Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=3)=[CH:11][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1.[Na]>CN(C)C=O>[C:20]([NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
350 mg (0.82 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butyl-pyridin-2-amine were dissolved in 30 ml of dry dimethylformamide and 110 μl (0.82 mmol) of p-trifluoromethyl-phenyl isocyanate were added to the resulting solution. The mixture was stirred overnight at room temperature, then poured into an aqueous solution of sodium hydrogenocarbonate and extracted with dichloromethane. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on a silica gel column (dichloromethane-acetone 9/1), affording 302 mg (60%) of the title compound.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[C:18]([O:20]C)=[O:19]>CN(C)C=O>[C:18]([CH:17]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:22])([OH:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(C(C)C(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of thymine (0.317 mole) and potassium carbonate (0.634 mole) in dimethylformamide (900 ml) is added methyl bromopropionate (0.634mole) and the mixture is stirred vigorously overnight under an atmosphere of nitrogen. The mixture is filtered, washed with ether and evaporated to dryness in vacuo. The solid residue is treated with water (300 ml) and 4N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C., filtered and washed with water (2×100 ml). The precipitate is treated with water and 2N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled at 0° C., filtered, and the title compound is precipitated by the addition of 4N hydrochloric acid (70 ml) to afford, after filtration, the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:61]1[CH2:66][CH2:65][CH:64]([N:67]2[CH2:73][CH2:72][C:71]3[CH:74]=[CH:75][CH:76]=[CH:77][C:70]=3[NH:69][C:68]2=[O:78])[CH2:63][CH2:62]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:61]4[CH2:62][CH2:63][CH:64]([N:67]5[CH2:73][CH2:72][C:71]6[CH:74]=[CH:75][CH:76]=[CH:77][C:70]=6[NH:69][C:68]5=[O:78])[CH2:65][CH2:66]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
(S)-2-(1,4-Dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (54 mg, 0.123 mmol) was dissolved in N,N-dimethylformamide (1.5 ml). N,N-Diisopropylethylamine (100 μL, 0.574 mmol) was added to the mixture followed successively by TBTU (42 mg, 0.131 mmol) and then 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (43 mg, 0.175 mmol). Reaction stirred at room temperature for 4 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 54% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.85 (s, 1H) 8.50 (s, 1H) 7.32 (s, 1H) 6.96-7.11 (m, 3H) 6.80 (s, 1H) 5.26 (s, 2H) 4.44-4.54 (m, 1H) 4.27-4.37 (m, 1H) 4.06 (d, J=14.04 Hz, 1H) 3.79-3.96 (m, 2H) 3.34-3.44 (m, 2H) 3.05-3.25 (m, 3H) 2.82-3.02 (m, 4H) 2.45-2.66 (m, 2H) 2.28-2.40 (m, 1H) 2.04-2.26 (m, 4H) 1.80-1.95 (m, 2H) 1.58-1.73 (m, 2H) 1.40-1.57 (m, 1H) 1.18 (bs, 6H). High resolution MS m/e (M+H)+=666.2756.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[CH:11])=[CH:4][N:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[C:11][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: C#Cc1cnc(N)c(C#N)n1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nc(C#Cc2ccc(C(F)(F)F)cc2)cnc1N

Procedure:
A solution of 3.2 grams (0.022 mole) of 2-amino-3-cyano-5-ethynylpyrazine, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst)of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture is filtered to remove a solid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is triturated with methylene chloride and filtered. The filtrate is subjected to column chromatography on silica gel. Elution is accomplished using methanol/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[(4-trifluoromethylphenyl)ethynyl]pyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:5][C:6]=1[CH3:7].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:5][C:6]=1[CH3:7]
Reactant: COC(CNCc1cc(Br)c(C)s1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COC(CN(Cc1cc(Br)c(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-((4-bromo-5-methylthiophen-2-yl)methyl)-2,2-dimethoxyethanamine (14.5 g, 49 mmol) was dissolved in DCM (100 ml) and TEA (14 ml, 99 mmol) was added. The reaction was cooled to 0° C. with an ice bath and 4-tosyl chloride (8.5 ml, 59 mmol) was added portionwise. The reaction was allowed to warm up to RT and stirred overnight. The reaction was then diluted with DCM and water. The layers were separated and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30 to 70% EtOAc in hexanes to give N-((4-bromo-5-methylthiophen-2-yl)methyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide as light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30]>>[OH:31][C:29]([C:28]([F:33])([F:32])[F:27])=[O:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2csc(-c3ccc(F)cc3)n2)CC1
Reactant: O=C([O-])C(F)(F)F
Product: Fc1ccc(-c2nc(CN3CCNCC3)cs2)cc1
Product: O=C(O)C(F)(F)F

