Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[CH2:13]([NH:20][C:21]1[C:22]([NH2:34])=[CH:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:22]=1[NH:34][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: CN1CCN(c2ccc(N)c(NCc3ccccc3)c2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (210.000 mg; 1.256 mmol), N2-Benzyl-4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine E-1.1 (363.000 mg; 1163.422 μmol) and triethylamine (0.435 ml; 3.141 mmol) in THF (3.000 ml) is added N-propylphosphonic acid anhydride, cyclic trimer (0.880 ml; 1.508 mmol). The mixture is stirred for 5 h at RT. The reaction is quenched with 1M NaOH, diluted with 50 ml water and extracted twice with ethyl acetate (50 ml). The combined organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is used in the next step without further purification
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:6])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:20])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)ccc21
Solvent: ClCCl
Product: CCOC(=O)C(C)N1C(=O)COc2cc(C)c(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a solution of 2-(7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (21.0 g, 80 mmol) in DCM (250 mL) was added 1-bromopyrrolidine-2,5-dione (15.6 g, 88 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched by addition of a saturated solution of thiosulfate in water (50 mL). The organic phase was separated and the aqueous portion was extracted with DCM (3×20 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give -(6-bromo-7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as solid (23.1 g, 85%). LC/MS (Table 1, Method 3) Rt=1.259 min.; MS m/z: 342/344 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[CH:32]([N:35](C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH3:32])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (0.59 g, 1.33 mmol) was taken up in CH2Cl2 (75 mL), and diisopropylethylamine (0.7 mL, 4 mmol) was added followed by HATU (0.556 g, 1.46 mmol). Gaseous methyl amine was then bubbled in very slowly until reaction was complete. Aqueous workup followed by chromatography on silica gel (100 g) eluted with CH2Cl2 —90% EtOAc/CH2Cl2 gave the title compound as a white amorphous solid. mp 273-275° C. LC-MS m/z 456 (M+H)+, 1.85 min (ret time).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[S:56]([C:60]1[CH:61]=[C:62]([CH:64]=[CH:65][CH:66]=1)[NH2:63])([OH:59])(=[O:58])=[O:57]>CN(C=O)C.C(N(CC)CC)C>[S:56]([C:60]1[CH:61]=[C:62]([NH:63][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:64]=[CH:65][CH:66]=1)([OH:59])(=[O:58])=[O:57]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)Nc1cccc(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Boc-Glu-OtBu (75 mg, 0.247 mmol), HATU (112 mg, 0.296 mmol) and HOAt (41 mg, 0.296 mmol) were dissolved in 1 ml of DMF, and triethylamine (52 μl) was added to the solution. The mixture was stirred at room temperature for 10 minutes. 3-Sulfoaniline (43 mg, 0.247 mmol) was added to the mixture, followed by stirring at room temperature overnight. After the solvent was removed by distillation, the mixture was purified according to the purification step A. The resulting intermediate was dissolved in 2 ml of trifluoroacetic acid. After stirring for 3 hours at room temperature, the solvent was distilled off. The product was purified using the purification step A to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:27][C:26]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=2[F:24])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1nccnc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1F)c1nccnc1Cl
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a mixture of 3-chloropyrazine-2-carboxylic acid (Tyger Scientific, 500 mg, 3.15 mmol) in methylene chloride (30 mL) and DMF (0.1 mL) was added oxalyl chloride (593 mg, 4.7 mmol). After stirring 30 min the reaction mixture was concentrated in vacuo. The residue was taken up in acetonitrile (12 mL) and was treated with triethylamine (920 mg, 9.1 mmol) and 2,4-difluoroaniline (430 mg, 3.3 mmol) and stirred 30 min. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over anhydrous MgSO4, and then concentrated in vacuo. The resulting solid was recrystallized (ethyl acetate/hexanes) to give the amide (455 mg, 53%) as a solid. MS(ESI+) m/z 270 (M+H)+.
Reaction SMILES: BrBr.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:15][C:16]1[CH2:21][CH2:20][CH:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1
Reactant: FC(F)(F)C1CC=C(Cl)CC1
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: FC(F)(F)c1ccc(Cl)cc1

Procedure:
The solution is heated to 60°-70° C. with stirring, using a magnetic stirring bar. Bromine, 32 g (0.2 mole), is added dropwise sub-surface. The reddish color dissipates quickly and a gas evolution occurs. A catalytic amount of radical initiator such as azodiisobutyronitrile may be added intermittently to promote the reaction. When the color begins to sustain, the pot temperature is raised to 90°-100° C. The remaining bromine is added in the same fashion. The pot temperature can be raised to 110°-120° C. for 2-4 hours. During this period, an additional amount of bromine such as 1-2 g may be added to complete the conversion of (I). 4-chlorobenzotrifluoride can be obtained in a good yield by fractional distillation of the mixture.
Reaction SMILES: ClC(Cl)(Cl)C=O.[NH2:7][C@H:8]1[C:15](=[O:16])[N:14]2[C@@H:9]1[O:10][CH2:11][C:12]([O:24][CH3:25])=[C:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1C=CC=CC=1>[NH2:7][C@@H:8]1[C:15](=[O:16])[N:14]2[C@@H:9]1[O:10][CH2:11][C:12]([O:24][CH3:25])=[C:13]2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: COC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2OC1
Agent: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2OC1
Temperature: -40 °C
Yield: 27.5 %

