Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[C:5]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:1]([CH:16]([OH:17])[C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([C:5](=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=1)#[CH:2]
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 2 h

Procedure:
Ethynylmagnesium bromide (11.2 mmol) in tetrahydrofuran (20 cm3) was added dropwise to a stirred solution of 3-benzoylbenzaldehyde (2 g, 9.5 mmol, prepared as in Example 3(b) in tetrahydrofuran (30 cm3) through which purified acetylene was being passed. After 2 hours, saturated ammonium chloride solution (200 cm3) was added, and the mixture extracted with ether (3×50 cm3). The combined extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulphate, and the solvent removed in vacuo. The product was purified by thin layer chromatography on silica to give the title alcohol, yield 1.1 g (49%) nD20 1.6075.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([CH3:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.Cl[C:34]([O:36][C:37]([CH3:39])=[CH2:38])=[O:35].O>N1C=CC=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]([CH3:39])=[CH2:38])[CH:11]=2)[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[C:18]([F:31])=[CH:17][C:16]=2[CH3:32])[C:8]1=[O:14])[CH3:13]
Reactant: C=C(C)OC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2C)cc2cnc(N)cc21
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3ccccc3)c(F)cc1C)c(=O)n2CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (0.35 g, 0.811 mmol) in pyridine (5 mL) was treated with isopropenyl chloroformate (0.147 g, 1.217 mmol) and stirred at RT for 1 h. Water was added, the mixture stirred for 10 minutes and the resulting solid was collected via filtration and dried to afford prop-1-en-2-yl (1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (360 mg, 86% yield). MS (ESI) m/z: 516.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:15]Br>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:14])[CH2:13][Br:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrBr
Reactant: CCCCOc1ccc(C(C)=O)cc1
Product: CCCCOc1ccc(C(=O)CBr)cc1
Temperature: 25 °C

Procedure:
reacting p-n butoxyacetophenone in solution with bromine stirred in slowly at room temperature to form p-n-butoxyphenacyl bromide;
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([I:11])[S:9][CH:10]=1)=[O:5])C.BrC1SC=C(C(O)=O)N=1.[CH:21]1[CH:22]=[CH:23][C:24]2N(O)N=[N:27][C:25]=2[CH:26]=1.Cl.CN(C)CCCN=C=NCC.CC1CCCCN1>ClCCl.C(#N)C>[I:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([N:27]2[CH2:23][CH2:22][CH2:21][CH2:26][CH:25]2[CH3:24])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1csc(I)n1
Reactant: On1nnc2ccccc21
Agent: CC1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC1CCCCN1C(=O)c1csc(I)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
A solution of a mixture of 2-iodo-thiazole-4-carboxylic acid ethyl ester and 2-bromo-thiazole-4-carboxylic acid (from Step 2; 11.5 g), N,N-dimethylaminopyridine (11.2 g, 91.7 mmol), HOBT (10.0 g, 74.0 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (14.0 g, 73.0 mmol), and 2-methyl-piperidine (8 mL, 68.1 mol) in dry dichloromethane (150 mL) and dry acetonitrile (20 mL) was stirred at room temperature for 72 h. At this time, the reaction mixture was concentrated in vacuo. The resulting solution was diluted with dichloromethane (25 mL) and 1 N HCl (250 mL). The mixture was stirred for several hours at room temperature. At this time, the mixture was filtered and the solids were washed with dichloromethane (200 mL). The aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (450 mL) and brine (450 mL). The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash column chromatography eluting with a gradient of ethyl acetate in hexanes to give (2-iodo-thiazol-4-yl)-(2-methyl-piperidin-1-yl)-methanone (8.1 g, 30% yield from 2-amino-thiazole-4-carboxylic acid ethyl ester hydrobromide).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:34])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(OCc3ccc(Cl)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
2-{[4-(2-{4-[(4-Chlorobenzyl)oxy]phenoxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (420 mg) obtained in Example 50-3 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (260 mg) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:23][CH2:24][CH2:25][CH3:26])C(O)=O)=[CH:15][CH:14]=1.C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[N-:44]=[N+]=[N-].C(N(CC)CC)C.Cl.[OH-].[Na+]>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH2:44])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1
Reactant: CCCCC(C(=O)O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(N)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 70 °C

