Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 2-chloro-3-methylbenzoic acid (25.0 g, 0.146 mol), conc. sulfuric acid (2 mL) and methanol (160 mL) was stirred 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, and neutralized with 8N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a pad filled with basic silica gel. The solvent was concentrated under reduced pressure to give the title compound (18.0 g, 66%) as a pale-orange oil. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:12][CH2:13]C(F)(F)F)[C:6]([O:18][CH3:19])=[N:5]1)([CH3:3])[CH3:2].BrCC[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:12][CH2:13][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:6]([O:18][CH3:19])=[N:5]1)([CH3:2])[CH3:3]
Reactant: FC(F)(F)COCCBr
Reactant: COC1=NC(C(C)C)C(OC)=NC1CCC(F)(F)F
Product: COC1=NC(C(C)C)C(OC)=NC1CCOCC(F)(F)F
Yield: 65 %

Procedure:
This compound was made in 65% yield by the same procedure as 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine, substituting 1-Iodo-3,3,3-trifluoropropane with 2-(2-Bromoethoxy)-1,1,1-trifluoroethane. 1H-NMR: 400 MHz, (CDCl3) δ: 4.11-4.05 (m, 1H), 3.95 (t, J=3.5 Hz, 1H), 3.86-3.75 (m, 3H), 3.74-3.66 (m, 7H), 2.30-2.18 (m, 2H), 1.92-1.82 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH3:9])[CH2:5][CH3:6])#[N:2].[H-].[Na+].I[CH3:21]>CN(C)C=O>[C:1]([N:3]=[C:4]([N:7]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH3:9])[CH3:21])[CH2:5][CH3:6])#[N:2]
Reactant: CCC(=NC#N)NC(C)c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=NC#N)N(C)C(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.00 g of N′-cyano-N-[1-(2,4-dichlorophenyl)ethyl]propaneimidamide was dissolved in 25 ml of dimethylformamide, and 0.16 g of sodium hydride (60% pure in paraffin oil) was added at room temperature. After 30 minutes, 0.63 g of iodomethane was added. The mixture was stirred at room temperature overnight and, after removal of the solvent, purified chromatographically. This gave 0.86 g of N′-cyano-N-[1-(2,4-dichlorophenyl)ethyl]-N-methylpropaneimidamide of logP 2.80 and m.p. 148° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32]Cl)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32][N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCCNCCCC
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C(CCl)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Product: CCCCN(CCCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
A mixture of 10 parts of 3β-acetoxy-6-(chloromethyl)cholest-5-ene and 8 parts of dibutylamine is heated at 90°-95° for 3 hours, whereupon excess amine is removed by vacuum distillation and the residue is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation, affording 3β-acetoxy-6-(dibutylaminomethyl)cholest-5-ene as the residue.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH:7]=[O:8].C1(C)C=CC=CC=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:27]1([C:2]2[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=2[CH:7]=[O:8])[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCc1nc(I)c(C=O)[nH]1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)[nH]1
Reaction time: 0.08 h

Procedure:
A solution of 2.64 g (0.01 mol) of 4-iodo-2-n-propylimidazole-5-carboxaldehyde, toluene (40 mL), and 0.33 g (0.00029 mol) of tetrakistriphenylphosphine palladium (0) was stirred at room temperature under nitrogen, while a solution of 3.44 g (0.022 mol) of 1-naphthylboronic acid in 50 mL of ethanol was slowly added. The reaction was stirred for 5 minutes, after which 12 mL of 2M sodium carbonate was slowly added. After the addition was completed, the reaction was refluxed for 48 h and cooled. The reaction was filtered, the filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in 300 mL of methylene chloride, washed twice with 100 mL of saturated sodium chloride solution, washed twice with 100 mL of distilled water, and washed twice with 300 mL of 10% HCl. The HCl layer was made basic with 50% sodium hydroxide until the pH=10. At this point, the basic water layer was extracted three times with 300 mL of methylene chloride, the methylene chloride layer was dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.90 g (0.0034 mol, 34%) of product. NMR (CDCl3) δ 11.45 (m, 1H); 9.42 (s, 1H); 7.28 (m, 7H); 2.82 (t, 2H); 1.85 (m, 2H); 1.01 (t, 3H). ##STR75##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(OO)(=[O:10])C.C.[Cl:14]C(Cl)C>>[ClH:14].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:10]
Reactant: CC(Cl)Cl
Reactant: CC(=O)OO
Reactant: Nc1ccccn1
Product: Cl
Product: Nc1cccc[n+]1[O-]

