Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11](OC)[O:12]C)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncccc1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ncccc1C=O

Procedure:
To a solution of 3-(dimethoxymethyl)-2-pyridinecarboxylic acid methyl ester (1.02 g) in dioxane (20 mL) was added water (20 mL), followed by p-toluenesulfonic acid (0.30 g). This solution was heated at 55°-60° C. for 24 hours. The reaction mixture was cooled, diluted with water (50 mL), treated with aqueous saturated sodium bicarbonate until the pH was 7.5-8.0, and extracted with methylene chloride (3×). The combined organic extracts were washed with dilute brine (3×), dried (K2CO3) and evaporated to afford a light yellow solid which yielded 540 mg (62.5%) of an almost pure product.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[CH2:4][C@H:2]1[OH:3].C[O:21][P:22](OC)([O:24]C)=[O:23].P(Cl)(Cl)(Cl)=O>>[P:22]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[C@H:2]([OH:3])[CH2:4]1)([OH:24])([OH:23])=[O:21]
Reactant: COP(=O)(OC)OC
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)O)C[C@H]2O)c(=O)[nH]1

Procedure:
3′-Deoxyguanosine (Compound 1, commercial product from Sigma, 50 mg, 0.19 mmol) was stirred overnight with trimethylphosphate (2 mL) and phosphorus oxychloride (53 μL, 0.57 mmol) at 6° C. The reaction was quenched by adding 20 mL of water and neutralizing with 1 M NaHCO3. DEAE-Sephadex chromatography using a linear gradient of 0–0.9 M TEAB afforded Compound 3 (yield: 45 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)N(Cc2ccccc2)Cc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(Cc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 144-145° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([CH3:12])=[C:8]([CH:10]=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15]>>[CH2:18]([O:17][C:13](=[O:16])[NH:14][N:15]=[CH:10][C:8]1[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:6][C:7]=1[CH3:12])[CH3:19]
Reactant: CCOC(=O)NN
Reactant: Cc1[nH]c(C(C)(C)C)nc1C=O
Product: CCOC(=O)NN=Cc1nc(C(C)(C)C)[nH]c1C

Procedure:
A 6.17 gm. portion of 2-tert-butyl-5-methyl-4-imidazolecarboxaldehyde and 4.20 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 226°-228.5° C.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:11][N:6]1[C:5]2[CH:12]=[CH:13][C:2]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[CH:3][C:4]=2[N:8]([CH3:9])[C:7]1=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(=O)n(C)c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1c(=O)n(C)c2cc(-c3cccnc3)ccc21
Yield: 31.8 %

Procedure:
A mixture of 5-Bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (121 mg, 0.5 mmol), 3-pyridyl boronic acid (68 mg, 0.55 mmol), polymer-supported Pd(PPh3)4 (0.09 mmol/g, 278 mg, 0.025 mmol) and Na2CO3 (2 M in water, 0.55 mL, 1.1 mmol) in DME (3.3 mL) was heated to reflux for 1 hr. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-7.5%) and yielded the title compound (38 mg). MS (ESI) m/z 240.0 (M+H), retention time 1.00 min. 1H NMR (400 MHz, CD2Cl2) δ ppm 3.47 (s, 3H), 3.49 (s, 3H), 7.13 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 7.38-7.40 (m, 1H), 7.41-7.44 (m, 1H), 7.95-7.98 (m, 1H), 8.60 (m, 1H), 8.90 (s, 1H).
Reaction SMILES: Br.[CH3:2][O:3][CH:4]([O:24][CH3:25])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH2:33]([O:40][C:41](ON1C(=O)CCC1=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([O:40][C:41]([N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH:4]([O:3][CH3:2])[O:24][CH3:25])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(CNCCCCCCOCCCCc1ccccc1)OC
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(CN(CCCCCCOCCCCc1ccccc1)C(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 4.15 g (9.93 mmol) N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine hydrobromide in 40 ml acetone is added 1.4 ml triethylamine and 2.41 g (10.71 mmol) N-(benzyloxycarbonyloxy)succinimide. After allowing the mixture to stir for 2 hr at room temperature, acetone is evaporated of f and 40 ml Et2O is added thereto. The resulting mixture is washed three times with 40 ml H2O. Once separated, the ether phase is dried on anhydrous Na2SO4 and evaporated to dryness, to yield 4.46 g (95.3%) N-benzyloxycarbonyl-N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C(Cl)=NC(Cl)=NC=1[Cl:12]>>[Cl:12][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][CH3:1]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCC(O)CC
Product: CCCCCC(Cl)CC