Procedure:
This compound was synthesized from tert-butyl 4-((2-(4-fluorophenyl)thiazol-4-yl)methyl)piperazine-1-carboxylate as described for example 46 step 4 (43 mg, crude) as a trifluoroacetate salt and it was carried through without further purification. MS (ESI) m/z: Calculated for C14H16FN3S: 277.10. found: 278.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][CH:12]([CH3:14])[C:11](=O)[C:10]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26]O>>[CH2:1]([O:8][N:9]1[CH2:13][C:12]([CH3:14])=[C:11]([NH:18][C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:26])[C:10]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(OCc2ccccc2)C(=O)C1=O
Reactant: CNCc1ccccc1
Reactant: CO
Product: CC1=C(N[C@H](C)c2ccccc2)C(=O)N(OCc2ccccc2)C1
Yield: 78 %

Procedure:
1-Benzyloxy-4-methylpyrrolidin-2,3-dione (7.8 g, 35.6 mmol) and R-(+)-.varies.-methylbenzylamine (8 ml, 7.5 g, 62 mmol) were stirred in methanol (250 ml) at 55° C. for 14 h then refluxed for 4 h. The mixture was then cooled, evaporated and purified by flash chromatography, eluting with hexanes: ethyl acetate (4:1 v/v) to give (R)-1-benzyloxy-4-methyl-2-oxo-3-(1-phenylethylamino)-2,5-dihydropyrrole (8.95 g, 78%) as a slightly yellow oil. 1H NMR (360 MHz, CDCl3) δ7.2-7.5 (10 H, m, Ph's), 5.00 (2 H, s, OCH2), 4.64 (1 H, q, J=6.8 Hz, NCH), 4.1 (1 H, br s, NH), 3.50 (1H, d, J=16.2 Hz, NCHAHB), 3.43 (1 H, d, J=16.2 Hz, NCHAHB), 1.60 (3 H, s, CH3CCH2), 1.45 (3 H, d, J=6.8 Hz, CH3CHPh), m/z (CI, NH3) 323 (M+ +H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=3[C:22]3C(OC)=NC=[CH:26][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C=CC(C(N)=O)=CC=3C3CC3)CC3CC(CC(C3)C1)C2.CS(Cl)(=O)=O.[CH3:59][N:60]([CH3:65])[S:61](Cl)(=[O:63])=[O:62]>>[C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:19][S:61](=[O:63])(=[O:62])[N:60]([CH3:65])[CH3:59])=[O:18])=[CH:15][C:14]=3[CH:22]3[CH2:26][CH2:27]3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)S(=O)(=O)Cl
Agent: CS(=O)(=O)Cl
Agent: NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzamide and methanesulfonyl chloride with dimethylsulfamoyl chloride, the title compound was obtained as a colorless solid (0.19 g, 34%): 1H NMR (300 MHz, CDCl3) δ 8.65 (br s, 1H), 7.64-7.56 (m, 1H), 7.41-7.35 (m, 1H), 6.85-6.77 (m, 1H), 3.57 (s, 2H), 3.01 (s, 6H), 2.19-2.08 (m, 1H), 2.02 (br s, 3H), 1.79-1.58 (m, 12H), 0.99-0.91 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z: 431.2 (M−1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19](N(OC)C)=[O:20])#[N:2].[CH3:25][Mg]Br.CCOCC>O1CCCC1>[C:19]([C:4]1[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6]2[C:11]([C:3]=1[C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:20])[CH3:25]
Reactant: CON(C)C(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-cyano-1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (90 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added 3.0 M methylmagnesium bromide in ether (0.93 mL, 2.8 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-15% EtOAc/hexane) to give the desired product (43 mg, 56%). LCMS calculated for C17H12FN2O(M+H)+: m/z=279.1. Found: 279.0.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:13][CH2:14][Mg+].[Br-].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C1COCC1>[NH2:2][C:1]1([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CC[Mg+]
Agent: FB(F)F
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C2(N)CC2)cc1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Methyl 4-cyanobenzoate (2.6 kg, 16.1 mol) was dissolved in 40 L of toluene at −25° C. and Ti(Oi-Pr)4 (4.73 L, 16.1 mol) was added over 5 min, followed by EtMgBr (10.5 L of a 3.07M solution in THF, 32.3 mol) over 2 hr. After aging for 30 min, BF3.OEt2 (4.1 L, 32 mol) was added over 40 min and the mixture was aged for another 40 min. The reaction was quenched by the addition of 40 L of 3N HCl. The layers were separated and the aqueous layer was washed with 13 L toluene. The aqueous layer was then extracted with 2-MeTHF (2×26 L and 2×13 L). The combined 2-MeTHF layers were washed with 3N NaOH and the pH of the NaOH layer adjusted to 9 before separation of the layers. The organic layer was washed with 13 L of brine. Yield=43%. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 2H), 7.35 (d, 2H), 3.95 (s, 3H), 1.25 (t, 2H), 1.10 (t, 2H).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH2:17][C:18](=O)[CH3:19])/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10].[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[C:21]([CH:23]([CH:18]([CH3:19])[CH2:17][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
In 200 ml. of benzene was dissolved 50 g. of geranyl acetone, and then 42 g. of ethyl cyanoacetate, 6 g. of ammonium acetate and 6 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours while removing the produced water. The reaction mixture was washed with water and dried. To this was added dropwise a solution of 5.7 g. of sodium borohydride in 40 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 60 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was then removed by evaporation and the residue was purified by silica gel column chromatography to obtain 59 g. of the desired oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:18](OC(=O)C)(=O)[CH3:19].[Cl:25]([OH:29])(=[O:28])(=[O:27])=[O:26]>>[Cl:25]([O-:29])(=[O:28])(=[O:27])=[O:26].[CH3:17][O:16][C:14]1[O:15][CH2+:18]([CH3:19])[C:6]2[C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:13]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CC(=O)OC(C)=O
Product: COC1=Cc2cc(OC)c(OC)c(OC)c2[CH2+](C)O1
Product: [O-][Cl+3]([O-])([O-])[O-]
Yield: 67 %

