Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[CH3:2].C(N(CC)CC)C.Br.[Br:26][C:27]1[CH:28]=[C:29]([CH2:34]Br)[C:30]([NH2:33])=[N:31][CH:32]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:34][C:29]1[C:30]([NH2:33])=[N:31][CH:32]=[C:27]([Br:26])[CH:28]=1)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CNCCCN1CCN(C)CC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN(CCCN1CCN(C)CC1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
A solution of [3-(4-methyl-piperazin-1-yl)propylamino]acetic acid ethyl ester (1.80 g, 7.41 mmol) and triethylamine (2.3 mL, 16.4 mmol) in DMF (50 mL) was treated with 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (2.57 g, 7.41 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (100 mL) and then extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 90:10) gave the title compound (0.50 g, 16%) as a colorless oil: MS (ESI) m/e 428 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5](#N)[CH:6]=[CH2:7].[C:9](O)(=O)[CH:10]=[CH2:11]>>[CH3:7][C:6]1[CH2:5][CH2:4][C@@H:3]([C:10]([CH3:11])=[CH2:9])[CH2:2][CH:1]=1
Reactant: C=CC#N
Reactant: C=CC(=O)O
Reactant: C=CC=C
Product: C=C(C)[C@H]1CC=C(C)CC1
Reaction time: 0.27 h

Procedure:
Photopolymer plates based on a terpolymer of butadiene, acrylonitrile and acrylic acid were processed as in Example 1 with this solvent. Wash time for this type plate in this wash solution was 16 minutes. Plate exposure times equivalent to those required for perchloroethylene-n-butanol washed plates were necessary to hold 0.004" lines and 3%, 150 line half tones with this wash solvent.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH:13](Br)[C:12](=O)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([NH2:25])(=[S:24])[CH3:23]>C(O)C>[CH3:23][C:22]1[S:24][C:13]2[CH2:14][CH2:15][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[C:12]=2[N:25]=1
Reactant: CC(N)=S
Reactant: O=C1c2ccccc2N(C(=O)c2ccccc2)CCC1Br
Solvent: CCO
Product: Cc1nc2c(s1)CCN(C(=O)c1ccccc1)c1ccccc1-2
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 1-benzoyl-4-bromo-1,2,3,4-tetrahydrobenzo[b]azepin-5-one (11.0 g, 2.9 mmol) from Example E5.7 in ethanol (50 ml) was added thioacetamide (0.75 g, 10 mmol). The solution was stirred for 16 h. The resultant suspension was reduced in volume by evaporation and cooled. The precipitate was collected by filtration and the solid was washed with cold ethanol and dried to yield the title compound as a white solid (0.65 g, 70%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[Br:21][C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=1[NH2:24]>O>[Br:21][C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=1[NH:24][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Br)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (427 mg, 2.39 mmol, commercially available product) and triethylamine (410 μl, 2.94 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-bromo-5-(trifluoromethyl)aniline (480 mg, 2.00 mmol; commercially available product). The resulting mixture was warmed to room temperature and stirred for 24 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate). Thus, N-[2-bromo-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0612) (308 mg, 44.8%) was yielded as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[Br:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[Br:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([NH:51][C:34]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:40])[CH3:50])=[CH:45][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(Br)cc4)cc3)c2cc1OC
Yield: 117.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred stirred at room temperature for 75 min. Next, a solution of (1S)-1-(4-bromophenyl)ethylamine (46 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (68 mg, yield 55%).
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13](N)[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(#N)C.O.N([O-])=O.[Na+]>C(O)(=O)C>[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH:14]=[CH:13][C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(O[C@@H]1[C@@H](CO)C=C[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a well stirred solution of (−)-(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (6) (10.0 g, 25.5 mmol) in mixture of acetonitrile/water (1:1) was added sodium nitrite (8.8 g, 127.8 mmol) by portion wise at 0° C. After 15 minutes 50% aqueous acetic acid solution was added drop wise over a period of 0.5 hr and the mixture was vigorously stirred for 2 hr. The organic solvent was removed under reduced pressure and the rest of mixture was quenched with water. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography (20% EtOAc/hexane) to give compound 7. [α]24D −156° (c 1.0, CHCl3); 1H NMR (500 MHz, DMSO-d6): δ 8.05 (m, 2H), 7.89 (m, 2H), 7.52 (m, 2H), 7.38 (m, 2H), 7.28 (m, 2H), 6.11 (m, 3H), 5.54 (m, 1H), 3.87-3.82 (m, 2H), 3.27 (m, 1H), 2.29 (m, 1H). HR-MS Calcd. For (C25H29NO7+H)+ 339.1154, found 339.1286.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(O[C:26](OC2N=CC=CC=2)=[S:27])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:18]=[C:26]=[S:27])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1ccc(N)c2c1N(C(=O)OC(C)(C)C)CC2
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(N=C=S)c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 93.6 %

