Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:4]=[CH:5][N:6]=1.[H-].[Na+].[H][H].[C:26](Cl)(=[O:28])[CH3:27]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:26]([N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[C:20](=[O:21])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:28])[CH3:27]
Reactant: Cc1nccn1CC1CCc2[nH]c3ccccc3c2C1=O
Reactant: [H][H]
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3ccccc31)C(=O)C(Cn1ccnc1C)CC2
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A mixture of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (0.5 g) and 80% sodium hydride dispersion in mineral oil (0.07 g) in dry dimethylformamide (10 ml) was stirred under nitrogen until hydrogen evolution had ceased (ca. 0.5 h). The mixture was cooled to 0° and acetyl chloride (0.18 g) was added. The mixture was stirred at 0° for 1 h, diluted with 8% aqueous sodium bicarbonate (50 ml) and extracted with dichloromethane (2×50 ml). The dried (Na2SO4) extracts were evaporated to give a solid which was purified by flash chromatography (C) to give a solid (0.25 g). Recrystallisation from ethyl acetate-methanol afforded the title compound as crystals (0.12 g) m.p. 173°-175°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:19][OH:20])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(Cl)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from sodium hydride, (3-chloro-4-(3,4-difluorophenoxy)phenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[I:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.[K+].[Br-]>>[I:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][N:23]=[C:10]2[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:11]2=3)=[CH:18][CH:17]=1
Reactant: NNc1ccc(I)cc1
Reactant: O=C1CCC(=O)c2ncccc2N1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: O=C1CCC(=NNc2ccc(I)cc2)c2ncccc2N1

Procedure:
Prepared according to general procedure A from 176 mg (1.0 mmol) 5H-pyrido[3,2-b]azepine-6,9(7H,8H)-dione and 257 mg (1.5 mmol) (4-iodophenyl)hydrazine hydrochloride. Recrystallization from ethanol afforded an orange solid. Yield: 248 mg (63%); m.p. 204-205° C.; IR (KBr): 3211 cm−1 (NH), 2964/2900 cm−1 (CH-aliph.), 1691 cm−1 (C═O); 1H-NMR (DMSO-d6, 400 MHz): δ (ppm)=2.55-2.59 (m, 2H, azepine-CH2, part of AA′XX′-system), 3.01-3.04 (m, 2H, azepine-CH2, part of AA′XX′-system), 7.02-7.06 (m, 2H, arom. H), 7.37-7.44 (m, 2H, arom. H), 7.50-7.54 (m, 2H, arom. H), 8.41 (dd, 1H, 4.5/1.7 Hz, arom. H), 9.51 (s, 1H, NH), 9.82 (s, 1H, NH); C15H13IN4O (392.20).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42].CN(C)CCN>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:18]([NH:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)CNC(=O)[C@H](N)CCSC
Agent: CC(C)COC(=O)Cl
Agent: CN(C)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16.88 g of Boc-L-tyrosine in 50 ml of dry dimethylformamide is added 6.65 ml of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 7.84 ml of isobutylchloroformate is added. The reaction mixture is allowed to warm to 0° C. over a 15 minute period then 13.32 g of methyl D-methionyl-glycinate hydrochloride dissolved in 50 ml of dimethylformamide is added followed immediately by 5.2 ml of N-methylmorpholine. The reaction mixture is stirred for 30 minutes at 0° C. After storage overnight at 5° C., 3 ml of N,N-dimethylethylenediamine is added and the reaction mixture is stirred for 15 minutes at room temperature. The solvent is removed under vacuum at 35° C. and 1 mm of pressure and oily residue is dissolved in a mixture of 100 ml of water and 700 ml of ethyl acetate. The ethyl acetate layer is separated and washed three times with 80 ml of a 0.5 M solution of potassium bisulfate, 2 times with 80 ml of water, 2 times with 80 ml of a 0.5 solution of potassium carbonate, and 3 times with 100 ml of a 10% solution of sodium sulfate then dried over magnesium sulfate. The solvent is removed under pressure. The residue is dissolved in 1.2 liters of 5% ethyl acetate in chloroform and purified by low pressure chromatography on silica gel then reduced to dryness under reduced pressure and recrystallized from ethyl acetate to give methyl Boc-L-tyrosyl-D-methionyl-glycinate which is represented by the following formula
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCO
Product: COC(=O)c1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Temperature: 120 °C
Yield: 30.3 %

