Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:17]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:15]4[C:4]([CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12]2)=[CH:5][CH:6]=[C:7]3[CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
A mixed solution of 100 g of pyrene, 55.4 g of t-butylchloride and 400 ml of dichloromethane was cooled to 0° C. under an argon gas stream and then 70.4 g of aluminum chloride was added. This mixed solution was stirred at room temperature for 5 hours and poured into 500 g of ice, followed by stirring at room temperature for 30 minutes. After the mixed solution was suction-filtered, the filtrate was extracted twice with 300 ml of dichloromethane. The organic layer was washed with 300 ml of water, dried over magnesium sulfate and then evaporated. To the concentrated residue, 300 ml of methanol was added, followed by stirring at 80° C. and further filtration. Furthermore, 300 ml of methanol was added, followed by stirring at 80° C. and further filtration. To 59.1 g of the crude product obtained by vacuum drying among 110.7 g of the crude product, 150 ml of methanol was added. The resulting solution was stirred at 85° C. for one hour, filtered and then vacuum-dried to obtain 50.3 g (content: 83%) of 2-t-butylpyrene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24].O>ClCCl>[CH3:26][S:23]([O:15][CH2:14][CH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:25])=[O:24]
Reactant: COc1ccc2cccc(CCO)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cccc(CCOS(C)(=O)=O)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(7-Methoxy-1-naphthyl)ethanol (25 mmol) and triethylamine (30 mmol) are dissolved in 50 ml of dichloromethane and the reaction mixture is cooled to 0° C. using an ice bath. Mesyl chloride (30 mmol) is added dropwise and the reaction mixture is stirred at ambient temperature for 2 hours and then poured into 100 ml of water. The organic phase is washed with 1M hydrochloric acid solution and then with water, dried over magnesium sulphate and evaporated. The oil obtained is precipitated from a mixture of diethyl ether/petroleum ether (1/1). The title product is filtered off under suction and then recrystallised from to diisopropyl ether.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])C.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:14])[C:9](=[O:13])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Cl)cc1=O
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.925 g, 4.29 mmol) in a 4:1 mixture of THF:MeOH (20 mL) was added a 1 M solution of LiOH (8.6 mL). After stirring for 30 minutes, the reaction mixture was acidified to pH 1 with 10% HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give 0.732 g (91%) clean desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[C:13]([S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:12]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:8][CH:7]=1.Cl>C(S)(C)(C)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([S:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[C:12]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)(C)S
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Yield: 69.7 %

Procedure:
To a suspension of aluminum chloride (26.3 g, 198 mmol) in t-butanethiol (60 ml) at 0° C. was added a solution of ethyl 3-(1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl)-2,2-dimethylpropionate (32 g, 66 mmol), prepared as in step 2, in methylene chloride (90 ml) and the reaction mixture was stirred at 0° C. for 10 min and at ambient temperature for 3 hours. The reaction mixture was then poured into ice and acidified with 10% aqueous hydrochloric acid. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a white solid. The solid was washed with 20% solution of ethyl ether in hexane and dried in vacuo to afford 21.8 g of ethyl 3-(1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl)-2,2-dimethylpropionate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1.[BrH:12]
Reactant: BrBr
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Solvent: CO
Product: Br
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To 5 ml of methanol were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then nitrogen gas was introduced thereinto at a flow rate of 400 ml/minute for 20 minutes at room temperature. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 8 hours. The reaction mixture was then treated in the same manner as described in Example 5, whereby 10.2 g (62.7%) of ifenprodil hydrobromide were obtained as white crystals.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]([C:18](=[O:36])[C@H:19]([CH3:35])[NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:38]>C(O)(=O)C>[BrH:38].[CH2:33]([O:32][C:30]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:37])=[O:5])=[O:36])[CH3:35])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.17 h

Procedure:
5 g of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester obtained in Example 3 is dissolved in 5 ml of acetic acid, 20 ml of 25% hydrobromic acid in acetic acid is added to the solution, and the mixture is shaken for 10 minutes. The crystals which precipitate on addition of 300 ml of ethyl ether are collected by filtration to give 5 g of N-[1-(S)-ethoxycarbonyl-3phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrobromide as colorless crystals melting at 180°-183° C.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[H][H]>O1CCOCC1.[Pd]>[C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)OCc3ccccc3)cc2cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)O)cc2cc1Cl

