Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:24]3[N:28]=[C:27]([CH3:29])[O:26][N:25]=3)([CH3:23])[CH2:14][O:15]CC3C=CC=CC=3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([C:4]2[C:5]([O:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:24]3[N:28]=[C:27]([CH3:29])[O:26][N:25]=3)([CH3:23])[CH2:14][OH:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(COCc2ccccc2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(C(C)(CO)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a solution of 5-cyclopropyl-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-phenylmethoxypropan-2-yl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 112e, 570 mg, 1.16 mmol) in dry dichloromethane (6 ml) cooled down to 0° C. under an argon atmosphere was added a 1.0M solution of boron tribromide in dichloromethane (1.28 ml, 1.28 mmol). The reaction mixture was stirred at 0° C. for 15 minutes followed by stirring at room temperature for 1 hour. The reaction was diluted with dichloromethane, quenched by addition of a 2M aqueous solution of sodium carbonate and the bi-phasic mixture was stirred for 10 minutes. The bi-phasic mixture was poured into a separatory funnel and extracted. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (394 mg, 85%). MS (ESI, m/z): 401.6 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:37])=[CH:9][CH:8]=1)(C)(C)C.CC1C=C(OC2C(N3CCCC3)=CC=CC=2NC2C3C=CN=CC=3N=CN=2)C=CC=1C(O)=O>>[CH3:37][C:15]1[CH:16]=[C:17]([NH:20][C:21]2[C:22]3[CH:30]=[C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:28]=[CH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[CH:19][C:14]=1[O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:38])=[O:5])=[CH:8][CH:9]=1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cc1cc(Oc2c(Nc3ncnc4cnccc34)cccc2N2CCCC2)ccc1C(=O)O
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared from 4-[2-Methyl-4-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid tert-butyl ester by a procedure analogous to the synthesis of 3-[2-Methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino phenoxy]-benzoic acid. LRMS: 458.3 (MH+) HPLC Rf: 5.94 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:7][C@H:6]([OH:19])[C@@H:5]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:4]1.N1C=CN=C1.[CH:33]([Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])Cl)([CH3:35])[CH3:34]>CN(C)C=O.Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C@H:5]2[CH2:4][C@@H:3]([CH2:2][O:1][Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34])[N:8]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)(=[O:10])=[O:11])[CH2:7][C@@H:6]2[OH:19])=[CH:25][CH:24]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ccc([C@H]2C[C@@H](CO)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2O)cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2C[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2O)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 19.3 g of (3R,4R,6S)-6-hydroxymethyl-4-(4-methoxy-phenyl)-1-(toluene-4-sulfonyl)-piperidin-3-ol in 400 ml of N,N-dimethylformamide is added 10.9 g of imidazole and 6.79 g of triisopropylchlorosilane at room temperature. The reaction mixture is stirred overnight, diluted with 1N hydrochloric acid and extracted with tert-butyl methyl ether. The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by flash chromatography (SiO2 60 F) to afford the title compound as a light yellow oil. Rf=0.60 (EtOAc-heptane 1:1); Rt=6.39.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[NH:11].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CC(=O)CC>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:2]([CH3:1])[C:3]2=[NH:11])=[CH:15][CH:14]=1
Reactant: Cn1c(=N)[nH]c2ccccc21
Reactant: BrCc1ccc(Br)cc1
Solvent: CCC(C)=O
Product: Cn1c(=N)n(Cc2ccc(Br)cc2)c2ccccc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 1-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine (0.30 g, 2.04 mmol) in 2-butanone (30 ml) was added 4-bromobenzyl bromide (0.70 g, 2.81 mmol). The reaction was heated to 90° C. where it was stirred for 30 min. After this time, the resulting suspension was cooled to rt and filtered. The collected solids were partitioned between dichloromethane and a saturated solution of NaHCO3 and the mixture was stirred for 10 min. The organic layer was separated and the aqueous phase was extracted with additional dichloromethane. The organic fractions were combined, washed with H2O, dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure to give 1-(4-bromo-benzyl)-3-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine as a white solid (0.39 g, 61%). HPLC-MS 316, 318 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)(Cc1ccc(Br)cc1)NC=O
Agent: Cl
Solvent: O
Product: CC(C)(N)Cc1ccc(Br)cc1

