Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[O:4][N:3]=1.[N+:12]([NH:15][C:16](N)=N)([O-:14])=[O:13]>O>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:16]2=[N:15][N+:12]([O-:14])=[O:13])[O:4][N:3]=1
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: NCCNCc1cc(Br)no1
Solvent: O
Product: O=[N+]([O-])N=C1NCCN1Cc1cc(Br)no1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
N-(3-bromo-5-isoxazolylmethyl)ethylene diamine (4 g), prepared as described above, and nitroguanidine (2.5 g), were added to water (50 ml) and the reaction mixture stirred at 80° C. for 1 hour. The reaction mixture was partitioned with trichloromethane and the organic layer was separated, washed and dried. Thin layer chromatography showed a single product and was used to recover the product as a colorless solid (2.1 g). Recrystallization gave the title compound as colorless crystals (m.p. 149° C.).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[CH:8]=1>ClCCl>[OH:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[CH:8]=1
Reactant: COc1ccc2oc3ccccc3c(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c2ccccc2oc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Boron tribromide (1.0M dichloromethane solution, 50 ml, 50 mmol) was added to a mixture of 2-methoxy-9H-xanthen-9-one (5.66 g, 25.0 mmol) and dichloromethane (50 ml), and the mixture was stirred for 3 hours. The reaction mixture was poured into ice water and the reaction product was extracted with chloroform. The extract was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give the title compound (5.00 g, 23.6 mmol, 94%) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C[Li].[CH3:14]COCC>C1COCC1>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](=[O:6])[CH3:14]
Reactant: CCOCC
Reactant: Cc1cccc(O)c1C(=O)O
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1c(C)cccc1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
In a solution of 2-methoxy-6-methylbenzoic acid ethyl ester (5 g, 25.77 mmol) and NaOH (6.18 g, 154.64 mmol) in EtOH (100 mL) and water (40 mL) was stirred at reflux for 24 hours. EtOH was then removed using a rotary evaporator and the aqueous was acidified with HCl (1 N) to pH=4. Extract with CH2Cl2 (3×100 mL) followed by concentration using a rotary evaporator afforded 4.25 g, of 2-methoxy-6-methylbenzoic acid (100%) as a white solid. To a solution of 2-methoxy-6-methylbenzoic acid (1.66 g, 10 mmol) in CH2Cl2 (80 mL) at room temperature was added BBr3 in CH2Cl2 (20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 20 hour and then concentrated using a rotary evaporator. The resulting residue was re-dissolved in CH2Cl2 (50 mL), diluted with HCl (0.5 N), extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator to afford 1.52 g of 2-hydroxy-6-methylbenzoic acid (100%). To a solution of 2-hydroxy-6-methylbenzoic acid (1.52 g, 10 mmol) in THF (50 mL) at room temperature was slowly added CH3Li in ether (22 mL, 35 mmol) and the suspension was stirred at 60° C. for 6 hour. The reaction was quenched with HCl (0.5 N) aqueous and extracted with CH2Cl2 (3×100 mL). Concentration using a rotary evaporator afforded 1 g of 2′-hydroxy-6′-methylacetophenone (67%) as a brown oil. A solution of 2′-hydroxy-6′-methylacetophenone (1.0 g, 6.67 mmol) in CH2Cl2 (50 mL) at room temperature was mixed with isonicotinoyl chloride hydrochloride (2.136 g, 12 mmol) and triethylamine (3.9 mL, 28 mmol) sequentially. The resulting mixture was stirred at room temperature for 2 hours, quenched with water, and extracted with CH2Cl2 (3×100 mL) The volume was reduced using a rotary evaporator to minimal and triturated with hexanes. The solid was collected by filtration to afford 1.2 g of the corresponding isonicotinic aryl ester (70%). A solution of the above isonicotinic aryl ester (1.2 g, 4.70 mmol) in THF (50 mL) was mixed with potassium tert-butoxide (2.24 g, 20 mmol) and stirred at 65° C. for 2hours. The reaction was quenched with water and acidified with HCl (0.5 N) to pH=6. Extract with CH2Cl2 (3×100 mL) followed by concentration using a rotary evaporator afforded a yellow solid residue. It was purified by column (SiO2, hexane/EtOAc=1:1) to provide 0.72 g of the diketone (60%). A solution of the above diketone (0.7 g, 2.745 mmol) in HOAc (50 mL) was stirred at reflux for 2 hours. All the solvent was removed using a rotary evaporator to afford a solid residue. It was then diluted with water and neutralized with NaOH (0.5 N) to pH=8. The solid was collected by filtration and washed with water and hexanes sequentially to afford 0.32 g of 5-methyl-2-(pyridin-4-yl)-4H-chromen-4-one as a light yellow solid (49%).
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[C:27]1(OB(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[CH2:16][NH:15][C:13]([NH:12][C:7]1[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[NH:14]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1ncccc1Br
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1ncccc1-c1ccccc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.470 mmol) N-(3-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine acetate, 0.086 g (0.705 mmol) phenylboric acid, 0.149 g (1.411 mmol) sodium carbonate, and 0.038 g (0.033 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 20 hr at 110° C. under a nitrogen atmosphere. However, after this reaction time the starting material/product ratio was still 1:1. Therefore, further heating was performed for 16 hr, and then for an additional 25 hr. After a total reaction time of 61 hr the reaction was terminated due to increasing formation of by-products. After appropriate workup and purification via preparative HPLC, 41 mg pure N-(2,6-dimethoxybenzyl)-N′-(3-phenylpyridin-2-yl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1.2).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH3:12])[N:4]=1)#[N:2].[CH2:13]([SH:15])[CH3:14].[OH-].[Na+]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([S:15][CH2:13][CH3:14])=[C:5]([CH3:12])[N:4]=1)#[N:2]
Reactant: Cc1nc(C#N)c(C#N)nc1Cl
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Product: CCSc1nc(C#N)c(C#N)nc1C
Yield: 44.6 %

Procedure:
2,3-Dicyano-5-chloro-6-methylpyrazine (1.79 g; 0.01 mole), 0.62 g (0.01 mole) of ethanethiol and 0.40 g (0.01 mole) of sodium hydroxide were worked up in the same way as in Example 8. Recrystallization from ethanol afforded 0.91 g (yield 45%) of 2,3-dicyano-5-ethylthio-6-methylpyrazine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[C:12]#[N:13])=[C:4]([N+:22]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:26]>C(O)C.Cl>[ClH:26].[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[N:22]=[C:12]([NH2:13])[C:11]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:10]=3[NH:9][C:5]=2[CH:6]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)c(F)cc2Nc2ccc(C(F)(F)F)cc21
Yield: 63.8 %

Procedure:
Heat a solution of 2-(4,5-difluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (0.995 g, 2.90 mmol) in ethanol (15 ml) to 60° C. Add to this a solution of tin (II) chloride (1.65 g, 8.70 mmol) in 5.0 N hydrochloric acid (15 ml). Heat the resulting mixture to reflux for 18 hours. Cool the reaction to room temperature, add 30 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. Collect by filtration the precipitated product from the solution. Wash solid with 5.0 N hydrochloric acid to obtain 0.648 g of the title compound (1.85 mmol, 64% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 314(M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:35][S:36]C1C=CC(O)=CC=1>>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[CH:28][C:29]([S:36][CH3:35])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:32][CH:33]=1)=[O:4]
Reactant: CSc1ccc(O)cc1
Reactant: CN(C)C(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2ccccc2)cc1
Product: CSc1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(C(=O)N(C)C)cc2)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 1 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(4-dimethylcarbamoyl-phenoxy)-2-nitro-phenylamine obtained in Example 18 and 4-methylmercapto-phenol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34](=[O:50])[N:35]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:36]2=[O:41]>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:35]2[C:34](=[O:50])[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[CH2:31][NH:30][C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[O:9])[C:36]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: Cn1cccc1C(=O)O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cccc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
A mixture of 1-methyl-1H-pyrrole-2-carboxylic acid (0.3 g, 2.6 mmol) and carbonyl diimidazole (0.5 g, 3.0 mmol) in DMF (30 mL) was stirred for 2 hours. Triethylamine (0.8 g, 6.0 mmol) was added, followed by 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol). The mixture was stirred at 75° C. (oil bath) overnight. The mixture was cooled to room temperature and concentrated. The residue was stirred with EtOAc (80 mL) and water (30 mL). The EtOAc solution was washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 1-methyl-1H-pyrrole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.2 g, 25%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H), 4.86 (d, J=5.8 Hz, 2H), 5.13-5.20 (dd, J=5.5 and 12.7 Hz, 1H), 6.04 (t, J=3.4 Hz, 1H), 6.88-6.93 (m, 2H), 7.70-7.86 (m, 3H), 8.63 (t, J=5.8 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.98, 30.93, 36.19, 37.47, 48.86, 106.75, 112.63, 121.73, 124.98, 126.95, 128.07, 131.49, 132.96, 134.76, 140.06, 161.56, 166.98, 167.58, 169.82, 172.74; Anal. calcd. for C20H18N4O5+0.18H2O+0.1 ether: C, 60.49; H, 4.82; N, 13.83. Found: C, 60.54; H, 4.74; N, 13.50.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:24][C:25](=[O:31])OC(C)(C)C)[S:5][C:6]=1[C:7](=O)[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[S:15]C(=S)N(CC)CC.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(N(CC)C(SC1C=NC=CC=1NC(C1SC(N)=NC=1Br)=O)=S)C.C(O)=O>C([SiH](CC)CC)C>[Br:1][C:2]1[N:3]=[C:4]([NH:24][CH:25]=[O:31])[S:5][C:6]=1[C:7]1[S:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=1
Reactant: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1sc(NC(=O)OC(C)(C)C)nc1Br
Agent: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1sc(N)nc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=CO
Product: O=CNc1nc(Br)c(-c2nc3ccncc3s2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added tert-butyl 4-bromo-5-((3-(diethylcarbamothioylthio)pyridin-4-yl)carbamoyl)thiazol-2-ylcarbamate (1.0 g, 1.8 mmol) and a 1:1 mixture of TFA (0.14 mL, 1.8 mmol) and DCM (0.12 mL, 1.8 mmol) with a few drops of triethylsilane. The solution was then stirred at room temperature. LCMS indicated that the reaction was complete after about 1 hour. The solvents were removed, and the resulting oil was used without further manipulation. To a 100 mL round-bottomed flask was added 4-(2-amino-4-bromothiazole-5-carboxamido)pyridin-3-yl diethylcarbamodithioate (0.82 g, 1.8 mmol) and formic acid (0.070 mL, 1.8 mmol), and the mixture was heated at 100° C. for about 2 hours. LCMS indicated no remaining starting material, so the solvent was removed and 2 N ammonia in MeOH was added. An orange precipitate formed which was filtered and determined to be the product N-(4-bromo-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl) formamide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:9]=2)[C:4]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1.CN(C)C=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[C:74]([O:77][CH2:78]C)(=[O:76])C.CCCCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C.CO>[CH3:78][O:77][C:74]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[C:4]2[C:19]1[N:27]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:29])=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1)=[O:76]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OS(=O)(=O)C(F)(F)F)cc34)cc3cccnc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trifluoro-methanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl ester [300 mg, Reference Example 18(a)] in a mixture of dry dimethylformamide (10 mL), methanol (6 mL) and triethylamine (2 mL) was treated with palladium acetate (24 mg) and 1,3 bis(diphenylphosphino)propane and the mixture stirred at ambient temperature for 30 minutes. Carbon monoxide was introduced via a septum to the reaction vessel at a steady rate and the mixture heated at 90° C. until no starting material was present as indicated by TLC (ethyl acetate/pentane: 2/3). The mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with a saturated solution of lithium chloride, then dried over sodium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:3, v/v) to give the title compound (200 mg) as a colourless solid. MS: 460(MH+). HPLC (METHOD A):: RT=10.23 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[S:31][C:30](=[S:32])[NH:29][N:28]=1>C1COCC1>[S:32]=[C:30]1[S:31][C:27]([NH:26][C:6]([CH:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:7])=[N:28][NH:29]1
Reactant: CCOC(=O)C(C(=O)O)C(C)(C)C
Reactant: Nc1n[nH]c(=S)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Nc1n[nH]c(=S)s1)C(C)(C)C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of tert-butylmalonic acid monoethyl ester (3.0 g, 16.0 mmol) in THF (100 mL) is added carbonyldiimidazole (2.85 g, 17.6 mmol) and the reaction is stirred overnight. 5-Amino-(3H)-1,3,4-thiadiazole-2-thione (864 mg, 6.5 mmol) is added and stirring continued for an additional 72 hours. The reaction mixture is 35 poured into pH 4 buffer, extracted with methylene chloride, and the organic layers combined, dried (anhydrous sodium sulfate) and concentrated. Chromatography of the residue on silica gel (elution with 5% methanol/methylene chloride) gave 1.2 g (25%) of the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[S:19])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2Nc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1Nc2ccc(Cl)cc2Nc2ccccc21
Reaction time: 1 h

Procedure:
A mixture of 7-chloro-5,10-dihydro-11H-dibenzo[b,e]-[1,4]diazepin-11-one (30.5 g., 0.125 mole), phosphorus pentasulfide (27.8 g., 0.131 mole) and one l. of pyridine is heated at reflux temperature for 4 hours and the pyridine is evaporated in vacuo. The residue is stirred for 1 hour with one l. each of saturated aqueous sodium bicarbonate and methylene chloride and filtered to remove some solid product. The organic layer of the filtrate is washed successively with sodium bicarbonate solution and with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue is combined with the solid obtained above and triturated with hot chloroform and methanol. In this way, 12.2 g. of 7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione of melting point 274°-275° C is obtained. Concentration of the chloroform-methanol washings affords an additional 8.4 g. of product having the same melting point. Recrystallization from dimethylformamide-water gives an analytically pure sample in the form of pale yellow needles of melting point 276°-277° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH2:23][CH3:24])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[C:32]#[N:33])#[N:27].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:28]([C:26]#[N:27])[C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([CH3:37])[CH:36]=2)[C:32]#[N:33])[C:12]([CH2:23][CH3:24])=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(C#N)c1cc(C)cc(C#N)c1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a stirred mixture of 2,4-bis-benzyloxy-6-chloro-5-ethyl-pyrimidine (9.89 g, 27.87 mmol) and 3-cyanomethyl-5-methyl-benzonitrile (4.15 g, 26.55 mmol) in anhydrous DMF (50 mL) in an ice-water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (2.34 g, 58.4 mmol). After stirring for 1 hr, the mixture was stirred at room temperature for overnight. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and recrystallized from dichloromethane-hexane to afford 10.3 g (82%) a pale yellow solid; m.p. 139-141° C.; 1H NMR (200 MHz, CDCl3) δ: 1.00 (3H, t, J=7.6 Hz), 2.37 (3H, s), 2.52-2.58 (2H, m), 5.29 (1H, s), 5.49 (4H, s), 7.27-7.50 (10H, m); m/z (EI): 474 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])=[O:20])=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Product: O=C(NCC(F)(F)F)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 65 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran to the title compound (83 mg, 65%) which was obtained as a white solid. MS: m/e=379.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[C:13]([O:17][C:18]([O:20][C:21]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[C:30]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])=[CH:48][C:47]=3[CH:57]=[N:58]O)=[CH:42][CH:41]=2)[C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl.C(OCC)(=O)C.C(O)C>[C:13]([O:17][C:18]([O:20][C:21]1[C:33]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:31]=[C:30]([CH2:38][O:39][C:40]2[CH:41]=[CH:42][C:43]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])=[CH:48][C:47]=3[C:57]#[N:58])=[CH:44][CH:45]=2)[C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C=NO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Triethylamine (71 μl, 0.51 mmol) and methanesulfonyl chloride (23 μl, 0.31 mmol) were added to a solution of crude tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-[(hydroxyimino)methyl]-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (170 mg) obtained in the above in dichloromethane (4 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. Triethylamine (71 μl, 0.51 mmol) was added to a solution of the obtained residue in ethanol (4 ml) and the mixture was heated under reflux for 14 hours. The solvent was removed under reduced pressure and the obtained residue was subjected to silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=2/1) to give crude tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-cyano-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (125 mg).
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])=[O:6])C.C1(C)C=CC=CC=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([NH:31][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])=[O:6])[CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)C(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.3 %

Procedure:
To a suspension of 44.0 g (164 mmol) of N-(4-methoxy-2-nitro-phenyl)oxalamic acid ethyl ester [J. Med. Chem., 18, 926 (1975)] and 330 ml toluene 16.8 ml (170 mmol) of n-butylamin is added under 20° C. The reaction mixture is stirred at room temperature for 10 h, then concentrated and the residue is crystallized with diethyl ether, the precipitated product is filtered off, washed with diethyl ether and dried to yield 45.3 g (93.3%) of the title compound. Mp.: 127-128° C. (diethyl ether).