Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[C:3]1([CH3:12])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([NH2:11])=[NH:10])[CH:4]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>C(O)C>[C:3]1([CH3:12])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[NH:10][C:13](=[O:20])[CH2:14][C:15](=[O:16])[N:11]=2)[CH:4]=1
Reactant: Cc1cccc(C(=N)N)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(C2=NC(=O)CC(=O)N2)c1

Procedure:
To a stirred solution of 35.8 g. of sodium metal in one liter of absolute ethanol, there is added 88.5 g. of m-toluamidine hydrochloride followed by the dropwise addition of 91.5 g. of diethyl malonate over a fifteen minutes period. The reaction mixture is heated under reflux for four hours. The solution is filtered and the filter cake dissolved in water. The ethanol filtrate is evaporated to dryness and the solid residue added to the water solution. Upon acidification of the aqueous solution to pH2 with concentrated hydrochloric acid, a solid separates which is removed by filtration. After washing this material several times with water, the product is recrystallized from aqueous N,N-dimethylformamide to afford 2-(3-tolyl)-4,6-(1H,5H)-pyrimidinedione, m.p. 247.5°c.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCCO
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCCO

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and ethanolamine.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][C:22](I)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.O>CN(C)C=O.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>[OH:29][CH2:26][C:27]#[C:28][C:22]1[N:23]=[CH:24][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:21]=1
Reactant: Ic1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCC#Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of 1-trityl-3-iodo-1,2,4-triazole (26.24 g, prepared as described in Example 5), propargyl alcohol (3.56 ml) and triethylamine (40 ml) in dry N,N-dimethylformamide (750 ml) was treated successively with tetrakis(triphenylphosphine)palladium (2.77 g) and cuprous iodide (1.0 g). It was stirred for four hours at room temperature under nitrogen and allowed to stand overnight but the reaction had not proceeded to completion. Stirring was continued for a further four periods of seven hours, then the mixture was poured into water (11) and extracted with chloroform (5×250 ml). The extracts were dried over magnesium sulphate, evaporated under reduced pressure and chromatographed on silica, using ethyl acetate-hexane (4:1) as eluant. Trituration with ether gave 1-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)prop-2-yne (12.20 g). Recrystallisation from chloroform gave material m.p. 211° C. NMR (CDCl3): δ 4.45(2H,s), 7.1-7.3(15H,m), 7.95(1H,s). 13C NMR provided confirmation. M/S: M+ 365.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[C:9]3[N:10]=[C:11]([C:17]4[N:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=[N:19][N:18]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:22]([N:21]1[CH:20]=[N:19][N:18]=[C:17]1[C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:7]3[CH:6]=[C:5]([CH2:3][OH:2])[CH:26]=[CH:25][C:8]=3[C:9]=2[N:10]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(c1)OCCc1sc(-c3nncn3C(C)C)nc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CO)ccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid methyl ester (620 mg, 1.67 mmol) in THF (12 mL) at 0° C. was added LiAlH4 (152 mg, 4.02 mmol). The reaction mixture was stirred for 4 hours at RT before being quenched with H2O (0.15 mL), 15% NaOH(aq) (0.15 mL) and H2O (0.45 mL). The precipitate was removed by filtration, washing with methanol/DCM, and then the filtrate was concentrated in vacuo to yield the title compound as an orange solid (563 mg, 98%). LCMS: RT=3.71 min, [M+H]+=343
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=[O:4].[C:10]([O:13][CH2:14][CH3:15])(=[O:12])[CH3:11].[O-]CC.[Na+]>>[F:1][C:2]([F:9])([F:8])[C:3](=[O:4])[CH2:11][C:10]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)C(F)(F)F
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
Ethyl trifluoroacetate (142.1 g, 1.00 moles) is mixed with ethyl acetate (229.1 g, 2.60 moles) under nitrogen at 5-10° C. Sodium ethoxide (71.5 g, 1.05 moles) is added portion-wise at the same temperature. The addition is exothermic, bringing the temperature gradually to 40-55° C. The mixture is heated to 60-65° C. and kept at that temperature for 3 hours. GC indicates a conversion of 98.8%.
Reaction SMILES: C(O)C.Cl.[OH:5][C:6]1[C:7]([CH2:21][OH:22])=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH:11]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]2.[H][H]>[Pd].C(N(CC)CC)C>[OH:16][CH:12]1[C:13]2[C:8](=[C:7]([CH2:21][OH:22])[C:6]([OH:5])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]1[NH:17][CH:18]([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)NC1CCc2c(ccc(O)c2CO)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)NC1CCc2c(ccc(O)c2CO)C1O

