Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(Cl)OC(Cl)(Cl)Cl.[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:26][C@H:27]1[C@H:30]([S:31][CH3:32])[NH:29][C:28]1=[O:33].C1OC1C>C(Cl)Cl.C(N(CC)CC)C.CN(C=O)C>[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([NH:26][C@H:27]2[C@H:30]([S:31][CH3:32])[NH:29][C:28]2=[O:33])=[O:22])[N:18]=1)=[O:12]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CS[C@@H]1NC(=O)[C@H]1N
Agent: CC1CO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1SC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.228 g of DMF in 5 ml of methylene chloride is added at -10° C. 0.137 ml of diphosgene. The mixture is then stirred for 30 minutes at room temperature, to which is added at a temperature of -70° C. 15 ml of methylene chloride solution containing 0.80 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methyoxyiminoacetic acid and 0.316 g of triethylamine. The mixture is stirred for two hours at -25° C., then cooled to -70° C., followed by addition of 0.632 g of triethyl amine, 0.69 g of tosyl salt of (3R,4S)-3-amino-4-methylthio-2-oxoazetidine and 2 ml of propylene oxide. The temperature of the mixture is raised up to 0° C. in the course of one hour, while stirring. The mixture is stirred for further two hours at the same temperature, then concentrated, followed by addition of THF and removal of the resulting insolubles by filtration. The filtrate is concentrated and the residue is purified on a silica-gel column (AcOEt:CHCl3 :CH3OH=3:3:1) to yield 0.461 g of (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCCC2)C1
Yield: 96.3 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrolidin-3-yloxy-carbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), cyclohexanone (0.11 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 90 mg (96%) of the title compound.
Reaction SMILES: Cl.[N:2]1([CH:6]2[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1>CO>[N:2]1([CH:6]2[CH2:7][CH2:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:22][CH2:23]2)[CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCC3)CC2)CC1
Agent: Cl
Solvent: CO
Product: C1CN(C2CCC3(CCNCC3)CC2)C1

Procedure:
Hydrogen chloride in methanol (1.25 mol/l, 15.5 ml) was added to tert-butyl 9-(azetidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 3.24 mmol), and the mixture was refluxed for 45 min. The solvent was removed in vacuo and the residue was dissolved in a small amount of ethanol. A solid was then precipitated by addition of acetone, and finally diethyl ether was added and the resulting precipitate was filtered out with suction. Yield: 0.87 g (95%)
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][C:10](=[O:13])[C:9]([CH:14]=[O:15])=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:22]([CH3:25])([O-:24])=[O:23].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>O1CCCC1.C(O)(C)(C)C.CO.C(OCC)(=O)C.O>[C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([CH:14]=[O:15])[CH:8]2[CH2:25][N+:22]([O-:24])=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC1=CC(c2ccccc2)(c2ccccc2)CCC1=O
Reactant: C[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: O
Product: O=CC1C(=O)CCC(c2ccccc2)(c2ccccc2)C1C[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of 4,4-diphenyl-2-formyl-2-cyclohexen-1-one (29 g) and nitromethane (5.7 cc) in a mixture of tetrahydrofuran (250 cc) and tert-butanol (500 cc) is treated with a 35% strength solution (6.93 cc) of benzyltrimethylammonium hydroxide in methanol and stirred at 20° C. for 18 hours. The reaction mixture is diluted with ethyl acetate (500 cc) and water (2000 cc) and acidified to pH 2 with hydrochloric acid. The aqueous phase is extracted with ethyl acetate (200 cc) and the combined organic phases are washed with water (500 cc) and saturated sodium chloride solution (250 cc), then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The crystallized residue is stirred in a mixture (100 cc) of cyclohexane and ethyl acetate (80:20 by volume) and the crystals are drained and washed with the same mixture (20 cc) and with isopropyl ether (2×50 cc). 4,4-Diphenyl-2-formyl-3-(nitromethyl)cyclohexanone (24.7 g) is obtained in the form of cream-colored crystals, m.p. 188° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O.NC1C2C3C(CCC=3C=CC=2)=CC=1.[C:36]1([NH:42][C:43]2[C:53]3[C:54]4[C:46]([CH2:47][CH2:48][C:49]=4[CH:50]=[CH:51][CH:52]=3)=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[Cu].C1(C)C=CC=CC=1>[C:2]1([N:42]([C:43]2[C:53]3[C:54]4[C:46]([CH2:47][CH2:48][C:49]=4[CH:50]=[CH:51][CH:52]=3)=[CH:45][CH:44]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccc3c4c(cccc24)CC3)cc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: Nc1ccc2c3c(cccc13)CC2
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Temperature: 200 °C
Reaction time: 26 h
Yield: 75.7 %

