Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)[C:7](=[O:16])[CH:6]=1.[CH3:22][C:23]1([CH3:35])[O:27][C@H:26]([CH2:28][N:29]2[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]2)[CH2:25][O:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH2:28][C@@H:26]3[CH2:25][O:24][C:23]([CH3:35])([CH3:22])[O:27]3)[N:30]=2)=[O:13])[C:7](=[O:16])[CH:6]=1
Reactant: CC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid (0.090 g, 0.30 mmol) in dry N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49 0.075 g, 0.38 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.200 g, 0.45 mmol). To this mixture was added N,N-diisopropylethylamine (0.117 g, 0.91 mmol) and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with an ammonium chloride solution, a saturated sodium bicarbonate solution, saturated sodium chloride solution and then dried over sodium sulfate. The solvents were evaporated and the residue was purified by AnaLogix flash chromatography (AnaLogix SuperFlash Flash Column 23 g, 100% ethyl acetate) which afforded (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-butyramide (0.061 g, 42%) as a off-white solid: LR-ES-MS m/z calculated for C23H26F2N4O5 [M+H]+ 477 observed 477.
Reaction SMILES: [ClH:1].N[C@H](C(NC(C1CC1)C(OC)=O)=O)C.C(OC([NH:23][CH:24]([CH2:34][CH3:35])[C:25]([NH:27][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH3:29])=[O:26])=O)(C)(C)C>>[ClH:1].[NH2:23][CH:24]([CH2:34][CH3:35])[C:25]([NH:27][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH3:29])=[O:26]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OC
Agent: COC(=O)C(NC(=O)[C@H](C)N)C1CC1
Agent: Cl
Product: CCC(N)C(=O)N[C@@H](C)C(=O)OC

Procedure:
Following the procedure for the preparation of methyl (L-alanylamino)(cyclopropyl)acetate hydrochloride but substituting methyl N-{2-[(tert-butoxycarbonyl)amino]butanoyl}alaninate and making non-critical variations provided the title compound as a solid: 1H NMR (DMSO-d6) δ 0.86-0.92, 1.39-1.41, 1.62-1.82, 3.64, 3.92, 4.18-4.23, 8.36. 8.92.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.CI>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(-n2nc(-c3cccs3)cc2N)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(-n2nc(-c3cccs3)cc2N)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)acetate (0.244 g, 0.745 mmol) in THF (7.5 ml), thoroughly cooled to −78° C., was added KHMDS in PhMe (1.79 ml, 0.894 mmol, 0.500 M). The resulting very dark mixture was stirred at −78° C. for 1 h and then treated with MeI (0.056 ml, 0.894 mmol). The reaction was stirred with gradual warming to RT overnight. The completed reaction was quenched by addition of 3M HCl, diluted with EtOAc and the layers separated. The aqueous was extracted with EtOAc (2×) and the combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), filtered, and concentrated to yield ethyl 2-(4-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)propanoate (0.25 g) of crude which was used without further purification in the next reaction. MS (ESI) m/z: 342.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:28][S:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][C:30]([S:29][CH3:28])=[CH:31][CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CSc1ccc(CBr)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(SC)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methylsulfanyl-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 4): tR=1.12 min; Mass spectrum (ESI+): m/z=508 [M+Na]+.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[C:14]([O:23][CH2:24][CH3:25])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:22][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:23][CH2:24][CH3:25])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: CCOc1cc2c(nc1Cl)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(nc1Cl)N1[C@@H](CNC[C@H]1C)C2

