Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)/[CH:14]=[CH:15]\[O:16][CH2:17][CH3:18])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2](/[CH:14]=[CH:15]\[O:16][CH2:17][CH3:18])=[CH:7][N:6]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Clc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCO/C=C\c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (800 mg), CIS-tributyl[2-ethoxyethenyl] tin (1.80 g), PdCl2(PPh3)2 (30 mg), and toluene (10 mL) was stirred under a nitrogen atmosphere at an outside temperature of 100° C. for 4 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge KP-NH: 28 g, mobile phase: n-hexane/EtOAc=100/0 to 85/15 (v/v)) to yield 2-chloro-5-[(Z)-2-ethoxyethenyl]pyrimidine (250 mg, colorless solid).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:20])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Yield: 87 %

Procedure:
1-Ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (15 g, 63.8 mmol) was dissolved in POCl3 (100 mL), and the resulting solution was heated at reflux for 4 h. The remaining POCl3 was removed via evaporation under reduced pressure. The residual light brown solid was recrystallized from EtOH-hexane to afford the title compound as a white solid (14 g, 55.3 mmol, 87%): HPLC (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.84 minutes showed a purity of 96%; LRMS (m/z) 254 (MH+).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[S:17][C:13]=3[CH:12]=2)[CH:2]=1.[CH3:28][S:29](O)(=[O:31])=[O:30]>CCO>[CH3:28][S:29]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([CH2:10][N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)[CH:27]=[CH:26][C:14]=2[N:15]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)O
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CCO
Product: CS(=O)(=O)O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 55 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a suspension of (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (1.84 g, 4.88 mmol) in EtOH (100 mL) was added methanesulfonic acid (478 mg, 4.98 mmol) at rt. The reaction mixture was stirred at 55° C. for 2 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was diluted with 15 mL of water and freeze dried overnight to give (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol methanesulfonate as a tan solid (2.32 g, 100%). 1H NMR (300 MHz, MeOH-d4) δ 8.80 (s, 1H), 8.50 (dd, J=1.1, 4.7 Hz, 1H), 8.15 (dd, J=1.1, 8.1 Hz, 1H), 7.82 (s, 1H), 7.36-7.59 (m, 3H), 5.68 (s, 2H), 3.40-3.65 (m, 2H), 2.71 (s, 3H), 2.06 (d, J=12.2 Hz, 2H), 1.79 (d, J=6.6 Hz, 2H), 1.24-1.55 (m, 4H). LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].[Cl:25][C:26]([CH2:28]Cl)=[CH2:27]>CN(C=O)C>[Cl:25][C:26](=[CH2:27])[CH2:28][N:4]([CH2:3][CH:2]([OH:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[S:5]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: C=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CN(CC(O)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-2), 10.0 g, 31 mmol) was placed in a flame-dried 500 mL round bottom flask and dissolved in anhydrous DMF (100 mL). The resulting solution was cooled to −10° C. and treated with NaH (0.9 g, 37 mmol). The resulting bright orange suspension was stirred 30 min at −10° C. 2,3-dichloropropene (3.9 mL, 40 mmol) was added neat dropwise and the reaction immediately turned dark brown. N-Tetrabutylammonium iodide (100 mg, catalytic) was added and the reaction was removed from the ice/acetone bath and warmed to 25° C. The reaction was stirred overnight prior to, quenching with 5% NH4Cl (200 mL) and extraction with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×100 mL) and NaCl (sat. aq.) prior to drying with MgSO4 and filtration. Concentration under reduced pressure produced an amber oil that was purified by flash column chromatography (SiO2, 0-60% EtOAc/hexanes gradient over 30 min) to yield N-(2-chloroprop-2-enyl)-N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-3) as a light orange oil. 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.34 (m, 5H), 5.36 (s, 2H), 5.01 (dd, J=8.0, 4.0 Hz, 1H), 4.25 (d, J=16.2 Hz, 1H), 4.10 (d, J=16.2 Hz, 1H), 3.42 (m, 2H), 2.80 (br s, 1H); MS 379.3 found 379.8 (M−H2O) required.
Reaction SMILES: Cl[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[NH2:28][C:29]([NH2:31])=[S:30]>C(O)C>[NH2:31][C:29]1[S:30][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:28]=1
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CCl
Reactant: NC(N)=S
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(=N\OC1CCCCC1)c1csc(N)n1
Yield: 90 %

