Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[C:5]1([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc(C(=O)Cc2ccccc2)cc1

Procedure:
Chromatographed (E),(E)-1,1'-[1,4-phenylene]bis[2-phenyl-1-(diphenylamino)ethylene] (1.0 g, 0.0016 mol) was refluxed in a solution of THF (30 mL) and aqueous HCl (1.2M, 3.0 mL) for 1.25 h. The solution was worked-up as for the preparation of 1,2-diphenylethanone. Chromatography on silica (30 g) eluting with petroleum ether/benzene 3:2 removed the diketone. After solvent evaporation of the combined fractions and recrystallization of the residue from benzene/methanol gave small plates mp 171°-3° C. (85%). FTIR (CDCl3) v: 3089, 3066, 3033, 2900, 1692(C=O), 1676, 1568, 1492, 1454, 1404, 1325, 1309, 1272, 1217, 1202 cm-1H NMR (200 MHz, CDCl3) δ: 4.30 (s, 4H, --CH2Ph), 7.24-7.37 (m, 10H, ending phenyls), 8.06 (s, 4H, phenylene). MS [m/e (70 eV, % of base peak)] C22H18O2 314 (M+. , 0.8), 223 (M+. -PhCH2., 100), 104 (C6H4CO+,42.9), 91 (C7H7+,29).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25].[CH3:26][S-:27].[Na+].O1CCOCC1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:26][S:27][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25]
Reactant: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Reactant: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CSc1c(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cnn(CC(=O)O)c1=O
Yield: 90.2 %

Procedure:
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (220 mg, 0.533 mmol) and sodium thiomethoxide (112 mg, 1.60 mmol) in toluene (22 mL) were stirred at 80° C. for 3 hours. After cooling, the reaction solution was stirred with 1,4-dioxane (6 mL) and 1 M aqueous sodium hydroxide (1.59 mL) at room temperature for 4 hours. After completion of the reaction, the reaction solution was mixed with toluene and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (169 mg, 90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](O)=[CH:6][CH:7]=[N:8]2.O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(O)ccnc2c1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c2c(Cl)ccnc2c1

Procedure:
To a mixture of crude 5,7-dimethoxyquinolin-4-ol (5.36 g, 26 mmol) and Hunig'sBase (9.1 ml, 52 mmol) in toluene, was added POCl3(29 ml, 313 mmol). The mixture was refluxed for 5 h. Excess POCl3 was removed under reduced pressure and the mixture was azeotroped with toluene. The resultant gum was treated with sat. NaHCO3 until no gas generated. The mixture was extracted with EtOAc, the organic extracts were combined and washed with sodium bicarbonate and solvent removed under reduced pressure. The crude product was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 0-50% EtOAc/DCM) to afford 4-chloro-5,7-dimethoxyquinoline as a yellow solid. MS: m/z=[M+H]+. 224.2 Calc'd for C11H10ClN: 223.7.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:3][CH2:2]1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]([C:25]2[CH2:26][CH2:27][N:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH:24]=2)=[CH:9][NH:10]3)[CH2:2][CH2:3]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: c1cc(OCC2CC2)c2cc[nH]c2c1
Product: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCN(Cc2ccccc2)C1
Yield: 23.3 %

Procedure:
Beginning with 3.77 gm (20.1 mMol) 4-cyclopropylmethyloxy-1H-indole and 7.5 mL (40.3 mMol) 1-benzyl-4-piperidone, 1.68 gm (23%) of the title compound were recovered as an off white solid.
Reaction SMILES: [CH2:1]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)N)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O>Cl>[CH3:22][C:20]1[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:11]2[C:16]([C:19]=1[C:18]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(N(N)CCc2ccccc2)cc1
Agent: Cl
Product: CCOC(=O)c1c(C)n(CCc2ccccc2)c2ccc(C)cc12
Temperature: 110 °C
Yield: 61.1 %