Procedure:
10.5 g (30 mmol) of 2-[4-(quinolin-2-yl-methoxy)phenyl]-caproic acid and 7.7 ml (36 mmol) of phosphoric acid diphenylester-azide are dissolved in 100 ml of dimethylformamide at 0° C. and 10 ml (72 mmol) of triethylamine are added. The mixture is heated at 70° C. for 1 hour and cooled to 0° C., 75 ml of 5 normal hydrochloric acid are added dropwise and the mixture is again heated at 70° C. for 1 hour. The reaction mixture is poured onto water, rendered alkaline with 2-normal sodium hydroxide solution and extracted 5 times with ethyl acetate. After drying over Na2SO4, the extract is evaporated. The product crystallizes out.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:34])[CH2:28][CH2:27][CH2:26][O:25][C:24]2[C:29]([NH2:33])=[CH:30][CH:31]=[CH:32][C:23]1=2>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:7][C:2]([NH:33][C:29]2[C:24]3[O:25][CH2:26][CH2:27][CH2:28][C:22]([CH3:34])([CH3:21])[C:23]=3[CH:32]=[CH:31][CH:30]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)cccc21

Procedure:
The title compound was prepared from (2,5-dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine and 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine in an analogous manner to Example 179 heating at 140° C. Product was isolated as a white solid (46 mg, 52%). LCMS=461 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H, J=7.83 Hz), 7.86 (s, 1H), 7.76 (d, 1H, J=7.58 Hz), 7.66 (d, 1H, J=7.83 Hz), 7.41 (m, 2H), 6.98 (d, 1H, J=8.09 Hz), 6.88 (t, 1H, J=8.33 Hz), 6.56 (s, 1H), 3.92 (m, 2H), 1.69 (m, 2H), 1.61 (m, 2H), 1.32 (s, 6H).
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>O.CO>[CH2:11]([OH:12])[C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([CH:2]=[O:1])=[O:4]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CO
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To a solution of α-D-glucose (4.5 g) in water (10 ml), a solution of cupric acetate (20 g) in methanol (250 ml) was added, and the resultant mixture was heated on a water bath for 1 hour. The reaction mixture was cooled, and the precipitated cuprous oxide was eliminated by filtration. Hydrogen sulfide gas was introduced into the filtrate for about 1 minute to precipitate the unreacted cupric acetate in the form of cupric sulfide. After elimination of the precipitate by filtration, the filtrate was treated with a small amount of activated charcoal and concentrated under reduced pressure to give glucosone in a syrupy state.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[NH:4][N:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:18][CH2:19][CH2:20][Cl:21])[N:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(C)n[nH]c(=O)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(C)nn(CCCCl)c(=O)c2cc1OC

Procedure:
1-[4-Methyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloropropane was prepared analogous to Example 1 (a) by reaction of 4-methyl-6,7-dimethoxy-1(2H)-phthalazinone with 1-bromo-3-chloro-propane in dimethylformamide. Rf -value (chloroform/methanol = 9/1) : 0.9.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:34]C(=O)C)([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[C:29]([CH2:31][CH2:32][CH3:33])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8]C(=O)C)(=O)C.[Li+].[OH-]>C1COCC1.O>[NH2:34][C:6]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[C:29]([CH2:31][CH2:32][CH3:33])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)([CH2:7][OH:8])[CH2:5][OH:4]
Reactant: CCCc1cc(-c2ccc(-c3ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc3)cc2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(-c2ccc(-c3ccc(CCC(N)(CO)CO)cc3)cc2)no1

Procedure:
Acetic acid 2-acetoxymethyl-2-acetylamino-4-[4′-(5-propyl-isoxazol-3-yl)-biphenyl-4-yl]butyl ester (0.1 mmol) is dissolved in THF (1 mL) and treated with 2 N LiOH aqueous solution (0.5 mL). The resulting mixture is stirred at reflux for 1 h and diluted with H2O (10 mL). It is then extracted with EtOAc (3×5 mL) and the combined organic phase is washed with brine and dried over Na2SO4. After concentrated, the crude product is purified with LC-MS to give the desired product as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 3.53 (q, J=11.0 Hz, 4H), 2.81 (t, J=7.4 Hz, 2H), 2.71 (m, 2H), 1.79 (m, 4H), 1.04 (t, J=7.4 Hz, 3H). MS: (ES+): 381.2 (M+1)+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)C=C.Cl.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:23][CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Reactant: CN(C)c1ccccc1
Agent: Cl
Product: C=CCc1cc(C(=O)OC)ccc1O
Temperature: 210 °C
Yield: 64 %

