Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7][CH2:6]2)=[CH2:2].ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[O:19]1[CH2:2][CH:1]1[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7][CH2:6]2
Reactant: C=Cc1ccc2c(c1)CCOC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCCc2cc(C3CO3)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6-Vinyl-3,4-dihydro-1H-isochromen-1-one (36.0 g, 207 mmol, 1.0 eq) was added into a 500 mL round bottom flask and dissolved in dichloromethane (500 mL). The solution was cooled to 0° C., added portion wise 3-chloroperoxybenzoic acid (98.0 g, 413 mmol, 2.0 eq). The mixture was then purged with N2 and stirred at r.t. for 18 hr. To above solution was added water (100 mL). The crude product was extracted with dichloromethane. The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained. LC-MS (IE, m/z): 191.27 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 8.07 (1H, aromatic, d, J=8.1 Hz), 7.32 (1H, aromatic, d, J=8.0 Hz), 7.16 (1H, br-s, aromatic), 4.52 (2H, CH2—O—, t, J=5.7 Hz), 3.90 (1H, br-s), 3.20 (1H, m), 3.05 (2H, CH2—CH2—O—, t, J=5.7 Hz), 2.77 (1H, m).
Reaction SMILES: S([O-])([O-])(=O)=O.CS[C:8]([NH2:10])=[NH2+:9].CSC(N)=[NH2+].O.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][NH:25][C:8]([NH2:10])=[NH:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(N)=[NH2+]
Reactant: NOCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: N=C(N)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 30.0 g. (0.12 moles) of S-methylthiouronium sulfate in 200 ml. of H2O there is added a solution of 24.6 g. (0.20 moles) of benzyloxyamine in 250 ml. of 95% ethanol. The mixture is stirred for 72 hours at room temperature. The clear solution is heated at reflux for two hours under a stream of nitrogen. The solvents are removed in vacuo and the residue is treated with 300 ml. of isopropanol. The solid is removed by filtration and dissolved in 300 ml. of water. The solution is made basic with 90 ml. of 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried to give benzyloxyguanidine, m.p. 104°-5° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10]([CH:14]1CC2O[CH:15]1C=C2)(OC)=[O:11].Cl.C(Cl)Cl>O>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10](=[O:11])[CH:14]=[CH2:15])[CH3:2]
Reactant: COC(=O)C1CC2C=CC1O2
Reactant: CCCCC(CC)CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NCC(CC)CCCC
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 64.5 parts 2-ethylhexylamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 30° to 35° C. during cooling. The reaction medium is then stirred for 15 hours and neutralised with 4 parts concentrated hydrochloric acid. 100 parts methylene chloride and 50 parts water are added, the organic phase separated off, and the aqueous phase extracted twice with 25 ml methylene chloride in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and a vacuum of 20 Torr. The residue is heated under a high vacuum to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over. 66.6 parts N(2-ethylhexyl)acrylamide with a boiling point of 123° C. at 0.4 Torr are obtained.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](=[O:24])[CH3:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[CH3:29][N:30]([CH3:32])/[CH:31]=[CH:23]/[C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:26])[N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/C=C/N(C)C)cc2OCC3)n(C(C)C)n1
Reaction time: 8 h

Procedure:
1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)ethanone (2.6 g, 0.0074 mol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (0.98 mL, 0.0074 mol) was mixed in Xylenes (30 mL, 0.07 mol) and was heated to reflux and stirred overnight. LCMS showed complete conversion to desired product. The solvent was removed and (E)-3-(dimethylamino)-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)prop-2-en-1-one was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][N:39]2[N:42]=[CH:43][C:44](B3OC(C)(C)C(C)(C)O3)=[C:38]2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>O.CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:44]3[CH:43]=[N:42][N:39]4[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][C:38]=34)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccn2ncc(B3OC(C)(C)C(C)(C)O3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 21 %

