Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][CH:6]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C1CNCCN1
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 25 g, 78.6 mmol), piperazine (67.7 g, 0.79 mol) and dry acetonitrile was stirred at 60° C. overnight under nitrogen. The mixture was cooled and partitioned between water and methylene chloride. The organic layer was washed with water and brine. The solution was dried over Na2SO4 and then the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel (methanol-methylene chloride 5:95). There was obtained 17.5 g (72%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperazine as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.1-2.4 (m, 4H), 2.8-2.9 (m, 2H), 3.0 (m, 4H), 3.4-3.5 (m, 2H), 3.7-3.9 (m, 1H), 4.4 (s, 1H), 7.2-7.4 (m, 10H); LCMS: m/z 308 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:13]([OH:16])[CH2:14]Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]1[O:16][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
A solution of 11.4 g of 3(S)-(benzyloxyformamido)-1-chloro-4-phenyl-2(S)-butanol in 300 ml of ethanol containing 2.24 g of potassium hydroxide was left to stand for 15 minutes. The solvent was removed by evaporation and the residue was partitioned between water and dichloromethane. Working-up gave 10.1 g of crude 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane as an off-white solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1OC([Si](C)(C)C)=[CH:4][C:3]=1C=O.C[Si](C)(C)C1OC=C(C=O)C=1.CI.[CH2:26]([Si:28]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:29]1[O:30][CH:31]=[C:32]([CH:34]=[O:35])[CH:33]=1)[CH3:27].ICCCC>>[CH2:1]([C:31]1[O:30][C:29]([Si:28]([CH2:36][CH3:37])([CH2:26][CH3:27])[CH2:38][CH3:39])=[CH:33][C:32]=1[CH:34]=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1oc([Si](C)(C)C)cc1C=O
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: C[Si](C)(C)c1cc(C=O)co1
Solvent: CCCCI
Solvent: CI
Product: CCCCc1oc([Si](CC)(CC)CC)cc1C=O

Procedure:
Using the same procedure as for 5-methyl-2-trimethylsilyl-4-furaldehyde but substituting 2-trimethylsilyl-4-furaldehyde (Compound 30) and methyl iodide with 2-triethylsilyl-4-furaldehyde (Compound 31) and 1-iodobutane, respectively, gives 5-butyl-2-triethylsilyl-4-furaldehyde (Compound 41). IR (neat): 1690 cm-1; 'HNMR (CDCl3):0.73 (q, 6H, J=8.4 Hz), 0.95 (m, 12H), 1.36 (p, 2H, J=7.5 Hz), 1.69 (p, 2H, J=7.5 Hz), 2.94 (t, 2H, J=7.5 Hz), 6.89 (s, 1H) and 9.91 (s, 1H) 13CNMR (CDCl3): 3.03, 7.17, 13.6, 22.2, 26.8, 30.4, 118.6, 122.5 158.4, 170.2 and 184.8. LRMS m/e (% abundance):266 (M+, 20) 238 (20) 237 (100), 87 (10) and 75 (20); HRMS exact mass calculated for C15H26O2Si 266.1702, found 266.1690.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]([C@@H:14]1[C@@H:18]([CH2:19]O)[O:17][C@@H:16]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:15]1)=[N+:12]=[N-:13].[C:30]([CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl.CS(C)=O.C(Cl)Cl.C(N(CC)CC)C>[C:30]([CH:35]=[CH:19][C@H:18]1[O:17][C@@H:16]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:15][C@@H:14]1[N:11]=[N+:12]=[N-:13])([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
A solution of DMSO(426 μl, 6 mM) in methylene chloride (1.5 ml) was added to a stirred solution of oxalyl chloride (288 μl, 3.3 mM) in methylene chloride (7.6 ml) at -78° C. under nitrogen. After 5 minutes, a solution of 3'-azido-3'-deoxythymidine (801 mg; 3 mM) in DMSO/CH2Cl2 (1.12 ml/3.47 ml) was added over a ten minute period. Stirring was continued for 20 minutes, and then triethylamine (2.09 ml, 15 mM) was added and the reaction mixture was stirred for an additional 5 minutes. (Carbethoxymethylene)triphenylphosphorane (1.57 g; 4.5 mM) was added in a solution of methylene chloride (9 ml), and the reaction mixture was stirred at -78° C. for 30 minutes and then allowed to stand at room temperature for 1 hour. The crude reaction mixture was then quenched with cold water (20 ml) and extracted into ethyl acetate (2×50 ml), washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography (SiO2 : 60 g; 60% ethyl acetate/hexane) to afford 765 mg (76%) of the title compound. Rf -0.47(7/3 EtOAc/Hexane).