Procedure:
2-Aminopyridine (11.8 g.) was dissolved in 25 ml dichloroethane and the resulting clear solution chilled to 10°-15° C. Commercial 40% peracetic acid (20 g.) was slowly added over a 30-minute period with ice-cooling and stirring; the temperature was kept between 15°-20° C. After 1/2 hour stirring at 20°-30° C with very little cooling, the clear solution was allowed to react 15 hours at room temperature. Then was added 0.5 g. charcoal and the mixture kept at 70° C for 1 hour. The solution was filtered and the filtrate diluted with 100 ml dichloroethane. The clear solution was extracted twice with 30 ml of 20% hydrochloric acid. The acid extracts were washed with 30 ml dichloroethane and then evaporated under vacuum in a rotary evaporator to dryness to give 19.7 g. yellow crystals. Recrystallization from 1:1 ethanoltoluene mixture gave 13.7 g. nearly colorless crystals with m.p. 148° -152° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>O1CCCC1.C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-amino-5-chloro-3-iodopyridine (4.2 g, 0.017 mol), copper(I) iodide (0.032 g, 0.17 mmol) and triethylamine (7.0 mL, 0.050 mol) in anhydrous tetrahydrofuran (10 mL), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and ethynyl trimethylsilane (3.0 mL, 0.021 mol) were added and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with diethyl ether and removed the precipitate by filtration with C elite. The filtrate was concentrated to afford 2-amino-5-chloro-3-[(trimethylsilyl)ethynyl]pyridine as solid (4.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[N:28]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1(C)C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:16])[F:14])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[N:28]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: COc1ccc2c(N)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.3 %

Procedure:
300 mg (0.97 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 202 mg (1.16 mmol) of 5-amino-2-methoxyquinoline in 10 ml of acetic acid are refluxed for 5 hours. It is allowed to cool to room temperature, 640 mg (3 mmol) of sodium triacetoxy borohydride is added thereto, and it is stirred for 15 hours at room temperature. After toluene is added, the batch is concentrated by evaporation, the residue is taken up in ethyl acetate, washed with saturated NaHCO3 solution, dried and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 146 mg of the product as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[O:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH:26][CH:27](C)[CH2:28][O:29][C:30]1[CH:38]=[C:34]([C:35]([NH2:37])=[O:36])[C:33]([OH:39])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[C:35]([C:34]1[CH:38]=[C:30]([CH:31]=[CH:32][C:33]=1[OH:39])[O:29][CH2:28][CH2:27][N:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH:16]([OH:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:13][CH:12]=1)(=[O:36])[NH2:37]
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O

Procedure:
A solution of 14.3 g of 1-[2-(cyclopropyl-methoxy)-ethyl]-4-(2,3-epoxypropoxy)-benzene (German Offenlegungsschrift No. 2,649,605) and 16.3 g of 5-[2-(benzylamino)-propoxy]-salicylamide in 200 ml of isopropanol is refluxed for 18 hours. The reaction mixture is concentrated by evaporation to leave crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclopropylmethoxy)-ethyl]-phenoxy]-2-propanol in the form of brown oil, which can be further processed without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12](N)[CH:13]=[CH2:14].CCOCC>ClCCl>[CH2:14]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH:13]=[CH2:12]
Reactant: C=CCN
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 4-bromobenzenesulfonamide (6.80 g 26.6 mmol) in dichloromethane (50 mL) was added allylamine (5.0 mL, 66.5 mmol) at 0° C. The clear, colorless solution was stirred at room temperature for 1 h. The reaction mixture was poured into ether (100 mL) and washed with 10% aq HCl (50 mL), water (2×50 mL), and saturated aq NaHC03 (50 mL). The organic phase was dried (MgS04) and concentrated. The residue crystallized upon treatment with hexane to provide 7.03 g (96% yield) of the desired product as fine, white crystals. Mp: 63-65° C. (lit. 64-65° C. See Keasling, H. H.; Schumann, E. L.; Veldkamp, W. J. Med. Chem. 1965, 8, 548). 1H NMR (400 MHz, CDCl3): δ 7.77-7.72 (m, 2H), 7.69-7.64 (m, 2H), 5.71 (ddt, J=17.1, 10.2, 6.0 Hz, 1H), 5.18 (dq, J=17.1, 1.5 Hz, 1H), 5.12 (dq, J=10.2, 1.5 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H), 3.61 (tt, J=6.0, 1.5 Hz, 2H). 13C NMR (100 MHz, CDC13): δ 139.0, 132.6, 132.4, 128.6, 127.6, 118.0, 45.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].C(O)C>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:31])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN(c3ccc(N)cn3)CC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cn3)CC2)cc1

