Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])O1>>[Cl:7][C:6]1[S:5][C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])=[CH:3][C:2]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36]
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(-c3ccccc3O)c(Cl)s2)c1O
Yield: 24 %

Procedure:
The product was prepared from 3-{[(4-bromo-5-chlorothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 22) (20.6 mg, 0.050 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (11 μl, 0.055 mmol) according to the General Procedure 12, described in Example 135. The title compound was obtained in 24% yield (5.3 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 6.85 (ddd, J=7.60, 7.32, 1.15 Hz, 1 H) 6.87 (ddd, J=8.21, 1.15, 0.45 Hz, 1 H) 6.88 (t, J=7.95 Hz, 1 H) 7.15 (ddd, J=7.60, 1.71, 0.45 Hz, 1 H) 7.20 (ddd, J=8.21, 7.32, 1.71 Hz, 1 H) 7.39 (s, 1 H) 7.65 (dd, J=7.95, 1.65 Hz, 1 H) 7.71 (dd, J=7.95, 1.65 Hz, 1 H). MS (ESI+) m/z 426 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[C:5]([CH:14]=O)[C:4]=2[CH:3]=1.C([O-])(=O)C.[NH4+].[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[C:5]([CH:14]=[C:24]([N+:21]([O-:23])=[O:22])[CH3:25])[C:4]=2[CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c2n(c3ccc(Cl)cc13)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=Cc1c2n(c3ccc(Cl)cc13)CCC2)[N+](=O)[O-]
Temperature: 25 °C
Yield: 46 %

Procedure:
A stirred solution of 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde (1.0 g, 4.6 mmol) and ammonium acetate (0.4 g, 5.2 mmol) in nitroethane (10 mL) was heated to 100° C. for 1 h, cooled to room temperature, diluted with methanol (30 mL), cooled to 0° C., and filtered. The filter-cake was recrystallised (toluene) to give the product as yellow needles (0.58 g, 46%): mp 162-1623° C.; Found: C, 60.68; H, 4.67; N, 9.98%. C14H13ClN2O2 requires: C, 60.77; H, 4.73; N, 10.12%.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].CN1CCCCC1.C(C1C=C(C=CC=1)OC[C:28]([N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)=O)=O>>[CH3:28][N:30]1[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Solvent: CN1CCCCC1
Product: CN1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Yield: 66 %

Procedure:
2-(4-Formylphenoxy)acetic acid (53) was treated with 1-methylpiperidine in an analogous manner to Compound 49 to afford the desired product (66%) as a colorless oil. LCMS: 99.0% (M++1).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:22])=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH:6]([CH3:22])[CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1Br)C(C)CNC(C)C2
Reaction time: 3 h
Yield: 93432.5 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3 hours at 20 C. The product mixture was diluted with water (10 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4 and concentrated to give 0,020 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 730 (s, 1 H), 6.64 (s, 1 H), 6.06 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.30 (d, J=11 Hz, 1 H), 4.56 (s, 2 H), 3.03 (m, 2 H), 2.90 (dd, J=9, 14 Hz, 1 H), 2.80 (m, 1 H), 2.65 (d, J=14 Hz, 1 H), 2.55 (dd, J=10, 14 Hz, 1 H), 1.77 (bs, 1 H), 1.30 (d, J=7 Hz, 3 H), 1.20 (d, J=6 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:52]([Mg]Br)[CH3:53]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]([OH:51])[CH2:52][CH3:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)CC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 1k (0.3 g, 0.43 mmol, obtained from the synthetic method described in step 10 of example 1) in anhydrous tetrahydrofuran (10 mL) was added dropwise ethylmagnesium bromide (1.7 mL, 1.7 mmol, 1M) at 0° C. The mixture was stirred at room temperature for 16 hours, quenched with 2 mL of saturated aqueous ammonium chloride, and extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (5 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 3a as colorless oil (48 mg, 16.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.40 (m, 1H), 7.31 (m, 10H), 7.18 (m, 5H), 7.07 (m, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 4.93 (m, 2H), 4.77 (m, 2H), 4.29 (d, 1H), 4.21 (d, 1H), 4.03 (m, 3H), 3.96 (m, 4H), 3.81 (m, 1H), 3.65 (m, 2H), 2.23 (d, 1H), 1.51 (m, 2H), 1.38 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].CCN(CC)CC>CC#N>[CH2:11]([NH:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:12]#[CH:13]
Reactant: C#CCN
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chlorobenzoxazole (1.53 g, 10 mmol) in CH3CN (5 mL) was added dropwise to a mixture of propargyl amine (550 mg, 9.9 mmol) and Et3N (2.09 mmol, 15 mmol) and CH3CN (10 mL) under N2, and the resulting mixture was heated to reflux for 4 h, then stirred overnight at rt. The mixture was filtered, and the filtrate was partitioned between EtOAc (100 mL) and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated to dryness. The crude solid was diluted with heptane (20 mL) and Et2O (50 mL) and the mixture was heated to boiling and filtered hot. The filtrate was concentrated to dryness, then taken up in boiling Et2O (50 mL) and the solution was cooled and filtered. The filtrate was diluted with hexane (125 mL) and cooled to −20° C. for 4 h, and the crystallized product was collected by filtration (1.1 g, 64%). MS (APCI(+)) m/e 173.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:6]2=1.[H-].[Na+].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29]Cl)[CH3:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])[C:11]1[CH2:10][CH2:9][CH:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(c1ccccc1)CC3
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c1c(n2CCCN(C)C)CCC(c2ccccc2)C1
Temperature: 100 °C