Procedure:
Using a procedure analogous to that of Example 1, 81 g (0.522 mol) of 3-octanol is reacted with 62.1 g (0.337 mol) of cyanuric chloride over a period of 9 hours at a reaction temperature of 70° C. The liquid reaction phase after extraction with sodium hydroxide has the following composition:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([OH:13])[CH3:12])=[CH:3][CH:2]=1>ClCCl.[O-2].[Mn+2]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: CC(O)c1ccnc2ccccc12
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1ccnc2ccccc12
Temperature: 25 °C
Yield: 100 %

Procedure:
To the mixture of manganese oxide (8.69 g, 100 mmol, Aldrich) in dichloromethane (80 mL) was added 1-quinolin4-yl-ethanol (1.73 g, 10 mmol). The reaction mixture was refluxed for overnight and then cooled to room temperature. The solid was filtered out through Celite pad. The organic solution dried over anhydrous magnesium sulfate and concentrated via vacuo to give crude title compound as light yellow solid in 100% yield (1.71 g, 10.0 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:24]=[CH:23][C:22]=3[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:50])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:50])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:24]=[CH:23][C:22]=3[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 108.9 %

Procedure:
To a stirred solution of (2R,5R)-4-{2-[6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.572 g, 0.97 mmol) and triethylamine (0.22 mL, 0.157 g, 1.55 mmol) in DCM (10 mL) at −10° C. under nitrogen was added a solution of methanesulfonyl chloride (0.09 mL, 0.133 g, 1.2 mmol) in DCM (5 mL). Mixture was stirred at 20° C. for 18 h then partitioned between saturated aqueous NaHCO3 (50 mL) and DCM (3×30 mL) and combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (0.576 g) as an oil, used without further purification. MS: [M+H]+=545.
Reaction SMILES: [CH3:1][CH:2]1[CH2:12][CH2:11][CH2:10][C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]1=2)=O.[Cl:13][C:14]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:17]([NH2:18])=[C:16]([F:25])[CH:15]=1.O>C1(C)C=CC=CC=1.CN(C1C=CC=CN=1)C>[Cl:13][C:14]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:17]([N:18]2[C:8](=[O:9])[C:3]3[CH:2]([CH3:1])[CH2:12][CH2:11][CH2:10][C:4]=3[C:5]2=[O:7])=[C:16]([F:25])[CH:15]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: CC1CCCC2=C1C(=O)OC2=O
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(C2=O)C(C)CCC3)c(F)cc1Cl
Reaction time: 2 h
Yield: 81.9 %

Procedure:
15.4 g (0.093 mol) of 3-methyl-3,4,5,6-tetrahydrophthalic acid anhydride are dissolved in 90 ml of toluene. 18.4 g (0.093 mol) of 4-chloro-2-fluoro-5-isopropoxyaniline and 0.6 g of dimethylaminopyridine are added and the mixture is heated until the solvent and the water that has formed distil off. After approximately 2 hours at a bath temperature of 145° C. the reaction is complete. The residue is chromatographed over a column of silica gel with hexane/ethyl acetate 9:1. As main fraction there are obtained 26.8 g (82.0%) of the title compound (Compound No. 1.030) of the formula ##STR9## in the form of an oil, nD22 =1.5458.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C1CCCCC1>[CH2:20]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccc(C2c3ccccc3-c3nccn32)cc1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Brc1ccc(C2(Cc3ccccc3)c3ccccc3-c3nccn32)cc1
Temperature: -40 °C

