) when placed in a preheated bath at 295° C. Anal. calcd. for C5H8N6O: C, 36.59; H, 4.91; N, 48.76. Found: C, 36.73; H, 5.08; N, 48.51.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103 %

Procedure:
Mix 5-bromo-2-fluoro-nitrobenzene (10 g, 45 mmol) and 4-(2-aminoethyl)morpholine (11.8 mL, 90 mmol) in THF (100 mL). Stir at room temperature for 18 h. Remove the THF under reduced pressure and partition the residue between water (200 mL) and ethyl acetate (200 mL). Dry the organic layer (MgSO4) and concentrate to give 15.3 g (100%) title compound. HPLC (ISO80-10M) t=1.83 min (94%), MS (S) 331 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>C(Cl)Cl>[CH2:29]([NH:32][C:4]1[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:30]=[CH2:31]
Reactant: C=CCN
Reactant: CC1(c2ccc(F)cc2)CCc2c(Cl)nc(Cl)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNc1nc(Cl)nc2c1CCC2(C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation U, 1.00 g, 3.37 mmol) in DCM (13.46 mL) was added DIPEA (1.176 ml, 6.73 mmol), then allylamine (0.303 ml, 4.04 mmol). The reaction solution was allowed to stir at rt. The reaction was concentrated in vacuo. The residue was applied to silica gel and eluted with a 0 to 50% EtOAc/Hexane gradient to afford N-allyl-2-chloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (896.2 mg, 2.82 mmol, 84% yield) as a white solid. LC-MS (M+H)+=316.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.18-7.23 (2H, m), 6.91-6.98 (2H, m), 5.90-6.00 (1H, m), 5.26 (1H, dd, J=17.2, 1.4 Hz), 5.20 (1H, dd, J=10.1, 1.2 Hz), 4.62 (1H, br. s), 4.17 (1H, td, J=5.7, 1.7 Hz), 2.56-2.62 (2H, m), 2.43-2.50 (1H, m), 2.19-2.28 (1H, m), 1.63 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:19])[CH:10]=[C:11]([Br:18])[C:12]=3[NH2:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][C:3]=1Br.C1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=CC=CC=3)[C:28](=O)[C:27]=2C=CC=1>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:19])[CH:10]=[C:11]([Br:18])[C:12]=3[NH2:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][C:3]=1[O:37][C:35]1[CH:36]=[CH:27][CH:28]=[CH:29][CH:34]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1c(N)c(Br)cc(O)c1C2=O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1c(N)c(Oc3ccccc3)cc(O)c1C2=O

Procedure:
When 11.7 g of 1,8-diamino-4,5-dihydroxy-2,7-dibromoanthraquinone (compare Example 350a) are used as the anthraquinone component in Example 415a, then 4.5 g, corresponding to 37% of theory, of 1,8-diamino-4,5-dihydroxy-2-phenoxy-7-bromoanthraquinone are correspondingly obtained. Colour shade on silica gel: blue of Indicator Number 14 (Colour Index Hue Indication Chart).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48](=[O:49])[C:47]2[CH:51]=[CH:52][CH:53]=[C:45]([C:44]([F:43])([F:54])[F:55])[CH:46]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethyl benzoic acid is added and agitation is carried out for 6 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 307 mg of expected product is collected.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[NH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C1COCC1>[C:21]([N:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[CH:3]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Brc1c[nH]c2ccncc12
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(Br)c2cnccc21
Yield: 122.4 %

Procedure:
Referring now to the Scheme 1 as shown in FIG. 1, a solution of 3.5601 g (18.06 mmol) of 3-bromo-5-azaindole (2) and 0.4651 g (3.8 mmol, 21 mol %) of dimethylaminopyridine (DMAP) in 80 mL of THF was placed in a 250 mL three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 4.7769 g (21.88 mmol, 1.2 eq.) of BOC2O was added to the flask at 17° C., and the resulting mixture was stirred until starting 3-bromo-5-azaindole disappeared, as monitored by TLC (generally, overnight stirring at room temperature). The resulting yellow solution was concentrated on rotavap, washed with 100 mL of saturated sodium bicarbonate, and extracted with dichloromethane (3×80 mL). The organic phase was dried over Na2SO4 and concentrated on rotavap to afford 6.57 g of orange solid. This crude material was purified on CombiFlash using hexane/ethyl acetate as eluent to give 5.25 g (97% yield) of n-boc-3-bromo-5-azaindole (3) as a white solid.