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (354 mg, 1.0 mmol) and 4-bromobenzenesulfonamide (230 mg, 1.0 mmol) according to general procedure II. Obtained as an off-white (120 mg, 23%). MS (ISP) 511.3 [(M+H)+]; mp 278-280° C.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18](=[O:22])[CH:19](Br)[Br:20])=[CH:17][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[C:3]([C:23](=[O:27])[CH:24](Br)[Br:25])[CH:2]=1.CCN(CC)CC.P([O-])(OCC)OCC>C1COCC1>[CH:1]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18](=[O:22])[CH2:19][Br:20])=[CH:17][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[C:3]([C:23](=[O:27])[CH2:24][Br:25])[CH:2]=1
Reactant: O=C(c1ccc2c(c1)OCCCOc1cc(C(=O)C(Br)Br)ccc1-2)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc2c(c1)OCCCOc1cc(C(=O)CBr)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1′-(7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonine-3,11-diyl)bis(2,2-dibromoethanone) (1b) (0.38 g, 0.61 mmol) in THF (7 mL) at 0° C. was added Et3N (0.09 mL, 0.61 mmol) and diethyl phosphite (0.24 mL, 1.82 mmol). The reaction mixture was gradually warmed to room temperature, stirred for 1 h and concentrated under reduced pressure. The residual contents were partitioned between EtOAc and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to yield an yellow oil (1c) which was used in the next step without further purification (0.15 g, 53%). m/z 468.9 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C(=O)C.ClCCl.C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:32]1[CH2:33][CH2:34][CH:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])[CH2:30][CH2:31]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COCCOC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: COCCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 68.7 %

Procedure:
A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (150 mg, 0.50 mmol) in N,N-dimethylacetamide (4 mL) was treated with 4-(2-methoxyethoxy)piperidine hydrochloride (103 mg, 0.53 mmol) and triethylamine (0.210 mL, 1.51 mmol). O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (253 mg, 0.67 mmol) was added and the resulting solution was stirred at ambient temperature for 4.5 hours. The crude reaction mixture was filtered before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford a gum, which was taken up in a small amount of diethyl ether and dichloromethane and allowed to evaporate before drying under vacuum, at 55° C., for 2 hours to afford the desired compound as a white solid (151 mg, 68.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.36 (1H, m), 1.40-1.49 (1H, m), 1.68-1.75 (1H, m), 1.82-1.90 (1H, m), 2.99-3.06 (1H, m), 3.25 (3H, s), 3.26-3.32 (2H, m), 3.44 (2H, t), 3.53-3.58 (3H, m), 3.90-3.98 (1H, m), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.65 (M+H 440.6).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added p-anisaldehyde (79.2 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (184 mg, 89% yield) as pale yellow crystals.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])(C)C.[F-].[K+].[BH4-].[Na+].[NH4+].[Cl-]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [F-]
Solvent: CO
Product: C#Cc1cccc(CO)c1
Temperature: 22 °C
Reaction time: 6 h

Procedure:
To 3-trimethylsilanylethynyl-benzaldehyde 73(a1) from step 1a in methanol (540 mL, 0.3 M) was added KF (18.8 g, 324 mmol), and the resulting mixture stirred at 22° C. for 6 hours. After cooling to 0° C., NaBH4 (6.13 g, 162 mmol) was carefully added over 0.5 hours. Aqueous saturated NH4Cl was carefully added and the volatiles were removed in vacuo. Ethyl acetate (200 mL) was added, and the organic phase was washed with water and a saturated aqueous NaCl solution, dried over MgSO4 and filtered. The volatiles were removed in vacuo to afford crude (3-ethynyl-phenyl)-methanol 73(a2).