Procedure:
To a solution of 5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (5 g) in THF (100 mL) at −78° C. was added LAD solution (21.42 mL, 1.5 M in cyclohexane). After stirring for 15 minutes benzylbromide was added and the reaction mixture was stirred at −40° C. After 20 minutes more benzylbromide (3 mL) was added and continued to stir at −40° C. for 40 minutes. The reaction was then quenched with aqueous saturated NH4Cl and partitioned between aqueous saturated NH4Cl and EtOAc. Aqueous layer was extracted with EtOAc (2×). Combined organic layers were dried over Na2SO4 and concentrated. The resulting yellow solid was recrystallized from hot EtOAc to yield title compound as a white solid. HRMS. Found, 401.0647; calcd for (M+H)+, 401.0648. 1HNMR (500 MHz, CDCl3): δ 7.62 (d, J=7.1 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.36 (dd, J=7.1, 0.9 Hz, 1H), 7.33-7.27 (m, 2H), 7.24 (s, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.03 (t, J=7.8 Hz, 1H), 6.95 (t, J=7.8 Hz, 2H), 6.91 (s, 1H), 6.56 (d, J=7.6 Hz, 2H), 3.78 (s, 2H).
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[S:18])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(O[C@@H:26]1[NH:29][C:28](=[O:30])[C@H:27]1[O:31][CH3:32])(=O)C.O1CCOCC1.C(Cl)Cl>P([O-])([O-])([O-])=O>[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([S:18][C@H:26]2[NH:29][C:28](=[O:30])[C@@H:27]2[O:31][CH3:32])=[O:19])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C(NCCCC([O-])=S)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO[C@@H]1C(=O)N[C@H]1OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 55b), an aqueous solution of 480 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt is added to 159 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 6 ml of a phosphate buffer of a pH of 7 and 0.4 ml of dioxan. After working up and chromatography over silica gel, the title compound with the following IR spectrum (CH2Cl2) is obtained:
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[N:4][C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH2:62][C@H:63]1[CH2:66][CH2:65][N:64]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[N:4][C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([NH:61][CH2:62][C@H:63]1[CH2:66][CH2:65][N:64]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[O:8]
Reactant: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)O)cc2F)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)NC[C@H]3CCN3C(=O)OC(C)(C)C)cc2F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinic acid (14.3 g, 40 mmol) and DMF (300 mL) was added of HBTU (18.2 g, 48 mmol) and HOBT (6.49 g, 48 mmol). The mixture was cooled down to 0° C., 8.93 g (48 mmol) of (R)-tert-butyl 2-(aminomethyl)azetidine-1-carboxylate was added, followed by 13.9 ml of DIEA (80 mmol). The mixture was stirred at r.t for 1 hour and extracted with 300 mL EtOAc. The organic layer was washed with 500 mL brine, dried over MgSO4 and then concentrated. The residue was purified by Biotage silica gel chromatography using EtOAc:Hex (1:1) as eluant. (R)-tert-butyl 2-((5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)methyl)azetidine-1-carboxylate was obtained as a yellow solid (16.5 g, yield 80%). LRMS (M+H+) m/z 527.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br-].[Li+].[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])#[N:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CN1CCCC1=O
Agent: [Br-]
Agent: [Li+]
Product: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 175 °C
Reaction time: 24 h

Procedure:
In a flask were placed 1.13 grams (g) (5.0 mmol) 4-chloro-3-nitrobenzotrifluoride, 0.4478 g (5.0 mmol) cuprous cyanide, 0.4342 g (5.0 mmol) lithium bromide and 10 milliliters (ml) N-methyl-2-pyrrolidinone, under a nitrogen blanket. The reaction mixture was then heated to a temperature of 175° C. and reaction was continued at a range of 172°-178° C. over a period of 24 hours. At the end of that run, the heat source was removed and the reaction mixture cooled. Product was recovered by washing with water, 3M HCl, diethyl ether, again with 3M HCl, and again with ether. The ether extract was dried over magnesium sulfate, filtered and the solvent stripped, yielding 0.875 g (81% of theoretical yield) of an amber, somewhat tarry looking oil, which was identified by gas chromatographic analysis as the desired product.
Reaction SMILES: [CH:1]([NH:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:2].[C:15](Br)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH:1]([NH:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[CH:9][CH:8]=1)=[O:2]
Reactant: CC(C)(CCc1ccccc1)NC=O
Reactant: CC(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(CCC(C)(C)NC=O)cc1
Temperature: 25 °C