Procedure:
A mixture containing 6-methoxy-3-phenyl-1,2,3,4-tetrahydrocarbazole (5.5 g), 50% sodium hydride (1.0 g) in dimethylformamide (30 ml) is heated at 100° C. for 11/2 hours, and then dimethylamino propyl chloride is added. The mixture is heated at 80° C. for 2 hours, then cooled and water (40 ml) is added. The solid which precipitates is recrystallized with methylene chloride:ether (1:1).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[K+].CN(C)C=O.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1>CCO>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
In 20 ml of EtOH, 9.4 g (6.4×10−2 mole) of phthalimide and 4.2 g of KOH were stirred for 30 minutes, followed by addition of 100 ml of DMF (dimethylformamide) and 5.2 g (2.5×10−2 mole) of 6-chloro-3-pyridylmethyl chloride. The mixture was stirred at 60° C. for 1 hour. The EtOH and DMF were distilled off under reduced pressure and the residue was chromatographed on a silica gel column and eluted with CH2Cl2. The above procedure gave 6.7 g of the title compound as colorless needles.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1C=C(C)C=C(C)C=1S(O)(=O)=O.[C:20]([O:24][C:25](=[O:38])[NH:26][CH2:27][CH2:28][N:29]1[CH2:36][CH:35]2[O:37][CH:31]([CH2:32][NH:33][CH2:34]2)[CH2:30]1)([CH3:23])([CH3:22])[CH3:21].[O:39]1[CH2:41][C@H:40]1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=1>O>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([O:43][CH2:42][C@@H:40]([OH:39])[CH2:41][N:33]2[CH2:32][CH:31]3[O:37][CH:35]([CH2:36][N:29]([CH2:28][CH2:27][NH:26][C:25](=[O:38])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])[CH2:30]3)[CH2:34]2)=[CH:45][CH:46]=1)#[N:49]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Temperature: 75 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Aqueous sodium carbonate solution (1M, 53 mL) was added to a solution of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (50.0 g) in water (100 mL). Solid 4-[(2S)-oxiranylmethoxy]benzonitrile (19.1 g) was added and was rinsed into the reaction flask with water (50 mL). The reaction was heated to 75° C. for 3 hours and then left to stir at ambient temperature overnight. Toluene (350 mL) was added followed by aqueous sodium hydroxide (2M, 90 mL). The mixture was stirred for 5 minutes and then the phases were separated. The aqueous phase was discarded and the toluene phase washed with aqueous citric acid (10% w/v, 180 mL). The toluene phase was discarded. MIBC (240 mL) and aqueous sodium hydroxide (5M, 180 mL) were added to the citric acid phase. After mixing well the phases were separated and the aqueous discarded. The MIBC was washed with aqueous sodium chloride (20% w/v, 50 mL). The MIBC was concentrated under vacuum at <55° C. Solvent was collected (water 13 mL, MIBC 29 mL). The MIBC solution was cooled to ambient temperature and filtered, washing through with MIBC (50 mL). Solvent (152 mL) was distilled under vacuum at <66° C. and then distillation was stopped. IPE (360 mL) was added causing the temperature to fall from 65° C. to 37° C. After stirring for 15 minutes T fell by 2° C. to 35° C. and crystallisation started. The mixture was left to cool to ambient temperature overnight with stirring. The mixture was cooled to 5° C. and the product collected by filtration. The solid was washed on the filter with IPE (150 mL) and sucked dry. Further drying in vacuo at 55° C. gave the title compound as a white solid (41.2 g, 87%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:6]2[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]=2[CH:13]=1.[ClH:27]>C1(C)C=CC=CC=1>[Cl:27][CH2:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:6]2[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]=2[CH:13]=1
Reactant: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CO)cc21
Reactant: Cl
Solvent: Cc1ccccc1
Product: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CCl)cc21
Temperature: 25 °C