Procedure:
In a mixture of 20 ml. ethanol and 2 ml. of triethylamine is dissolved 200 mg. of 6-hydroxy-5-hydroxymethyl-2-isopropylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride and, with the addition of 50 mg. of 5 % palladium-on-carbon, the solution is agitated in a current of hydrogen for 15 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The resiude is dissolved in tetrahydrofuran. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethanol-ethyl acetate. The procedure yields colorless crystals of 1,6-dihydroxy-5-hydroxymethyl-2-isopropylamino-1,2,3,4-tetrahydronaphthalene which is identical with the product according to the procedure of Example 71. Yield 108 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][C@@H:31]([CH3:35])[C@@H:32]([CH3:34])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH:12]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:34][C@@H:32]1[C@H:31]([CH3:35])[O:30][C:29]([C:27]2[NH:28][C:24]([C:9]3[CH:10]=[C:11]([OH:13])[CH:12]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:8]=3)=[CH:25][CH:26]=2)=[N:33]1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
(4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dimethyl-4,5-dihydro-1,3-oxazole (700 mg, 1.39 mmol) synthesized in Example (109b) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 2.00 mL, 2.00 mmol) was added at room temperature, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (420 mg, yield 88%) as a yellow liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:29]1([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=4[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
1-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 315) (52 mg), imidazole (27 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (18 mg, 31%).
Reaction SMILES: C1(N2CC(F)(F)C(=O)N(C)C3C=NC(NC4C=CC(C(O)=O)=C(F)C=4F)=NC2=3)CCCC1.[CH:33]1([N:38]2[CH2:44][C:43]([F:46])([F:45])[C:42](=[O:47])[NH:41][C:40]3[CH:48]=[N:49][C:50]([NH:52][C:53]4[CH:68]=[CH:67][C:56]([C:57]([NH:59][CH:60]5CCN(C)CC5)=[O:58])=[C:55]([F:69])[C:54]=4[F:70])=[N:51][C:39]2=3)[CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O.C(OCC)(=O)C.O>[CH:33]1([N:38]2[CH2:44][C:43]([F:46])([F:45])[C:42](=[O:47])[NH:41][C:40]3[CH:48]=[N:49][C:50]([NH:52][C:53]4[CH:68]=[CH:67][C:56]([C:57]([NH:59][CH3:60])=[O:58])=[C:55]([F:69])[C:54]=4[F:70])=[N:51][C:39]2=3)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)c(F)c2F)CC1
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)c(F)c3F)ncc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)c(F)c1F
Reaction time: 0.25 h

Procedure:
A mixture of 0.0804 g of the 2:1 mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-benzoic acid and 4-{4-[(2-carboxy-2,2-difluoro-ethyl)-cyclopentyl-amino]-5-methylamino-pyrimidin-2-ylamino}-2,3-difluoro-benzoic acid (from example 243) in 7 mL of dimethylformamide was treated with 0.1546 g (0.406 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.1558 g (1.206 mmole) of diisopropylethylamine. After 15 minutes, 0.0243 g (0.356 mmole) of methylamine hydrochloride in 1 mL of dimethylformamide was added. The reaction mixture stirred for 30 minutes and then diluted with 150 mL of ethyl acetate and 25 mL of water. The mixture was then washed successively with 20 mL of ammonium chloride, 20 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0411 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-N-methyl-benzamide (I-245) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10]C=C2[C:3]=1[CH:4]=[CH:5]C=[C:7]2[CH2:12][OH:13].CC1C=C(C(F)(F)F)C=CC=1B(O)O.C([O-])([O-])=O.[K+].[K+].[O:34]1CCO[CH2:36][CH2:35]1>CCOC(C)=O.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.O>[CH3:36][CH2:35][O:34][C:12]([CH3:7])=[O:13].[CH3:10][CH2:11][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1COCCO1
Reactant: OCc1cccc2c(Br)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCC
Temperature: 100 °C