Procedure:
33.85 g (0.2 mol) of 5-aminoacenaphtthene was mixed with 102.1 g (0.5 mol) of iodo benzene, 1.3 g (0.02 mol) of copper powder, 34.5 g (0.25 mol) of anhydrous potassium carbonate and 100 ml of nitrobenzene, and the mixture was stirred at 200° C. for 26 hours. The reaction was determined to be finished when disappearance of 5-aminoacenaphthene and 5-(N-phenylamino)acenaphthene as an intermediate was identified. 300 ml of toluene was added thereto to dissolve a product, and the resultant mixture was filtrated and concentrated. The concentrated product was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4) to obtain 48.7 g (yield: 75.7%, melting point: 168.5°-170.5° C.) of 5-(N,N-diphenylamino)acenaphthene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC[P:19]([Cl:21])[Cl:20])C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][P:19]([Cl:21])[Cl:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCc1ccccc1
Reactant: ClP(Cl)CCCc1ccccc1
Product: ClP(Cl)CCc1ccccc1

Procedure:
This compound was prepared from 2-phenylethylbromide (230g, 1.24 mole) by the method described above for the preparation of 3-phenylpropylphosphonous dichloride. 2-Phenylethylphosphonous dichloride was obtained as a pungent colourless liquid (115g, 45%), b.p. 64-66 at 0.001 mm.
Reaction SMILES: Cl.CN.[OH-].[K+].[CH3:6][C:7]([CH3:19])([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:11])[CH3:8].[C:20]([BH3-])#[N:21].[Na+].Cl>CO>[CH3:6][C:7]([CH3:19])([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:21][CH3:20])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
Methylamine hydrochloride (2.36 g) is dissolved in methanol (50 ml) and potassium hydroxide pellets (0.60 g) and N-(1,1-di-methylethoxycarbonyl)-4-piperidone are added. Sodium cyanoborohydride (0.69 g) in methanol (5 ml) is added and the mixture is stirred 2 hrs. Potassium hydroxide pellets (1.96 g) are added to the mixture which is stirred 1 hr and acidified to pH 2 with 6M hydrochloric acid and concentrated. The mixture is diluted with water (50 ml) and extracted with ether (3×80 ml) which is discarded. The aqueous layer is basified to pH 11 with potassium hydroxide pellets, saturated with sodium chloride and extracted with ether (6×80 ml). The combined organic extracts are dried with magnesium sulfate and concentrated to afford an oil which is chromatographed on silica gel with a methanol/chloroform gradient (5-30%). Fractions are pooled on the basis of TLC (Rf =0.13, 20% methanol/chloroform) to give the title compound, NMR (CDCl3) 4.04, 2.79, 2.54, 2.46, 2.33, 1.88, 1.46, and 1.26 δ.
Reaction SMILES: C([C:3]([CH2:8][OH:9])([CH2:6]O)CC)O.[C:10]([OH:14])(=[O:13])C=C.C(O)(O)CCCCC.C(O)(=O)CCCCC(O)=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].C1C=CC(C(N=C=O)[N:77]=C=O)=CC=1.[N-]=C=O.[N-]=C=O.O=C1CC(C)(C)CC(C)=C1>>[C:8]([OH:9])(=[O:13])[CH:3]=[CH2:6].[NH2:77][C:10]([O:9][CH2:8][CH3:3])=[O:14]
Reactant: CCC(CO)(CO)CO
Reactant: O=C=NC(N=C=O)c1ccccc1
Agent: C=CC(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: CCCCCC(O)O
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CCOC(N)=O
Reaction time: 5 h

Procedure:
661.9 g of the ethylene oxide polyether started from trimethylolpropane esterified with 2 mol acrylic acid (12 mol ethylene oxide per mol trimethylolpropane) and 164.4 g of a polyester polyol from hexanediol and adipic acid (OH number 314, equivalent weight 178.5 g), 1.0 g 2,6-di-tert-butyl-4-methyl-phenol and 1.0 g tin octoate were initially introduced into the reaction vessel. 148.8 g Desmodur® T80 (toluylene diisocyanate, commercial product of Bayer AG, Leverkusen) were metered in at 50 to 60° C. After a further 5 h 31.6 g isophorone-diisocyanate were metered in. The reaction was carried out at 60° C. for a further 5 h and 74.0 g of the ethylene oxide polyether started from trimethylolpropane esterified with 2 mol acrylic acid (12 mol ethylene oxide per mol trimethylolpropane) were then added. The reaction was subsequently carried out at 60° C. until the NCO content of the solution was less than 0.10 wt. %.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[C:2]#[CH:3].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-2].[Mg+2]>CC(N(C)C)=O>[CH2:18]([O:17][C:15]([CH2:14][N:4]([CH2:1][C:2]#[CH:3])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:16])[CH3:19]
Reactant: C#CCNc1cccc(C#N)c1
Reactant: CCOC(=O)CBr
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Product: C#CCN(CC(=O)OCC)c1cccc(C#N)c1