Procedure:
To a 25 mL reaction flask equipped with magnetic stir bar and thermometer was added tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol) and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (124 mg, 0.479 mmol), followed by potassium carbonate (325 mesh powder) (110 mg, 0.798 mmol), DMA (10 mL), and water (0.667 mL). The mixture was stirred at room temperature for 3 min before degassing with vacuum and N2 back-fill (5×). To the resulting deep purple mixture was added Pd-118 (10.89 mg, 0.016 mmol). The reaction mixture was degassed again with vacuum and N2 back-fill (5×). The flask was wrapped tightly with plastic film, placed in an oil bath, and the reaction mixture was stirred at 80° C. for 18 hours. Solid N-acetyl cysteine (65.2 mg, 0.399 mmol) was added and the mixture was stirred at 70° C. for 2 h. The mixture was subsequently diluted with water and extracted with EtOAc (200 mL). The organic layer was dried and concentrated to give a residue, which was purified by preparative HPLC, eluting with a gradient of 45-70% ACN (0.035% TFA) and water (0.05% TFA). The fractions were collected to give, upon basic work-up, the title compound as a light yellow solid (50 mg, 21%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:2]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:16])[CH:2]=1
Reactant: OCCCCCCc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCCCCc1cccnc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A solution of 22 g of 6-(3-pyridyl)hexanol in 100 ml of chloroform was cooled in an ice bath and treated with a solution of 21.9 g of thionyl chloride in 50 ml of chloroform. The reaction mixture was allowed to warm to room temperature over 1 hour, was heated to a bath temperature of 60° C. for 1 hour and was concentrated. The residue was taken up in chloroform, washed with saturated potassium carbonate, dried, and evaporated. The residue was distilled to give 20.5 g (84%) of 6-(3-pyridyl)hexylchloride, bp 180°-190° C./0.15 mm.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Br-].[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:19][CH2:20]2)=[CH:16][CH:15]=1.[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O>CCCCCC>[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:18]1[C:17]2[C:21](=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH2:20][CH:19]=1
Reactant: COC(=O)CCCCCC=O
Reactant: COc1ccc2c(c1)CCC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)CCCCCCC1=CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 9.625 g. of potassium t-butoxide in 60 ml. of dimethylsulfoxide is added dropwise a solution of 40 g. of the phosphonium salt of Example 1 in 300 ml. of dimethylsulfoxide. After six minutes an equimolar amount (12.93 g.) of methyl-6-formylhexanoate is added dropwise just discharging the red color of the reaction mixture. The mixture is stirred for 1 hour at room temperature, and then poured into 1 liter of ice-water and 350 ml. of hexane. It is shaken, the white triphenylphosphine oxide is filtered off and the aqueous layer is extracted with ten 75 ml. portions of hexane. The combined hexane extracts are successively washed with four 250 ml. portions of (1:1) dimethylsulfoxide-water, four portions of water and one 300 ml. portion of saturated salt solution. After drying over magnesium sulfate the hexane mixture is concentrated to a yellow oil containing 6-methoxy-Δ3,ω -indanheptanoic acid methyl ester (Compound 3). The yellow oil is dissolved in chloroform (200 ml.) and to this is added 5 drops of trifluoroacetic acid. The mixture is allowed to stand at room temperature for 4.5 hours and then concentrated to dryness in vacuo. Upon trituration with hexane (15 ml.) 6-methoxy-3-indeneheptanoic acid methyl ester (Compound 4) separates in crystalline form, m.p. 30°-31.5°C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH:25](=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CCCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere and at −78° C., n-butyl lithium (a 1.60M hexane solution, 0.688 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The mixture was stirred at −78° C. for 1 hour. After addition of butanal (0.108 ml, 1.20 mmol), the mixture was stirred at −78° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane) as a low-polarity isomer to yield by a colorless solid. The solid thus obtained was washed with hexane, whereby the title compound (30.5 mg, 8%) was obtained as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[CH3:12][NH2:13]>C1C=CC=CC=1>[CH3:12][NH:13][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: CN
Solvent: c1ccccc1
Product: CNc1ccc2n[nH]c(=O)n2n1