Procedure:
1-t-Butoxycarbonyl-4-amino-2,3-dihydro-7-methylindole (1.625 g, 6.55 mmol) is dissolved in methylene chloride (15 mL). To this solution is added 4-dimethylaminopyridine (0.160 g, 1.31 mmol) and di-2-pyridyl thionocarbonate (1.52 g, 6.55 mmol). The volume of solvent is brought to 30 mL, and the solution is allowed to stir for one hour. The solution is diluted to 150 mL with chloroform and washed first with four 75-mL portions of aqueous citric acid solution followed by three 100-mL portions of aqueous potassium carbonate. The organic layer is dried over anhydrous potassium carbonate, filtered and the solvent is removed by rotary evaporation to yield an orange, oily solid. The crude product is purified by silica gel flash column chromatography using 4% ethyl acetate/hexanes to afford 1.78 g of N-t-butoxycarbonyl-2,3-dihydro-4-isothiocyanato-7-methylindole as a white solid (94% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]2=[O:30])=[CH:9][CH:8]=1)(=O)=O.[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C1COCC1>[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][B:36]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]3=[O:30])=[CH:9][CH:8]=2)[O:35]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c2ncccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-n3c(=O)n(COCC[Si](C)(C)C)c4cccnc43)cc2)OC1(C)C
Temperature: 100 °C

Procedure:
The mixture of 4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (2.6 g), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 mL), triethylamine (2.23 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.218 g) and THF (21.2 mL) was heated at 100° C. for 3 h under microwave irradiation. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccccc3)cn2)CC1
Yield: 80.7 %

Procedure:
A mixed solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1.00 g, 2.92 mmol), phenylboronic acid (535 mg, 4.38 mmol), ethanol (2.5 ml), 2N aqueous solution of sodium carbonate (12 ml), tetrakis(triphenylphosphine)palladium (404 mg, 0.350 mmol) and toluene (23 ml) was stirred at 95° C. for 12 hours under a nitrogen atmosphere, and the solvent was distilled away under reduce pressure. The residue was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound 800 mg (80.7%) as solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[NH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])N>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:8]([CH3:15])([CH3:14])[C:7]3[NH:17][C:19]4[C:26]([C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4
Reactant: N#Cc1cccc(NN)c1
Reactant: COc1cc2c(cc1Cl)CCC(=O)C2(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Cl)Cc1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound I1-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g, 1.2 eq.) were dissolved in TFA (91 mL), and stirred at 90° C. for 3 hr. According to the concentration under reduced pressure, TFA was removed and the residues were added with saturated aqueous solution of NaHCO3, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with 11-3 (red powder, 6.46 g).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:16]=O)[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:21]>CCO.CCOCC>[ClH:1].[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH2:16][NH:18][C:19]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:21])[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2cc2c(Cl)cccc12
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccccc2cc2c(Cl)cccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 4-chloro-9-anthracenecarbaldehyde (11A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((4-chloro-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride, mp 225°-226° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 44.3 %

Procedure:
Imidazole (1.3 g) was dissolved in. THF (15.5 ml), potassium carbonate (5.3 g) was added to the mixture, and a solution of 1-(3-bromopropyl)-4-nitrobenzene (3.1 g) in THF (15.5 ml) was added dropwise to the mixture. The mixture was stirred for 60 hours at 50° C., and cooled to room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-[3-(4-nitrophenyl)propyl]imidazole (1.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[C:28][CH2:29][OH:30]>>[OH:30][CH2:29][C:28]#[C:27][CH2:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OCC#CCO
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 48.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 2.5 g (6.46 mmoL) of tert-butyl(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.667 g (7.752 mmol) of 2-butyne-1,4-diol gave 1.42 g of tert-butyl(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])[CH3:28]>O1CCOCC1.O>[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:4]2[N:9]=[C:8]([N:10]3[C:18]4[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11]3)[CH:7]=[CH:6][N:5]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 110 °C
Yield: 99.7 %