Procedure:
A mixture of 0.78 g (5 mmol) of 3-propargylamino-benzonitrile, 0.55 ml (5 mmol) of ethyl bromoacetate and 0.2 g (5 mmol) of magnesium oxide are stirred in 20 ml of dimethylacetamide for 6 days at 75° C. Then the mixture is filtered, the filtrate is diluted with ethyl acetate and washed with water. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([CH3:37])([CH3:36])[C:30]#[C:31][CH:32]=[CH:33][CH2:34]O>ClCCl>[Br:1][CH2:34][CH:33]=[CH:32][C:31]#[C:30][Si:29]([CH3:37])([CH3:36])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)C#CC=CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
N-Bromosuccinimide (85.3 g, 0.48 mol) was added in portions to a nearly homogeneous solution of triphenylphosphine (128.2 g, 0.49 mol) and 5-trimethylsilylpent-2-en-4-yn-1-ol (72.5 g, 0.47 mol) in dichloromethane (600 mL) under nitrogen and cooled in a dry ice/2-propanol bath to an initial temperature of below −20° C. The internal temperature of the reaction mixture was maintained at −10° C. to 0° C. throughout the addition by adjusting the rate of addition. The bath was allowed to warm to ambient temperature. After 2 hours, the reaction was complete. The reaction mixture was concentrated under vacuum to a thick paste and the residue was triturated with hexane (250 mL). The suspension was filtered and the solids and silica gel were rinsed with hexane (10×150 mL). The filtrate was concentrated under vacuum (30° C./60 mtorr) to obtain 44 g (89% yield) of 1-bromo-5-trimethylsilylpent-2-en-4-yne, a compound of formula (P), as a pale yellow oil:
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20].[H-].[K+]>C1COCC1>[CH2:2]([CH:3]([O:6][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 3-pentanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 4-(1-ethyl-propoxy)-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[CH2:25]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:28]#[CH:29])[CH3:26].C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:26]#[C:25][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[N:21][CH:20]=1
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc2nnc(CNc3ccnc4cc(OC)cnc34)n2n1)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an argon flushed pressure vial (15 mL) was added copper (I)iodide (0.0070 g, 0.037 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 mmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.050 g, 0.15 mmol), and triethyl(ethynyl)silane (0.13 ml, 0.73 mmol) in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol). The vial was sealed and stirred at room temperature overnight The solution was concentrated and purified by MPLC (eluted with 0-10% (90:10:1 DCM:MeOH:NH4OH)) to yield the product as a light yellow solid. MS m/z=446.1 [M+1]+. Calc'd for C23H27N7OSi: 445.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.O>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:11]#[N:12]
Reactant: COc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)cc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in dry DMF (45 mL) was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried, and concentrated to give 20.0 g (91% yield) of the product as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J=10.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J=8.8 Hz, 8.4 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:20][N:21]([CH:34]=[C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36](OCC)=[O:37])[C:22]1[S:26][C:25]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:20][N:21]1[CH:34]=[C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36](=[O:37])[C:23]2[N:24]=[C:25]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[S:26][C:22]1=2
Reactant: CCOC(=O)C(=CN(C)c1cnc(CN2CCOCC2)s1)C(=O)OCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)nc2c1=O
Temperature: 110 °C
Yield: 27.9 %