Procedure:
20.5 g. of 6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one (0.12 mol.) and a solution of 14.85 g. of methylamine (0.48 mol.) in 160 ml. of benzene are heated in an autoclave at 120° for 5 hours. After cooling, the precipitated product is filtered off and the filtrate is evaporated to dryness. Both portions of 6-methylamino-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one are treated with dilute aqueous hydrochloric acid, filtered off and recrystallized from water to give 15.8 g. (80%) of material, m.p. > 348° .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of the product of Example 364A (24.2 g, 0.0678 mol), 4-amino-benzenethiol (12.7 g, 0.102 mol, 1.5 equiv.), and sodium acetate trihydrate (46.1 g, 0.339 mol, 5.0 equiv.) in 500 mL of ethanol was heated under reflux under nitrogen with stirring for 2 hours. The reaction mixture was then allowed to cool to room temperature and 200 mL of water added. The mixture was stirred for 30 minutes, filtered, and dried in vacuo to give the title compound (29.8 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([O:27][CH3:28])[CH:5]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([O:27][CH3:28])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Reaction time: 48 h
Yield: 35.7 %

Procedure:
A solution of 3-methoxy-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (875 mg, 2.25 mmol) in ethyl acetate was treated with 10% palladium on activated carbon (83 mg). The reaction was stirred under a balloon of hydrogen gas for 6 h. At this time, the reaction was filtered through a pad of Celite®, rinsed with ethyl acetate and concentrated in vacuo. LCMS indicated incomplete conversion to the desired product. Due to solubility issues, the residue was dissolved in acetone (200 mL) at 25° C. and was treated with 10% palladium on activated carbon (83 mg). The reaction was stirred under a balloon of hydrogen gas for 2 d. At this time, the reaction was filtered through a pad of Celite®, rinsed extensively with acetone and concentrated in vacuo. LCMS still indicated incomplete conversion to the desired product. The residue was dissolved in methylene chloride (150 mL) at 25° C. and was treated with 10% palladium on activated carbon (83 mg). The reaction was stirred under a balloon of hydrogen gas for 4 d. At this time, the reaction was filtered through a pad of Celite®, rinsed with methylene chloride (2×50 mL) and concentrated in vacuo. Flash chromatography (40 g silica column, 10-25% ethyl acetate/hexanes) afforded 3-methoxy-4-[3-oxo-3-(2-phenylamino-pyridin-3-yl)-propyl]-benzoic acid methyl ester (313.4 mg, 35.6%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1ccc2nccc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), 4-pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K2CO3 (7.02 g, 50.76 mmol, 25.4 mls of 2M solution) in DMF (100 mL) was heated at 100° C. for 3.0 h and cooled to room temperature. The mixture was filtered through Celite and the Celite was washed with EtOAc. The filtrate was transferred to a separatory funnel, washed with water and saturated NaCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% MeOH:CH2Cl2) to give the title compound (2.03 g, 51%) as a tan solid. MS (ES)+ m/e 235 [M+H]+.
Reaction SMILES: C1(CBr)CC1.CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=O)=O)=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])[S:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:18]1([CH2:17][N:36]2[CH2:37][CH2:38][N:34]([C:26]3[S:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([CH3:23])[N:25]=3)[C:35]2=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCC3)C2=O)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with cyclopentylmethyl 4-methylbenzenesulfonate to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 62% yield: 1H NMR (300 MHZ, CDCl3) δ 4.20 (q, J=7.2 Hz, 2H), 4.04-3.99 (m, 2H), 3.52-3.41 (m, 2H), 3.17 (d, J=7.5 Hz, 2H), 2.46 (s, 3H), 2.16-1.08 (m, 12H); MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([P:14]([OH:16])[OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[CH2:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[C:20]([NH:19][CH2:18][P:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])[OH:15])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NCO)c1ccccc1
Reactant: OP(O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(NCP(=O)(O)c1ccccc1)c1ccccc1
Yield: 72.7 %

