Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]CC=C)[O:8][C:7](=[O:16])[CH:6]=[CH:5]2.CCN([C:22]1[CH:23]=CC=C[CH:27]=1)CC>CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:23][CH:22]=[CH2:27])[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2
Reactant: C=CCOc1cc2oc(=O)ccc2cc1C
Reactant: CCN(CC)c1ccccc1
Solvent: CCCCCC
Product: C=CCc1c(O)c(C)cc2ccc(=O)oc12

Procedure:
A solution of 6-methyl-7-hydroxycoumarin (IV) (11.4 g) in diethylaniline (80 ml) was refluxed for 2 h. After cooling the solution was diluted with n-hexane (500 ml) yielding a precipitate, which was collected by filtration, washed several times with n-hexane and crystallized from EtOAc, yielding 6-methyl-7-hydroxy-8-allylcoumarin (VII) (6.3 g; m.p. 161°-2° C.). ##STR13##
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[CH:5]=[CH2:6]>O1CCCC1>[CH2:1]([NH:3][CH2:6][CH2:5][C:4]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To 110 ml of a 2M solution of ethyl amine in tetrahydrofuran (THF) at 0° C. was added dropwise ethyl acrylate (8.0 ml, 73.92 mmol) in 40 ml of tetrahydrofuran (THF). The reaction mixture was stirred overnight at room temperature. The reaction solution was filtered through a cotton wool plug and concentrated under reduced pressure to yield the title compound 10 (9.01 g, 84%) as a clear liquid. υmax/cm−1 3319.68, 2969.10, 1732.07, 1191.87 (FT-IR: FIG. 8)
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:20])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>O.O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:20])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[NH:28][CH2:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1cccnc1
Reactant: O=c1[nH]nc(OCCCSc2ccccc2)c(Cl)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc(OCCCSc2ccccc2)c(NCc2cccnc2)c1Cl
Yield: 74.8 %

Procedure:
After 0.3 g of 4,5-dichloro-6-[3-(phenylthio)propyloxy]-3(2H)-pyridazinone and 0.243 g of 3-picolylamine were dissolved in a solvent mixture of water-dioxane (1:1), the mixture was heated to reflux for 8 hours. After completion of the reaction, the reaction mixture was poured onto water and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off. The resulting crystals were recrystallized from isopropanol to give 0.273 g of the objective compound. Yield, 73%, Melting point, 152°-155° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][NH:27][NH2:28]>>[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][N:27]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:28]1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNCc1cccc(O)c1
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(Cc2cccc(O)c2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 3-hydroxybenzyl hydrazine dihydrochloride according to the procedure of Example 28.
Reaction SMILES: [OH:1][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH2:12][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[C:8]([CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[OH:1][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[C:8]([CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCCc1ccc(OCC(C)O)c2c1OC(C(=O)OCC)CC2=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
A mixture of ethyl 2,3-dihydro-5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate and N-bromosuccinimide (1.1 g) was heated at reflux in carbon tetrachloride (100 ml) for 6 hours. The solution was cooled, washed with water, dried and evaporated. The solid residue was crystallised from ethanol giving ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=2)[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2.C(#N)C>>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=34)[CH:3]=[N:2]2)[CH2:29][N:28]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([NH:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[CH:32][CH:31]=2)[CH2:27]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Temperature: 50 °C
Yield: 100.3 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (0.811 g, 2.58 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-N-isopropylbenzamide (0.625 g, 2.45 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (190 μL, 1.3 mmol) in acetonitrile (8 mL, 200 mmol) was heated at 50° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. The residue was diluted with dichloromethylene, neutralized with 0.5 N HCl aqueous solution to about pH 7. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (1.40 g, 84.3%), which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=570.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cccc(OCc3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cccc(OCc3ccccc3)c2c1

