Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:19]([CH:21]([OH:35])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20].N1C=CC=CC=1>CCOCC>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:35][CH:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride (4.58 mmol) in ether (5 ml) is added to an ether (20 ml) solution of α-cyano-m-phenoxybenzyl alcohol (4.58 mmol) and pyridine (0.5 ml). The mixture is stirred overnight and filtered. The filtrate and the washings are evaporated and the residual oil is purified on 5×2 mm silica gel plates using 1:1 methylenechloride-hexane as eluent. The band with Rf=0.55 is extracted with ether and evaporated to give the desired ester (0.85 g).
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:14])=O.[S:15]([O-:18])([OH:17])=[O:16].[Na+].[OH-].[Na+]>O>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[C:6]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:5][C:4]=1[OH:14]
Reactant: O=S([O-])O
Reactant: O=Nc1c(O)ccc2cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(O)cc(S(=O)(=O)O)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
84.8 g (0.337 mol) of crude 1-nitroso-6-bromo-β-naphthol were stirred into a solution of 97.5 g (0.939 mol) of sodium hydrogen sulfite and 4.0 g (0.1 mol) of sodium hydroxide solution in 376 ml of water at room temperature. The suspension was made up to 1350 ml with water and stirred for 24 hours at room temperature. Then 6.8 g (8% of the amount taken) of the solution residue were separated off by filtration. Then acidification was carried out with 119.4 g (1.17 mol) of 96%-strength sulfuric acid at no more than 30° C. and the product was crystallized out for 48 hours at room temperature. After filtration by suction and drying, 92.0 g (86%) of 1-amino-2-hydroxy-6-bromo-4-naphthalene sulfonic acid were obtained.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@H:15](C)[CH2:16][OH:17])=[O:13])[C:5]([CH3:23])=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NCCO>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:23])=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Solvent: NCCO
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 70 %

Procedure:
The title compound was prepared in a similar manner as described for (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-[(1R)-2-hydroxy-1-methylethyl]-4-methylbenzamide substituting R-2-amino-1-propanol with 2-aminoethanol. Yield 70%. 1H NMR (CD3OD/400 MHz) δ 7.91 (d, 1H, J=1.6 Hz, & 6.4 Hz), 7.68 (d, 1H, J=2.0 Hx), 7.60 (m, 1H), 7.54 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.57 (abq, 2H), 3.67 (t, 2H, J=6.0 Hz), 3.49 (t, 2H, J=6.0 Hz), 2.17 (s, 3H), and 2.13 (s, 3H); ES-HRMS m/z 508.0659 (M+H calcd for C22H21N3O4F2 Br requires 508.0678). 19F NMR (CD3OD/400 MHz) −111.85 (m) and −115.90 (m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH2:11].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[C:3]([CH2:12][S:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH:11][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(SCCN)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(SCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 5 h

Procedure:
2-((3-Methyl-4-(2-aminoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (8.5 g) was dissolved in ethanol and thereto was added benzaldehyde (2.8 g). The mixture was stirred at 50°-55° C. for 5 hours and sodium borohydride (0.98 g) was added thereto under ice-cooling. The mixture was stirred at room temperature for 2 hours. After the completion of the reaction, ethanol was distilled away and the residue was eluted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away. The residue was purified by column chromatography to give 2-((3-methyl-4-(2-benzylaminoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[N:19]=[C:18]([N:20]2[C@H:25]([CH3:26])[CH2:24][O:23][C@H:22]([CH2:27][OH:28])[CH2:21]2)[CH:17]=[C:16]([Cl:29])[N:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][S:9]([O:28][CH2:27][C@H:22]1[O:23][CH2:24][C@@H:25]([CH3:26])[N:20]([C:18]2[CH:17]=[C:16]([Cl:29])[N:15]=[C:14]([NH2:13])[N:19]=2)[CH2:21]1)(=[O:11])=[O:10]
Reactant: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.1 %

Procedure:
Triethylamine (0.65 mL, 4.69 mmol) and methanesulfonyl chloride (0.34 mL, 4.36 mmol) were added dropwise to a solution of [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methanol (1.00 g, 3.88 mmol) in CH2Cl2 (35 mL), and the mixture was stirred at room temperature under nitrogen. After 75 minutes another portion each of triethylamine (0.16 mL, 1.16 mmol) and methanesulfonyl chloride (0.076 mL, 0.97 mmol) were added dropwise and stirring continued for an additional 30 minutes. The reaction mixture was then poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×75 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (1.53 g, about 85% purity) as a white foam. LC-MS (ES) m/z=337, 339 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1)#[N:27]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: N#Cc1ccc(CC(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Cc2ccc(C#N)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl- 6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(4-Cyanophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-[α-(4-cyanophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)nc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCC2)nc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 89 %

