Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[N:39]=[N:40][NH:41][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(C#N)ccc2-n2c(C)nnc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3nn[nH]n3)ccc2-n2c(C)nnc21
Temperature: 100 °C

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-cyano-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 7) (68.4 mg) was dissolved in DMF (5 ml). Triethylamine hydrochloride (45.0 mg) and sodium azide (21.23 mg) were added and the reaction mixture was heated at 100° C., under nitrogen, overnight. The temperature was raised to 120° C. and the reaction mixture was heated overnight. The reaction mixture was allowed to cool to room temperature, partitioned between ethyl acetate and water. The organic phase was washed with water (2×10 ml) and brine (10 ml). The aqueous layer was passed through a pre equilibrated Biotage 103 column. The organic content was eluted with methanol, the methanolic solution was evaporated and the residue was chromatographed (10-20% methanol:DCM). Trituration with diethyl ether gave (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(2H-tetrazol-5-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (25.6 mg) as a yellow solid. LCMS (formate): MH+ 462/464, RT 0.75 min
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[Cl:20])[N:4]=1.C(OC(=O)[NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl>C(O)CCC.C1COCC1>[NH2:27][CH2:28][C@@H:29]([N:37]1[C:9](=[O:11])[C:8]2[CH:7]=[N:6][C:5]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[Cl:20])=[N:4][C:3]=2[CH2:2]1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1CBr
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ncc2c(n1)CN([C@H](CN)Cc1ccccc1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of ethyl 4-(bromomethyl)-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxylate (284.0 mg, 0.7898 mmol), tert-butyl[(2S)-2-amino-3-phenylpropyl]carbamate (198 mg, 0.791 mmol), and N,N-diisopropylethylamine (0.275 mL, 1.58 mmol) in 1-butanol (5.0 mL) was stirred at 140° C. for 2 h. The reaction mixture was evaporated under reduced pressure to give an oil residue, which was dissolved in 4 M HCl aqueous solution (2 mL, 8 mmol) and THF (2 mL). The resulting solution was stirred at room temperature for 1 hour. Direct purification on prep.HPLC afforded 81 mg (25.6% yield) of the desired product. LC-MS found: 383.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][OH:3].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[OH:3][CH2:2][CH2:1][NH:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(NCCO)c1ccccc1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
128.3 g of 2-ethanolamine (2.1 mol) and 150 g of water are introduced into a 1 liter reactor equipped with a thermostatically-controlled jacket, a stirrer and a dropping funnel. 353 g of benzenesulphonyl chloride (2 mol) are introduced into the dropping funnel. The reactor is heated to approximately 60° C. and the benzenesulphonyl chloride is then allowed to run dropwise into the reactor at the rate of approximately 3 ml/min. The exothermicity of the reaction is thus controlled and the temperature changes to reach 70 to 75° C. at the end of addition. The pH is prevented from falling below 9 by gradual addition of a 20% solution of sodium hydroxide in water. After a few hours, the reaction is complete. The reaction mixture is then extracted with a third water-insoluble solvent, such as ethyl acetate. This organic phase is collected. The aqueous phase is extracted and the combined organic phases are distilled under vacuum in order to remove the extraction solvent. 384 g of N-(2-hydroxyethyl)benzenesulphonamide are thus obtained, i.e. a yield of 95.5% with a purity of greater than 99%. This product, which is liquid at room temperature, is characterized by IR spectroscopy and NMR spectro-scopy, as well as by GC and HPLC analysis.