Procedure:
A solution of ethyl 5-benzyloxyquinoline-3-carboxylate (3.07 g, 10 mmol) prepared in stage A and LiOH (0.4 g, 20 mmol) in THF (20 mL)and water (0.5 mL) was refluxed for 2 hours. After cooling, the solvents were evaporated under vacuum. The solid residue was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[F:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][C:24]=1[F:31]
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-chloro-3-fluorophenyl)methanol (114 mg) and tributylphosphine (258 μl) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (265 mg). The mixture was stirred under sonication at 60° C. for 2 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (25 mg) as an off-white solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[C:32][C:33]#[C:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O.CS(Cl)(=O)=O.C(N(CC)CC)C.CCCCCCCCCCCCC#CC#CCCCCCCCCCCCOS(C)(=O)=O.[N-:91]=[N+:92]=[N-:93].[Na+]>C1COCC1.C(Cl)Cl.[Cl-].[Na+].O.CN(C=O)C.CCCCC>[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[C:32][C:33]#[C:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:91]=[N+:92]=[N-:93]
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCCCCO
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCCCCCCC#CC#CCCCCCCCCCCCOS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC#CC#CCCCCCCCCCCCN=[N+]=[N-]
Reaction time: 1 h

Procedure:
In a glass reaction vessel, 650 milligrams (1.3 mmol) CH3(CH2)10CH2C≡C—C≡C(CH2)11OSi(Me2(CMe3)) was dissolved in 6.5 milliliters THF. To this stirred solution was added 2.0 milliliters TBAF (1 molar solution in THF). After 1 h of stirring, the reaction mixture was filtered and concentrated to 520 milligrams of CH3(CH2)10CH2C≡C—C≡C(CH2)11OH which was used without further purification. In a glass reaction vessel, the CH3(CH2)10CH2C≡C—C≡C(CH2)11OH was dissolved in 6.5 milliliters CH2Cl2 and 150 μL (2.0 mmol) methanesulfonyl chloride and 360 μL (2.6 mmol) triethyl amine were added. The reaction was stirred for 2 h and worked up using CH2Cl2 and brine. The CH2Cl2 layer was dried (MgSO4), filtered, and concentrated to 680 milligrams of CH3(CH2)10CH2C≡C—C≡C(CH2)11OS(O2)CH3 which was used without further purification. In a glass reaction vessel, the CH3(CH2)10CH2C≡C—C≡C(CH2)11OS(O2)CH3 was dissolved in 6.5 milliliters DMF and 570 milligrams (8.8 mmol) sodium azide was added. The reaction was stirred for 20 h and worked up using pentane and brine. The pentane layer was dried (MgSO4), filtered and concentrated. This material was purified using column chromatography eluting with 9% dichloromethane in hexanes to yield 260 milligrams of CH3(CH2)10CH2C≡C—C≡C(CH2)11N3. In a glass reaction vessel, the CH3(CH2)10CH2C≡C—C≡C(CH2)11N3 was dissolved in 10 milliliters THF and 0.5 milliliters water and 330 milligrams (1.3 mmol) triphenyl phosphine was added. After 20 h of stirring, hydrogen chloride gas was bubbled through the mixture for 30 seconds. The resulting solid was filtered and washed with diethyl ether to yield 190 milligrams CH3(CH2)10CH2C≡C—C≡C(CH2)11NH3Cl.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)(=O)C>O.CO>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1
Reactant: CC(=O)OCCCCn1cc(C=O)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1cn(CCCCO)c2ncccc12
Temperature: 60 °C
Yield: 78 %

Procedure:
A solution of sodium hydroxide (0.2 g, 17.5 mmol) in water (35 ml) was added to a solution of 1-(4-acetoxybutyl)-7-azaindole-3-carboxaldehyde (2.3 g, 8.8 mmol) in methanol (40 ml). The mixture was heated at 60° C. for 0.5 h, then the solvent was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water (50 ml:50 ml) and the water layer was separated out. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was used without further purification. Yield 78%. m.p. 90° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[NH2:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:31][C@H:32]([C:37]([O:39][C:3]([CH3:22])([CH3:4])[CH3:2])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:12][CH:13]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:30]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CS(=O)(=O)OCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Product: CC(C)C[C@H](NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC(C)(C)C

