Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C[CH2:19][O:20]CC.C([Li])CCC.CN(C)C=O>O>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C=Cc2csc3ccccc23)s1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a chilled (-70° C.), stirred solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (16.98 g) and ether (300 ml) was added n-butyllithium (23 ml of a 2.5M solution in hexanes), under nitrogen, over 5 mins. After stirring for 1.5 hrs, the mixture was added via canula to a solution of N,N-dimethylformamide (19.3 g) and ether (500 ml). The mixture was allowed to warm to room temperature, stirred overnight, and then poured into water (500 ml). The aqueous phase was separated, and the organic phase was washed with 10% aqueous hydrochloric acid, water, and 5% aqueous sodium bicarbonate solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give 14.9 g of solid. A lot of similarly prepared material (4.1 g) was combined with the solid, and the combined material was purified by high performance liquid chromatography (silica gel, loaded and eluted with 10% hexane in dichloromethane). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to give 9.25 g (51%) of product, mp 105°-107° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:31]([N:17]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCCCCCSC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCCCCCCCCSC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from dodecyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-thiocarboximidate and benzoyl chloride, there is obtained dodecyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]-azepine-6-thiocarboximidate as a resin, mass spectrum m/e: M+ 526 (23), 357 (18), 194 (94), 105 (100);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37].O>C(Cl)Cl>[C:36](=[O:37])([O:38][CH3:39])[O:17][C:16](=[O:18])/[CH:15]=[CH:14]/[C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])=[N:11][C:12]=1[CH:19]([CH3:20])[CH3:21]
Reactant: COC(=O)Cl
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)OC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl](2E)-propenoic acid (5 g, 0.012 m) was dissolved in methylene chloride (25 ml) and triethylamine (1.54 g, 0.015 m) was added at 25° C. The mixture was cooled to 0° C. and methyl chloroformate (1.31 g, 0.013 m) was added to the reaction mass slowly over a period of 10 min keeping the temperature below 5° C. The reaction mixture was stirred at 0-5° C. for 30 min and water (25 ml) was added to it. The organic layer was separated and washed with aqueous sodium bicarbonate solution (5% w/v, 20 ml) followed by water (20 ml). Methylene chloride was distilled out under reduced pressure at 40-45° C. to obtain the product as an oily mass, which was crystallized from n-hexane to obtain while crystalline solid (Yield: 5.4 g, 98%).
Reaction SMILES: ClCl.[CH:3](=[N:10][OH:11])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1.[C-:12]#[N:13].[K+]>CCOCC.C(Cl)Cl.CO>[N:10](=[C:3]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)[C:12]#[N:13])[OH:11]
Reactant: ON=CC1CCCCO1
Reactant: [C-]#N
Agent: ClCl
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: N#CC(=NO)C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
7.8 g of chlorine were passed into a cooled solution of 12.9 g of 2-formyltetrahydropyran oxime in 140 ml of ether at below 0° C. Thereafter, the volatile constituents of the reaction mixture were stripped off, the residue was taken up in 200 ml of methylene chloride, and the mixture was kept at room temperature for 24 hours. This liquid was then added dropwise to a suspension, cooled to 10°-15° C., of 6.8 g of potassium cyanide in 75 ml of methanol, and the mixture was stirred for a further 3 hours at room temperature. The precipitated potassium chloride was filtered off under suction, the filtrate was evaporated down, the residue was taken up in ether, the solution was washed three times with water and dried over magnesium sulfate, and the solvent was stripped off under 0.005 mbar and at 30° C. to give 11.3 g of α-oximino(tetrahydropyran-2-yl)-acetonitrile as a yellowish solid which melted from 45° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[I:10]I>C(O)C.CCOC(C)=O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:1][C:2]1[CH:7]=[C:6]([I:10])[C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1
Reactant: II
Reactant: Nc1ccc(Br)cc1F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1c(F)cc(Br)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
(4-bromo-2-fluorophenyl)amine (6 g) was dissolved in ethanol (200 mL), silver sulfate (10.8 g) was added and then iodine (8.8 g) was added in small portions. After the addition was complete, the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and evaporated to leave a dark oil which was taken up in EtOAc, washed with saturated sodium thiosulphate (100 mL×2), sodium carbonate solution (100 mL×2) and water. The organic layer dried over anhydrous Na2SO4 and evaporated. The crude product was purified by column chromatography to give (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (8.6 g) as a yellow solid. MS (ES): C6H4BrFIN requires 315; found 315.9 (M+H+).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](N)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].N([O-])=[O:16].[Na+]>C(O)(=O)C.O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:16])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=N[O-]
Reactant: C=CCn1cnc2nc(N)[nH]c(=O)c21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 7-allyl-2-amino-1H-purin-6(7H)-one (20 g, 104.7 mmol) in acetic acid (500 mL) and water (70 mL) was added a solution of sodium nitrite (30 g, 434.8 mmol) in water (70 mL) dropwise at 50° C. The reaction was stirred at 50° C. for 1 h. The reaction was concentrated and poured into ice-water. The solids that formed were filtered and the filter cake was washed with water and ethanol, then dried under vacuum to give 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 74.4% yield) as yellow solid. LCMS retention time 0.555 min; LCMS MH+ 193.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][O:21][CH3:22])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CC(C)=O>[CH2:30]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:23])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][O:21][CH3:22])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCOc1ccc2c(c1)OCC(C)(c1ccc(O)cc1)C2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc2c(c1)OCC(C)(c1ccc(OCc3ccccc3)cc1)C2=O
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a mixture of 3-(4-hydroxyphenyl)-7-methoxymethyloxy-3-methylchroman-4-one (3.55 g, 11.293 mmol) and potassium carbonate (9.35 g, 67.76 mmol) in acetone (130 ml) was added benzyl bromide (5.795 g, 33.879 mmol) at room temperature and stirred overnight. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate=9:1 to 7:3) to give 4.59 g (yield: quant.) of the title compound as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:15])[CH2:7]1.[Br:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C=O>[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:18](=[O:19])[CH2:17][Br:16])=[CH:14][C:9]=2[S:8](=[O:15])[CH2:7]1
Reactant: CN1CS(=O)c2ccccc21
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN1CS(=O)c2cc(C(=O)CBr)ccc21