Procedure:
43.2 g (0.424 mol) of acetic anhydride were cooled to 10° C. A solution of 28.2 g (0.2 mol) of benzenephosphonous acid in 40 ml acetic acid were then added dropwise at 15° C., with stirring and cooling. After this, 30.2 g (0.2 mol) of N-hydroxymethylbenzamide were added in portions in the course of 10 minutes at 15° C., with cooling. After this, the cooling was removed, during which process the internal temperature rose to 35° C. After this, the mixture was refluxed for 3 hours and subsequently cooled. 175 ml of water were then added; during this process, the temperature rose to 35° C. The mixture was refluxed again, and finally cooled again, with stirring. After crystallisation, a total of 40 g (73% of theory) of benzoylaminomethylphenylphosphinic acid of a melting point of 158°-160° C. were obtained. CHNP analysis revealed:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH:14]=O)([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl>C(O)C.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH:14]=[N:29][NH:28][C:25]([NH2:27])=[NH:26])([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: N=C(N)NN
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=O)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=NNC(=N)N)O2
Yield: 98.3 %

Procedure:
In a mixed solvent of 20 ml of ethanol and 8 ml of pyridine was dissolved 3.9 g of 5-acetoxy-4,6-di-t-butyl-2-formyl-2-methyl-2,3-dihydrobenzofuran, and 1.42 g of aminoguanidine hydrochloride was added at room temperature. After heating under reflux for 14 hours and then cooling, ethanol and excess pyridine were distilled off using an evaporator, and the concentrate was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 4.48 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methylideneamino]guanidine (rotamer mixture) as a pale yellow oil (yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10](O)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[NH2:39]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([NH:39][C:38]3[CH:37]=[CH:36][N:35]=[CH:34][C:33]=3[C:32]([F:41])([F:31])[F:40])=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Reactant: Nc1ccncc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)Nc2ccncc2C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a suspension of [5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (15 mg, 0.041 mmol) (see step 2 in Example 16) in DCM (0.5 mL) was added oxalyl chloride (58 mg, 0.454 mmol), followed by addition of DMF (1 drop) and then, following bubbling cessation, by addition of 3-(trifluoromethyl)pyridin-4-amine (201 mg, 1.239 mmol). After 10 minutes, the reaction mixture was concentrated, taken up in MeOH/DMSO, and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title compound. 1H NMR (CDCl3) δ 8.1 (m, 3H), 8.50 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.55 (m, 2H), 7.41 (m, 1H), 7.27 (m, 1H), 7.07 (s, 1H), 5.60 (s, 2H). HRMS (M+1)=507.0363
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:2]2[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(N[C@@H]1CCN(C(=O)C2CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([C:12]1[CH2:13][CH2:14][N:15]([S:18]([CH2:21][C@@:22]2([CH3:29])[NH:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])(=[O:20])=[O:19])[CH2:16][CH:17]=1)#[CH:11]>>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([C:11]#[C:10][C:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][C@@:22]3([CH3:29])[NH:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])(=[O:20])=[O:19])[CH2:14][CH:13]=2)=[CH:7][N:6]=1
Reactant: C#CC1=CCN(S(=O)(=O)C[C@@]2(C)NC(=O)NC2=O)CC1
Reactant: COc1ncc(Br)cn1
Product: COc1ncc(C#CC2=CCN(S(=O)(=O)C[C@@]3(C)NC(=O)NC3=O)CC2)cn1

Procedure:
The title compound was prepared from 5-bromo-2-methoxypyrimidine and (5S) -5-{[(4-ethynyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dione in the same way as described in Example 1.