Reaction SMILES: C[Si]([C:5]1[NH:10][C:9](=[O:11])[N:8]([Si](C)(C)C)[C:7](=[O:16])[C:6]=1[F:17])(C)C.F[C:19]1[C:20](=[O:26])NC(=O)NC=1.[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH:41]2[O:45][CH2:44][CH2:43][O:42]2)[CH:34]=[CH:35][C:36]=1[O:37][C:38](=[O:40])[CH3:39])(=[O:29])[CH3:28].C(OC1C=C(C=CC=1OC(=O)C)C=O)(=O)C>C(O)CO>[C:20]([O:42][CH2:43][CH2:44][O:45][CH:41]([N:10]1[CH:5]=[C:6]([F:17])[C:7](=[O:16])[NH:8][C:9]1=[O:11])[C:33]1[CH:34]=[CH:35][C:36]([O:37][C:38](=[O:40])[CH3:39])=[C:31]([O:30][C:27](=[O:29])[CH3:28])[CH:32]=1)(=[O:26])[CH3:19]
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(=O)Oc1ccc(C2OCCO2)cc1OC(C)=O
Agent: CC(=O)Oc1ccc(C=O)cc1OC(C)=O
Solvent: OCCO
Product: CC(=O)OCCOC(c1ccc(OC(C)=O)c(OC(C)=O)c1)n1cc(F)c(=O)[nH]c1=O

Procedure:
Bis(trimethylsilyl)-5-fluorouracil prepared from 5-fluorouracil (10 g) , and 2-(3,4-diacetoxyphenyl)-1,3-dioxolan (26.6 g) prepared from 3,4-diacetoxybenzaldehyde and ethyleneglycol were treated as in Example 10 and the product was acetylated to give 7.4 g of crystalline 1-[α-(2-acetoxyethoxy)-3,4-diacetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 92 %

Procedure:
A 500 mL round-bottom-flask equipped with an addition funnel, stirring bar, and gas inlet was charged with 4-bromo-biphenyl (50 g, 0.215 mol) and chloroform (200 mL) then purged with nitrogen. Chlorosulfonic acid (18 mL, 0.27 mol) was added dropwise to the solution from the addition funnel then stirred for 1 hour. The resulting precipitate was collected by vacuum filtration, washed with cold chloroform, and dried under vacuum to give 61.97 g of 4′-bromo-biphenyl-4-sulfonic acid (92% yield).
Reaction SMILES: C[CH:2]([CH2:12][CH2:13][CH:14]=[C:15](C)[CH2:16][CH2:17][CH:18]=[C:19](C)C)[CH2:3][CH2:4][O:5]C1CCCCO1.[CH3:23]OCCOC.BrN1C(=O)CCC1=O>O>[CH3:23][CH:4]([OH:5])[CH2:3][CH2:2][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(C)=CCCC(C)=CCCC(C)CCOC1CCCCO1
Reactant: COCCOC
Agent: O=C1CCC(=O)N1Br
Solvent: O
Product: CCCCCC=CCCCC(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 22.0 g (71 mmol) of tetrahydro-2-[(3,7,11-trimethyl-6,10-dodecadienyl)oxy]-2H-pyran, 80 ml of 1,2-dimethoxyethane and 16 ml of water is treated at -50° within 30 minutes with 13.5 g (76 mmol) of N-bromosuccinimide. The mixture is subsequently stirred at 0° for a further 2 hours and at room temperature for 30 minutes. The reaction mixture is then poured into ice-water, whereupon the mixture is extracted three times with ethyl acetate. The combined organic phases are washed firstly with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. There is obtained crude (E)-3-bromo-2,6,10-trimethyl-12-[(tetrahydro-2H)-pyran-2-yl)oxy]-6-dodecen-2-ol which is subsequently dissolved in 100 ml of methanol and treated at 0° with 14.0 g (0.1 mol) of potassium carbonate. After stirring at 0° for 15 hours the mixture is filtered over Hyflo, whereupon the filtrate is evaporated and the residue is taken up in 600 ml of ice-water and extracted three times with ether. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with hexane-ethyl acetate 4:1. There is obtained (E)-2-[(10,11-epoxy-3,7,11-trimethyl-6-dodecen-1-yl)oxy]tetrahydro-2H-pyran which is subsequently boiled under reflux for 18 hours together with 8.0 g (40 mmol) of aluminum isopropylate in 80 ml of toluene. The reaction mixture is then evaporated and the residue is taken up in 300 ml of 2N hydrochloric acid. After two-fold extraction with ether the combined organic phases are washed firstly with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. There is obtained (E)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6-dodecadien-3-ol which is dissolved in 130 ml of methanol and stirred at room temperature for 4 hours together with 13 g of strongly acidic ion-exchanger (Dowex 50 W X 8). After filtration and removal of the solvent in a rotary evaporator there remains behind a yellowish oil which is chromatographed on silica gel with hexane-ethyl acetate 2:1 with the addition of 0.1% triethylamine. There is obtained (E)-3,7,11-trimethyl-6,10-dodecadiene-1,10-diol in the form of a colourless oil. MS: 240 (M)+, 222 (M--H2O)+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2[OH:24])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