Procedure:
A mixture of Eaton's Reagent (1.5 mL) and diethyl 2-((methyl(2-(morpholin-4-yl-methyl)-1,3-thiazol-5-yl)amino)methylene)malonate (Preparation 29, 452 mg) is heated to 110° C. for 20 min. with a stream of nitrogen over the reaction. The mixture is cooled to ambient temperature and transferred to a cooled beaker. The solution is diluted with ice chips and neutralized by dropping Na2CO3 into the solution. The mixture is then extracted with CH2Cl2 (3×50 mL), the organic layer dried (MgSO4), and the solvent is removed. The residue is purified by column chromatography (eluent 5% MeOH/CH2Cl2) to afford 111 mg (28%) of the title compound as a brown solid. Physical characteristics: 1H NMR (CDCl3) δ1.39, 2.67, 3.77, 3.89, 3.90, 4.38, 8.25; IR (diffuse reflectance) 1726, 1716, 1679, 1632, 1614, 1609, 1586, 1507, 1330, 1300, 1236, 1194, 1113, 863, 801 cm−1. Anal. Found (C15H19N3O4S.0.75 H2O): C, 51.34; H, 5.94; N, 11.88.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[C:6](/[CH:13]=[CH:14]/[O:15][CH3:16])[N:5]=1.Cl>O.O1CCCC1>[Br:3][C:4]1[NH:8][C:7]([C:9]([OH:11])=[O:10])=[C:6](/[CH:13]=[CH:14]/[O:15][CH3:16])[N:5]=1
Reactant: CO/C=C/c1nc(Br)[nH]c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CO/C=C/c1nc(Br)[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.20 g lithium hydroxide in 175 ml of water is added to a solution of 3.50 g methyl 2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylate in 140 ml of tetrahydrofuran. The solution is stirred for 4 h at ambient temperature. Then 92 ml aqueous 1 M hydrochloric acid are added, and the solution is cooled in the ice bath. The precipitate is separated off, washed with water and dried.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1ccc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2c1
Yield: 12 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 1.06 g (3.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6-methoxyquinazoline was used in place of 4-chloro-6,7-dimethoxy-quinazoline. As a result, 154.4 mg (yield: 12%) of Compound 84 was obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:18]([O:20]CC)=O.C(O)(=O)C.[CH:27](N)=[NH:28]>C(O)C>[O:20]=[C:18]1[NH:28][CH:27]=[N:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:12]=3)[NH:4][C:3]1=2
Reactant: N=CN
Reactant: CCOC(=O)c1ccc(-c2cc(N)c(C(=O)OCC)[nH]2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc3nc[nH]c(=O)c3[nH]2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of ethyl 3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylate (3.36 g), formamidine acetate (1.74 g) and ethanol (60 mL) was heated under reflux for 15 hrs. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 60° C. to give the title compound (2.97 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[CH3:15][O:16]C(Cl)Cl.Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[CH:15]([C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])=[O:16]
Reactant: COC(Cl)Cl
Reactant: COC(=O)CCc1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OC)c(C=O)c1
Temperature: -20 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
Methyl 3-(4-methoxyphenyl)propanoate (500 mg, 2.56 mmol) was dissolved in 30 mL of anhydrous dichloromethane. TiCl4 (2.1 mL, 19 mmol) and MeOCHCl2 (0.81 mL, 9.0 mmol) were added subsequently at −20° C. under Argon. The reaction mixture was stirred at −20° C. for 6 hours. Then the reaction mixture was slowly poured into a diluted hydrochloric acid solution. The dichloromethane layer was separated and washed with water followed by brine then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Then the crude residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10) to obtain methyl 3-(3-formyl-4-methoxyphenyl)propanoate (ss-2) as a colorless oil (429 mg, 75% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.O>ClCCl>[CH3:8][N:9]([CH3:40])[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(-c2ccc3c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C)c1ccc(-c2ccc3c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c3c2)cc1

Procedure:
Trifluoroacetic acid (4.00 ml, 54 mmol) was added to a suspension of tert-butyl 2-(7-(4-(dimethylamino)phenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.057 g, 0.13 mmol) in dichloromethane (2.00 ml). After stirring at room temperature for 10 min water was added and the solution loaded in SCX MEGA BE column. The column was flushed with methanol extensible followed by 2M ammonia in methanol. The fractions obtained from the ammonia in methanol were collected and the solvent removed in vacuo. The residue was treated with 5N NaOH (2 ml) in THF (1 ml) and stirred at room temperature for 1 hour. The suspension was acidified with 5N HCl and the solids collected by filtration. The solids were washed with water, ether, dried in a vacuum oven at 50° C. to afford green solids (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1F
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2k (210 mg, 0.650 mmol), 6-mercaptopurine monohydrate (122 mg, 0.715 mmol), K2CO3 (99 mg, 0.715 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 240 mg of an off-white solid (84%), mp 244.0° C. 1H NMR (DMSO-d6) δ 13.56 (br s, 1H); 8.50 (s, 1H); 8.45 (s, 1H); 7.81 (t, J=8.0 Hz, 1H); 7.74 (t, J=7.7 Hz, 1H); 7.67 (d, J=8.1 Hz, 1H); 7.62 (d, J=7.7 Hz, 1H); 7.46-7.55 (m, 1H); 7.29-7.42 (m, 2H); 4.47-4.59 (m, 2H). 13C NMR (DMSO-d6) ppm: 158.4, 157.3 (d, J=249 Hz), 156.4, 153.8, 151.0, 149.1, 143.2, 135.0, 132.9, 131.8 (d, J=8.0 Hz), 130.8, 129.9, 126.7, 125.3 (d, J=3.5 Hz), 123.6 (d, J=13 Hz), 117.0, 116.2 (d, J=19 Hz), 31.7. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS: C, 54.74; H, 2.76; Cl, 8.08; N, 19.15; S, 7.31. Found: C, 54.42; H, 2.88; Cl, 8.08; N, 18.87; S, 7.08.