Procedure:
7.7 g of molecular sieve 3 Å and, after a few minutes, 2.3 ml (23.5 mmols--4.7 equivalents) of anhydrous trichloroacetaldehyde were added to a solution of 1.35 g (5 mmols) of tert.-butyl (6R, 7R)-7-amino-3-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 81 ml of benzene. The mixture was heated at the boiling point for 2.5 hours, with stirring, cooled, filtered rapidly and concentrated in vacuo. The residue was dissolved in 23 ml of anhydrous tetrahydrofuran and the solution was cooled to --40° C. 0.89 ml (5.1 mmols--1.02 equivalents) of ethyldiisopropylamine was added and the mixture was stirred at -40° C. and then allowed to warm to 0° C. At this temperature, a precooled solution of 2.18 mg of potassium borohydride in 35 ml of 50 percent strength aqueous tetrahydrofuran was added rapidly and the mixture was stirred for 5 minutes. The reaction was then quenched with a mixture of 38 ml of 2N HCl and 17 ml of acetonitrile at 0° C. and the mixture was subsequently stirred for a further 2 hours. For working up, the mixture was poured into saturated NaHCO3 solution and extracted with methylene chloride and the extract was washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 120 g of silica gel (ethyl acetate:acetone 6:4), 372 mg (28%) of the title compound were obtained as a colorless rigid foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21]C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=[O:21]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Temperature: 90 °C
Yield: 98.1 %

Procedure:
A mixture of 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (565 mg, 1.55 mmol) and 2M hydrochloric acid (5 ml) was heated at 90° C. for 90 minutes and allowed to cool. The solution was neutralised with aqueous sodium hydrogen carbonate, and the water removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/ammonia (100/8/1) to give 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (440 mg, 98%yield). This material was used without further characterisation.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH3:7].[C@@H:8]1([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CO>[CH3:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH3:1].[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]([O:14][CH2:13][C@H:12]2[O:15][C@@H:8]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:9][C@@H:10]2[OH:11])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: CC=CCCCC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Compound (2a) (340 mg, 1.05 mmol) was azeotroped three times with anhydrous pyridine. The mixture was added with anhydrous pyridine (2.0 ml) and 4,4′-dimethoxytrityl chloride (427 mg, 1.26 mmol) which has been deaerated for 1 hour, and subsequently with DMAP (38 mg, 0.31 mmol). Finally, triethylamine (170 μl, 1.26 mmol) was added and the mixture was stirred for 13 hours at room temperature. After characterization by TLC (CHCl3:MeOH=95:5), the product was purified with silica gel column chromatography using the development solvent of CHCl3 and MeOH while varying the ratio of CHCl3:MeOH from 98:2 to 95:5 to obtain the target Compound (3a) as a pale yellow solid (304 mg, 0.49 mmol, yield 46%). The target compound was determined by 1H NMR for identification. Further, mass analysis was carried out by MALDI-TOF MS and it was identified as the target compound (calcd. for C37H43N2O7 [M+H]+ 627.306, found 627.455).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15](N)[C@H:12]2[S:11][CH2:10][C:9]=1C(SC1NN=NN=1)CCNS(C)(=O)=O)=[O:7])(C)(C)C.FC(F)(F)CS(CC(O)=O)(=O)=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[S:11]1[C@@H:12]2[CH2:15][C:14](=[O:17])[N:13]2[C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNS(C)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CS(=O)(=O)CC(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 9.34 g (0.019 mol) of 7-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g (0.019 mol) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g (0.019 mol) of dicyclohexylcarbodiimide in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7β-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl[-3-cephem-4-carboxylic acid t-butul ester.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[H][H]>O.[Pd]>[C:2]1(=[O:1])[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Yield: 100 %