4-Dimethylaminopyridine (2.62 g, 21.4 mmol) was added portionwise with stirring to a solution of 4-tert-butylbenzoyl chloride (3.8 ml, 19.5 mmol) and 2-amino-4-nitrophenol (3.0 g, 19.5 mmol) in 60 ml methylene chloride. The resulting solution was stirred overnight at room temperature. The reaction solution was diluted with 60 ml methylene chloride and washed with 3×50 ml water. The methylene chloride solution was separated, filtered to remove precipitated solid, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure to yield the title compound as a brownish solid (5.01 g, 82% yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[I:29])=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[I:21])[CH:13]=1)[C:6]([O:8]C)=O.[NH3:31]>C(O)CO.[Cl-].[Na+].O>[I:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:31][C:3](=[O:2])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21]
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccccc2I)c(Nc2ccccc2I)cc1C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccccc3I)c(Nc3ccccc3I)cc21

Procedure:
Analogously to Example 1, 1.48 g (2.36 mmol) of 4,5bis(2-iodoanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 19 hours. The reaction mixture is cooled, diluted with brine and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The residue obtained after concentration by evaporation is filtered through silica gel with dichloromethane and the product fractions are combined and concentrated by evaporation. The residue obtained after concentration by evaporation is crystallized from boiling dichloromethane, yielding the title compound in the form of yellow crystals, m.p. 108°-110° C., FAB-MS: 582 [M+ +H].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([CH3:33])[CH3:32])[CH:21]=1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1>>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([CH3:33])[CH3:32])[CH:21]=1
Reactant: CC(C)Oc1cc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)ccc1OC(F)F
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Product: CC(C)Oc1cc(-c2[nH]c3cn[nH]c(=O)c3c2Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 247 mg (0.495 mmol) of 3-chloro-2-(4-difluoromethoxy-3-isopropoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 40-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, active carbon was added to the reaction suspension, and the mixture was stirred at room temperature for further 2 hours, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, the obtained solid was dissolved by adding a small amount of tetrahydrofuran, followed by addition of water, and the solid precipitated by ultrasonic wave treatment was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 175 mg of the title compound as a white solid. (Yield: 96%)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:15][CH2:13][CH3:14]
Reactant: CCS
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of 2-chloro-2', 4'-difluoroacetophenone (10 g, 0.053 mol) and ethyl mercaptan (3.6 g, 0.058 mol) in methanol (200 ml), potassium carbonate (8.8 g, 0.064 mol) was added under ice cooling, followed by stirring at room temperature for 1.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ether. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting oil was distilled under reduced pressure (bp: 115 to 118° C., 2 mmHg), whereby 2', 4'-difluoro-2-(ethylthio)acetophenone (11.4 g, yield: 99.9%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9](P(OC)(OC)=O)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9](=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([OH:20])[CH:22]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1cccc(O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (Fluka, Cat. #09659) (0.97 g, 3.3 mmol) and 3-hydroxybenzaldehyde (0.400 g, 3.28 mmol) were combined in methylene chloride (14 mL) at r.t. under nitrogen. To this DBU (0.68 mL, 3.9 mmol) was added and the reaction was stirred at r.t. for 2 h. The reaction was taken up in ethyl acetate, washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as an oil. The product was purified by Flash chromatography on a silica gel column eluting hexane: ethyl acetate gradient to give methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)acrylate (0.92 g, 96%) as a clear oil Analytical LCMS (M+H-Boc)+: m/z=193.