Procedure:
210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm3 ground-necked flask surmounted by a condenser, and 43 cm3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 33 g (0.20 mol) of 3-methylbenzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70° C. using an oil bath. 19.8 cm3 (0.24 mol) of bromoacetyl chloride are then added gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70° C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed with water until the filtrate is neutral and dried. The product is recrystallized in 95° strength alcohol.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[C:23][CH3:24]>CC(C)=O>[CH2:21]([O:13][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCBr
Reactant: CCCc1cc2c(cc1O)OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc2c(cc1CCC)CCO2
Temperature: 25 °C

Procedure:
Following the same procedure as in Example 3 c), a mixture of 5.0 g (0.026 moles) of 5-propyl-6-hydroxy-2,3-dihydrobenzofuran (title 93.5%), 3.9 g (0.028 moles) of anhydrous potassium carbonate in ml 30 of acetone was added with 3.7 g (0.028 moles) of 1-bromo-2-butyne: the mixture was heated to reflux for 6 hrs. After cooling to room temperature, the mixture was filtered and the filtrate evaporated u.v (20° C./21 mbar). The residue so obtained was purified by chromatography on silica column (eluant n-hexane/ethyl acetate 3/1 (v/v)). A liquid product (3.8 g, purity 96%) was obtained, whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [CH2:1]([CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26]>C(O)C.Cl.Cl.NNC(N)=N>[ClH:26].[ClH:26].[C:21]([NH:24][N:25]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH2:1][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[N:25][NH:24][C:21](=[NH:22])[NH2:23])[CH:4]=1)(=[NH:23])[NH2:22]
Reactant: O=Cc1cccc(OCCOc2cccc(C=O)c2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=Cc1cccc(OCCOc2cccc(C=NNC(=N)N)c2)c1
Yield: 78.5 %