Procedure:
By essentially following the procedures outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 6-[2-(1-pyrrolidinyl)ethoxy]pyrid-3-yl ketone (Part B) in 89% yield as a yellow solid following radial chromatography (SiO2, 5% MeOH in CH2Cl2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2cc[nH]c2c1

Procedure:
A yellow solution of 5.2 g. 6-nitroindole in 150 ml. ethyl acetate was added to 1.25 g. of pre-reduced 10% w/w palladium-on-charcoal in 50 ml. ethyl acetate. The mixture was shaken under 3.45 bar hydrogen overnight and then filtered through diatomaceous earth. The residue was washed with 150 ml. hot chloroform and the combined colourless filtrate and washings were evaporated to give a quantitative yield of 6-aminoindole as a dark oil; NMR: 3.5 (br s, 2H, NH2), 6.4 (m, 1H, H3), 6.5 (m, 2H, H5 +H7), 7.0 (dd, 1H, H2), 7.4 (d, 1H, H4), 7.8 (br, 1H, NH).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5](Cl)[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.[OH2:28]>>[NH2:2][C:3]1[N:4]([CH2:17][CH2:18][CH2:19][CH3:20])[C:5](=[O:28])[C:6]([C:14]#[N:15])=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=1
Reactant: O
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCCCNc1cc(N)n(CCCC)c(=O)c1C#N
Yield: 75 %

Procedure:
3.2 gms (.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano-pyridinium chloride (compound 6 - Table 1) was dissolved in hot water, 4.0 gms (0.04 mole) of triethylamine added and the solution refluxed on a boiling water bath. After 2 hours 2.0 gms (75% yield) of 2-amino-1-n-butyl-4-n-butylamino-5-cyano-pyridine-6-one (compound 87 - Table 6) had precipitated and was filtered off. (MPt 177° - 179°C).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH2:37][NH:36][CH2:35][CH2:34][C:10]=3[N:11]=[C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[CH:17][N:18]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[N:13]=2)[CH2:6][CH2:5][N:4]([C:38](=[O:40])[CH3:39])[CH2:3]1.FC(F)(F)S(O[C:47]1[CH:52]=[C:51]([C:53]2([CH3:57])[CH2:56][O:55][CH2:54]2)[CH:50]=[CH:49][C:48]=1[CH3:58])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH2:37][N:36]([C:49]4[CH:50]=[C:51]([C:53]5([CH3:57])[CH2:56][O:55][CH2:54]5)[CH:52]=[CH:47][C:48]=4[CH3:58])[CH2:35][CH2:34][C:10]=3[N:11]=[C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[CH:17][N:18]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[N:13]=2)[CH2:6][CH2:5][N:4]([C:38](=[O:40])[CH3:39])[CH2:3]1
Reactant: Cc1ccc(C2(C)COC2)cc1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CNCC3)[C@H](C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C4(C)COC4)ccc2C)CC3)[C@H](C)C1
Temperature: 140 °C