Procedure:
This compound was prepared in analogy to Example 1 from (4R,9aR)-6-chloro-7-ethoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and trifluoroacetic acid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=C(CCC[O:29]CCN2C3C4C(=CC=CC=4)N4N=NN=C4C=3N=C2)C=1.Cl.O>ClC1C=CC=CC=1Cl>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7](=[O:29])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cncc(CCCOCCn2cnc3c2c2ccccc2n2nnnc32)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (27.0 g, 115 mmol) was added to a solution of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (28.7 g, 76.9 mmol) in 1,2-dichlorobenzene (1 L). The reaction was heated at reflux temperature overnight. The dark red solution was cooled to room temperature and treated with 1N HCl (225 ml). A tan precipitate formed. The resulting mixture was concentrated in vacuo to yield a dark red/brown solid. This material was treated with 500 ml water and vigorously stirred. Excess triphenylphosphine and triphenylphosphine oxide formed as precipitates and were removed by vacuum filtration. The solid was washed with several portions of water followed by a final wash with dilute HCl (1:5, 1N HCl:water). The red/brown filtrate was collected, washed with ether (3×150 ml), and treated with 10% NaOH solution until the pH reached 12. The crude product formed as a tan precipitate and was collected by filtration. Purification of the crude material was accomplished by treatment (2×) with activated charcoal (Darco-G60) in refluxing methanol. The charcoal was removed by filtration. The desired product formed as a precipitate during concentration of the filtrate.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Br)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg) in THF (5 ml) were added p-bromobenzyl alcohol (332 mg), (E)-bis(2-methoxyethyl)diazene-1,2-dicarboxylate (541 mg) and triphenylphosphine (606 mg), and the mixture was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/MeOH), followed by crystallization from hot EtOAc to give the title compound (502 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[S:33]1(=[O:39])(=[O:38])[CH2:37][CH2:36][CH2:35][NH:34]1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:5]4[CH:4]=[CH:3][C:2]([N:34]5[CH2:35][CH2:36][CH2:37][S:33]5(=[O:39])=[O:38])=[CH:7][C:6]=4[N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCN(C)C2=O)CC1
Yield: 38.4 %

Procedure:
Using 1-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (79 mg) described in Preparation Example 242 and isothiazolidine 1,1-dioxide (32 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (36 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][S:14]([CH2:17][CH2:18][NH2:19])(=[O:16])=[O:15].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CS(=O)(=O)CCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCNC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-amino-3-bromobenzoic acid (0.8 g, 3.70 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (0.709 g, 4.44 mmol, ChemBridge Inc.) in EtOAc (15 mL) followed by DIEA (1.61 mL, 9.26 mmol) and T3P (2.59 mL, 4.07 mmol, Sigma Aldrich). The mixture was stirred at RT for 2 h, then quenched with sat. NaHCO3. EtOAc (100 mL) was added and the layers were separated. The organic layer was washed with sat. NaHCO3 (20 mL), brine (15 mL), then dried (MgSO4), filtered and concentrated to give the crude product 485 mg. MS (ESI, pos. ion) m/z: 321 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CCOC(C)=O.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: C/C=C\[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 40 h
Yield: 98 %

Procedure:
To a stirred solution of 4.2 (0.055 g, 0.11 mmol) in EtOAc (4.00 mL, 41 mmol) at 23° C. was added quinoline (0.500 mL, 4.2 mmol) followed by Lindlar's Catalyst (0.012 g, 0.11 mmol). The reaction mixture was placed under an atmosphere of hydrogen and stirring was continued for 40 hours. The mixture was filtered through a pad of silica gel. The filtrate was washed with 1N HCl (3×10 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give compound 8.1 as a clear oil (0.0529 g, 96% yield). MS ESI (pos.) m/e: 513.3 (M+Na)+, 508.3 (M+H2O)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH2:21][CH2:22][CH3:23])[CH2:18][C:17]3=[O:24])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[OH-:25].[Na+].C(#N)C.O>CCCCCC.C(OCC)(=O)C>[OH:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH2:21][CH2:22][CH3:23])[CH2:18][C:17]3=[O:24])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1
Reactant: [OH-]
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(Cl)nn23)C1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(O)nn23)C1
Temperature: 150 °C
Yield: 10 %

Procedure:
A solution of 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 30 (500 mg, 1.38 mmol), sodium hydroxide (110 mg, 2.77 mmol, 2 eq) in 5 ml of a 1/1 mixture of acetonitrile and water is heated in a microwave oven for 20 min (Tmax 150° C.). Acetonitrile is removed from reaction mixture under reduced pressure, the aqueous layer is acidified using aqueous hydrochloric acid solution and the crude product is then extracted by ethyl acetate (3×20 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure leading to an oily residue which is purified by preparative chromatography on silicagel (dichloromethane/isopropanol 99/1). The resulting solid is dried in a vacuum oven and recrystallized in ethyl acetate to afford 1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 45.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2ccc(I)cc12
Product: Ic1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1

Procedure:
JP-A-10-152477 describes a process for preparing a 4-arylaminoquinazoline compound from a quinazolin-4-one, which comprises the steps of chlorinating 4-iodoquinazolin-4-one using an excessive amount of oxalyl chloride to produce 6-iodo-4-chloroquinazoline (intermediate compound), concentrating the reaction product under reducing pressure to isolate the resulting product; reacting the 6-iodo-4-chloroquinazoline with 5-aminoindole to give 6-iodo-4 (5-indolylamino)quinazoline. Unfortunately, the yield is not high. Further, it should be noted that the intermediate compound, i.e., 4-chloroquinazoline compound, shows no satisfactory stability in the presence of water and no satisfactory resistance to heat. Accordingly, the compound should be handled carefully.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH:16]=O)[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH:25]([C:28]1[S:29][CH:30]=[C:31]([C:33]([N:35]2[CH2:40][C:39]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[O:38][CH2:37][CH2:36]2)=[O:34])[N:32]=1)([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(O)(=O)C.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][N:43]2[CH2:44][CH2:45][C:39]3([O:38][CH2:37][CH2:36][N:35]([C:33]([C:31]4[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][CH:30]=4)=[O:34])[CH2:40]3)[CH2:41][CH2:42]2)[CH:12]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)cs1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4csc(CCO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-3-carbaldehyde (0.6 g) (example 278, step c) was added to (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (0.94 g) (example 22, step b) in a mixture of N-methyl-2-pyrrolidinone (5 mL) and acetic acid (0.13 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.71 g) was then added and the mixture stirred overnight. The reaction was poured into water (100 mL), the pH was adjusted to 8 using saturated sodium bicarbonate solution and the resulting aqueous solution extracted with ethyl acetate (3×100 mL). The combined organic solutions were washed with water (3×100 mL), brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 77.5:17.5:5 i-hexane:ethyl acetate:triethylamine to 47.5:47.5:5 i-hexane:ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 0.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](N(OC)C)=[O:16])=[O:12])[C:4]=2[CH:3]=1.C(=O)=O.[CH3:30][C:31](C)=O.C([Mg]Br)=C>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:16])[CH:30]=[CH2:31])=[O:12])[C:4]=2[CH:3]=1
Reactant: CON(C)C(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)=O
Agent: C=C[Mg]Br
Agent: O=C=O
Solvent: C1CCOC1
Product: C=CC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[[(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepin-10yl)-carbonyl]amino]-N-methoxy-N-methylacetamide (3.2 grams) in anhydrous tetrahydrofuran (35 mL) at -70° C. (dry ice/acetone bath) under a nitrogen atmosphere was added dropwise a solution of vinylmagnesium bromide (1.0M in tetrahydrofuran; 28 mi) in tetrahydrofuran (15 mL). The ice bath was removed, and the reaction was stirred to room temperature for one hour. The reaction was poured into 1M NaH2PO4 (250 mL) and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate extracts were washed with 1M NaH2PO4 (2×250 mL) and brine (250 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (500 mL) using 9:1 methylene chloride:ethyl acetate to yield a colorless glass. The yield of the title compound was 2.25 grams (77%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(-c4ccncc4)nc3s2)cc1
Yield: 26 %

Procedure:
The titled compound (yield=26%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except that 1D (Example 1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 7.68 (d, J=8.34 Hz, 2H) 8.12 (d, J=8.34 Hz, 2H) 8.29-8.46 (m, 4H) 8.87 (br. s., 2H) 13.15 (br. s., 1H); ESI-MS: m/z 391.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([N:5]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[O:4].[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]([F:28])([F:27])[C:3]([N:5]([CH2:20][P:21]([O:25][NH:35][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([O:23][NH:35][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:22])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[O:4]
Reactant: CCCCCCCCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: NC1CCCCC1
Solvent: CCOCC
Product: CCCCCCCCCCOC(=O)CN(CP(=O)(ONC1CCCCC1)ONC1CCCCC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of decyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.63 g, 0.015 mole) in 200 ml. of ether was added with good stirring cyclohexylamine (5.95 g, 0.06 mole) in 50 ml. of ether. The reaction was stirred overnight at room temperature, then filtered, and the filtrate concentrated in vacuo. The residue was dissolved in fresh ether, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was eluted through a dry column chromatograph with ethyl acetate to yield decyl N-trifluoroacetyl-N-(bis(cyclohexylamino)phosphonomethyl)glycinate, m.p. 79.5°-82.5° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58](ON2C3C=CC=CC=3N=N2)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O>[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH:16][CH:17]([CH3:18])[CH3:19])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 84.7 %

Procedure:
To a solution of 7β-amino-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.35 g, 3.63 mmol) and triethylamine (0.735 mg, 7.26 mmol) in dimethylacetamide (17 ml) was added 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (3.05 g, 5.44 mmol). The mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.45 g, 84.8%).