Procedure:
1-phenethyl-1-p-tolylhydrazine (3.7 g, 16.3 mmol) was dissolved in ethanolic HCl (40 mL, pH of the solution was acidic) and ethyl acetoacetate (2.0 mL, 16.3 mmol) was added to it. The reaction mixture was heated at 110° C. for 1.5 h at which point the reaction was found complete by TLC and LC-MS. The reaction mixture was concentrated under reduced pressure, the residue was suspended in saturated aqueous NaHCO3 (pH 9) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain a crude product as dark brown oil. Purification of crude product by flash column chromatography (silica gel, 230-400 mesh, eluent: 5-10% ethyl acetate-hexanes) furnished 3.2 g of pure product as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.8 %

Procedure:
A mixture of 2-bromo-4-isopropylaniline (5.05 g, 23.6 mmol), acetic anhydride (2.4 mL, 25 mmol), and triethylamine (3.5 mL, 25 mmol) in dichloromethane (25 mL) was stirred at ambient temperature for 4 days. The mixture was diluted with dichloromethane, washed sequentially with saturated aqueous Na2CO3 and 1M HCl, dried (MgSO4), filtered, and concentrated to provide the desired product (5.85 g). MS (DCI) m/e 256, 258 (M+H)+; 273, 275 (M+NH4)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCOCCCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
A solution of diethyl malonate (15.2 mL, 99.8 mmol) in ethanol (10 mL) was added dropwise to a solution of sodium ethoxide in ethanol [freshly prepared from sodium (2.3 g, 100 mmol) and ethanol (30 mL)] at ambient temperature and stirred for 10 min. Bis(2-chloroethyl)ether (12 mL, 102 mmol) was added dropwise then the mixture was heated at reflux overnight. It was then cooled to 10° C. before another portion of freshly-prepared sodium ethoxide in ethanol [prepared from sodium (2.3 g, 100 mmol) and ethanol (30 mL)] was added. The mixture was heated at reflux for 48 h then cooled, filtered to remove the precipitated sodium chloride then the filtrate was concentrated to dryness. Water was added to the residue which was then extracted with ether (3×25 mL). The combined ether layers were washed with water, brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded tetrahydropyran-4,4-dicarboxylic acid diethyl ester (10.1 g, 44%) as a mobile oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11])#[N:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10]([Cl:26])=[O:11])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Temperature: 98 °C

Procedure:
A stirred slurry of 1.1 grams (0.003 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid and 1.0 mL of thionyl chloride in 20 mL of toluene was heated at about 72° C. for 25 minutes. The slurry was warmed to 98° C. over a 45 minutes period, during which time the reaction mixture became homogeneous. The reaction mixture was heated at 98° C. for 35 minutes. After this time, the reaction mixture was cooled and concentrated under reduced pressure, yielding 1.1 grams of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride. The acid chloride was used without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:25][NH:26][O:27][CH3:28].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:3]([C:9]([N:26]([O:27][CH3:28])[CH3:25])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ncc(F)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a suspension of 3,5-difluoropicolinic acid (3.5 g) in THF (70 ml) was added CDI (3.92 g) at room temperature. The mixture was stirred at room temperature for 30 min and at 50° C. for 1 h. After cooling to room temperature, N,O-dimethylhydroxylamine hydrochloride (3.22 g) and DIPEA (5.76 mL) were added. The mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[Cl:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Solvent: Cc1ccccc1
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 62 h
Yield: 79 %