Procedure:
A mixture of 3-(5-hydroxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde (1.25 g, 3.41 mmol) (example 10c) and 12N HCl (8.5 mL) in toluene (35 mL) was heated at reflux for 1 hour. The solution was cooled to room temperature and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic combined extract was washed with water, brine, dried (MgSO4), filtered and evaporated. To the residue obtained (3-[5-chloromethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde) (example 10e), diluted in dimethylformamide (35 mL), were added potassium carbonate (3.49 g, 25.25 mmol) then dimethylamine hydrochloride (1.47 g, 18.04 mmol). The mixture was stirred at room temperature for 3 hours. Water was added and the layers separated. The mixture was extracted with ethyl acetate and the organic combined extract was washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (10% methanol in dichloromethane) to afford 742 mg of 3-(5-Dimethylaminomethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde. 56% yield. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 6H), 2.30 (s, 6H), 3.47 (s, 2H), 4.25 (s, 2H), 7.06 (s, 1H), 7.16 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.90 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 10.03 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:12][NH2:13].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[C:8]([F:10])[CH:9]=1
Reactant: NN
Reactant: N#Cc1c(F)cc(Br)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1n[nH]c2cc(Br)cc(F)c12
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 410.7 %

Procedure:
Five batches of the below reaction were run in sequence in a microwave reactor: To a 5-mL microwave vial was added 4-bromo-2,6-difluorobenzonitrile (3 g, 13.76 mmol), hydrazine (0.864 mL, 27.5 mmol), Hunig's base (4.81 mL, 27.5 mmol) and ethanol (10 mL). The vial was capped and stirred for 10 minutes at 150° C. in a microwave reactor. The reaction mixture was cooled (ice-water bath) and a yellow precipitate formed. The yellow precipitates were collected, combined and the solids were washed with cold ethanol to yield pale yellow rods of the title compound (13.0 g). LC-MS (ES) m/z=230 and 232 (1:1 intensity) [M+H]+.
Reaction SMILES: [Cr](O)(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[NH:18][C:19](=[O:27])[C:20]([CH:22]3[CH2:25][CH:24]([OH:26])[CH2:23]3)=[CH:21][C:16]2=[N:15][N:14]=1.[CH:28](O)([CH3:30])C.O>CC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[N:18]=[C:19]([O:27][CH2:30][C:28]3[N:15]([CH3:16])[N:14]=[CH:13][N:17]=3)[C:20]([CH:22]3[CH2:23][C:24](=[O:26])[CH2:25]3)=[CH:21][C:16]2=[N:15][N:14]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Reactant: CC(C)O
Agent: O=[Cr](=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1CC(=O)C1