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:27])[CH2:16][NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.Cl.[Na].O>CO.C(OCC)(=O)C>[C:21]1([S:18]([NH:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:28])=[O:8])=[O:27])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CNS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)CNS(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 45.6 %

Procedure:
N-benzenesulfonylglycyl-L-proline benzylester (1.91 g, 4.7 mmole) was dissolved in methanol (6 ml), 1N aqueous sodium hydrochloride (6 ml) was added, and stirred for 3 hours at a temperature between 30° C. and 35° C. Water (20 ml) was added to the solution and the mixture was washed with two 20 ml portions of diethyl ether and then adjusted to pH 1.5 with 1N aqueous hydrochloric acid. The solvent was removed by distillation under reduced pressure and the solid material thus obtained was dispersed in ethyl acetate (50 ml) and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a glassy residue and it was recrystallized from ethyl acetate and petroleum ether to obtain N-benzenesulfonylglycyl-L-proline(yield: 0.67 g, 45.2%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][C:16]=3[CH2:23][CH3:24])=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=[C:5]([CH2:25][CH3:26])[CH:4]=1)[CH3:2].[CH2:27]([O:29][CH2:30][C:31]([NH:33][NH2:34])=O)[CH3:28]>C(O)CCC>[CH2:1]([C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][C:16]=3[CH2:23][CH3:24])=[N:10][CH2:11][C:12]3[N:13]([C:31]([CH2:30][O:29][CH2:27][CH3:28])=[N:33][N:34]=3)[C:7]=2[CH:6]=[C:5]([CH2:25][CH3:26])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2=NCC(=S)Nc3cc(CC)cc(CC)c32)c(CC)c1
Reactant: CCOCC(=O)NN
Solvent: CCCCO
Product: CCOCc1nnc2n1-c1cc(CC)cc(CC)c1C(c1ccc(CC)cc1CC)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6,8-diethyl-5-(2,4-diethylphenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with ethoxyacetic acid hydrazide to give 7,9-diethyl-1-(ethoxymethyl)-6-(2,4-diethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:12][S:13]([NH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1cc(N)cs1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(C)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-aminothiophene-2-carboxylate (Int. 41) (theoretical 1.785 mmol) in pyridine (20 ml), methanesulfonyl chloride (0.239 ml, 3.07 mmol) was added and the mixture was stirred overnight at RT. The solvent was evaporated and the residue was partitioned between 1N HCl and EtOAc; the aqueous phase was extracted with EtOAc and the combined organic layers were dried over sodium sulfate and evaporated to afford ethyl 4-(methylsulfonamido)thiophene-2-carboxylate (Int. 42) which was used without any additional purification (370 mg, 1.484 mmol, MS/ESI+249.8 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[N:12]1C=CC=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[N:12][C:13]([CH3:14])=[N:1]2
Reactant: COc1cccc(N)c1C=O
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1cccc2nc(C)ncc12
Yield: 85.4 %

Procedure:
To a stirred solution of 2-amino-6-methoxybenzaldehyde [K. Tsuda et al., Chem. Pharm. Bull. 1962, 10, 856] (1.3 g, 8.6 mmol), pyridine (0.81 g, 10.3 mmol) and toluene (60 mL) was added acetic anhydride (0.97 g, 9.5 mmol). The resulting mixture was heated at reflux for 18 h, cooled, then partitioned between saturated aqueous NaHCO3 (100 mL) and ether (50 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by chromatography on silica with 0-50% ether in hexane gradient elution to give a colourless solid (1.28 g). The latter was dissolved in 2 M methanolic ammonia (100 mL) and the solution heated at reflux for 3 h, cooled, then evaporated in vacuo. Chromatography of the residue on silica with 0-100% ether in dichloromethane gradient elution gave the title compound (0.92 g, 62%) as a colourless solid.