Procedure:
A mixed solution of methyl 4-(2-propen-1-yl)oxybenzoate (19.17 g, 0.10 mol) and N,N-dimethylaniline (40 mL) was heated to reflux at 210° C. for 18 hours. The reaction solution was added with dilute hydrochloric acid (1 mol/L) and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (12.26 g, yield 64%) was obtained as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:10][CH:11]([CH2:22][CH3:23])[C:12]([NH:14][C:15]([CH3:21])([CH3:20])[C:16]#[C:17][CH2:18][CH3:19])=[O:13])[CH:7]=[N:8][CH:9]=1)([OH:3])=O.[CH:24]([NH:27][CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>CN(C)C=O.O>[CH:24]([N:27]([CH:28]([CH3:30])[CH3:29])[C:1]([C:4]1[CH:5]=[C:6]([O:10][CH:11]([CH2:22][CH3:23])[C:12]([NH:14][C:15]([CH3:21])([CH3:20])[C:16]#[C:17][CH2:18][CH3:19])=[O:13])[CH:7]=[N:8][CH:9]=1)=[O:3])([CH3:26])[CH3:25]
Reactant: CC(C)NC(C)C
Reactant: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C(=O)O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C(=O)N(C(C)C)C(C)C)c1
Temperature: 25 °C

Procedure:
The product from Stage 3 (0.22 g) in dry N,N-dimethylformamide (5 ml) containing N-(3-(dimethylaminopropyl))-N′-ethylcarbodiimide hydrochloride (0.14 g) was stirred at ambient temperature and treated dropwise with diisopropylamine (0.20 ml). The mixture was stirred at ambient temperature for 2 hours, diluted with water, extracted with diethyl ether (three times) and the organic fractions combined, washed with aqueous sodium hydrogen carbonate (twice), water (twice) and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residual gum was fractionated by chromatography (silica; ethyl acetate) to give the required product as a colourless gum, 0.06 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C@@H:10]([CH3:16])[C:11](OCC)=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C[O-].[Na+].Cl>CO.[Ni]>[CH3:16][C@@H:10]1[NH:9][C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][NH:2][C:11]1=[O:12]
Reactant: CCOC(=O)[C@H](C)Nc1ncccc1C#N
Agent: [Ni]
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: C[C@@H]1Nc2ncccc2CNC1=O
Reaction time: 6 h
Yield: 23.4 %

Procedure:
To a solution of (S)-ethyl 2-(3-cyanopyridin-2-ylamino)propanoate (720 mg, 3.28 mmol) in methanol (10 mL) and sodium methoxide (3.28 mmol) is added a pinch of Raney nickel and the reaction was stirred under hydrogen for 6 h. Once the reaction was complete, 1 eq of HCl was added and the solution filtered through celite, and washed with methanol. The solution was concentrated and re-solvated in ethyl acetate (10 mL) and washed with water (20 mL), the organic layers were combined, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to yield a white solid (136 mg, 23%): 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.32 (s, 1H), 6.60-6.57 (m, 1H), 4.99 (d, J=16.4 Hz, 1H), 4.12-4.10 (m, 1H), 3.87 (d, J=16.4 Hz, 1H), 1.38 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[C:21]1([O:27][CH2:28][CH2:29][CH2:30]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N12CNCC1=CCCC2>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:30][CH2:29][CH2:28][O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:20]
Reactant: CC1CCCCC1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reactant: BrCCCOc1ccccc1
Agent: C1=C2CNCN2CCC1
Product: CC1CCCCC1n1c(=O)n(CCCOc2ccccc2)c2cnc3[nH]ccc3c21
Temperature: 60 °C