Procedure:
Ethyl 4-chloro-(Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (0.68 g) was dissolved in ethanol (6 ml) and N,N-dimethylaniline (0.30 g) and thiourea (0.19 g) added with stirring. After 18 h the mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography eluting with ethyl acetate/hexane gave the title compound as a cream solid (0.66 g, 90%). A sample was crystallised from cyclohexane, m.p. 133°-4° C.; νmax (CHCl3) 2940, 1730, 1605 cm-1 ; δH (CDCl3) 1.34 (3H, t), 1.3-2.0 (10H, br m), 4.3 (1H, br m), 4.36 (2H, q), 5.4 (2H, br s, exch D2O), and 6.68 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:5][CH2:4][CH2:3]1.S(Cl)([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[Cl:29][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:16]=2[F:25])=[C:7]([C:6]2[C:2]([CH3:26])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a solution of 66.53B (0.2574 g, 0.706 mmol) in dry DCM (10 mL) and dry DMF (0.07 mL) was added thionyl chloride (0.11 mL, 1.51 mmol)at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.53C (242.8 mg, 90% yield). 1H NMR (400 MHz, CDCl3) 6 ppm 7.60 (2H, m), 7.40 (1H, m), 7.35 (2H, m), 7.21 (1H, m), 5.52 (1H, td, J=2.4, 0.9 Hz), 4.66 (2H, m), 2.24 (2H, td, J=7.0, 2.3 Hz), 1.68 (2H, m), 0.84 (6H, s).
Reaction SMILES: [OH:1][CH:2]([CH3:33])[CH2:3][N:4]([CH2:29][CH:30]([OH:32])[CH3:31])[C:5]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([O:1][CH:2]([CH3:33])[CH2:3][N:4]([CH2:29][CH:30]([O:32][S:35]([CH3:34])(=[O:37])=[O:36])[CH3:31])[C:5]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[O:8])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CN(CC(C)O)c1c(C(=O)NCCOC2CCCCO2)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: CC(CN(CC(C)OS(C)(=O)=O)c1c(C(=O)NCCOC2CCCCO2)cc([N+](=O)[O-])cc1[N+](=O)[O-])OS(C)(=O)=O
Yield: 100 %

Procedure:
Reaction of 18 with MsCl as above gave 1-methyl-2-[{2-[(methylsulfonyl)oxy]propyl}-2,4-dinitro-6-({[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}carbonyl)anilino]ethyl methanesulfonate (19) (2.52 g, 100%): as a yellow foam; which was used directly for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: Cc1nc(C(=O)N2CCCC(C)C2CN)c(-c2ccc(F)cc2)s1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chloro-5-(trifluoromethyl)pyridine, and K2CO3 in DMAC was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a pale yellow oil which solidified. MS (ESI) 493.01 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1>>[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][C:2]3[N:7]=[C:6]([NH:15][C:14]4[CH:16]=[CH:17][C:18]5[O:19][CH2:20][CH2:10][O:11][C:12]=5[CH:13]=4)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:13][C:12]=2[O:11]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=3.6 Hz), 7.23 (d, 1H, J=2.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.00 (dd, 1H, J=3 and 8.1 Hz), 6.98 (dd, 1H, J=3 and 8 Hz), 6.83 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.7(s, 1H), 6.58 (s, 1H), 4.23 (m, 4H), 4.24(m, 4H); 19F NMR (CDCl3): δ −47445; LCMS: ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C(Cl)Cl>[C:1]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[C:19]([N:30]([O:29][CH3:25])[CH3:31])=[O:21])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 g of (N-Boc)-4-cyanophenylalanine, 2.32 g of TBTU, 2.40 ml of DIPEA and 806 mg of N,O-dimethylhydroxylamine hydrochloride are mixed together in 30 ml of DCM. After stirring for 24 hours at RT, the reaction mixture is concentrated to dryness and the residue is then extracted with EtOAc. The organic phase is washed with a pH 2 buffer solution, a saturated NaHCO3 solution and then a saturated NaCl solution. The expected compound crystallizes from a mixture of isopropyl ether and pentane (1.89 g).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nn3)nc2n1C1CCCC1
Yield: 41.2 %

Procedure:
Following General Procedure D, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.68 mmol) and 4-(6-amino-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (210 mg, 0.75 mmol) to give 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 46%). MS(ESI) m/z 536.3 (M+H)+
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCCCN
Product: CCCCNC(=O)C(F)(F)F
Yield: 54.4 %

Procedure:
Ethyl trifluoroacetate (298 g, 2.1 m) was reacted in a manner similar to Example 5 with n-butylamine (169 g, 2.3 m), except that the amine was added as a liquid within 1 hour. After the exotherm (peak 56° C.) had subsided, the reaction mixture was heated under reflux for 31/2 hours (pot temperature 96° to 98° C.). The mixture was then distilled to yield 193 g of a liquid which boiled at 83° C./7 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH2:21]([O:20][C:18]([C:17]1[N:15]=[CH:16][N:4]2[C:5]3[C:10](=[C:9]([Br:13])[CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=12)=[O:19])[CH3:22]
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c3cccc(Br)c3c(=O)n(C)c12