Procedure:
To a mixture of the product of part (ii) (1.2 g, 4.2 mmole) and triethylamine (0.5 g, 5 mmole) in methylene chloride (20 ml) was added, dropwise, phenyl chloroformate (0.8 g, 5.1 mmole) and the resulting mixture was stirred at room temperature for 20 hours. The reaction was quenched by the addition of water, the aqueous phase separated and re-extracted with methylene chloride. The combined organic extracts were washed with aqueous sodium bicarbonate solution then water, dried over magnesium sulphate and concentrated under reduced pressure to provide a solid. Trituration of this solid material with ethanol yielded the desired product, m.p. 197°-198° (1.4 g, 83%), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)=[O:11].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:35])[CH:31]=C(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:21]2[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:30](=[O:35])[CH:31]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)=CC(=O)Nc1ccccc1CN
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccccc1C1C(=O)Nc2ccccc2CN1Cc1ccc(F)cc1

Procedure:
Prepared similarly to Example 3 with reductive amination using 4-fluorobenzaldehyde, and the use of 2-formylphenylboronic acid. Prepared in 34% overall yield without isolation of intermediates starting from the product of Example 1. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.83-7.79 (m, 1H), 7.64-7.60 (m, 1H), 7.40-7.34 (m, 2H), 7.29-7.19 (m, 3H), 7.70-6.95 (m, 5H), 6.32 (s, 1H), 5.09 (d, J=15.4 Hz, 1H), 5.01 (d, J=15.4 Hz, 1H), 4.56 (d, J=15.3 Hz, 1H), 4.47 (d, J=15.3 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-:18].[Na+].[OH-].[Na+].Cl>O1CCOCC1>[CH:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:15]=[CH:16][C:4]=1[C:1]([OH:3])=[O:18]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2sc3ccccc3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2sc3ccccc3c2c1
Reaction time: 5 h

Procedure:
2-Acetyldibenzothiophene (2.24 g.), sodium hypochlorite solution, (47 ml. containing 5.7% available chlorine), normal sodium hydroxide solution (50 ml.) and dioxan (50 ml.), were heated on a steam bath with stirring for 5 hr. The mixture was acidified with excess hydrochloric acid, and the precipitated colourless solid filtered off, washed with water, and recrystallise twice from acetic acid to give dibenzothiophene-2-carboxylic acid, m.pt. 281°-283° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][C:25]=3[CH3:26])[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1ccoc1-c1cc2cccc(Cl)n2n1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccoc1-c1nn2c(Cl)cccc2c1C=O
Reaction time: 2.5 h
Yield: 760 %