Procedure:
N-Formyl-3-phenyl-1, 1-dimethylpropanamine (115 g) was dissolved in 1,2-dichloroethane (850 ml) at 0° C. Acetyl bromide (116 ml) was added followed by the portionwise addition of aluminum chloride (263 g) over 0.5 h. At the end of addition the mixture was allowed to warm to room temperature and then refluxed for 1h. The hot solution was poured onto crushed ice (3 Kg) and the mixture extracted with chloroform. The chloroform extracts were washed with water, sodium bicarbonate and dried (MgSO4). Evaporation of the solvent gave an oil of which 25 g was chromatographed on Kieselgel 60 (1 Kg). Elution with 1% methanol-chloroform gave the title compound as an oil (18 g). τ(CDCl3) 8.6 (6H, s) 8.4-7.75 (2H, m), 7.45 (3H, s), 7.5-7.05 (2H, m), 3.0-4.0 (1H, broad), 2.7 (2H, d, J=8 Hz), 2.15 (2H, d, J=8 Hz) 1.2 (1H, d, J=5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Cl)=[N:6][C:5]=1[C:12]([F:15])([F:14])[F:13].[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:20]=1B(O)O)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:20]2[C:21]([CH2:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:17][CH3:18])=[N:6][C:5]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)c(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloro-2-trifluoromethyl-nicotinic acid methyl ester (1.0 g, 3.7 mmol), 2,6-diethyl-phenyl boronic acid (0.78 g, 4.4 mmol), sodium carbonate (2 M aqueous solution, 4.4 mL, 8.8 mmol), and Pd(PPh3)4 (206 mg, 0.18 mmol) is refluxed in toluene for 48 hours and then cooled to room temperature. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layers are dried and the solvent removed. The crude product is purified by flash column (hexanes/ethyl acetate 8:1) to give 4-chloro-6-(2,6-diethyl-phenyl)-2-trifluoromethyl-nicotinic acid methyl ester as a white solid. 1H NMR: (CDCl3) 7.58 (s, 1H), 7.25 (t, 1H), 7.20 (d, 2H), 4.02 (s, 2.28 (q, 4H), 1.04 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C[O:15][CH2:14]C1>CCOC(C)=O>[N+:1]([C:4]1[C:5]2[NH:11][C:14](=[O:15])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Yield: 88 %

Procedure:
To 3-nitro-1,2-phenylenediamine 3a (2 g, 13.06 mmol) dissolved in THF (50 ml) was added in one portion DCI (1.5 equiv., 19.6 mmol, 3.176 g) and the reaction was refluxed for 2 hours. (TLC AcOEt 1/petroleum ether 1). The reaction was filtrated and the yellow solid material was washed with THF and diethyl ether obtaining 2 g of the product that was used for the following step without further purification. Yield=88% 1HNMR (DMSO, 200 MHz) δ 7.11 (1H, t, J=7.6 Hz), 7.31 (1H, dd, J=7.8 Hz, J′=1.2 Hz), 7.74 (1H, dd, J=8.6 Hz, J′=1 Hz), 11.45 (2H, bs)
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)C.C(O)(=O)C.[NH2:34]N>ClCCl>[CH:28]1[CH:27]=[CH:26][N:18]2[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]4[NH:34][N:2]=[CH:4][N:5]=4)=[CH:8][CH:9]=3)=[O:14])[CH2:16][C:17]=12
Reactant: NN
Reactant: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(-c2ncn[nH]2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 42.4 %

Procedure:
A mixture of N-(dimethylaminomethylene)-4-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzamide (1.0 g) from Example 46, glacial acetic acid (15 ml), and anhydrous hydrazine (0.16 g) was refluxed for 15 hours and the volatiles removed in vacuo. Saturated aqueous sodium bicarbonate solution was added and the resultant solid was recovered by filtration. The solid was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.39 g), m.p. 225-227° C.; MS, m/z: 355 (M)+.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:28]([NH:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1NC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Pyridine (43 μL, 0.54 mmol) was added to a stirred solution of aniline 21 (50 mg, 0.18 mmol) in DCM (0.9 mL) at room temperature under nitrogen atmosphere. After 5 min, benzoylchloride 3 (22.5 μL, 0.198 mmol) was added and the reaction was stirred for 2 h before being diluted with DCM and washed with HCl (3×, aq, 1M), NaHCO3 (aq, sat), and brine. The organic phase was dried over Na2SO4, concentrated and purified by column chromatography (toluene:acetone 100:0→98:2) to give benzamide 23a in 62% yield (36 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]=1[F:18].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH:10][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]=1[F:18]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cn2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.9 %

Procedure:
5-Amino-2-fluoro-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (560 mg, 1.9 mmol) was dissolved in 20 mL methylene chloride, and the mixture was cooled to 0° C. Isobutyryl chloride (221 mg, 2.1 mmol) and triethyamine (575 mg, 5.7 mmol) were added, and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 690 mg (99%) of 2-fluoro-5-isobutyrylamino-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester.