Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:10]1[C:11]([CH3:24])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])=[O:17])=[N:14][CH:15]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)(=[O:26])=[O:27])[C:10]1[C:11]([CH3:24])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:23])=[O:43])=[O:17])=[N:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCCS(C)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methyl-N-[3-(methylthio)propyl]pyridine-2-carboxamide (149 mg, 0.293 mmol) in methylene chloride (5 ml), 3-chloroperbenzoic acid (51 mg, 0.293 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. 3-Chloroperbenzoic acid (20 mg, 0.116 mmol) was added to the reaction solution under ice cooling, and the resulting mixture was stirred for 15 minutes. 1 N aqueous sodium hydroxide was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. Ethylacetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (122 mg, 0.232 mmol, 79%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[N:22]#[C:23]Cl.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:21][C:15]1[CH:14]=[C:13]([C:10]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:23]#[N:22])=[C:6]([CH3:9])[CH:5]=2)([CH3:12])[CH3:11])[CH:18]=[C:17]([CH3:19])[C:16]=1[OH:20]
Reactant: Cc1cc(C(C)(C)c2cc(C)c(O)c(C)c2)cc(C)c1O
Reactant: N#CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)c2cc(C)c(OC#N)c(C)c2)cc(C)c1O
Temperature: 0 °C
Yield: 99.5 %

Procedure:
28.4 g (0.1 mol) of 2,2-bis-(3,5-dimethyl-4-hydroxyphenyl)-propane are suspended in 500 ml of water and 300 ml of dichloromethine. After cooling to 0° C, 15 ml (0.3 mol) of cyanogen chloride are added. 10.6 g (0.1 mol) of Na2CO3, dissolved in 50 ml of water, are then added dropwise over the course of 2 hours, with vigorous stirring, in such a way that a pH value of between 7.5 and 8.5 is maintained constantly in the reaction mixture. At the same time, the reaction temperature is kept at about 0° C by cooling. Thereafter, the reaction is terminated by slow addition of 1 N NaOH, the 1 N NaOH being added in such a way that a pH value of 7.5 to 8.0 is constantly maintained in the reaction mixture and persists as the final value. After the end of the reaction, the organic phase is separated off, washed with 50 ml of water and concentrated at room temperature. 30.8 g (99% of theory) of 2-(3,5-dimethyl-4-hydroxyphenyl)-2-(3,5-dimethyl-4-cyanatophenyl)-propane are obtained as the residue.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[CH:19]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[CH:19]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)on1
Reactant: CN(C)C=O
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]
Product: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Temperature: 80 °C

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C36) (0.100 g, 0.189 mmol), zinc cyanide (0.027 g, 0.227 mmol), tetrakis(triphenylphosphine)palladium(0) (0.127 g, 0.110 mmol) and N,N-dimethylformamide (6 mL) were added to an Emrys microwave reaction vial. The vial was sealed and purged with nitrogen gas for 10 minutes with stirring. After that time, the vial was placed on a Biotage microwave processor and heated to 80° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The layers were separated and aqueous layer was extracted further with ethyl acetate (3×50 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane) afforded the product as an off-white solid. Yield: 51 mg, 57%. LCMS m/z 477.3 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ8.09 (br s, 2H), 7.83-7.87 (m, 2H), 7.40-7.59 (m, 4H), 4.97 (d, J=9.2 Hz, 1H), 4.30 (dd, J=11.7, 1.6 Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd, J=12.9, 3.9 Hz, 1H), 2.82 (dd, J=13.2, 3.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=O.[CH3:14][N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([CH:17]1[CH2:18][CH2:19][N:15]([CH3:14])[C:16]1=[O:20])=[O:11]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CN1CCC(C(=O)c2cncc(Br)c2)C1=O
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A suspension of NaH (60% in oil, 1.84 g, 46 mmol) was washed with toluene (3×10 ml) under nitrogen atmosphere. The resulting slurry in 50 ml of toluene was refluxed for 30 minutes under nitrogen and to it was added slowly a toluene (25 ml) solution of methyl 5-bromonicotinate (5 g, 23.26 mmol) and 1-methyl-2-pyrrolidone (4.58 g, 46.5 mmol) for 45 minutes. Then the reaction mixture was refluxed for 10 h. After completion of the reaction cooled to room temperature and added 10 ml of saturated ammonium chloride. The separated organic layer was dried over with sodium sulfate, filtered and evaporated under reduced pressure to obtain crude residue which was purified by silica-gel column chromatography using EtOAc/hexane (60:40) as an eluent to afford an off white solid (1.6 g, 24.4% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3=[N:27][C:28](N)=[CH:29][CH:30]=[C:25]3[CH2:24][C@H:23]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.[ClH:40].[N+]([O-])([O-])=O.[Na+].[OH-].[Na+]>[Cu]Cl>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3=[N:27][C:28]([Cl:40])=[CH:29][CH:30]=[C:25]3[CH2:24][C@H:23]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1
Reactant: Nc1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Reactant: Cl
Agent: Cl[Cu]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2ccc(Cl)nc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To the mixture of (6R,9R)-2-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (45 mg, 0.084 mmol), HYDROCHLORIC ACID (3 mL, 36.5 mmol) was added COPPER(I) CHLORIDE (16.67 mg, 0.168 mmol) and SODIUM NITRATE (21.47 mg, 0.253 mmol) at −5° C. The reaction was stirred at this temperature for 1 hour and stirred at room temperature for 1 hour. NaOH (1N) was added to the reaction mixture before extract with ethyl acetate twice. The ethyl acetate layer was washed by brine before separated, dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 4% to 8% to give the desired product (6.4 mg, 12%). MS(ESI)[M+H+]=554.09.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH:17]([O:30][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])[CH2:13][CH:12]([OH:38])[C:11]1=[O:39].C1C=CN=CC=1.F.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH:17]([OH:30])[CH2:18][CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])[CH2:13][CH:12]([OH:38])[C:11]1=[O:39]
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C(O)C[C@@H]1/C=C/C(CCc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C(O)C[C@@H]1/C=C/C(O)CCc1sc2ccccc2c1Cl
Reaction time: 2 h