Procedure:
To a stirred and cooled (ice-bath) solution of 24.8 grams methyl 3,4,5-trimethoxyphenyl-acetate (0.103 mol) in 51.8 grams acetic anhydride (0.508 mol) was slowly added 70% perchloric acid (14 ml, 0.163 mol) over a 20 minute period. The cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled again in an ice-bath and 600 ml diethyl ether was added with stirring. The orange crystalline perchlorate salt that precipitated was isolated by filtration, washed with diethyl ether and dried to provide 25.3 grams of Compound 8c (67.2% yield) having a melting point of 160°-162° C. (with decomposition).
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=[O:12].C(O)(=O)C>CO.O>[OH:12][N:11]=[C:14]1[CH:19]=[CH:18][C:17](=[C:8]([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:9]#[N:10])[CH:16]=[CH:15]1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: N#CCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: N#CC(=C1C=CC(=NO)C=C1)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
9.5 g of KOH are dissolved in 50 ml of methanol. To the solution are added 5 g (41 mmol) of thiophene-2-acetonitrile followed by 4.2 ml (41 mmol) of nitrobenzene. After the reaction mixture is stirred at room temperature for 2 hrs, 200 ml of water are added with stirring. The resulting solution is acidified by addition of 30 ml of acetic acid in 25 ml of water, leading to a dark orange precipitate. The mixture is then filtered, and the solid is washed with a mixture of methanol and water, and methanol. The crude product is dried in air and recrystallized from toluene. 4.7 g (50%) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-thiophen-2-yl-acetonitrile are obtained in the form of a dark orange powder having a melting point of 151-155° C. (dec.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:26]3[C:25]4[N:24]=[C:23]([NH:27][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[N:22]=[CH:21][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:33]([NH2:35])=[O:34])=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C.O=[Pt]=O>[CH:28]1([NH:27][C:23]2[N:22]=[CH:21][C:20]3[CH2:19][CH2:18][C:17]4[C:16]([C:33]([NH2:35])=[O:34])=[N:15][N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[C:26]=4[C:25]=3[N:24]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: NC(=O)c1nn(C2CCN(Cc3ccccc3)CC2)c2c1CCc1cnc(NC3CCCC3)nc1-2
Agent: O=[Pt]=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=O)c1nn(C2CCNCC2)c2c1CCc1cnc(NC3CCCC3)nc1-2
Yield: 80 %