Procedure:
(5-Bromonaphthalen-1-yl)methanol (165 mg), 2-methyl-4-trifluoromethylphenylboronic acid (170 mg, 1.2 eq.), Pd(PPh3)4 (80 mg, 0.1 eq.), and K2CO3 (288 mg, 3 eq.) were combined in a flask with 5 mL dioxane and 2.5 mL H2O and degassed. Reaction mixture was then refluxed at 100° C. overnight. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow oil (208 mg, 95% yield). 1H NMR (400 MHz) (CDCl3) δ 8.24 (d, J=8 Hz, 1H), 7.65-7.64 (m, 1H), 7.63-7.56 (m, 2H), 7.40-7.36 (m, 5H), 5.23 (s, 2H), 2.10 (s, 3H). 13C NMR (100 MHz) (CDCl3) δ144.16, 139.06, 137.81, 136.68, 131.92, 131.42, 130.74, 126.63, 126.51, 126.20, 125.82, 125.56, 123.73, 122.52, 122.48, 63.84, 20.06.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:10])[CH2:6][CH2:7][CH:8]=[O:9])(=[O:3])[CH3:2].[Cl-].[CH3:12][NH2+]C.C=O>>[C:1]([O:4][CH:5]([CH3:10])[CH2:6][C:7](=[CH2:12])[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: C[NH2+]C
Reactant: CC(=O)OC(C)CCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CC(C)OC(C)=O
Yield: 93.9 %

Procedure:
18.0 g (124.8 mmol) of 4-acetoxypentanal, 11.5 g (140.7 mmol) of dimethylammonium chloride and 11.0 ml (146 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The reaction mixture is allowed to cool and then extracted three times with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving 18.3 g of 4-acetoxy-2-methylene-pentanal as a colourless oil which is further reacted without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([Cl:17])=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(N)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (795 mg, 3.51 mmol) produced in Example D17(i) in N,N-dimethylformamide (15 mL) was added 1-chloropyrrolidine-2,5-dione (493 mg, 3.69 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 15 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (727 mg, 79%) as a yellow solid.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[C:17]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C1CCc2ccccc21
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2ccccc2C1=O
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
1-Indanone (1.5 g, 11.36 mmols) was dissolved in dry THF in a three neck flask equipped with nitrogen inlet, septum and a guard tube. The flask was cooled to -20° C. for 10 minutes. Then butyl lithium (11.37 ml, 12.48 mmols) was added dropwise through the septum using the syringe. The reaction mixture was allowed to stand at -20° C. for 45 minutes and then ethyl chloroformate (1.08 ml, 10 mmols) was added dropwise using a syringe. The reaction mixture was stirred at -20° C. for 30 minutes and slowly brought to room temperature in about one hour. The reaction was worked-up by evaporating the THF and the product was chromatographed to yield 2-carbethoxy-1-indanone. NMR: (CDCl3):δ:1.25 (t, 3H, OCH2CH3); 3.45 (d, 2H, benzylic CH2); 3.65 (t, 1H, COCHCO); 4.2 (q, 2H, OCH2CH3); 7.4-7.5 (m, 4H, Ar-H).
Reaction SMILES: [Cl:1][Si:2]([Cl:9])([Cl:8])[CH2:3][Si:4]([Cl:7])([Cl:6])[CH3:5].C(Cl)(Cl)(Cl)[Cl:11]>CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][Si:2]([Cl:9])([Cl:8])[CH2:3][Si:4]([Cl:7])([Cl:6])[CH2:5][Cl:11]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: ClC[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Reaction time: 12 h