Procedure:
A solution of L-ascorbic acid (23.1 g, 0.13 mol) in 170 ml of water was hydrogenated using 10% Pd/C (2.2 g) in a Parr hydrogenator at 50° C. and 50 psi hydrogen pressure for 24 hours. The catalyst was removed by filtration and the water removed in vacuo to afford 23.2 g (0.13 mol, 99%) of a white crystalline solid. Upon recrystallization from methanol-ethyl acetate, 22.0 g of the desired product was obtained. 1H NMR (DMSO): δ 5.80 (d, 1H), 5.30 (d, 1H), 4.95 (d, 1H), 4.65 (t, 1H), 4.45 (m, 1H), 4.23-4.15 (m, 2H), 3.75 (m, 1H), 3.48 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][C@@H:39]1[CH2:43][CH2:42][C@@H:41]([CH3:44])[NH:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C@@H:39]1[CH2:43][CH2:42][C@@H:41]([CH3:44])[N:40]1[C:26]([N:12]1[CH2:13][CH:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH2:15][CH:10]([NH:9][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:11]1)=[O:27]
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@H](C)N1C(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 46 mg (0.47 mmol) of (2R,5R)-2,5-dimethylpyrrolidine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 12 mg (15% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[CH2:11][CH:12]([OH:14])[CH3:13])[CH:6]=[N:7][CH:8]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:14][CH:12]([CH2:11]/[CH:10]=[CH:9]/[C:5]2[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1cncc(/C=C/CC(C)O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cncc(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-ol (3.50 g, 18.13 mmol) in dry pyridine (15 mL) at 0° C. was added p-toluenesulfonyl chloride (6.91 g, 36.27 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 5.25 g (83.5%) of a dark-brown, viscous oil.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[O:26])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1>C(OC(=O)C)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([N:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[C:29](=[O:30])[CH:28]=[CH:27][C:25]4=[O:26])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:1](=[O:3])[CH3:2])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(c1cccc(Br)c1)c1ncnc2ccc(N3C(=O)C=CC3=O)cc12
Temperature: 25 °C
Yield: 39 %

Procedure:
Sodium acetate (0.10 g, 1.2 mmol) was added to a suspension of 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z) (0.25 g, 0.61 mmol) in 5 mL of acetic anhydride, and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, the reaction was filterd and the filtrate concentrated to dryness in vacuo. The residue was taken up in EtOAc and washed sequentially with saturated sodium bicarbonate, water, and brine. The EtOAc portion was dried over magnesium sulfate, filtered and concentrated to afford a faintly pink solid. The solid was recrystallized twice from EtOAc to afford N-(3-bromo-phenyl)-N-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-quinazolin-4-yl]-acetamide (0.104 g, 39%) as an off-white powder, mp 174-175° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=O)[CH2:4][C:5](OCC)=O.ClC1[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([Cl:24])=[CH:17][N:16]=1.Cl>COCCOC.O.CCCCCC.C(OCC)(=O)C>[Cl:24][C:18]1[CH:19]=[C:20]2[C:5]([CH2:4][C:3](=[O:11])[NH:21]2)=[N:16][CH:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Cc2ncc(Cl)cc2N1
Reaction time: 8 h

Procedure:
In a dry flask fitted with a nitrogen inlet and mechanical stirrer was placed sodium hydride as a 60° suspension in oil (4.0 g, 0.10 mol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry 1,2-dimethoxyethane (DME) (125 mL). To the resulting slurry was added dropwise, with stirring, a solution of diethyl malonate (15.7 mL, 0.10 mol) in DME (50 mL). The mixture was stirred at room temperature for 1 hour after which a solution of 2,5-dichloro-3-nitropyridine (10 g, 51.8 mmol) in DME (75 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was diluted with water. Following acidification to pH 2 with 1N HCl solution, the mixture was extracted with ether. The ether phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave a red oil. This was subjected to flash chromatography on silica gel using 9:1 hexane/ethyl acetate as eluant. All fractions containing the desired product were combined and concentrated to yield 2-bis(ethoxycarbonyl)methyl-5-chloro-3-nitropyridine as an oil (13.6 g, 82%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH:12]=[O:13])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[C:1]([NH:5][S:6]([C:9]1([CH2:12][OH:13])[CH2:10][CH2:11]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)C1(C=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)C1(CO)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round-bottom flask equipped with a stir bar was charged with a solution of N-(tert-butyl)-1-formylcyclopropane-1-sulfonamide (8.89 g, 43.3 mmol) in MeOH (110 mL). The solution was cooled to 0° C. and to the solution was added portionwise sodium borohydride (1.64 g, 43.3 mmol). The solution was stirred for 1 h. To the solution was added brine and the mixture was stirred for 15 min. The mixture was concentrated in vacuo to remove MeOH and the aqueous solution was then transferred to separatory funnel and was twice extracted with EtOAc. The combined organics were washed with sat. aq. NaCl; dried over MgSO4; filtered; and then concentrated in vacuo to afford N-(tert-butyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide as a colorless, crystalline solid (8.66 g, 96%). 1H NMR (400 MHz, CDCl3) δ 4.35 (br. s., 1H), 3.86 (d, J=6.0 Hz, 2H), 2.77 (t, J=6.0 Hz, 1H), 1.50-1.45 (m, 2H), 1.39 (s, 9H), 1.06-1.01 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:23][N:24]([CH2:26][C:27]1C=CC(N)=[CH:29][CH:28]=1)[CH3:25]>>[CH3:23][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:1]([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([B:14]3[O:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:20])[O:18]3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][CH:2]=1)[CH3:25]
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CN(C)Cc1ccc(N)cc1
Product: CN(C)Cc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using 4-((dimethylamino)methyl)aniline as the amine component.