Procedure:
28.0 g (109 mmol) N-[2-(4-bromo-phenyl)-1,1-dimethyl-ethyl]-formamide (I35) are added to 102 mL water and 101 mL (1218 mmol) conc. HCl and stirred at reflux for 8 h. Then heating is stopped and the mixture is stirred at r.t. over night. The precipitate is filtered, washed with TBME and dried in vacuo.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:21])[NH:9][CH:10]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[CH2:11]O)(C)(C)C>C1COCC1>[F:19][C:17]1[CH:18]=[C:13]([CH:10]2[CH2:11][O:21][C:8](=[O:7])[NH:9]2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(CO)c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(c2cc(F)cc(F)c2)CO1
Reaction time: 3 h

Procedure:
Into a well-stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at R.T. was added a solution of [1-(3,5-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in THF (20 mL) via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et2O, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf=0.15, 3:2 hexane-EtOAc) to obtain 4-(3,5-difluorophenyl)-oxazolidin-2-one as a white flaky solid (2.8 g, 77% yield). M.P. 81–83° C.; 1H NMR (300 MHz, CDCl3) δ 7.23–7.03 (m, 3H), 6.08 (br s, 1H), 4.94 (dd, J=6.6 Hz, J=8.7 Hz, 1H), 4.73 (t, J=8.7 Hz, 1H), 4.13 (dd, J=6.6 Hz, J=8.7 Hz, 1H). The enantiomers were separated by HPLC on a Chiralcel OD (20×250 mm) column using 80% hexane/20% isopropyl alcohol as the eluting system at 12.0 mL/min (U.V. 254 nm). The retention times for the two isomers were 16.19 min and 20.08 min respectively.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.BrC[C:21]1[CH:26]=[CH:25][CH:24]=C[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[CH:25][CH:26]=[CH:21][N:22]=2)[CH:3]=1
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(Br)cc1NCc1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 2-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 1 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give the title compound (336 mg, 68%) as a yellow solid:
Reaction SMILES: C=C1C(C([O-])=O)N2C(=O)C[C@H]2SC1.C=C1C(C(O)=O)N2C(=O)C[C@H]2SC1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)CC.CC(O[CH2:60][C:61]1[CH2:70][S:69][C@@H:64]2[C@H:65]([NH2:68])[C:66](=[O:67])[N:63]2[C:62]=1[C:71]([OH:73])=[O:72])=O.O(CC)C([S-])=S>[Ni]>[CH2:60]=[C:61]1[CH:62]([C:71]([OH:73])=[O:72])[N:63]2[C:66](=[O:67])[CH:65]([NH2:68])[C@H:64]2[S:69][CH2:70]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Ni]
Agent: C=C1CS[C@@H]2CC(=O)N2C1C(=O)O
Agent: C=C1CS[C@@H]2CC(=O)N2C1C(=O)[O-]
Solvent: CCC(=O)O
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)O

Procedure:
Consequently, when it is desired to prepare a 3-methylenecepham-4-carboxylate of the Formula I, wherein R1 is a carboxylic acid protecting group which is susceptible to cleavage under the conditions of the reductive displacement reaction, the unprotected 3-methylenecepham-4-carboxylic acid can be first prepared. Following the reductive displacement reaction the 3-methylenecepham-4-carboxylic acid reduction product can be isolated and then protected with the desired ester group by esterification or the mixed anhydride thereof with acetic or propionic acid can be prepared according to well known procedures. For example, 3-ethoxythionocarbonylthiomethyl-7-amino-Δ3 -cephem-4-carboxylic acid, obtained by the reaction of 7-aminocephalosporanic acid (7ACA) with ethyl xanthate, is hydrogenated in the presence of Raney nickel to yield 3-methylene-7-aminocepham-4-carboxylic acid. The cepham acid is then acylated and esterified according to known procedures to obtain the desired ester of the Formula I.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:38])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C@@H:16](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].O.Cl>N1C(C)=CC(C)=CC=1C>[C:1]([O:4][CH2:5][C:6](=[O:38])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 78.5 %

