Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5][CH3:6].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.Cl[CH2:28]Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH:5]([CH3:28])[CH3:6]
Reactant: CC[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC
Reactant: OB(O)c1ccsc1
Reactant: ClCCl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc(-c2ccsc2)cc1)C(C)C
Yield: 1273.1 %

Procedure:
A mixture of (2R)-(4-bromobenzenesulfonylamino)butyric acid methyl ester (9.911 g, 2.6 mmol), 3-thiopheneboronic acid (1.0 g, 7.81 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (0.117 g, 0.14 mmol) and tribasic potassium phoshate (2.21 g, 10.4 mmol) in 20 mL of dimethoxyethane is heated at reflux for 16 h. The reaction is cooled and concentrated, and the residue is suspended in 100 mL of dichloromethane. The insolubles are removed by filtration and the filtrate is concentrated. Chromatography on silica gel (eluant; 1/9—EtOAc/hexane) affords 0.63 g (68%) of 3-methyl-(2R)-[4-(thiophen-3-yl)benzenesulfonylamino]butyric acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=[O:8].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][CH2:23]Cl.O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:21][O:22][CH3:23])[CH:4]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(OC)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxysalicylaldehyde (7.54 g) and N-ethyl diisopropylamine (17 ml) in dichloromethane (250 ml) was cooled to 0° C., to which was added dropwise chloromethyl methyl ether (6.0 ml). The mixture was then warmed up to room temperature, which was stirred overnight. To the reaction mixture was added water to quench the reaction, which was subjected to extraction with chloroform. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 4-methoxy-2-methoxymethoxy benzaldehyde (8.82 g) (Compound B-4), whose physico-chemical properties are shown in Table 5.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[CH2:26][CH3:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:26]([C:3]1[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]
Reactant: OB(O)c1ccccc1
Reactant: CCc1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 53.6 %

Procedure:
Using tert-butyl {[5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.13 g), phenylboronic acid (462 mg), sodium carbonate (789 mg) and tetrakis(triphenylphosphine)palladium (431 mg), a procedure as in Reference Example 56 was performed to give the title compound as a brown oil (yield 602 mg, 54%).
Reaction SMILES: [C:1]([C:3]1([C:37]([O:39]C(C)(C)C)=[O:38])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][N:26]=5)[C:21](=[O:28])[C:20]([C:29]([NH:31][CH:32]5[CH2:34][CH2:33]5)=[O:30])=[CH:19]4)[CH:13]=3)=[CH:8][CH:7]=2)[C:4]1([CH3:36])[CH3:35])#[N:2]>C(Cl)Cl.FC(C(O)=O)(F)F.CSC>[C:1]([C:3]1([C:37]([OH:39])=[O:38])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][N:26]=5)[C:21](=[O:28])[C:20]([C:29]([NH:31][CH:32]5[CH2:34][CH2:33]5)=[O:30])=[CH:19]4)[CH:13]=3)=[CH:8][CH:7]=2)[C:4]1([CH3:36])[CH3:35])#[N:2]
Reactant: CC(C)(C)OC(=O)C1(C#N)C(c2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)C1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CC1(C)C(c2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)C1(C#N)C(=O)O

Procedure:
The ester from step 3 (1 eq) in CH2Cl2-TFA-DMS (3:2:1, 0.2M) was stirred at rt for 48 h. The volatiles were evaporated, the residue triturated in ether and then isolated by filtration to afford the title compound as a white solid.
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].Cl>O.C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([C:18]#[N:19])=[N:3][OH:4]
Reactant: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
85% Potassium hydroxide (0.40 g, 6 mmol), toluene (5 ml) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.26 g, 5 mmol). The mixture was stirred at room temperature for 8 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with hydrochloric acid, extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide (1.30 g, Yield: 92.84, E/Z=15/85).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:19][S:20]([NH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:22])=[O:21].[NH:34]1[C:42]2[C:37](=[CH:38][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:40][N:41]=2)[CH:36]=[CH:35]1>>[CH3:19][S:20]([NH:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([C:39]4[CH:38]=[C:37]5[CH:36]=[CH:35][NH:34][C:42]5=[N:41][CH:40]=4)=[N:7][C:6]=3[C:8]=2[CH3:12])[CH:30]=1)(=[O:22])=[O:21]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Product: Cc1c(-c2cccc(CNS(C)(=O)=O)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (50 mg) was coupled to 3-methanesulphonylamino methyl benzeneboronic acid, and then reacted with 7-azaindole-5-boronic acid pinacol ester via General Procedure F. The product was purified by reverse phase HPLC to yield 34.5 mg of 424. MS (Q1) 535.2 (M)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:31])[CH3:30])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:33])([CH3:32])[C:5]1=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:56][CH:57]([F:61])[C:58](O)=[O:59]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:56][CH:57]([F:61])[C:58]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:30])[CH3:31])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:32])([CH3:33])[C:5]1=[O:34])=[O:59]
Reactant: CC(C)N(C(=O)c1ccc2c(c1)N(CCN)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)c1ccc2c(c1)N(CCNC(=O)C(F)F)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To tert-butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (300 mg) were added WSC (210 mg), HOBt (150 mg), triethylamine (0.30 ml), chloroform (5 ml), and difluoroacetic acid (79 mg), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (170 mg) as colorless amorphous.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[IH:11]>C(Cl)Cl>[I:11][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: I
Reactant: CSc1nc(C)nc(Cl)n1
Solvent: ClCCl
Product: CSc1nc(C)nc(I)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
A mixture of 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (2110 mg, 12.01 mmol) and 67% hydriodic acid solution (2.260 mL, 30.0 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 3 h. The solid was filtered off and washed with CH2Cl2. The solid was treated with sat. aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give crude product as a yellow solid. This was purified by silica gel chromatography eluting with 50% CH2Cl2/hexanes to give 2-iodo-4-methyl-6-(methylthio)-1,3,5-triazine (2.1 g, 7.86 mmol, 65.4% yield). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H); 2.51 (s, 3H). m/z (ESI, +ve ion) 267.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:27][S:28]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([Cl:38])=[O:37])=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][N:11]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Fc1ccc(NCCN(CCc2ccccc2)Cc2ccccc2)cc1
Product: CS(=O)(=O)Nc1ccc(C(=O)N(CCN(CCc2ccccc2)Cc2ccccc2)c2ccc(F)cc2)cc1
Product: Cl