Procedure:
From Intermediate 4J and L-Leucine tbutyl ester. LC/MS: m/z 522 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ: 9.40-9.10 (2H, m), 7.59-7.44 (5H, m), 7.38-7.30 (4H, m), 5.71 (1H, d, J=9.6 Hz), 4.00 (1H, brs), 3.40-3.28 (1H, m), 3.25-3.15 (1H, m), 3.10-3.00 (2H, m), 1.80-1.70 (3H, m), 0.96 (6H, d, J=5.1 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[C:17]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:27]([N:35]([CH2:73][CH2:74][CH3:75])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[N:53]([C:54]([C:67]5[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=5)([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[N:52]=[N:51][N:50]=4)=[CH:39][CH:38]=3)=[N:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:76]C(F)(F)C(Br)(F)F.[Cl-].[NH4+]>C1COCC1.CN1CCCN(C)C1=O>[C:17]1([CH2:23][CH2:24][N:25]2[C:29]([Br:76])=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:27]([N:35]([CH2:73][CH2:74][CH3:75])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[N:53]([C:54]([C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=5)([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=5)[C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[N:52]=[N:51][N:50]=4)=[CH:39][CH:38]=3)=[N:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nn(CCc2ccccc2)cc1C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Temperature: 25 °C

Procedure:
1.52 ml of 1.0M lithium bis(trimethylsilyl)amide/hexane solution were added to THF solution (20 ml) containing 395 mg of N-[1-(2-phenylethyl)-4-ethoxycarbonylpyrazol-3-yl]-N-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-n-propylamine and 0.18 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at room temperature, and then heated under reflux for 30 minutes. 0.60 ml of 1,2-dibromo-1,1,2,2-tetrafluoroethane was added thereto and heated under reflux for further 30 minutes. 10 ml of ammonium chloride were added to the reaction solution, THF was distilled off under reduced pressure, and the resultant was extracted with 150 ml of dichloromethane. The resulting extract was dried over magnesium sulfate and subjected to silica gel column chromatography (n-hexane-ethyl acetate=2:1) to obtain 363 mg of the intended compound as a pale red, amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.O1CCOCC1.Cl[CH:19]([F:21])[F:20]>[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:19]([F:21])[F:20])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: FC(F)Cl
Reactant: CSc1nc(O)cc(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(OC(F)F)n1
Temperature: 40 °C
Yield: 84.6 %

Procedure:
6.8 g (0.036 mole) of 4-chloro-6-hydroxy-2-methylthiopyrimidine are suspended in 25 ml 50% potassium hydroxide solution, 25 ml of water and 100 ml of dioxane. After the addition of 0.5 g of 18-crown-6, the reaction mixture is heated to 40° C., and 10 g of chlorodifluoromethane are subsequently introduced over 3 hours. The mixture is then cooled to room temperature, the phases are separated and the organic phase is evaporated to dryness. The residue is crystallised from methanol/water, affording 6.9 g (84.4% of theory) of 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine with a melting point of 36°-37° C. The substance has a boiling point of 76°-78° C. at 0.15 mbar.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH:10]([NH2:19])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1>C1COCC1>[NH2:19][CH:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:9][OH:8]
Reactant: COC(=O)C(N)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)c1ccc(F)c(F)c1
Temperature: 0 °C