Procedure:
An acetonitrile (0.35 mL) solution of 7 (9 mg, 0.015 mmol) was treated with HF-pyridine (0.07 mL). The solution was allowed to stir for 2 h and then 20 mL of saturated NaHCO3 solution was added. The mixture was extracted with dichloromethane (3×15 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by preparative thin layer chromatography (50% ethyl acetate/hexanes) gave two diastereomers of diol 8 (2 mg each, 0.004 mmol each, 27% for each).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1)=O.O.[NH2:21][NH2:22]>CN(C1C=CN=CC=1)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:22][N:21]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1C
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1C
Yield: 90.5 %

Procedure:
Prepared as in Example 104 from (2,3-difluorophenyl)-(4-methoxy-3-methyl-phenyl)-methanone (0.9 g, 3.45 mmol), hydrazine hydrate (1.06 mL, 34 mmol) and DMAP (0.42 g, 3.45 mmol) to give the product (0.80 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17].[OH-].[Na+].Cl>C1OCCOC1>[CH2:19]([O:18][C:16]([NH:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: NC1(C(=O)O)CCc2ccccc2C1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)COC(=O)NC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice cooled solution of amino acid from Example 53B (248 mg, 1.3 mmol) and anhydrousl, 4-dioxane (6 mL) was added isobutyl chloroformate (0.23 mL, 1.69 mmol). The solution's pH was maintained at 11 using 2M NaOH. The reaction was allowed to warm to room temperature. After 1 hour the reaction was complete. The pH was adjusted to 2 with 2 M HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the titled compound as a sticky white solid (341 mg, 90%). 1H (δ, DMSO-d6): 12.45 (br s, 1H), 7.39 (s, 1H), 7.03–7.15 (m, 4H), 3.6–3.8 (m, 2H), 3.1–3.2 (m, 2H), 3.07 (d, 1H), 2.71 (br s, 1H), 2.25 (br s, 1H), 1.9–2.0 (m, 1H), 1.77–1.9 (m, 1H). MS (DCI/NH3): 292.1 (M+1), 309.2 (M+H+NH4+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([CH:28]([OH:30])[CH3:29])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([C:28](=[O:30])[CH3:29])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(O)C1Cc2ccccc2N(Cc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)C1Cc2ccccc2N(Cc2ccccc2)C1
Temperature: -65 °C
Reaction time: 3 h

Procedure:
0.78 ml of oxalyl chloride is dissolved in 15 ml of methylene chloride and the solution is cooled to -65° C. First 0.85 ml of dimethyl sulfoxide and then a solution 1.6 g of 1-benzyl-3(R,S)-(1-hydroxyethyl)-1,2,3,4-tetrahydroquinoline and 3.3 ml of triethylamine in 25 ml of methylene chloride are added dropwise at this temperature. After 3 h, 10 ml of a 20% potassium hydrogen sulfate solution are added. The crude product is extracted with methylene chloride and purified by means of FC over 500 g of silica gel (mobile phase D): Rf (D)=0.27.
Reaction SMILES: [CH:1]1([NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[CH:1]1([N:4]([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](NC2CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.150 g, 0.710 mmol) in CH2Cl2 (2.5 mL) were added diisopropylethylamine (0.173 ml, 0.994 mmol), 4-chlorobenzoic acid (0.0866 ml, 0.852 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.470 g, 1.85 mmol) sequentially. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc-hexane. The desired amide product was obtained as a colorless oil (0.199 g). MS: 350 (M+1), C19H24ClNO3.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH:17]C(=O)[O-]>[Pd].CO>[CH3:1][C:2]1([CH3:21])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH2:17]
Reactant: CC1(C)[C@@H](c2ncn(C3CCCCO3)n2)C[C@H]1NC(=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC1(C)[C@H](N)C[C@@H]1c1ncn(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 119.1 %