Procedure:
120 g (0.46 mole) of 1,1,1,3,3-pentachloro-1,3-disilabutane and 1.2 g of a reaction initiator, AIBN in carbon tetrachloride as solvent were reacted in the same apparatus as Example 10. The obtained reactant was photoreacted for 12 hrs using sun lamp, while bubbling chlorine gas and refluxing carbon tetrachloride. The produced reaction mixture was distilled under vacuum to obtain 32 g of 1,1,1,3,3,4-hexachloro-1,3-disilabutane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:26][OH:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1
Reactant: NO
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Stir, at room temperature under argon, a mixture of 2.0 g of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, 1.26 g of hydroxylamine hydrochloride and 2.48 g of sodium acetate in 100 ml of ethanol. The following day, evaporate the reaction medium to dryness under vacuum, take the residue up with 100 ml of dichloromethane and wash with 100 ml of water. The organic phase is dried over magnesium sulphate and evaporated to dryness under vacuum. After drying at 40° C. under vacuum, we obtain 1.88 g of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E) in the form of a beige solid with the following characteristics:
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(COC)OC>[NH2:1][C:2]1([CH2:9][NH2:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(N)(C#N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CN1CCC(N)(CN)CC1
Yield: 85.6 %

Procedure:
A solution of 4-amino-4-cyano-1-methylpiperidine (3.60 g) in dry dimethoxyethane was added to mechanically stirred suspension of LiAlH4 (3.0 g) in dry dimethoxyethane under nitrogen atmosphere, at such a rate that the temperature didn't rise over 50° C. At the end of the addition the mixture was heated under reflux for 6 hr. Excess LiAlH4 was destroyed by adding to the cold (0° C.) stirred reaction mixture, under nitrogen, 4M NaoH (10 ml), water (3 ml), saturated NaOH solution (10 ml) and water (5 ml). The organic solvent was separated and the aqueous phase was extracted several times with hot THF. The organic solvent which was separated and the THF extracts were combined, dried (Na2SO4) and the solvents were removed to give the title compound as a viscous oil (3.17 g) which was purified by distillation b.p. 60°-62° C. (0.8 mm).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=S)[CH2:2][CH3:3].C(O)(=[O:31])C>O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:31])[CH2:2][CH3:3]
Reactant: CC(=O)O
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: O
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 0.5 h

Procedure:
Mercuric acetate (0.38 g) is added with stirring to a solution of N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (0.6 g) in acetic acid (10 cc), and stirring is continued for 4 hours 30 minutes at a temperature in the region of 20° C. The black reaction mixture is diluted with distilled water (25 cc) and ethyl acetate (50 cc), and then filtered and alkalinized with stirring with 4 N aqueous sodium hydroxide solution to pH 13. After settling ha taken place, the organic phase is separated and the aqueous phase is extracted with ethyl acetate (20 cc). The combined organic phases are washed successively with saturated aqueous sodium chloride solution (50 cc). After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C., the residual yellow oil (0.43 g) is dissolved in ethanol (2 cc) and then treated with a solution of fumaric acid (0.14 g) in ethanol (5 cc), concentrated to half the volume under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and treated with ethyl ether (20 cc). After 2 hours' stirring at a temperature in the region of 20° C., the solid formed is drained and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-Propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide acid fumarate (0.38 g) is thereby obtained in the form of a pale yellow solid, m.p. 75-80° C. (melts forming a paste).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[C:11]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[N:14][N:13]([CH3:19])[C:12]=2[S:20]([NH2:23])(=[O:22])=[O:21]>C(#N)C>[CH3:6][N:4]([CH3:5])[CH:3]=[N:23][S:20]([C:12]1[N:13]([CH3:19])[N:14]=[C:15]2[C:11]=1[C:10]([OH:9])=[CH:18][CH:17]=[CH:16]2)(=[O:21])=[O:22]
Reactant: COC(OC)N(C)C
Reactant: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1c2c(O)cccc2nn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
21.3 g (174 mmol) of dimethylformamide dimethylacetal was dropwise added to a solution containing 33 g (145 mmol) of 4-hydroxy-2-methyl-2H-indazole-3-sulfonamide in 200 ml of acetonitrile, at room temperature. The mixture was stirred for one hour, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, then concentrated and purified by column chromatography to obtain 35.2 g (yield: 86.3%) of the desired product. Melting point: 118°-119° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[Na].[CH3:11][OH:12]>>[NH2:1][C:2]1[C:7]([O:12][CH3:11])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CO
Agent: [Na]
Product: COc1nc(Br)cnc1N

Procedure:
2-Amino-3,5-dibromopyrazine (7 g.) is boiled for about 9 hours with 0.65 g. sodium in 18.5 ml. methanol to give 2-amino-3-methoxy-5-bromopyrazine.