Procedure:
A mixture of (3,4-dichlorophenyl)methanamine (1.010 mL, 7.58 mmol), TEA (1.218 mL, 8.74 mmol), and methyl 6-chloronicotinate (1 g, 5.83 mmol) in ethanol (29 mL) was heated at 120° C. for 5 min in a microwave oven. The reaction mixture was further heated at 100° C. for 54 h, then concentrated. The residue was purified by flash chromatography on silica gel using 5-35% ethyl acetate in hexanes. The desired fractions were concentrated to give methyl 6-(3,4-dichlorobenzylamino)nicotinate as a pale yellow solid (0.55 g, 33%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (1H, s), 8.01 (1H, dd, J=8.78, 2.01 Hz), 7.33-7.52 (2H, m), 7.19 (1H, d, J=8.03 Hz), 6.37 (1H, d, J=8.78 Hz), 5.37 (1H, br. s.), 4.58 (2H, d, J=6.02 Hz), 3.88 (3H, s). LCMS: R.T.=2.81; [M+H]+=311.18.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][C:42]=1[F:43])[O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH:36][C:37](=[O:39])[CH3:38])=[N:35][C:30]2=[CH:29][CH:28]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:37]([NH:36][C:34]1[S:33][C:31]2[C:30]([N:35]=1)=[CH:29][CH:28]=[C:27]([O:26][C:25]1[CH:40]=[CH:41][C:42]([F:43])=[C:23]([NH:22][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[C:2]=3[Cl:1])[CH:24]=1)[N:32]=2)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(OC(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (0.12 g, 0.5 mmol) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and a solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) produced in Example C64(ii) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (24 mg, 14%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8](SC)=[N:7][C:6]=1[NH2:12])=[O:4].[CH3:13]O.O[O:16][S:17]([O-:19])=O.[K+]>O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([S:17]([CH3:13])(=[O:19])=[O:16])=[N:7][C:6]=1[NH2:12])=[O:4]
Reactant: COC(=O)c1sc(SC)nc1N
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1sc(S(C)(=O)=O)nc1N
Reaction time: 24 h

Procedure:
After adding 45.2 g of 4-amino-2-methylsulfanylthiazole-5-carboxylic acid methyl ester [CAS No. 60093-05-2] to 2 l of a water:methanol=1:1 mixed solvent at room temperature, 408 g of Oxone® was gradually added over a period of 30 minutes while stirring. Stirring was continued for 24 hours at room temperature, and then the reaction mixture was poured into a mixture of 10 l of ethyl acetate and 10 l of water. The organic layer was washed with 5 l of brine and dried over anhydrous magnesium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure to obtain the target compound (37.6 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
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: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.33 h
Yield: 19.5 %

Procedure:
13.9 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1 mL of 1,4-dioxane, and 6.3 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of Na2CO3, and 0.2 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:ethanol=15:1) to obtain 3.2 mg (19.7% yield) of the title compound.
Reaction SMILES: [Na].C(O[C:5](=[O:17])[CH:6]([C:15]#[N:16])[CH2:7][CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])C.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[NH2:16][C:15]1[N:21]=[C:19]([SH:20])[N:18]=[C:5]([OH:17])[C:6]=1[CH2:7][CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: CCOC(Cc1c(N)nc(S)nc1O)OCC
Temperature: 85 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in small portions. The solution was stirred until complete dissolution of the sodium metal. 2-Cyano-4,4-diethoxy-butyric acid ethyl ester (J. Chem. Soc., 1960, 131-138) (9.292 g, 40.5 mmol) was then added as a solution in ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4 mmol). The solution was heated at 85° C. for 18 hours, and then cooled to room temperature. The solution was concentrated, and saturated aqueous ammonium chloride solution (150 ml) was added. The mixture was stirred at room temperature for 18 hours, after which time the solid was collected by filtration, and washed with water (20 ml) to yield the product (3.376 g, 36%).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.[CH2:32]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:33]1[O:35][CH2:34]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=C(C)C=C(C)C=1.C(OCC)(=O)C>[C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:17][C:16]=2[OH:22])[N:14]=1
Reactant: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: CCCCOCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCOC(C)=O
Product: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3c(C)cc(C)cc3C)n2)c(O)c1
Temperature: 140 °C
Reaction time: 21 h
Yield: 104.8 %