Procedure:
A solution of (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g) in collidine (350 ml) was heated under reflux for 2 h. The reaction mixture was poured into water (3.5 l) containing hydrochloric acid (614 ml; 5M) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave a mixture (3:1) (18.8 g) of (5α)-21-(acetyloxy)pregn-2-ene-11,20-dione and its 3-ene-isomer.
Reaction SMILES: [CH3:1][CH:2]([C:4]1([S:14][CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH3:3].Cl[CH2:17][CH2:18][O:19]C1CCCCO1>>[OH:19][CH2:18][CH2:17][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH:2]([CH3:1])[CH3:3])([S:14][CH3:15])[C:5]1=[O:13]
Reactant: ClCCOC1CCCCO1
Reactant: CSC1(C(C)C)C(=O)Nc2ccccc21
Product: CSC1(C(C)C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-(1-methylethyl)-3-methylthio-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(C#N)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cccc(C#N)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 3-(3-cyano-phenyl)-acrylic acid methyl ester (3.24 g, 17.31 mmol), prepared in Step B of Preparation 44, and palladium on carbon (10%, 0.600 g) in EtOAc (30 mL) was hydrogenated at 25 psi in a Parr shaker for 1h. The catalyst was removed via filtration through Celite and the solution was concentrated in vacuo. Medium pressure chromatography (6:1 hexanes:EtOAc) provided the title compound of Step A as a clear oil (2.98 g). 1H NMR (400 MHz, CDCl3) δ 7.50-7.36 (m, 4H), 3.65 (s, 3H), 2.97 (t, 2H), 2.63 (t, 2H); MS 190 (M+1).
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[CH:12]1([C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(O)[CH:16]=[CH2:17])[CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=[O:2])[CH2:14][CH2:13]1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: C=CC(O)(c1ccc(Cl)cc1)C1CC1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a stirred solution of 51.3 grams (0.192 mole) of pyridinium chlorochromate in 210 mL of methylene chloride was added in one portion a solution of 20.0 grams (0.096 mole) of 1-cyclopropyl-1-(4-chlorophenyl)-2-propen-1-ol in 25 mL of methylene chloride. Upon completion of addition the reaction mixture was stirred at ambient temperature for two hours. The supernatent liquid was decanted from a residue, and the residue was extracted with diethyl ether. The decantate and the extract were combined and were washed in turn with two 100 mL portions of aqueous 5% hydrochloric acid, and a 50 mL portion of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel using 5% diethyl ether in hexane as the eluant. The appropriate fractions were combined and concentrated under reduced pressure yielding 6.8 grams of 3-cyclopropyl-3-(4-chlorophenyl)propenal.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[C:4]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1COS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of the product of part (d) (1 g) and triethylamine (0.51 ml) in dichloromethane (10 ml) was cooled to 0° C. Methanesulfonyl chloride (0.29 ml) was then added dropwise and the reaction was allowed to reach room temperature. After stirring for 3 hours the reaction was diluted with dichloromethane, washed with water, NaHCO3 (aq), brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as an oil (1.13 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>CC(N(C)C)=O>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([CH2:6][N:1]=[N+:2]=[N-:3])[CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
Add sodium azide (0.3 g, 4.8 mmol) to a solution of methyl 3-bromomethylbenzoate (1.00 g, 4.4 mmol) in 10 mL of dimethylacetamide. Stir at room temperature for several h, pour mixture into ice water and extract with EtOAc. Wash combined extracts 4 times with H2O, brine and dry over sodium sulfate. Filter the mixture and concentrate to afford 0.81 g, 97% yield of 3-azidomethyl-benzoic acid methyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.C[Li].[Cl-].[NH4+].[C:16](OCC)(=O)C>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=1[C:7](=[O:9])[CH3:16]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 5-bromo anthranilic acid (50 g, 0.231 mol) in anhydrous THF (500 mL) at 0° C. under nitrogen was added in a dropwise manner methyllithium (1.4 M in diethyl ether, 661 mL, 0.926 mol). After addition, the reaction mixture was slowly allowed to warm to room temperature, stirred overnight, and treated with aqueous saturated ammonium chloride solution (1000 mL). Ethyl acetate (400 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Mg2SO4) and concentrated. The residue was purified by a flash chromatography on silica gel (hexane:ethyl acetate/9:1) to afford the title compound as a brown solid (29.3 g, 59%). MS (ES) m/z 214/216 ([M+H]+, 100%).
Reaction SMILES: Cl.C([N:4]1[CH2:9][CH2:8][N:7]([C:10]([NH:13][NH2:14])=[N:11][CH3:12])[CH2:6][CH2:5]1)=O>CO>[NH:13]([C:10](=[N:11][CH3:12])[N:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)[NH2:14]
Reactant: CN=C(NN)N1CCN(C=O)CC1
Agent: Cl
Solvent: CO
Product: CN=C(NN)N1CCNCC1
Reaction time: 8 h