Procedure:
A dry flask charged with dry N,N-dimethylformamide (100 mL) was treated with phosphorous oxychloride (8.8 mL, 94 mmol). The resultant solution was stirred at room temperature for 1 hour. 7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine (14.6 g, 63 mmol) was added and the reaction mixture was stirred for 2.5 hours. Water and dichloromethane were added to quench the reaction. The aqueous phase and organic phase were separated. The aqueous phase was extracted with dichloromethane. The organics were combined and washed with water, dried over magnesium sulfate, filtered and the filtrate was concentrated. Crystallization from a small amount of methanol gave 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (12.4 g, 760%) as a peach color crystalline compound. 1H NMR (CDCl3): δ 10.58 (s, 1H), 8.43 (d, 1H), 7.58 (d, 1H), 7.48 (t, 1H), 7.21 (d, 1H), 6.51 (d, 1H), 2.56 (s, 3H). MS m/261 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:46]1[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[C:48]([CH3:56])[N:47]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:46]2[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[C:48]([CH3:56])[N:47]=2)=[N:6]1
Reactant: Fc1ccccc1Cn1nc(I)c2cccnc21
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 1.50 g (4.25 mmol) of the compound from Example 33A were initially charged in 1,4-dioxane (37.5 ml), and the reaction mixture was purged with argon for 10 min. Thereafter, 3.22 ml (6.37 mmol) of hexabutylditin and 881 mg (4.67 mmol) of 2-chloro-6-methyl-5-nitropyrimidin-4-amine were added. Subsequently, 1.49 g (2.12 mmol) of bis(triphenylphosphine)palladium(II) chloride were added and the reaction mixture was heated to reflux overnight. Thereafter, the mixture was cooled to RT and filtered through Celite, and the filtrate was washed through with methanol. The solids formed were filtered off and discarded. The remaining filtrate was concentrated, ethyl acetate was added, and the solids formed were filtered off and dried under high vacuum. This gave 640 mg (69% purity, 27% of theory) of the title compound. The crude product was converted further without further purification.
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.NC1C=CC=CC=1S.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][CH:31]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:32]([OH:36])[C:33]([NH2:35])=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClC1C=CC=CC=1>[OH:36][C@H:32]1[C:33](=[O:34])[NH:35][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C@H:31]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccccc1S
Solvent: Clc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Yield: 82.6 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (3.86 g) and chlorobenzene (77 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (2.75 g) and ferric chloride hexahydrate (0.54 mg) in methanol (0.1 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes. The reaction mixture is subjected to HPLC analysis* to confirm the production of 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (6.09 g) [(2S,3S)/(2S,3R)=91.5/8.5]. To the reaction mixture is added p-toluenesulfonic acid monohydrate (0.76 g), and the mixture is refluxed for 32 hours, and concentrated under reduced pressure to remove the chlorobenzene. To the residue is added methanol (25 ml), and the mixture is refluxed for one hour, and cooled with ice overnight. The precipitated crystals are collected by filtration, washed with methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (4.76 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:11]=O.[NH:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=[CH:14]1.[OH-].[Na+]>C(O)(=O)C.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:15]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:13][CH:14]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: c1ccc2c(c1)CCNC2
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(c1)CCN(Cc1c[nH]c3ncccc13)C2
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (1.37 g, 10.0 mmol) was dissolved in acetic acid (4 ml) and water (2 ml). 37% Aqueous formaldehyde (0.9 ml, 12 mmol) was added and the reaction mixture stirred for five minutes, 1H-pyrrolo[2,3-b]pyridine (1.18 g, 9.99 mmol) added and the resulting solution stirred at room temperature for 20 h. The reaction mixture was poured into 2M aqueous sodium hydroxide solution (50 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (50 ml) and brine (50 ml). The organic phase was dried (MgSO4) and concentrated in vacuo to give a lemon solid. Recrystallisation from toluene gave the title compound (0.935 g, 36%), as an off-white solid, m.p. 190°-192° C.; (Found: C, 77.51; H, 6.50; N, 15.57. C17H17N3 requires C, 77.54; H, 6.51; N, 15.96%); δH (DMSO-d6) 2.68 (2H, t, J 7.8 Hz, CH2), 2.77 (2H, d, J 7.5 Hz, CH2), 3.55 (2H, s, CH2), 3.79 (2H, s, CH2), 6.97-7.07 (5H, m, ArH), 7.41 (1H, d, J 1.8 Hz, ArH), 8.03 (1H, dd, J 7.8, 1.5 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1.5 Hz, 6-H), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 264 (M+1)+.