Procedure:
A mixture of 20.0 g (0.048 mol) of 2-mesityl-4,6-bis(2,4-dihydroxyphenyl)-1,3,5-triazine (compound 1b), 13.8 g (0.105 mol) of n-butyl glycidyl ether (purity 95%) and 1.8 g (4.8 mmol) of ethyltriphenylphosphonium bromide (purity 97%) in 100 ml of mesitylene (purity 99%) is stirred at 140° C. under nitrogen for 21 hours. Decantation and evaporation of the remaining solvent gives 41.2 g of crude product. This is dissolved in 100 ml of ethyl acetate and filtered through a 10.5 cm layer of silica gel 60 (230-400 mesh) of diameter 7.5 cm, with elution with 3 l of ethyl acetate/hexane (1:1 mixture). The 34.0 g of solid obtained after removal of the solvent are re-dissolved in 25 ml of ethyl acetate. 250 ml of hexane are added to the viscous solution. The mixture is stirred at 0° C. for 2 hours and filtered, and the solid is dried for 24 hours at 80° C. and a pressure of 60 mmHg (8000 Pa), giving 23.0 g of the title product (compound 2) of the formula ##STR105## of m.p. 125°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:27]C.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[OH:27]
Reactant: COc1cc(C(=O)c2nc(Nc3cc(C)[nH]n3)c3ccccc3n2)ccc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(O)c3)nc3ccccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a stirred suspension of (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 76 (100 mg, 0.265 mmol) in DCM (4 mL) at 0° C., was added dropwise 1.0 M boron tribromide/DCM (2.12 mL, 2.12 mmol). The mixture was stirred at 0° C. for 30 min. Additional 1.0 M boron tribromide/DCM (1.50 mL, 1.50 mmol) was added and the mixture was allowed to warm to rt and stir for a further 2.5 h. Water (10 mL) was added, and the mixture was extracted with 25% 2-propanol/DCM (2×). T The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried. The solid was further purified by reverse-phase HPLC eluting with a mixture of water and acetonitrile to afford (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a yellow solid (20 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 6.51 (s, 1H), 7.28 (dd, J=10.8, 8.4 Hz, 1H), 7.39 (m, 1H), 7.58 (dd, J=8.7, 1.8 Hz, 1H), 7.67 (ddd, J=8.1, 8.1, 1.5 Hz, 1H), 7.83-7.92 (m, 2H), 8.73 (d, J=8.4 Hz, 1H), 10.65 (br s, 1H), 12.22 (br s, 1H); LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH2:10].CCN(C(C)C)C(C)C.C1C(=O)N([O:27][C:28]([C:30]2[C:35]([C:36]3[C:46]4[CH:47]=[CH:48][C:49]([OH:51])=[CH:50][C:45]=4[O:44][C:43]4[C:37]=3[CH:38]=[CH:39][C:40]([CH:42]=4)=[O:41])=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[CH:33]1[CH:32]=[CH:31][C:30]([C:28]([OH:29])=[O:27])=[C:35]([C:36]2[C:37]3[CH:38]=[CH:39][C:40]([OH:41])=[CH:42][C:43]=3[O:44][C:45]3[C:46]=2[CH:47]=[CH:48][C:49]([CH:50]=3)=[O:51])[CH:34]=1.[NH2:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C(ON1C(=O)CCC1=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: Cl
Agent: NCCSSCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cystamine dihydrochloride (68 mg, 0.301 mmol) and DIEA (110 μL, 2.1 eq.) were dissolved in DMF (10 mL), followed by addition of NHS-fluorescein, a mixture of 5- and 6-carboxyfluorescein (300 mg, 0.634 mmol) and the resulting reaction mixture was stirred overnight at room temperature. Then it was diluted with ethyl acetate and washed three times with water and one time with brine. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, redissolved in small amount of methanol and ethyl acetate, and then triturated with diethyl ether to obtain 140 mg of fluorescein-cystamine adduct as a bright orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:6]([O:8]C)=[O:7].[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]([F:18])([F:19])[F:20])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCCOC(F)(F)F)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCCOC(F)(F)F
Temperature: 60 °C
Yield: 82 %