Procedure:
10 g of the hydrochloride of 1-formyl-4-[hydrazino(methylimino)methyl]piperazine are dissolved in 250 ml of methanol. 50 ml of HClconc. are added, the mixture obtained is stirred overnight and the solvent is evaporated. A solid residue is obtained which is dried over solid KOH. The trihydrochloride of 1-[hydrazino(methylimino)methyl]piperazine is obtained in form of a white product.
Reaction SMILES: [CH3:1][Li].[N:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CCOCC.O1CCCC1>[OH:20][C:13]1([CH3:1])[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[CH:10]=[C:9]([N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2
Reactant: [Li]C
Reactant: O=c1c2ccccc2cc(N2CCCCC2)c2ccccc12
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2C=C(N2CCCCC2)c2ccccc21
Temperature: 0 °C

Procedure:
A solution of 140 ml. of 1.8 molar methyl lithium in ether and 250 ml. of ether at 5°-10° C. under nitrogen was treated dropwise with a solution of 59 g of 10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-one in 250 ml of tetrahydrofuran. After a total of 2 hours, the mixture was poured onto ice and allowed to stand until the ice melted. The mixture was extracted well with ether and the extract was dried (Na2SO4), filtered, and concentrated to dryness, the residue being used directly in the next step.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)([CH3:4])=[O:3].[Cl-].[NH4+]>CO.O.[Fe]>[CH3:4][P:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([CH3:1])=[O:3]
Reactant: CP(C)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CP(C)(=O)c1cccc(N)c1
Yield: 100.1 %

Procedure:
To a solution of compound 286 (1.5 g, 7.5 mmol) in methanol (62 ml) and water (12 ml) under nitrogen at room temperature was added ammonium chloride (0.604 g, 11.3 mmol) and iron (1.68 g, 30.1 mmol). The resulting mixture was heated to reflux for 30 min then filtered through celite. The celite pad was rinsed with methanol. The filtrate and washings were combined and concentrated and the residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) to afford compound 287 as a yellow solid (1.27 g, 7.51 mmol, quantitative). MS (m/z): 170.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([F:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[C:17]([F:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added dropwise to 90 (180 mg, 0.551 mmol) dissolved in CH2Cl2 (3 mL) at 0° C. The reaction mixture was stirred at RT for 2 h and the volatiles were removed under reduced pressure. Water (30 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (30 mL), brine (30), and dried over MgSO4. Concentration followed by recrystallization (EtOAc) afforded 99 mg (64%) of 91 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (br s, 6H), 2.13 (br s, 4H), 6.51 (d, J=16.0 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.85-6.91 (m, 4H), 7.59 (d, J=16.0 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H), 9.36 (s, 1H), 12.51 (br s, 1H). LRMS (APCI): m/z 353 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:13])[NH:5][CH:6]=[N:7]2)=[C:2]([O:17][CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: CC(C)O
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Product: CC(C)Oc1cc(F)cc2nc[nH]c(=O)c12
Yield: 73 %

Procedure:
5,7-Difluoro-3,4-dihydroquinazolin-4-one was reacted with isopropanol to give 7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one in 73% yield; NMR Spectrum: (DMSOd6) 1.31 (s, 6H), 4.73 (m, 1H), 6.89 (m, 1H), 6.95 (m, 1H), 7.96 (s, 1H); Mass Spectrum: M+H+ 223.