Procedure:
7-Butyryloxy-3-carboxymethylaminocarbonyl-6-chlorocoumarin was prepared as follows. 920 mg (2 mMol) 7-butyryloxy-3-benzyloxycarbonylmethylaminocarbonyl-6-chlorocoumarin were dissolved in 50 ml dioxane. 100 mg palladium on carbon (10%) and 100 microliters acetic acid were added to the solution and the suspension stirred vigorously in a hydrogen atmosphere at ambient pressure. After the uptake of hydrogen seized the suspension was filtered. The product containing carbon was extracted five times with 25 ml boiling dioxane. The combined dioxane solutions were let to cool upon which the product precipitated as a white powder. Reduction of the solvent to 20 ml precipitates more product. The remaining dioxane solution is heated to boiling and heptane is added until the solution becomes cloudy. The weights of the dried powders were 245 mg, 389 mg and 58 mg, totaling 692 mg (1.88 mMol, 94%) of white product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)C(C)C2)cc1
Solvent: CC#N
Product: COc1ccc(-c2cc(C)c(=O)[nH]n2)cc1
Temperature: 70 °C
Yield: 73 %

Procedure:
A mixture of the product from step 1 (6-(4-methoxy-phenyl)-4-methyl-4,5-dihydro-2H-pyridazin-3-one; 1.96 g, 9 mmol) and Cu(II)Cl2 (2.48 g, 2 eq.) in of acetonitrile (15 mL) was heated to 70° C. for 2 h. The reaction was quenched with ice-water (˜100 mL), the resulting solid was collected and crystallized from isopropanol to give 1.42 g (73%) of 6-(4-methoxy-phenyl)-4-methyl-2H-pyridazin-3-one: Mp 265-7° C.; MS m/z 217 (M+H).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br>C(#N)C>[Br:22][C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH:10]=2
Reactant: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Reactant: BrBr
Solvent: CC#N
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)c(Br)n(C)c2c1
Temperature: -6 °C
Yield: 87.2 %

Procedure:
The mixture of isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (50.0 g, 0.175 mol) and acetonitrile (393 g) was cooled to −6±3° C. Bromine (33.6 g, 0.210 mol) was added while the batch was maintained at −6±3° C. The resulting slurry was stirred at −6±3° C. for at least 30 min. When HPLC showed ≧94% conversion (the HPLC sample must be quenched immediately with aqueous 4-methylmorpholine/sodium thiosulfate solution), the mixture was quenched with a solution of sodium thiosulfate (15.3 g) and 28.4 g 4-methylmorpholine in water (440 g) while the temperature was maintained at −5±5° C. After it was stirred at 0±5° C. for at least 2 h, the batch was filtered and rinsed with 85 wt % methanol/water solution (415 g), followed by water (500 g), and dried until water content is ≦30%. The wet cake was suspended in 2-propanol (675 g), and heated to 75±5° C. The resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g) and then with 135.0 g water at a rate to maintain the batch at 75±5° C. The suspension was stirred at 75±5° C. for at least 30 min, cooled to 15±2° C. over 30-40 min, and held at 15±2° C. for at least 1 h. The batch was filtered, rinsed with 75 wt % 2-propanol/water solution (161 g), and dried in vacuo (≦200 Torr) at 50-60° C. until the water content was ≦0.4% to give isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate as a solid (55.6 g, 87% yield) in 99.5 A % (240 nm) and 97.9 Wt %.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccc(O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.11 mol) in 200 ml of CCl4, was slowly added bromine (18.8 g, 0.11 mol) dissolved in 10 ml of CCl4 at 0° C. for 30 min. The reaction mass was stirred for another 30 min at 0° C. After completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with water, and 10% sodium bi-sulfite solution, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-4-hydroxyphenyl)acetate in 78% yield. (22.4 g). 1HNMR (CDCl3): 7.42 (s, 1H); 7.14 (d, 1H); 6.97 (d, 1H); 5.53 (bs, 1H); 4.13 (q, 2H); 3.52 (s, 2H); 1.16 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[H-].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>COCCOC>[CH2:19]([O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[CH3:20]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Nc1ccccc1OC(F)(F)F
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to −5° C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+)).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[C:2]#[CH:3]>FC(F)(F)C(O)=O.O>[CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
tert-Butyl 4-propargylpiperazine-1-carboxylate of step 2(ii) above (570 mg, 2.545 mmol) was dissolved in trifluoroacetic acid (10 ml) and water (2.5 ml). The mixture was then stirred at room temperature overnight. The solution was evaporated to dryness in vacuum. The residue was dissolved in water (10 ml) and then basified with Na2CO3 (pH 11), and extracted with Et2OAc (3×50 ml). The organic layer was washed with brine (2×50 ml) and dried over Na2SO4 overnight. Evaporation in vacuum gave N-propargylpiperazine (D7) as white solid. (crude, 193 mg, 62% yield). H1 NMR (250 MHz, CDCl3) 1.64 (s, 1NH), 2.26 (m, 1H), 2.55 (dd, J=4.73, 4.50 Hz, 4H), 2.93 (dd, J=4.96, 4.84 Hz, 4H), 3.29 (d, J=2.44 Hz, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C1COCC1.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 24 h