Procedure:
3,3′-(ethylenedioxy)dibenzaldehyde (1.08 g), aminoguanidine hydrochloride (1.105 g), and aminoguanidine dihydrochloride (0.005 g) were heated in 96% ethanol (6.25 mL) for 18 hr under nitrogen. Cooling and filtration gave 1.428 g of 3,3′-(ethylenedioxy)dibenzaldehyde bis(amidinohydrazone) dihydrochloride, mp 264-6° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[F:19][C:20]1([F:41])[CH2:25][N:24]([C:26]([C:28]2[N:29]=[C:30]([CH:33]([CH3:35])[CH3:34])[S:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:21]1.C(N(CC)CC)C>C(#N)C>[F:41][C:20]1([F:19])[CH2:25][N:24]([C:26]([C:28]2[N:29]=[C:30]([CH:33]([CH3:35])[CH3:34])[S:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:40][CH2:39][N:38]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][OH:11])[CH:4]=3)[CH2:37][CH2:36]2)[O:21]1
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)cs1
Reactant: OCCc1cccc(CBr)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.21 g) was added to a mixture of (2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone trifluoroacetate (example 44, step b) (0.40 g) and triethylamine (0.37 mL) in acetonitrile (15 mL). The reaction mixture was stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.40 g.
Reaction SMILES: [CH:1]([O:14][C:15](=[O:44])/[C:16](/[C:19]1[N:20]=[C:21]([NH:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:22][CH:23]=1)=[N:17]\[OH:18])([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.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:52][C:53]#[N:54].C(OCC)C>CS(C)=O>[CH:1]([O:14][C:15](=[O:44])/[C:16](=[N:17]\[O:18][CH2:52][C:53]#[N:54])/[C:19]1[N:20]=[C:21]([NH:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:22][CH:23]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCCl
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
In 70 ml of dimethylsulfoxide was dissolved 11.9 g (0.02 mole) of (Z)-2-(2-tritylamino-4-thiazolyl)-2-(hydroxyimino)acetic acid benzhydryl ester and after adding thereto 2.76 g of a powder of potassium carbonate and 1.7 g (0.0225 mole) of of chloroacetonitrile, the mixture was allowed to react overnight at room temperature. After the reaction was over, the reaction mixture was poured into 150 ml of ice water, the product was extracted first with 150 ml of ethyl acetate and then with 100 ml of ethyl acetate. The organic layers were collected, and washed twice with 50 ml of water and then with 10 ml of a saturated aqueous sodium chloride solution. The ethyl acetate layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off to provide a caramel. To the caramel was added 100 ml of ethyl ether to powder the caramel. 11.5 g (yield: 90.7%) of (Z)-2-(cyanomethyloxyimino)-2-(2-tritylamino-4-thiazolyl)acetic acid benzhydryl ester was obtained. ##STR15##
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.C([N:21]([CH2:32][CH3:33])[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[CH3:30])C.[CH2:34]([N:41]1[CH2:45]C[CH:43](C#N)[CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([N:41]1[CH2:42][CH2:43][CH:33]([C:32]2[NH:21][C:22](=[O:31])[C:23]3[C:24]([CH:30]=2)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[CH2:45]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N#CC1CCN(Cc2ccccc2)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(C3CCN(Cc4ccccc4)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
A solution (400 mL) of diisopropylamine (26.9 g) in tetrahydrofuran was cooled to −5° C. and 1.57 M n-butyllithium hexane solution (154 ml) was added dropwise to the solution. After stirring at 0° C. for 30 min, the mixture was cooled to −78° C. and a solution (50 mL) of N,N-diethyl-2,3-dimethylbenzamide (45.1 g) in tetrahydrofuran was added dropwise. After stirring at −78° C. for 1 hr, a solution (50 mL) of 1-benzyl-3-cyanopyrrolidine (37.18 g) in tetrahydrofuran was added dropwise. After completion of the dropwise addition, the reaction mixture was heated to room temperature and the mixture was stirred overnight at room temperature. The mixture was further stirred under reflux for 1 hr and the reaction mixture was concentrated to about half. Water and methylene chloride were added and the organic layer was partitioned, washed with water, dried over magnesium sulfate and concentrated, The obtained residue was purified by column chromatography (ethyl acetate) to give (±)-3-(1-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (66.38 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N+]=[N-])[C:5](=[O:10])[CH2:6][CH2:7][CH:8]=[CH2:9]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]12[CH2:9][CH:8]1[CH2:7][CH2:6][C:5]2=[O:10])=[O:13]
Reactant: C=CCCC(=O)C(=[N+]=[N-])C(=O)OC
Solvent: c1ccccc1
Product: COC(=O)C12CC1CCC2=O
Yield: 59316.3 %