Procedure:
M.p. 272° C. by reaction between 3-methyl-5-bromo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](SSC2SC3C=C([N+]([O-])=O)C=CC=3N=2)[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([S:51](=[S:66])([O:53]C2SC3C=C([N+]([O-])=O)C=CC=3N=2)=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:53][S:51]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)(=[O:66])=[O:52])[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=[N+]([O-])c1ccc2nc(OS(=O)(=S)c3ccccc3)sc2c1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 198 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(6-nitrobenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 113 mg of 6-nitrobenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 8 hours. The precipitated 6-nitrobenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 79%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>C(#N)C>[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:50])=[O:49]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccn3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 733 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0728 g, 0.158 mmol) was dissolved in acetonitrile (2.0 mL), and the solution was treated with triethylamine (0.0660 mL, 0.473 mmol) and 2-pyridinesulfonyl chloride (0.0680 g, 0.315 mmol) to obtain 4-(2-pyridinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.698 g, yield 73%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.Br[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([CH2:10][CH2:9][CH2:8][N:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCOc1ccccc1
Reactant: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCCOc2ccccc2)C1
Yield: 71.3 %

Procedure:
Prepared as in Intermediate I-15 from (3R)pyrrolidin-3-ol (commercially available) and (3-bromopropoxy)benzene. The yield was 2.26 g (71.3%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4](=[CH:9][CH:10]1[CH2:14][O:13][C:12](C)(C)[O:11]1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18]O>>[CH3:8][O:7][C:5]([CH:4]1[C:3](=[O:2])[O:17][CH:10]2[CH2:14][O:13][CH:12]([O:11][CH3:18])[CH:9]12)=[O:6]
Reactant: CO
Reactant: COC(=O)C(=CC1COC(C)(C)O1)C(=O)OC
Product: COC(=O)C1C(=O)OC2COC(OC)C21

Procedure:
Due to the fact that the obtained di-carboxylated intermediate is a viscous oil, i.e. 2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethylene)-malonic acid dimethyl ester, it needs to be introduced into the subsequent Michael addition as a solution in methanol. Methanol distillation after quench into aqueous NaHCO3 solution, after the acidic Nef and cyclization reactions, but before extraction with an organic solvent such as ethyl acetate has disadvantages. Since the intermediate resulting from the acidic Nef and cyclization reactions, i.e. 4-methoxy-2-oxo-hexahydro-furo[3,4-b]furan-3-carboxylic acid methyl ester, is a labile compound in water, and the methanol distillation requires relatively high temperatures (up to 30° C. to 40° C.), decomposition of the intermediate occurs to polar compounds. These polar compounds remain in the aqueous phase and are further lost because they are not extracted to the organic phase. Since the methanol can not be removed prior to the extractions, a considerable volume is required in the work-up of 4-methoxy-2-oxo-hexahydro-furo[3,4-b]furan-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[CH3:13][N:14](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[Cl:1][C:2]1[N:3]=[C:4]([C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)Oc1ccc(I)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C#N)nc1Cl
Temperature: 100 °C
Yield: 88 %

Procedure:
2-Chloro-6-iodo-3-isopropoxy-pyridine (2.00 g, 6.722 mmol) was dissolved in DMF (15 mL). Zn(CN)2 (592 mg, 5.04 mmol) was added, and the mixture was bubbled with nitrogen gas prior to the addition of Pd(PPh3)4 (600 mg, 0.519 mmol). The reaction system was sealed and heated under microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous sodium bicarbonate solution (75 mL) followed by brine (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a clear oil which was purified by silica gel column chromatography: 0-30% EtOAc/hexane gradient to provide 6-chloro-5-isopropoxy-pyridine-2-carbonitrile (1.17 g, 88%) as a clear colourless oil that crystallized upon standing. ESI-MS m/z calc. 196.0, found 197.3 (M+1)+; Retention time: 1.46 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.67 (dt, J=12.1, 6.1 Hz, 1H), 1.45 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8]C)[O:4]1.C(O)(C)C.[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8][CH:14]([CH3:19])[CH3:24])[O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO[C@@H]1OC[C@@H](CBr)O1
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CC(C)O[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis and trans 4-(bromomethyl)-2-methoxy-1,3-dioxolane (example 1) (5.37 g, 27.3 mmol) in benzene (100 mL) was added isopropanol (2.2 mL, 28.6 mmol, 1.05 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 24 hr at 88°-90° C. followed by addition of isopropanol (0.5 mL, 0.24 eq.). The mixture was stirred for further 24 hr at 90° C., cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in quantitative yield consisting of a mixture of isopropoxy and methoxy orthoesters in a 9:1 ratio respectively. The ratio of cis and trans isomers was about 1:1.