Procedure:
Amine preparation: To a solution of 1-BOC-piperazine (867 mg) in dry THF (8 mL) was added triethylamine (0.97 mL) followed by dimethylcarbamoyl chloride (0.51 mL). After stirring for 24 h the reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield 4-dimethylcarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (940 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].C(N(CC)CC)C.[CH3:16][N:17]=[C:18]=[O:19].P(=O)(O)(O)O>O>[CH3:16][NH:17][C:18]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:19]
Reactant: CSC(C)(C)C=NO
Reactant: CN=C=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=CC(C)(C)SC
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
Into a one liter glass resin kettle equipped with a metal pitched-blade agitator, a pressure-equalizing dropping funnel with Teflon® tube for subsurface addition, a thermometer and a dry ice/acetone cooled condenser was added 66.5 grams (0.50 mole) of 2-methyl-2-(methylthio) propionaldehyde oxime and 112 milliliters of water. After cooling the mixture to a temperature of 2° C.-3° C. with a water/salt/ice bath, 0.52 grams (0.005 mole) of triethylamine was added to the kettle under a nitrogen atmosphere. A stoichiometric amount of methyl isocyanate (29.5 milliliters, 0.50 mole) was then added over a period of 30 minutes at a temperature of 4° C.-14° C. with vigorous stirring. The water/salt/ice bath was removed and the mixture was stirred for an additional 75 minutes at a temperature of 10° C.-18° C. after which an additional 2.0 milliliters (0.03 mole) of methyl isocyanate was added and the mixture stirred for an additional period of 30 minutes. The water/salt/ice bath was then put back in place and 2.9 grams of phosphoric acid in 10 milliliters of water was added in a slow stream subsurface. The resulting solid product was filtered off on a sintered glass funnel and rinsed with hexane to give 104.4 grams (wet weight) of a fluffy white powder. High pressure liquid chromatographic analysis (internal standard) indicated the following: 84.00 percent 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (89.1 percent yield based on aldicarb oxime) and 2.38 percent 2-methyl-2-(methylthio) propionaldehyde oxime; 13.62 percent water content was determined by Karl Fischer titration.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HATU (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE: EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.[Br:10]Br>C(O)(=O)C.O>[Br:10][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: O=C1NCc2ccsc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1NCc2cc(Br)sc21
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A solution of 4H-thieno[2,3-c]pyrrol-6(5H)-one (1.0 g, 7.2 mmol) in acetic acid (9 mL) and water (7 mL) was cooled to 0° C. Bromine (407 μL, 7.92 mmol) was added and the reaction was maintained at 0° C. for 1.5 h. At completion, water (30 mL) was added and the mixture was and extracted with EtOAc (2×50 mL). The combined organics were washed with 5% aq. Na2SO3 (30 mL), sat. aq. NaHCO3 (30 mL) and brine (30 mL), then dried over Na2SO4, filtered, concentrated. The crude material was purified by flash chromatography over silica gel (5% MeOH/DCM) to yield 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (1.3 g, 83% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.28 (s, 1H), 4.39 (s, 3H); MS (EI) m/z=140.2 [M+1]+.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:21](=[O:24])([O-])[O-].[Na+].[Na+].[CH2:27]1[CH2:31]O[CH2:29][CH2:28]1>C(OCC)(=O)C>[CH3:19][N:11]1[C@H:12]2[C@@:27]([CH3:31])([C:27]3[CH:31]=[CH:10][C:4]([C:16]4[CH:15]=[C:14]5[C:19](=[CH:18][CH:17]=4)[N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[CH:12]=[CH:13]5)=[CH:5][C:28]=3[CH2:29][CH2:13]2)[CH2:28][CH2:29][C:21]1=[O:24]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)ccc32)cc1
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(-c4ccc5c(c4)CC[C@H]4N(C)C(=O)CC[C@]54C)ccc32)cc1
Reaction time: 24 h
Yield: 15 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), N-tosyl-5-bromoindole (228 mg, 0.65 mmol), 0.65 mL of sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was beamed a 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 49 mg (15%) of the title compound as an amorphous foam. FDMS: m/e=498.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(=O)C.O>[O:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:19]1[C:18]1[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Yield: 7.6 %

Procedure:
In an acetic acid solvent in the presence of sodium acetate (NaOAc) (3.0 eq.), a solution including 2-aminophenol (1.0 eq.) and 4-hydroxybenzaldehyde (1.0 eq.) was refluxed. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (4:1) to obtain a solid Compound 123.