Procedure:
A mixture of 1-(2-methylcyclohexyl)-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in N,N-dimethylformamide, 1.00 mL), 3-bromopropyl phenyl ether (12.9 mg), 1,8-diazabicyclo[4,3,0]non-5-ene (0.013 mL), was heated at 60° C. for 16 hours. The solvent was removed in vacuo and purification by preparative high performance liquid chromatography gave 1-(2-methylcyclohexyl)-3-(3-phenoxypropyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (2.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].O>C(Cl)Cl.CCOCC>[C:23]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:25])[CH3:24]
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
229 g (1.04 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 2 ml of methylene chloride, treated with 115 g (1.14 mol) of triethylamine, and 89.5 g (1.14 mol) of acetyl chloride in 400 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour, the mixture was poured into water, extracted with methylene chloride, and the methylene chloride phase was dried with magnesium sulphate. Distillation of the solvent in vacuo gave a crude product which was suspended in 500 ml of ether and filtered off. There was obtained 4-acetyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline of melting point 106°-108°. Concentration of the mother liquor and chromatography (silica gel/chloroform) gave a further portion of melting point 106°-108°.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][N:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: CN(C)c1cnc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1cnc(N)cn1
Yield: 74.8 %

Procedure:
A solution of dimethyl-(6-nitro-pyrazin-3-yl)-amine (1.27 g, 7.55 mmol) in ethanol (90 mL) was treated with 10% palladium on activated carbon (0.40 g). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure overnight. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethanol. The filtrate was concentrated in vacuo, and the resulting black-orange solid was triturated with petroleum ether to afford N5,N5-dimethyl-pyrazine-2,5-diamine (0.78 g, 75%) as a black solid: mp 71.5–74.2° C.; EI-HRMS m/e calcd for C6H10N4 (M+) 138.0905, found 138.0903.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([CH3:14])=[CH2:13])[NH:6][C:5]2=[O:15].[Si]([CH:20]=[N+:21]=[N-:22])(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1([CH3:14])[CH2:13][CH:20]=[N:21][NH:22]1)[NH:6][C:5]2=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)c1nc2ccc(Cl)cc2c(=O)[nH]1
Solvent: C1CCOC1
Product: CC1(c2nc3ccc(Cl)cc3c(=O)[nH]2)CC=NN1

Procedure:
6-Chloro-2-isopropenyl-3H-quinazolin-4-one (1 mmoL) in THF (5 mL) was treated with TMSCHN2 (1.0 N, 3.0 mmoL) at 50° C. for 4 h. The solvent was removed and the residue was purified by silica gel column chromatography to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:36]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=1)(=[O:44])=[O:43]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3,4-dimethoxybenzenesulfonyl chloride (12 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 28 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3,4-dimethoxybenzenesulfonamide (percentage yield: 96%), was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][CH:13]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][CH:13]2[CH2:14][NH:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: COc1cc(NC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC2CNC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl 3-(3-methoxy-4-nitrophenylamino)azetidine-1-carboxylate (9 g) was added TFA (18 mL) at room temperature. The reaction mixture was stirred for 15 min at room temperature and then was concentrated under reduced pressure at 40° C. to give the title compound as TFA salt (7.24 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]2[CH:13]=[N:14][N:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[N:9]2[CH:13]=[N:14][N:15]=[C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1
Reactant: CCOC(=O)c1cc(O)n2cnnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)n2cnnc2n1
Temperature: 60 °C

Procedure:
7-Ethoxycarbonyl-5-hydroxy-s-triazolo[4,3-a]pyrimidine (10 g) was added to 50 ml of phosphorus oxychloride at room temperature, the mixture was heated at 60° C. for one hour, and excess phosphorus oxychloride was removed by distillation under reduced pressure. The remaining dark red oil was shaken with 200 ml of chloroform and 100 ml of water, and the aqueous layer was again extracted with 100 ml of fresh chloroform. The chloroform layers were joined together and washed with 80 ml of saturated sodium bicarbonate solution and 100 ml of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure to about 50 ml, and the residue was recrystallized from 100 ml of n-hexane. The crystals were collected by filtration, affording 6.2 g of the objective compound as faint yellow crystals.