Procedure:
The reaction was carried out using the same equipment as described in Example 1. The flask was charged with 53.9 g (0.143 mole, 82% assay) of 2-(5-amino-2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one and 24 grams of toluene. The mixture was heated to reflux and 15.6 mL (23 g, 0.20 mole) of methanesulfonyl chloride (Aldrich, 99.5%) added dropwise over 22 minutes. The solution was heated at reflux for 4.5 hours after the completion of the addition, and a further 3.9 mL (5.75 g, 0.05 mole) of methanesulfonyl chloride was added over 10 minutes. After an additional 2.5 hours at reflux, the reaction mixture was diluted with 75 mL of toluene, allowed to cool to room temperature, and stirred over the weekend (62 hours). The resulting slurry was warmed to dissolve the solids, transferred to a 1-L round bottomed flask equipped with a mechanical stirrer, and rinsed in with 200 mL of toluene. The mixture was warmed to 80° C. and washed twice with 150 mL portions of water, with the washes being removed via pipette. The solution was allowed to cool slowly to 40° C. and the resulting slurry then cooled in an ice bath for 2.5 hours. The product was collected by filtration and the filter cake washed with a total of 120 mL of cold toluene and dried in a vacuum oven to provide 48.6 g (79% yield) of 90% assay of N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl]methanesulfonamide as a tan solid.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=1)([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][C:7]=2[C:8]([OH:10])=[O:9])[CH2:17]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(C)C)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(C(=O)O)c(OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 65 °C
Yield: 83.6 %

Procedure:
The methyl 4-isopropyl-2-(1-tert-butoxycarbonyl-piperidin-3-ylmethoxy)benzoate (1.53 g, 3.90 mmol) was dissolved in THF (15 mL). Then LiOH.H2O (0.36 g, 8.58 mmol) in water (5 mL) was added. The mixture was heated at 65° C. for 24 h. The reaction mixture was concentrated in vacuo and then redissolved in a mixture of EtOAc (100 mL) and cold dilute HCl. The mixture was shaken in a separatory funnel. The layers were separated and the organic layer was washed with cold water (100 mL), dried (MgSO4), and concentrated to give 1.23 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[S-:17].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([S:17][C:16]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:15]=2[F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Fc1ccc([S-])c(F)c1
Reactant: N#Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(Sc2ccc(F)cc2F)c([N+](=O)[O-])cc1Cl
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A mixture of 2,5-dichloro-4-nitrobenzonitrile (2.5 g) and potassium 2,4-difluorothiophenoxide (2.54 g) in toluene was stirred overnight. Ethyl acetate was added and the resulting mixture was washed with water, dried and evaporated. The residue was filtered and washed with toluene to give pale brown crystals of 2-chloro-5-(2,4-difluorophenylthio)-4-nitrobenzonitrile (1.7 g).
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:52][O:53][C:54]([C:57]([OH:59])=[O:58])(C)C)[C:23]([NH:25][CH:26]2[C:50](=[O:51])[N:28]3[C:29]([C:47]([OH:49])=[O:48])=[C:30]([CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=4[N+:44]([O-:46])=[O:45])[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:52][O:53][CH2:54][C:57]([OH:59])=[O:58])[C:23]([NH:25][CH:26]2[C:50](=[O:51])[N:28]3[C:29]([C:47]([OH:49])=[O:48])=[C:30]([CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=4[N+:44]([O-:46])=[O:45])[CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12)c1csc(N)n1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(C=Cc4ccc([N+](=O)[O-])cc4[N+](=O)[O-])CS[C@H]23)cs1
Yield: 73 %