Procedure:
In a manner similar to Example 1 react N-(4-fluorophenyl)-N'-(2-phenylethyl)-N'-phenylmethyl-1,2-ethanediamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].Cl>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 90 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (-)-2-[2-[(dipropylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 90% of theory. Colourless crystals, m.p. 164°-165° C. (acetonitrile); [α]D20 =-7.62° (dilute aqueous hydrochloric acid).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].I[CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>CS(C)=O.CO>[CH:32]([O:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: CC(C)CC[C@H](CO)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)CC[C@H](COC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Powdered KOH (375 mg, 6.68 mmol) was taken up in dry DMSO (1 ml) at RT under N2. The mixture was stirred for 10 minutes before the addition of {(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl acetic}acid (Step 1, 67 mg, 0.167 mmol) in dry DMSO (0.5+0.5+0.5 ml), followed by 2-iodopropane (0.334 ml, 3.34 mmol). After 24 hr MS further 2-iodopropane (0.334 ml, 3.34 mmol) was added and the reaction was maintained at RT for 3 days. The reaction was quenched with saturated aqueous NH4Cl and then partitioned between DCM and H2O. The aqueous layer was extracted with DCM (×3). The combined extracts were evaporated and the residue was diluted with MeOH and loaded on to a SCX cartridge (2 g). The cartridge was eluted with MeOH to wash off the DMSO, then 2N NH3 in MeOH to elute the products. The NH3/MeOH fractions were combined and evaporated. The residue was taken up in MeOH (2 ml) and 4N NaOH (aq, 0.2 ml, 0.8 mmol) was added. The mixture was stirred and heated to 60° C. for 2 hrs. After cooling to RT the MeOH was removed in vacuo and the residue was partitioned between DCM and H2O. 2N HCl (0.5 ml) was added. The pH of the aqueous layer was adjusted to ˜7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase HPLC (ABZ+ column) to give the title compound (10 mg) as a colourless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH:4](C)[CH3:5].BrC[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:18]1COCC1>CCCCCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:10]([O:7][CH:3]([CH3:18])[CH2:4][CH3:5])=[O:17])[CH3:16]
Reactant: CC(C)CO
Reactant: CCOC(=O)CC(=O)CBr
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)OC(C)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sodium hydride dispersion in mineral oil, 160.0 grams (60%, 4.0 moles) was placed in a 12 L round bottom flask equipped with mechanical stirrer, thermometer, addition funnel and nitrogen inlet. The flask was cooled with an ice bath and 3.5 L of dry THF added with sting, while maintaining the temperature below 20° C. To the suspension of stirred sodium hydride was added 376.4 grams (4.0 moles) of iso-butanol dissolved in 0.3 L of THF. The addition was carried out over about 2 hrs. at such a rate so as to maintain the temperature below 10° C. The mixture was then allowed to warm to room temperature and stired for 1 hour. To the re-cooled solution, over the course of 1 hour, was added 418 grams (2.0 moles) of ethyl 4-bromoacetoacetate (A. Svendsen, and P. M. Boll, Tetrahedron 1973 29, 4251-4258) dissolved in 0.3 L of THF. The rate of addition was controlled so as to keep the temperature below 10° C. The ice bath was removed and the brown slurry stirred overnight at room temperature. The reaction was quenched by pouring into 2.2 L of 1.0 N hydrochloric acid and the phases separated. The aqueous phase was extracted with 0.5 L of diethyl ether; the combined organic phase washed with 1.0 L of saturated brine and dried over MgSO4. After filtering and removal of solvent 830 g of a red-brown oil was obtained. The product was dissolved in 0.4 L of hexane and applied to a column of 8.0 L of silica wet-packed in hexane. The column was eluted with 4.0 L of hexane; 8.0 L of 3:1 hexane to diethyl ether and 12.0 L of 2:1 hexane to diethyl ether. The second fraction, 459.3 gram, was reapplied to a column of 4.0 L of silica wet-packed in hexane. The column was eluted with 3.0 L of 95:5 hexane to diethyl ether; 2.0 L of 9:1 hexane to diethyl ether; 2.0 L of 4:1 hexane to diethyl ether and 12.0 L of 3:1 hexane to diethyl ether. The major fraction was bulb-to-bulb distilled using a Kugelrohr apparatus and an oven temperature of 40-45° C. at <1.0 torr. The desired product was obtained as an oil, 145.9 gram (33%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH3:15][C@@H:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:17]1([C@H:16]([N:23]2[C:10](=[O:11])[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH3:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](c1ccccc1)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 180 °C
Yield: 72.7 %