Procedure:
A mixture of ((1R,3S)-2,2-dimethyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)cyclobutyl)carbamate (438 mg, 1.14 mmol) and palladium on activated carbon (10% Pd, 50 mg) in MeOH (15 mL) was stirred at 25° C. under hydrogen atmosphere for 5 h. The reaction mixture was filtered through celite and the filtrate was concentrated to afford the crude title compound (340 mg, crude). MS (ESI) m/z 251.2[M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:3][C:4](=C)[CH2:5][C:6]([NH:17][CH:18]=[O:19])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].ClC(C)=CC.C(Br)C=C>C(OCC)(=O)C.C(O)C>[NH2:1][CH:2]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:3][CH:4]=[CH:5][C:6]([NH:17][CH:18]=[O:19])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=C(CC(N)C(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Agent: CC=C(C)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: CCOC(=O)C(N)CC=CC(NC=O)(C(=O)OCC)C(=O)OCC

Procedure:
Using the procedure for the preparation of triethyl 5-amino-1-(formylamino)-3-methylene-1,1,5-pentanetricarboxylate, chloro-methylpropene replaced the allyl bromide to obtain the expected product in the form of an oil with an Rf=0.4 in ethyl acetate/ethanol 4:1.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[O:13]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 4-phenoxy-benzylamine (0.106 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.095 g, 61%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.79 (s, 2H), 6.98-7.54 (m, 12H), 7.89 (d, 1H). GC-MS: m/z 315 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C.O>[F:29][C:24]1[C:23]([C:12]2[CH:13]=[C:14]3[C@:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]4[CH:3]=[C:2]([C:43]5[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=NC2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@]2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 100 °C

Procedure:
To a vial was added (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (50 mg, 0.122 mmol), potassium phosphate (78 mg, 0.365 mmol), 2-fluoropyridin-4-ylboronic acid (34.3 mg, 0.243 mmol), and 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (4.31 mg, 6.09 μmol), dioxane (609 μL) and water (203 μL). The reaction mixture was purged with N2 gas and heated at 100° C. in microwave reactor for 15 mins. It was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated in vacuo to give the crude material. The crude was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 25% to 40% to 80% DCM/MeOH (90/10) in DCM, to provide (R,E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid. MS m/z=472.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1 H) 2.24-2.41 (m, 1 H) 3.39 (dt, J=11.25, 5.62 Hz, 2 H) 4.37-4.47 (m, 1 H) 4.47-4.61 (m, 1 H) 6.13 (br. s., 2 H) 7.41 (d, J=8.31 Hz, 1 H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1 H) 7.60 (dt, J=8.39, 1.87 Hz, 1 H) 7.67-7.75 (m, 2 H) 7.89-7.95 (m, 1 H) 8.03-8.16 (m, 2 H) 8.25 (dt, J=4.82, 1.50 Hz, 1 H) 8.38 (d, J=5.28 Hz, 1 H) 8.66-8.77 (m, 1 H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10].CN(C=O)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)C>[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9]([O:11][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: C=CCC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCC(C)(C)C(=O)OCc1ccccc1

Procedure:
To a mixture of K2CO3 (1.58 g, 11.5 mmol), 2,2-dimethylpent-4-enoic acid (1.30 g, 10.1 mmol) and DMF (8.1 mL) was added benzyl bromide (1.40 g, 8.19 mmol) slowly over 15 minutes. After 4 hours the mixture was diluted with a mixture of water (80 mL) and diethylether (80 mL). The organic layer was separated and sequentially washed with 80 mL of 5% aqueous sodium bicarbonate, saturated copper sulfate, slightly acidic water, half-saturated brine, and then saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used without further purification. MS: m/z=219 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=C)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])=[O:15].[Na+].[Na+].O>C(O)(C)(C)C>[C:1]([O:5][C:6]1[N:7]=[C:8]([CH:12]=[O:15])[CH:9]=[N:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1cncc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
After adding 7.20 g of AD-mix-5 to 60 ml of 50% aqueous tert-butanol, a solution of 1.00 g of 2-tert-butoxy-6-vinylpyrazine in tert-butanol (5 ml) was added and the mixture was stirred overnight at room temperature. Next, 8.40 g of sodium sulfite was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, and then water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methanol, an aqueous solution of 2.35 g of sodium periodate (20 ml) was added while stirring on ice, and stirring was continued at room temperature for 40 minutes. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (954 mg, 96% yield).
Reaction SMILES: [ClH:1].[N+]([C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1)([O-])=O>>[Cl:1][C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[N:9]=1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: Cl
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 67 %

Procedure:
In NON-PATENT DOCUMENT 3, after concentrated hydrochloric acid is added to 2,4-dinitroimidazole, the resultant solution is refluxed for 3 hours to perform chlorination reaction, and 2-chloro-4-nitroimidazole is produced at a yield of 67% by performing cooling, filtration and washing.