Procedure:
This compound (238 mg, 0.22 mmol), anisole (0.5 ml, 4.5 mmol) and trifluoro acetic acid (2.5 ml, 33.8 mmol) were used to conduct the procedure similar to that shown in (2) of Example 1 to obtain 120 mg (yield: 73%) of the titled compound as yellow powder.
Reaction SMILES: [CH3:1][O:2][B:3](OC)OC.[F:8][C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>O1CCCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([B:3]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COB(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Trimethylborate (1.0 ml, 8.75×10−3 mol) is added dropwise to a freshly prepared solution of p-fluorophenyl magnesium bromide (18.4 ml, 1 M, 1.84×10−2 mol) in tetrahydrofuran (30 ml) under argon at −78° C. The mixture is warmed to room temperature and stirred overnight. The solution is cooled to −78° C. and excess grignard reagent is destroyed by the dropwise addition of methanol until no more effervescence is observed. The solvents are removed in vacuo and the residue dissolved in diethyl ether and washed with water. The organic layer is dried (MgSO4), filtered and the solvents removed in vacuo to give methyl di(p-fluorophenyl)borinate (1.93 g, 89%) as a solid which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl>CC(C)=O.O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc(OCC(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 1 g (5.15 mmoles) of 2,4-dihydroxy-3-propylacetophenone and 2.0 g (5.15 mmoles) of ethyl 4-bromomethylphenoxyacetate in 50 ml of dry acetone was stirred and refluxed with 800 mg of K2CO3 for 48 hours. The reaction mixture was diluted with H2O, rendered acidic with 6N HCl and extracted into CH2Cl2. Evaporation of the CH2Cl2 gave an oil that was chromatographed on silica gel by gradient elution with 50% CH2Cl2 /hexane to 75% CH2Cl2 /hexane to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:37]5[CH2:38][CH2:39][O:34][CH2:35][CH2:36]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), tetrahydropyran-4-one (27 mg, 0.27 mmol) and AcOH (50 μL) in DCE (2 mL) was allowed to stir at r.t. for 20 min before the addition of sodium triacetoxyborohydride (104 mg, 0.49 mmol). The resulting mixture was allowed to stir for 18 h then partitioned between DCM and H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with MeCN and H2O and the resulting solid dried in vacuo affording 827 (92 mg, 82%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.65-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.40-4.10 (4 H, brd s), 3.91 (2 H, d, J=8.05 Hz), 3.80-3.79 (6 H, m), 3.71 (3 H, s), 3.41 (2 H, d, J=8.07 Hz), 3.28-3.26 (4 H, m), 3.02 (3 H, s), 2.37-2.28 (1 H, m), 1.67-1.63 (2 H, m), 1.34 (3 H, t, J=7.43 Hz), 1.23-1.10 (2 H, m)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([O:17][C:18]([NH:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH:15]=[CH2:16]>N1C=CC=CC=1>[CH2:14]([O:17][C:18]([NH:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:11])[CH:29]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH:15]=[CH2:16]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(N)c1
Solvent: c1ccncc1
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
3-Nitrophenylsulphonyl chloride was added at 0° C. to a solution of 11.6 g ethyl 3-{[(allyloxy)-carbonyl]-amino}-3-(3-aminophenyl)-propanoate from Example II.2.d in 110 ml of pyridine. After a reaction time of 2 h, the mixture was concentrated, 1 N hydrochloric acid was added, and the solution was extracted with dichloromethane. After drying the organic phase over magnesium sulphate, the solvent was removed and the crude product was purified by chromatography on silica gel (dichloromethane/methanol=40:1) to give 17.8 g of a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[CH:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:33]4[N:32]=[CH:31][NH:30][CH:34]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2c[nH]cn2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-imidazole-4-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:9]([NH:11]C(=O)OC(C)(C)C)[CH3:10])=[N+:6]([O-:8])[CH:7]=1.Cl.O1CCOCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:9]([NH2:11])[CH3:10])=[N+:6]([O-:8])[CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c[n+]1[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(F)c[n+]1[O-]
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [(1R)-1-(5-fluoro-1-oxidopyridin-2-yl)ethyl]carbamate (1.47 g, 5.74 mmol) in dichloromethane (28.7 mL) was added 4 M hydrochloric acid in 1,4-dioxane (43.0 mL, 172 mmol). After 2 h, concentration gave the title compound as a hydrochloride salt (1.396 g). MS 157.1 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.55 (dd, J=4.3, 2.4 Hz, 1 H); 7.70 (dd, J=9.0, 6.7 Hz, 1 H); 7.52 (ddd, J=9.1, 7.1, 2.4 Hz, 1 H); 4.80 (q, J=7.0 Hz, 1 H); 1.74 (d, J=7.0 Hz, 3 H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[NH:27][C:19]3=[N:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H][H]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]2[NH:27][C:19]3=[N:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[CH:23]=[C:18]3[CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)O)cnc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)O)cnc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
A mixture of 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (540 mg, 1.40 mmol) and 10% palladium on activated carbon (162 mg) in methanol (300 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb and kept for 5 h. The mixture was cooled to 25° C., filtered off solids and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-butyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (400 mg, 73%) which was used without further purification.