Procedure:
A mixture of (R)-1-(3-methyl-4-(2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone (0.155 g, 0.278 mmol), 2-methyl-5-(3-methyloxetan-3-yl)phenyl trifluoromethanesulfonate (0.086 g, 0.278 mmol) prepared as described in Example 13, cesium carbonate (0.272 g, 0.834 mmol) and chloro(2-dicyclohexylphosphino-2′-4′-6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butylether adduct (CAS#1028276-56-5) (0.031 g, 0.042 mmol) in THF (4 mL) was heated in a microwave reactor at 140° C. for 3 h. The reaction was then filtered and concentrated, the resulting residue was purified by FCC (60-100% EtOAc/DCM) to provide (R)-1-(3-methyl-4-(2-(3-methyl-1-tosyl-1H-indol-4-yl)-6-(2-methyl-5-(3-methyloxetan-3-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone. MS (ESI+) m/z 719.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[C:14]([O:18][C:19]([NH:21][C@@H:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23]I)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:23][CH:9]([C:10]#[N:11])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:25]([O:27][CH3:28])=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCc1cccc(F)c1F
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C#N)c1cccc(F)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:14]=[C:15]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[S:24]([O:22][C@H:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1)[CH2:20][CH3:21])(=[O:26])(=[O:25])[CH3:23]
Reactant: CC[C@H](O)c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.07 g, 8.3 mmol) is added to a mixture of (S)-1-(3-nitrophenyl)propanol (XXI, PREPARATION 1, 1 g, 5.5 mmol) in methylene chloride (20 mL). The mixture is cooled to −20° and methanesulfonyl chloride (0.69 g, 6.02 mmol) is added. The reaction is held at −20° for 10 min, then held at 0° for 40 min. The reaction is diluted with methylene chloride, sodium bicarbonate (5%) is added and the phases are separated. The methylene chloride is evaporated to give the title compound, [α]D=−79.9° (ethanol, c=1); TLC (silica gel GF, ethyl acetate/hexane, 20/80) Rf=0.19; NMR (CDCl3, TMS) 0.96-1.01, 1.88-2.17, 2.89, 5.54-5.59, 7.57-7.62, 7.70-7.73 and 8.20-8.24 δ.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[S:12]([NH2:16])([NH2:15])(=[O:14])=[O:13].[BH4-].[Na+]>C(O)C.O>[S:9]1[CH:8]=[C:7]([CH2:10][NH:15][S:12]([NH2:16])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thianaphthene-3-carboxaldehyde (1.62 g, 10.0 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.0 g, 42 mmol) was added and the mixture was heated to reflux for 16 hours. The mixture was cooled to room temperature. Sodium borohydride (0.416 g, 11.0 mmol) was added and the mixture was stirred at room temperature for three hours. The reaction was diluted with water (50 mL) and extracted with chloroform (3×75 mL). The extracts were concentrated and chromatographed (5% methanol in DCM) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][CH2:8]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30].CCOCC>C1COCC1>[Br:30][CH2:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(Cl)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccc(CCBr)s1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(5-chloro-2-thienyl)-ethanol* (12.2 g) and triphenylphosphine (21.4 g) in anhydrous THF (150 ml) at 0° C. was added carbon tetrabromide (27.5 g). The reaction was stirred at 5° C. for 15 min then at room temperature for 2.5 h. Ether was added and the reaction was then filtered and the filtrate concentrated. The resultant residue was purified by flash column chromatography (silica, eluting with cyclohexane:DCM 8:1) to give the title compound (15 g) as an oil. * Schick et al., J. Amer. Chem. Soc., 70, 1948, 1646.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH2:21]3)=[CH:13][CH:14]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
2-Ethyl-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.4 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g) were dissolved in dichloromethane (4 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.32 g, 80%) as a colorless amorphous solid.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:12]=12>C(O)C>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([N:26]=[CH:1][C:2]4[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=4[OH:4])=[CH:22][CH:21]=3)[C:12]=12
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N=Cc4ccccc4O)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (0.063 g, 0.000513 mol) and tert-butyl 4-[4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.200 g, 0.000489 mol) were combined in absolute ethanol (5 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate which was used without further purification. Trimethylsulfoxonium iodide (0.269 g, 0.00122 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.049 g, 0.00122 mol) was added at once. After 10 min., the solution of tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (70 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. The crude compound was dissolved in ethyl acetate (5 mL )and treated with a 4N aqueous solution of hydrochloric acid (1.5 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield 3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.038 g, 0.000078 mol) as a white solid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]2[CH:13]=[C:14]([C:16]([O:18]CC)=O)[N:15]=[C:4]2[CH:3]=1.O.[NH2:22][NH2:23]>CCO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]2[CH:13]=[C:14]([C:16]([NH:22][NH2:23])=[O:18])[N:15]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 7-bromo-5-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylate (3.96 g, 11.8 mmol) in EtOH (100 mL) was added hydrazine hydrate (5.91 mL, 0.118 mmol) and the mixture stirred overnight at rt. After 3 days, the reaction was almost complete by LCMS so stirring was maintained for 1 more night. The mixture was diluted with EtOH (50 mL), filtered and the solids washed with EtOH (2×50 mL), EtOAc (2×50 mL) and heptane (50 mL) before being air dried. The yield was 3.56 g (94%) LCMS MS: 321.01, 322.98 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:32])[CH2:24][C:25](=[O:31])[C:26]([O:28]CC)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:32])[CH2:24][C:25](=[O:31])[C:26]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
A solution of ethyl 4-(2,4-dibenzyloxyphenyl)-2,4-dioxobutanoate (2 g) in methanol (100 mL) is treated with 10% aqueous potassium hydroxide (10 mL) and the mixture stirred at room temperature for 18 hours. The reaction mixture is evaporated to low bulk and the residue partitioned between ethyl acetate (100 mL) and 1 N hydrochloric acid (50 mL). The organic phase is washed with water, dried over magnesium sulphate and evaporated in vacuo. The residue iscrystallised from a mixture of ethyl acetate and cyclohexane to give 4-(2,4-dibenzyloxyphenyl)-2,4-dioxobutanoic acid (0.6 g), in the form of a white solid, m.p. 160-164° C. [Elemental analysis:- C,71.3; H,4.93%. Calculated:- C,71.3; H,4.99%].