Reaction SMILES: [P:1](Cl)(=[O:20])([O:11][C:12]([Br:19])([Br:18])[C:13]([CH3:17])([CH3:16])[CH2:14][Br:15])[O:2][C:3]([Br:10])([Br:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Br:6].[OH2:22]>C1C=CC=CC=1>[P:1]([OH:20])([O:11][C:12]([Br:19])([Br:18])[C:13]([CH3:17])([CH3:16])[CH2:14][Br:15])([O:2][C:3]([Br:10])([Br:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Br:6])=[O:22]
Reactant: O
Reactant: CC(C)(CBr)C(Br)(Br)OP(=O)(Cl)OC(Br)(Br)C(C)(C)CBr
Solvent: c1ccccc1
Product: CC(C)(CBr)C(Br)(Br)OP(=O)(O)OC(Br)(Br)C(C)(C)CBr

Procedure:
A solution of bis(tribromoneopentyl) phosphorochloridate in benzene was stirred with water. Crystalline solids slowly came out, and were removed by filtration. The product was a colorless crystalline solid, m.p. 130°C. Titration with standard 0.1-N NaOH in aqueous acetone medium or KOH in methanol showed it to have an equivalent weight of 710 corresponding to [(CHBr)3CCH2O]2P(O)(OH), bis(tribromoneopentyl) hydrogen phosphate. The aqueous acetone sodium salt solution or the alcoholic potassium salt solution was applied to cotton polyester fabric to obtain a dry add-on of 20% of the alkali metal salt of bis(tribromoneopentyl) acid phosphate. Fixation of the finish was achieved by applying a solution of magnesium chloride, which gives in situ formation of the water-insoluble magnesium salt of bis(tribromoneopentyl) hydrogen phosphate. The resultant finish imparts flame retardant properties and is wash-durable.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[N+:13]([O-:15])=[O:14].[CH2:16]([O:18][C:19]([P:24]([O:27][CH2:28][CH3:29])([CH3:26])=[O:25])([O:21][CH2:22][CH3:23])[CH3:20])[CH3:17].C(=O)=O.CC(C)=O.C([Li])CCC.CCCCCC>O1CCCC1>[CH2:22]([O:21][C:19]([P:24]([CH2:26][CH:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:12][N+:13]([O-:15])=[O:14])([O:27][CH2:28][CH3:29])=[O:25])([O:18][CH2:16][CH3:17])[CH3:20])[CH3:23]
Reactant: CCOC(C)(OCC)P(C)(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/[N+](=O)[O-]
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(CC(C[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1C)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Adapting literature known protocols (U.S. Pat. No. 8,344,028; and Baylis, Tetrahedron Lett., 1995, 36(51), 9385-9388), 2-[1-[(1,1-diethoxyethyl(ethoxy)phosphoryl)-methyl]-2-nitro-ethyl]-1-methyl-4-nitro-benzene (19b) is prepared from 1-methyl-4-nitro-2-[(E)-2-nitrovinyl]benzene (19a) through 1,4-conjugate addition of lithiated commercial 1-[1-ethoxy-1-(ethoxy(methyl)phosphoryl)ethoxy]ethane (Baillie, et al., U.S. Pat. No. 4,339,443 (1982). To a solution of [1-ethoxy-1-(ethoxy(methyl)phosphoryl)ethoxy]ethane (2.65 mL, 2.69 g, 12.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) and under a nitrogen atmosphere and at a temperature of about −78° C. (dry ice/acetone bath) is dropwise added a solution of n-butyllithium (nBuLi) in hexane (12.0 mL, 12.0 mmol). After about 30 min, the solution of the lithiated compound is added via a cannula within about 5 minutes to a cooled solution (−78° C.; dry ice/acetone bath, nitrogen atmosphere) of (19a) (2.08 g, 10.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL). The reaction is stirred at this temperature for about 30 minutes followed by gradual warming to about 0° C. (ice/water bath). Stirring is continued at this temperature for another 30 minutes. Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (19b).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([Cl:41])[N:21]=3)[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].CCO>C1COCC1.[Cl-].[NH4+]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([Cl:41])[N:21]=3)[C@H:14]2[CH3:42])[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: CCOC(=O)CCc1ccc(OC)c(-c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCC(=O)O)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32) (500 mg, 0.966 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (INTERMEDIATE 2) (370 mg, 1.107 mmol), potassium carbonate (1M aqueous) (3 ml, 3.00 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (94 mg, 0.145 mmol) in THF (5 ml) was stirred at RT under nitrogen overnight. The reaction was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting EtOAc in hexanes to afford 582 mg of ethyl 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoate. 294 mg (0.456 mmol) of this ester was combined with LiOH (1M aqueous) (1 ml, 1.000 mmol) in THF (2 ml)/EtOH (0.5 ml) and stirred at RT under nitrogen overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic was dried over sodium sulfate and the solvent was evaporated under reduced pressure to afford 267 mg of 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoic acid, 30 mg of which were combined with copper (spatula tip) and piperidine (5 ml, 50.5 mmol) and was heated at 150° C. for 5 hours in a sealed tube. The reaction was concentrated and purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 666.2 (M+1). 1H NMR (500 MHz, CD3OD) (atropisomers) δ 7.96 (s, 1H); 7.88 (s, 2H); 7.30 (d, J=8.7 Hz, 1H); 7.20 (dd, J=2.2, 8.4 Hz, 1H); 7.02 (s, 1H); 6.95 (d, J=8.5 Hz, 1H); 6.73 (d, J=8.5 Hz, 1H); 5.76 (br s, 1H); 4.60 (br s, 1H); 3.49-4.34 (m, 9H); 2.87 (t, J=7.1 Hz, 2H); 2.57 (br s, 2H); 1.61-1.73 (m, 6H); 0.56 (br s, 3H).