Procedure:
8N Chromic acid was added to a solution of 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.36 g, 1.2 mmol) in acetone (50 ml) dropwise, until excess was present (red colour remained). The reaction was then stirred for 2 hours before isopropanol was added until the blue colour remained and no excess chromic acid was present. Water (50 ml) was added and the aqueous layer extracted with ethyl acetate (4×50 ml), organic layers were combined, washed with brine (50 ml), dried (MgSO4), filtered and concentrated to give the desired product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO) δ3.41 (2H, s), 3.43 (2H, s), 3.73-3.78 (1H, m), 7.42-7.50 (2H, m), 7.64-7.72 (1H, m), 7.83-7.88 (1H, m), 8.38 (1H, s); MS (ES+) m/e 299 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].OO.[OH:23]S(O)(=O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[C:14]([OH:23])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred suspension of 5-(benzyloxy)-2-methoxybenzaldehyde (7, 1.12 g. 4.6 mmol) in MeOH (8 mL) at room temperature was added a solution of KOH (1.04 g, 18.5 mmol) in water (1.4 mL). The mixture was heated to 65° C. and H2O2 (35 wt %; 4.0 mL, 46 mmol) was added dropwise over 105 min. The reaction mixture was stirred at 65° C. for 1 h. Then it was cooled to room temperature and acidified to pH 2 with 6N H2SO4. The precipitate was collected, washed with water and dried in vacuo to afford the title compound (1.16 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.94 (br s, 1H), 7.80 (d, J=3.3 Hz, 1H), 7.44-7.37 (m, 4H), 7.35-7.32 (m, 1H), 7.19 (dd, J=9.0, 3.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 5.08 (s, 2H), 4.04 (s, 3H); ESI MS m/z 257 [M−H]−.
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
1,2-Diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (15.6 g, 40.2 mmole) in pyridine (106 ml) is heated overnight at 100° C. with benzoyl chloride (9.4 ml, 80 mmole) giving a redbrown solution and after 2 hrs a brown suspension. The reaction mixture is concentrated in vacuo and the residue is triturated for 2.5 hr in sat. aqueous ammonium chloride solution (300 ml), while neutralizing to pH 6-7 with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water (40 ml) and dried affording 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (6.78 g, 61.6%) as an off-white solid. mp.: 189-191° C. MS: m/z=276.1, 274.2 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Br:37]C(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][Br:37])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Under nitrogen atmosphere, a solution of triphenylphosphine (0.94 g) in THF (4 ml) was added slowly to a mixture of 4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g) and tetrabromomethane (1.19 g) in THF (15 ml). The mixture was stirred at room temperature for 16 hours, then ethyl acetate (100 ml) and a saturated solution of sodium carbonate (30 ml) were added and the organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 8/2) to afford 4-(3-bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.66 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]N(C=O)C.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:19])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(thioxo) pyrazolo[3,4-d]pyrimidin-4-one (5.2 g, 19.6 mmol), DMF (50 mL) and K2CO3 (2.76 g, 20 mmol) was stirred at ambient temperature for 25 minutes and then dimethyl sulfate (3.88 mL, 40 mmol) was added. The reaction mixture was stirred for 2 hours, then was poured into cold water. The product was collected by filtration, washed with water, recrystallized from cyclohexane/ether and dried at 70-75° C. in vacuo to afford 4.6 g of 1-cyclopentyl-3-ethyl-6-(methylthio) pyrazolo[3,4-d]pyrimidin-4-one, m.p.200-202° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=2[I:16])=[O:8])[CH2:4][O:3]1.[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>>[C:30]([O:33][CH2:34][CH2:35][N:9]([C:10]1[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=1[I:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:29])([CH3:1])[O:6]1)=[O:8])(=[O:32])[CH3:31]
Reactant: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(NC(=O)C2COC(C)(C)O2)c1I
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carbamido)-2,4,6-triiodo-1,3-di-(acetoxymethyl) benzene was alkylated with 2-bromoethyl acetate according to Example 30a. The crude product, containing some O-alkylated material was used directly in next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>CC(C)=O>[C:28](=[O:29])([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)[O:30][CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (2.50 g; 0.00783 mole) in acetone (50 ml) at 0° was treated with triethylamine (0.87 g; 0.00861 mole) followed by isobutyl chloroformate (1.17 g; 0.00861 mole) dropwise, during 30 minutes at 0°-2°.