Procedure:
Into a well-stirred suspension of LiAlH4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of amino-(3,4-difluorophenyl)-acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0° C. The resulting greenish brown suspension was heated at reflux temperature for 2 h. The reaction mixture was cooled to 0° C. and then carefully quenched sequentially with 5 mL of water, 5 mL of 3N NaOH followed by 15 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the filter cake was added 100 mL Et2O and the suspension was heated at reflux temperature for 20 min. The suspension was filtered and the combined filtrates were dried over MgSO4, filtered and the solvent was removed in vacuo. 2-Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassy syrup which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C(O)C.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
In a round bottom flask were combined 4-Bromo-2-nitroaniline (4.03 g, 18.6 mMol), ethanol (190 proof, 93 mL), and tin chloride dihydrate (8.38 g, 37.1 mMol) and a water-cooled condenser attached. The reaction was heated to reflux in an oil bath and stirred for three days. The mixture was then cooled to room temperature and diluted with ethyl acetate (250 mL). Saturated sodium bicarbonate solution was added until the pH was basic. The slurry was then filtered thru Celite and the filtrate transferred to a separatory funnel. The aqueous layer was discarded and the organics washed with saturated sodium bicarbonate (2×50 mL), brine (50 mL), and then dried with magnesium sulfate, filtered, and concentrated to dryness to yield 3.07 g (88% yield) of 4-Bromo-1,2-phenylenediamine as an orange-brown solid. 1H NMR (DMSO-d6): δ=6.63 (d,1H,J=2.3Hz), 6.5-6.3 (m,2H), 4.71 (br s,2H), 4.56 (br s,2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[CH:31]=[CH:30][C:29]3[C:33](=[O:36])[CH2:34][CH2:35][C:28]=3[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[CH2:14][CH2:15][CH3:16])(=[O:12])=[O:11])([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:41](Cl)([CH3:43])=[O:42]>C1([N+]([O-])=O)C=CC=CC=1.O>[C:41]([C:24]1[CH:23]=[CH:22][C:21]2[N:20]([CH2:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[C:32]3[CH:31]=[CH:30][C:29]4[C:33](=[O:36])[CH2:34][CH2:35][C:28]=4[C:27]=3[C:26]=2[CH:25]=1)(=[O:42])[CH3:43]
Reactant: CCCN(CCCn1c2ccccc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCN(CCCn1c2ccc(C(C)=O)cc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
Compound 47 (0.638 g, 1.26 mmol) was dissolved in PhNO2 (7 mL). The solution was cooled on an ice bath, AlCl3 (0.67 g, 5.02 mmol) and then AcCl (0.45 mL, 6.31 mmol) were added. The mixture was kept for 40 min (LC/MS monitoring), diluted with water. The product was extracted with CH2Cl2. The extract was evaporated. The residue was evaporated, and the product was passed through Celite, eluent: CH2Cl2-ethyl acetate 100:0→50:50. Yield of 48: 0.453 g (66%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][Mg]Br.O>C(OCC)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:11])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1cccc(Br)n1
Reaction time: 3 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanone (5 g, 25.0 mmol) in diethyl ether (77 mL) at 0° C. was treated with methyl magnesium bromide (8.33 mL, 25.0 mmol). After 3 hours, water was added to quench the excess methyl magnesium bromide, and then concentrated aqueous hydrogen chloride solution was added until two layers were obtained. The layers were separated and the aqueous layer was extracted with diethyl ether (3×50 mL) The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]=[C:10]([C:8]1[N:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-(6-Acetyl-pyridin-2-yl)-ethanone 2 (22.2 g, 0.0136 mole), 15.0 g (0.124 mol) of 2,6-dimethyl-phenylamine 3, 300 ml of n-propanol, and a few crystals of p-toluenesulfonic acid were stirred at room temperature for 36 h in 500 ml flask under a flow of nitrogen. The resultant yellow precipitate was filtered and washed by 20 ml of methanol. It was then dried at 1-mm vacuum overnight. The yield of 1-{6-[1-(2,6-dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 was 12.86 g (39%) as a yellow solid. 1H NMR (500 MHz, CD2Cl2, TMS): δ 2.00 (s, 6H, Me), 2.20 (s, 3H, Me), 2.70 (s, 3H, Me), 6.90 (t, 3JHH=8.1 Hz, 1H, Arom-H), 7.10 (d, 3JHH=8.1 Hz, 2H, Arom-H), 7.95 (t, 3JHH=8.0 Hz, 1H, Pyr-H), 8.10 (d, 3JHH=8.0 Hz, 1H, Py-H), 8.55 (d, 3JHH=8.0 Hz, 1H, Py-H). 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 167.1 (C═N), 200.1 (0=0). Anal. Calculated for C17H13N2O (Mol. Wt.: 266.34): C, 76.66; H, 6.81; N, 10.52. Found: C, 76.69; H, 6.84; N, 10.57.