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH:11](N1C=C(C2C=CC(C3C=CC=CC=3)=CC=2)N=C1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:34]1[CH2:51][C:50]2=[CH:52][N:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=32)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:35]1=[O:53].CC[N:56]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:32])[CH:10]([CH:34]1[CH2:51][C:50]2=[CH:52][N:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=32)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:35]1=[O:53])[CH2:11][C:12]([NH2:56])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(C(=O)O)n1cnc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Reactant: N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)CC(C(=O)OCc1ccccc1)C1Cc2cn(c3ccccc23)CCCCCCNC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-biphenyl-4-yl-imidazol-1-yl)succinic acid 4-benzyl ester (450 mg, 1.05 mmol), (10S)-10-amino-9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (284 mg, 0.95 mmol), EDCI (302 mg, 1.5 mmol), HOBT (142 mg, 1.05 mmol), N-methylmorpholine (0.14 mL) and DMAP (50 mg) in DMF (10 mL) was stirred at room temperature overnight. The solution was diluted with 100 mL of EtOAc and washed with brine and saturated NaHCO3 and dried. The crude product obtained after removal of solvents was purified by column chromagraphy to give (3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-bromophenol was dissolved in dichloromethane. Triethylamine (1 eq) and acetic anhydride (2 eq) were added and the mixture was stirred at room temperature for 5 hours. The solvent was eliminated by vacuum evaporation. The evaporation residue was taken up in dichloromethane then dried on magnesium sulfate. The solvent was eliminated by vacuum evaporation.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH:12][CH2:13][CH:14]1[CH2:18][O:17][C:16](=[S:19])[NH:15]1.N1C=CC=CC=1>C1COCC1>[S:19]=[C:16]1[NH:15][CH:14]([CH2:13][O:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=2)[CH2:18][O:17]1
Reactant: OCC1COC(=S)N1
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=Cc1ccc(C(=O)OCC2COC(=S)N2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
A solution of 4-vinylbenzoyl chloride (21.0 g, 126 mmol) in dry THF (50 mL) was added to a solution of 4-hydroxymethyl-1,3-oxazolidine-2-thione (14.0 g, 105 mmol) in dry THF (250 mL) and pyridine (10.2 mL, 126 mmol) at 0° C. After 12 hours of stirring at room temperature, pyridine hydrochloride was filtered off, and the solvent was evaporated out in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate/acetone (1/1=v/v), followed by recrystallization from a mixed solvent [n-hexane/ethyl acetate (3/1=v/v)] to afford 4-vinylbenzoic acid 2-thioxo-oxazolidin-4-ylmethyl ester as a colorless solid. Yield 73% (24.1 g, 91.5 mmol). 1H NMR (DMSO-d6): δ=4.25–4.77 (5H, >CH—, —CH2—O(CO)—, and —(SC)O—CH2—), 5.45 (d, J=10.8 Hz, 1H, —CH═CH2), 6.03 (d, J=17.8 Hz, 1H, —CH═CH2), 6.84 (dd, J=11.3 and 17.7 Hz, 1H, —CH═CH2), 7.64 (d, J=8.1 Hz, 2H, —C6H4—), 8.01 (d. J=8.1 Hz, 2H, —C6H4—), 10.3 (broad s, 1H, —NH—) ppm. 13C NMR (DMSO-d6): δ=55.0 (CO—CH2—CH<), 65.1 (>CH—), 71.8 (—CH2—O(CO)—), 117.7 (—CH═CH2), 126.5, 128.6, 130.1 (—C6H4—), 136.0 (—CH═CH2), 142.2 (—C6H4—), 165.6 (—O(CO)—C6H4—), 189.3 (>C═S) ppm. IR (KBr): 3185, 1712 (—OCOPh), 1504 (C═S), 1280, 1180, 1110, 971 cm−1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH:21]1([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[C:30]([F:43])[CH:29]=2)=[O:26])[CH2:23][CH2:22]1>>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:3][C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH:27][C:25]([NH:24][CH:21]4[CH2:23][CH2:22]4)=[O:26])=[CH:29][C:30]=3[F:43])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 4 %

Procedure:
Method as example 143 using (S)-1-(2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 24) (212 mg, 0.5 mmol) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (182 mg, 0.57 mmol) as starting materials. Reaction mixture was partitioned between EtOAc (50 ml) and water (35 ml), the organic layer passed through a hydrophobic frit and concentrated in vacuo to leave a purple solid. The solid was purified by prep. HPLC at high pH to afford a brown/red solid which was re-purified by prep. HPLC at low pH to afford a yellow solid (9 mg, 4%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:25][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CCC(NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Agent: BrB(Br)Br
Product: CCC(N)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 71.2 %

Procedure:
Following General Procedure F, tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (40 mg, 0.08 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.48 mL, 0.48 mmol) to afford the desired product (12 mg, 40%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.65-7.56 (m, 3H), 7.46-7.39 (m, 2H), 7.30 (s, 1H), 6.02 (d, J=5.4 Hz, 1H), 4.32 (dd, J=9.1, 6.0 Hz, 1H), 2.21-2.02 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); ESI MS m/z 385 [C20H17N2O2S+H]+; HPLC 95.9% (AUC), tR=9.15 min.