Procedure:
386 mg of 3-nitrophthalic anhydride and 242 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 430 mg of the desired product as a light yellow powder. Yield: 73%. m.p. 115-117° C.; MS(EI+) 296(M)+
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=2)=[CH:22][N:21]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=2)=[CH:22][N:21]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: COc1ccnc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Solvent: CCO
Product: COc1ccnc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)c1

Procedure:
Reaction of 2-[3-(dimethylaminomethyl)benzylthio]ethylamine with 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone in refluxing ethanol gives 2-[2-(3-(dimethylaminomethyl)benzylthio)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone which when reacted with boron tribromide gives 2-[2-(3-(dimethylaminomethyl)benzylthio)ethylamino]-5(4-hydroxy-2-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][NH:3]1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].C(N(CC)CC)C.[OH:31][C:32]1[CH:33]=[C:34]([CH:39]=[N:40][NH:41]C(OC(C)(C)C)=O)[CH:35]=[CH:36][C:37]=1[OH:38]>C(OCC)(=O)C.ClCCl>[OH:31][C:32]1[CH:33]=[C:34]([CH:39]=[N:40][NH:41][S:18]([NH:21][C:22]([N:3]2[CH2:4][C@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[O:1])=[O:23])(=[O:20])=[O:19])[CH:35]=[CH:36][C:37]=1[OH:38]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(O)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NN=Cc2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.61 g (30 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 90 ml of ethyl acetate was added 2.62 ml (30 mmol) chlorosulfonyl isocyanate, and the mixture was stirred for one hour at room temperature. After the addition of 45 ml of dichloromethane, the solution was cooled to 0° C., and 12.54 ml (90 mmol) of triethylamine was added, followed by solution A. The mixture was stirred over the weekend at room temperature and the precipitate filtered off by suction. To the filtrate were added 100 ml of ice water, and the mixture was washed two times with ethyl acetate. The aqueous phase was adjusted to pH 2 by adding 2N hydrochloric acid and extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with ether, filtered off by suction and dried in vacuo; yield: 5.58 g.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C[N:13]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20]C=1)[S:14]([CH3:17])(=[O:16])=[O:15].[Cl:33][C:34]1[CH:35]=[C:36]([CH:49]=[CH:50][CH:51]=1)[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[O:47][CH3:48]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:49]=[CH:50][CH:51]=1)[O:37][C:38]1[CH:43]=[CH:42][C:41]([C:4]2[CH:3]=[C:2]([CH:22]3[CH2:23][CH2:18][N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:20][CH2:21]3)[N:10]3[C:5]=2[C:6]([NH2:11])=[N:7][CH:8]=[N:9]3)=[CH:40][C:39]=1[O:47][CH3:48]
Reactant: CN(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: COc1cc(B(O)O)ccc1Oc1cccc(Cl)c1
Product: COc1cc(-c2cc(C3CCN(S(C)(=O)=O)CC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1

Procedure:
By the same procedure as Example 14, Example 15 and Example 16 in series using 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (1.71 mg) instead of the compound prepared in Example 5, N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide instead of 3-methoxyphenylboronic acid, and 4-(3-chlorophenoxy)-3-methoxyphenylboronic acid instead of the compound prepared in Example 10, the title compound having the following physical data was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: COc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
The compound was prepared analogous to Example 1 from 2-chloro-8-(4-methoxyphenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 196°-199° C.) and piperazine.