Procedure:
A mixture of 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (25 g, 64 mM) and 4-amino-cyclohexanecarboxylic acid ethyl ester (16.3 g, 95.3 mM) in dioxane (400 mL) and heated at 110° C. for approximately 5 h. The solution was concentrated in vacuo to give a white residue. The residue was suspended in H2O, filtered and washed in H2O, and dried at 60° C. in vacuo to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (31.7 g, 99.7%).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][NH:16][CH2:15][CH2:14]4)=[CH:7][N:6]=2)[CH2:4][CH2:3]1.[CH3:21][C@@:22]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1>C(Cl)Cl.C1COCC1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][N:16]([S:30]([CH2:29][C@@:22]3([CH3:21])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])(=[O:31])=[O:32])[CH2:15][CH2:14]4)=[CH:9][N:10]=2)[CH2:4][CH2:3]1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: c1nc(C2CC2)ncc1-c1cc2c(cn1)CNCC2
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4cnc(C5CC5)nc4)ncc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a stirred solution of 6-(2-cyclopropylpyrimidin-5-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride (0.12 g, 0.42 mmol) in DCM (10 mL) was added TEA (0.12 mL, 0.84 mmol) followed by the dropwise addition of [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.090 g, 0.40 mmol) in THF (10 mL) at −10° C. The mixture was stirred at RT overnight, concentrated, taken up in water (10 mL) and extracted four times with EtOAc. The combined organic phases were dried, filtered and concentrated. Purification by prep-HPLC gave 0.12 g (64%) of the title compound as a white solid.
Reaction SMILES: [C:1](#N)C.CO.S([O:11][CH3:12])(OC)(=O)=O.O[C:14]1[C:23]2[C:18](=[C:19]([OH:24])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>[OH-].[Na+].C(Cl)(Cl)Cl.CN(C)C=O>[CH3:1][O:24][C:19]1[C:18]2[C:23](=[C:14]([O:11][CH3:12])[CH:15]=[CH:16][CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC#N
Reactant: Oc1cccc2c(O)cccc12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cccc2c(OC)cccc12
Reaction time: 2 h

Procedure:
1,4,5,8-tetramethoxynaphthalene (3) is synthesized from 1,5-dihydroxynaphthalene (2) as a starting material through a known three-phase reaction, and then 1,4,5,8-tetramethoxynaphthalene (3) is demethylated to produce 5,8-dimethoxy-1,4-naphtoquinone(4) as a synthesis intermediate. A detailed synthesis method is disclosed in cited references presented in the reaction schemes above, and a solvent used herein may be a solvent that does not adversely affect the reaction, and examples of such a solvent are sodium hydroxide, acetonitrile, anhydrous methanol, N, N-dimethylformamide, and chloroform. The initial methylation is performed in such a manner that dimethyl sulfate is dropped to 1,5-dihydroxynaphthalene dissolved in sodium hydroxide in the presence of a nitrogen gas for 1 hour and the reaction was performed for 2 hours. The reaction product is re-crystallized with benzene to produce 1,5-dimethoxynaphthalene.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])=O.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>CCO.O.C(OC)(C)(C)C>[OH:23]/[N:22]=[CH:1]/[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(C=O)c(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(/C=N/O)c(C(F)(F)F)c1

Procedure:
4-Formyl-3-(trifluoromethyl)-N-[(trimethylsilyl)methyl]benzamide (15.0 g, 49.4 mmol), Hydroxylamine hydrochloride (6.9 g, 98.8 mmol) and sodium acetate (6.1 g, 74.1 mmol) in EtOH and H2O were stirred at room temperature over night. The reaction mixture was diluted with t-BuOMe, and washed with brine and dried over MgSO4. After evaporation the product was found to be 15.0 g (95%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5](O)=[O:6].C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=C(O)C(CCBr)c1ccc(Cl)c(Cl)c1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Dissolve the product of Step 2 (8.1 g, 25.96 mmoles) in 20 ml. of dry CH2Cl2. Add oxalyl chloride (8.1 g, 62.3 mmoles), followed by 50 μl of dry DMF and heat the solution to reflux for 3 h. Cool the solution to room temperature and remove the solvent and excess reagent using reduced pressure. Yield: 8.2 g (IR: 1785 cm- 1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[CH:6][CH:5]=1.O[NH:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=[NH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:34]1([C:32]2[N:33]=[C:26]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]4)=[O:17])[CH2:13]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Reactant: N=C(NO)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCS(=O)(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.23 mmol) of the compound from Example 37A and 46 mg (0.46 mmol) of N-hydroxycyclopropanecarboximidamide were initially charged in 0.8 ml of DMF and reacted with 132 mg (0.35 mmol) of HATU and 0.12 ml (90 mg, 0.69 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 46 mg (37% of theory)