Procedure:
500 mg (1.1 mmol) of 1-(1-benzylpiperidin-4-yl)-8-(cyclopentylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 50 mL of acetic acid and 50 mg of PtO2 were added. The mixture was submitted to hydrogenation at 60 psi at room temperature. After 12 hors the catalyst was filtered on celite and the filtrate evaporated. The residue was redissolved with dicholoromethane and washed with aqueous NaHCO3. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The title compound (80% yield) was collected by filtration after trituration with diethylether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cccc(-c2cccc(N)c2)c1
Yield: 67.2 %

Procedure:
Iron (35 g, 625.00 mmol, 5.02 equiv.) was added to a solution of methyl 3′-nitrobiphenyl-3-carboxylate (32 g, 124.40 mmol, 1.00 equiv.) in ethanol (300 mL) and water (50 mL). At about 50° C., acetic acid (38 g, 633.33 mmol, 5.09 equiv.) was added dropwise to the stirred solution. The solution was heated at reflux for about 60 minutes. After filtering the solution, the filtrate was concentrated in vacuo, and then water (250 mL) and ethyl acetate (250 mL) was added. The organic phase was separated and the mother liquid was extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:7)) to give the title product as a light yellow solid (19 g, yield=67%). 1H NMR (300 MHz, CDCl3) δ: 8.28 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.29 (m, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.97 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]C)=O)[CH2:3][CH2:2]1.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]([C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[NH2:14]
Reactant: COC(=O)CN1CCOCC1
Reactant: CNN
Solvent: CCO
Product: CN(N)C(=O)CN1CCOCC1
Temperature: 95 °C
Yield: 49.6 %

Procedure:
In a 25 mL, sealed tube, methyl 2-morpholinoacetate (0.5 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Methylhydrazine (0.16 g, 1.1 eq.) was introduced dropwise at RT and the reaction mixture was refluxed at 95° C. for 48 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude N-methyl-2-morpholinoacetohydrazide (0.27 g) which was used without further purification in the following step.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CC#N>[N+:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of 2-phenyl-5-nitroindole (prepared as described in J. Org. Chem. (1966), 31(1), 65-9) (1.5 g; 6.3 mmol) in CH3CN (50 ml) was added K2CO3(1.7 g; 12.6 mmol). To the mixture thus obtained was then added dropwise ethyl 4-bromobutanoate (3.3 g; 16 mmol) and the resulting mixture was heated to 120° C. under stirring for 18 hours. After cooling, the mixture was poured into water (500 ml) and the crude product was filtered, dried under vacuum to give ethyl 4-(5-nitro-2-phenyl-1H-indol-1-yl)butanoate which was used in the following reaction without any further purification.
Reaction SMILES: CC(F)(F)F.C([Cl:11])C(F)(F)F.[CH2:12]([Cl:17])[C:13]([Cl:16])([F:15])[F:14].[CH:18]([C:21]([F:24])(F)[F:22])([Cl:20])[Cl:19].C(C(Cl)(Cl)Cl)(F)(F)F.CC(F)(F)Cl>>[CH2:12]([Cl:17])[C:13]([Cl:16])([F:15])[F:14].[CH:18]([Cl:20])([Cl:19])[C:21]([Cl:11])([F:24])[F:22]
Reactant: FC(F)(F)C(Cl)Cl
Reactant: FC(F)(F)CCl
Agent: CC(F)(F)Cl
Agent: CC(F)(F)F
Agent: FC(F)(Cl)CCl
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Product: FC(F)(Cl)C(Cl)Cl

Procedure:
An alternative approach to HCFC's is the chlorination of fluorocarbons such as CH3CF3 (HFC-143a). For example, McBee (Industrial and Engineering Chemistry, Vol. 39, pp. 409-412 (1947)) reported that vapor phase chlorination of HFC-143a afforded a mixture of HCFC-133a, HCFC-132b, CHCl2CF3 (HCFC-123), and the fully chlorinated CF3CCl3 (CFC-113a). McBee also reported the chlorination of CH3CClF2 (HCFC-142b) to give HCFC-132b, HCFC-122, and the fully chlorinated CClF2CCl3 (CFC-112a). Again, using this technique --CH2Cl and --CHCl2 groups dominate the attainable substitution pattern.