Procedure:
In argon atmosphere, 2-diazo-3-oxo-6-heptenoic acid methyl ester (34 g, 0.187 mmol) was dissolved in benzene (300 ml). An acetyl acetone-copper complex (1 g) was added to the solution. The mixture was stirred for one night under refluxing. After cooling it, the solvent was distilled off under a reduced pressure. The residue was purified by a distillation to obtain 17.1 g of 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester. Yield: 60%. Boiling point: 83° to 85° C/0.3 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][C:19]1[CH:27]=[C:26]([O:28]C)[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:17][CH2:18][C:19]4[C:20](=[CH:24][CH:25]=[C:26]([OH:28])[CH:27]=4)[C:21]3=[O:22])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: COc1ccc(C(=O)Cl)c(CCCl)c1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2)C1

Procedure:
According to Method A, [1-(4-amino-phenyl)-pyrrolidin-3-yl]-dimethylamine was reacted with 2-(2-chloroethyl)-4-methoxy-benzoyl chloride. The dihydroisoquinolinone thus obtained was treated with hydrogen bromide according to Method L. In this way the product was obtained with molecular weight 351.45 (C21H25N3O2); MS (ESI): 352 (M+H+).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][C:7]=1[CH3:16].C([O:20][CH2:21][C:22]([N:24]=[C:25]([N:28]([CH3:37])[N:29]=CC1C=CC=CC=1)SC)=O)(=O)C.Cl>C1(C)C=CC=CC=1>[OH:20][CH2:21][C:22]1[N:24]=[C:25]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]2[S:10][C:6]([CH:2]=[O:3])=[C:7]([CH3:16])[CH:8]=2)[N:28]([CH3:37])[N:29]=1
Reactant: CSC(=NC(=O)COC(C)=O)N(C)N=Cc1ccccc1
Reactant: Cc1cc(CCCCN)sc1C1OCCO1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(CCCCNc2nc(CO)nn2C)sc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
A mixture of 4-[5-(1,3-dioxolan-2-yl)-4-methyl-2-thienyl]-butanamine (2.73 g) and methyl N-[2-(acetoxy)acetyl]-1-methyl-2-(phenylmethylene)-hydrazinecarboximidothioate (3.38 g) was heated to 60° for 2 h. Toluene (20 ml) and 5N hydrochloric acid (12 ml) were added and the mixture stirred at room temperature for 18 h. The mixture was basified to pH 8, washed with toluene, basified to pH 10 and extracted with ethyl acetate. The extract was evaporated to give an oil which was purified by column chromatography on silica using 3:1 ethyl acetate:methanol as eluent to give the title compound as a pale yellow solid (0.6 g) m.p. 118°-121° (softens).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29]C(C)(C)C)=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[CH3:41][N:42](C)[C:43](Cl)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([N:42]([CH3:43])[CH3:41])=[O:29])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[1-tertbutyloxycarbonyl-4-piperidinylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reaction with dimethylcarbamoyl chloride and triethylamine. Melting point: 187°-188° C.; Rf : 0.59 (alumina; petroleum ether/ethyl acetate/methanol=10:10:2)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.O.[NH2:13][NH2:14].N>Cl>[NH:13]1[CH:2]=[CH:3][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:1])=[N:14]1
Reactant: Oc1ccnc2ccccc12
Reactant: NN
Agent: Cl
Agent: N
Solvent: O
Product: Nc1ccccc1-c1cc[nH]n1

Procedure:
1.1. 10.0 g of 4-quinolinol in 30g of hydrazine hydrate are heated to 170° C. in an autoclave for 6 h. After cooling, the reaction mixture is dissolved in aqueous hydrochloric acid (total volume of the solution about 300 ml, pH about 1). Then, the mixture is made slightly alkaline (pH about 9) with concentrated aqueous ammonia solution. The separated crystals are filtered off and dried. There are obtained 8.0 g of 2-(1H-pyrazol-3-yl)aniline of m.p. 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][NH:18][CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]([S:33]([CH3:32])(=[O:35])=[O:34])[CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CNCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN(C)S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 12.9 %

Procedure:
To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (150 mg, 0.367 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by methanesulfonyl chloride (38 μL, 0.5 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (21.3 mg, 13% yield). 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.58 (2H, s), 4.29 (2H, s), 3.71 (2H, t, J=5.8 Hz), 3.38 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.89 (3H, s), 2.78 (3H, s). HRMS calcd for C17H22Cl2N3O5S (M+H): 450.0657. found: 450.0658.