Procedure:
Methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate (crude from Step 1) was dissolved in THF (5 mL) and a suspension of LiOH (550 mg, 23 mmol) in water (5 mL) was added. The mixture was stirred vigorously and heated at 60° C. for 6 h before it was concentrated to half volume. Water (5 mL) was added and the mixture was extracted with diethyl ether (1×10 mL). The aqueous layer was acidified with 4N HCl to pH 2. The resulting mixture was extracted with ethyl acetate (3×10 mL) and the combined organics were washed (1×10 mL H2O, 1×10 mL brine), dried over MgSO4 and evaporated to give 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid (1.0 g, 82%) as a white solid. ESI-MS m/z calc. 280.1, found 281.3 (M+1)+; Retention time: 1.34 minutes (3 min run).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9]([Cl:15])=[C:10]([Cl:14])[C:11]([OH:13])=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:13][C:11]1[C:10]([Cl:14])=[C:9]([Cl:15])[C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[CH:12]=1)[CH3:22]
Reactant: CC(=O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Yield: 42.6 %

Procedure:
To a solution of 9.0 g of 2-acetyl-6,7-dichloro-5-hydroxybenzo[b]thiophene and 200 ml of 2-butanone is added a solution of 6.62 g of ethyl bromoacetate in 50 ml of 2-butanone, 5.2 g of potassium carbonate and 2.2 ml of dimethylformamide. The reaction mixture is heated under reflux for 2 hrs, allowed to cool and filtered. The filtrate is extracted with ether (3 times). The layers are separated and the organic phase is washed with water, saturated sodium chloride solution, dried and filtered. The filtrate is evaporated. The residue is dissolved in dichloromethane and chromatographed on alumina, using dichloromethane as the eluant. Evaporation of the eluant gives 5.1 g of ethyl[(6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].[N+:11]([O-:14])([OH:13])=[O:12]>C(O)C>[N+:11]([O-:14])([O-:13])=[O:12].[C:2]1([NH:1][C:9]([NH2:10])=[NH2+:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: O=[N+]([O-])O
Reactant: Nc1ccccc1
Solvent: CCO
Product: NC(=[NH2+])Nc1ccccc1
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Yield: 32 %

Procedure:
To a room temperature solution of aniline (10.0 g, 107 mmol) in ethanol (100 mL) was added cyanamide (9.6 mL, 50 wt % in water, 123 mmol) followed by the dropwise addition of concentrated nitric acid (7.56 mL). The mixture was heated at reflux for 3.5 hours and allowed to cool to room temperature. The mixture was concentrated in vacuo and the residue was crystallized from methanol/ethyl acetate/dichloromethane to yield N-phenylguanidinium nitrate (6.7 g, 32%) as a white crystalline solid. 1H NMR (DMSO-d6): δ 9.63 (s, 1 H), 7.44 (t, 2 H), 7.37 (broad s, 3 H), 7.29 (t, 1 H), 7.23 (d, 2 H);
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH:20]4[CH2:22][CH2:21]4)=[N:18][NH:17][C:16](=O)[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[N:17]=[N:18][C:19]([CH:20]2[CH2:22][CH2:21]2)=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CC2)n[nH]1
Product: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CC2)nn1
Temperature: 90 °C
Yield: 29 %

Procedure:
A suspension of 5-(4-cyclohexyloxy-phenyl)-6-cyclopropyl-2H-pyridazin-3-one (0.86 mmol, 0.29 g) in phosphorous oxychloride (4.30 mmol, 0.40 mL) was heated at 90° C. for 20 min with stirring during which period the starting material was fully consumed as judged by TLC. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (5 mL), washed with water (2 mL), saturated NaHCO3 (2×2 mL) and dried (Na2SO4). The residue was purified on a 12 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to afford 6-chloro-4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-pyridazine (0.082 g).